An Introduction To Brain and Behavior

AN INTRODUCTION TO BRAIN AND BEHAVIOR

ABOUT THE COVER Dr. Greg Dunn (artist and neuroscientist) and Dr. Brian Edwards (artist and applied physicist) created the artwork Self Reflected to elucidate the nature of human consciousness, bridging the connection between the macroscopic brain and the microscopic behavior of neurons. This work of art and science is not a scan of any kind, but was meticulously made from scratch through a complex process of hand drawing, deep neuroscience research, algorithmic simulations, photolithography, gilding, and strategic lighting design. Self Reflected offers an unprecedented insight of the brain into itself, revealing through a technique called reflective microetching the enormous scope of beautiful and delicately balanced neural choreographies designed to reflect what is occurring in our own minds as we observe this work of art. Self Reflected was created to remind us that the most marvelous machine in the known universe is at the core of our being and is the root of our shared humanity. As of 2018, Self Reflected is the most complex artistic depiction of the brain in the world. You can find more information about the project including video, images, prints, and descriptions of the process, as well as other brain and mind themed artwork, at gregadunn.com. Self Reflected was funded by the National Science Foundation, #ISE/AISL #1443767.

AN INTRODUCTION TO BRAIN AND BEHAVIOR SIXTH EDITION BRYAN KOLB University of Lethbridge IAN Q. WHISHAW University of Lethbridge G. CAMPBELL TESKEY University of Calgary

This book is dedicated to our longtime collaborator and friend Timothy Schallert, a Professor of Psychology at The University of Texas at Austin, who passed away on May 30, 2018, with Parkinson disease. Tim loved playing basketball and throwing the football, which he did with his children and with us. He also loved studying behavior. Tim had a gift for behavioral analysis and was the best rat whisperer. He could watch an animal that was not moving and ask, “Why?” Then later, he could tell you why. He traveled the world, collaborating with both neurologists and neuroscientists, showing others how to properly analyze behavior. His research, focused on Parkinson disease, resulted in numerous novel observations and insights about the behavior of a rat model of Parkinsonism. He had a wonderful sense of humor and is widely missed by the neuroscience community.

Senior Vice President, Content Strategy: Charles Linsmeier Program Director, Social Sciences: Shani Fisher Executive Program Manager for Psychology: Daniel DeBonis Development Editor: Andrew Sylvester Editorial Assistant: Anna Munroe Marketing Manager: Clay Bolton Marketing Assistant: Chelsea Simens Media Editor, Social Sciences: Stefani Wallace Director, Content Management Enhancement: Tracey Kuehn Senior Managing Editor: Lisa Kinne Senior Content Project Manager: Vivien Weiss Project Managers: Andrea Stefanowicz & Misbah Ansari, Lumina Datamatics, Inc. Media Project Manager: Joe Tomasso Senior Workflow Project Manager: Paul Rohloff Senior Photo Editor: Cecilia Varas Photo Researcher: Richard Fox, Lumina Datamatics, Inc. Director of Design, Content Management: Diana Blume Design Services Manager: Natasha Wolfe Cover Design Manager: John Callahan Art Manager: Matthew McAdams New Illustrations: Eli Ensor and Lumina Datamatics, Inc. Composition: Lumina Datamatics, Inc. Cover Art: Self Reflected, 22K gilded microetching under multicolored light, 2014-2016. Greg Dunn and Brian Edwards

Library of Congress Control Number: 2018958217 ISBN: 978-1-319-15248-2 (ePub) Copyright © 2019, 2016, 2014, 2011 by Worth Publishers All rights reserved. 1 2 3 4 5 6 23 22 21 20 19 18 Worth Publishers One New York Plaza Suite 4500 New York, New York 10004-1562 www.macmillanlearning.com

ABOUT THE AUTHORS Bryan Kolb received his Ph.D. from Pennsylvania State University in 1973. He conducted postdoctoral work at the University of Western Ontario and the Montreal Neurological Institute. He then moved to the University of Lethbridge in 1976, where he is Professor of Neuroscience and holds a Board of Governors Chair in Neuroscience. His current research examines how neurons of the cerebral cortex change in response to various factors—including hormones, experience, psychoactive drugs, neurotrophins, and injury—and how these changes are related to behavior in the normal and diseased brain. Kolb has received the distinguished teaching medal from the University of Lethbridge. He is a Fellow of the Royal Society of Canada and of the Canadian Psychological Association (CPA), the American Psychological Association, and the Association of Psychological Science. A

recipient of the Hebb Prize from the CPA and from the Canadian Society for Brain, Behaviour, and Cognitive Science, Kolb has also received four honorary doctorates. He is a Senior Fellow of the Experience-Based Brain and Behavioural Development program of the Canadian Institute for Advanced Research. In 2017, he was appointed as an Officer of the Order of Canada. He and his wife train and show horses in Western riding events. Ian Q. Whishaw received his Ph.D. from Western University and is a Professor of Neuroscience at the University of Lethbridge. He has held visiting appointments at The University of Texas at Austin, the University of Michigan, Cambridge University, and the University of Strasbourg. He is a fellow of Clair Hall, Cambridge, and of the Canadian Psychological Association, the American Psychological Association, and the Royal Society of Canada. Whishaw has received the Canadian Humane Society Bronze Medal for Bravery and the Ingrid Speaker Gold Medal for Research, as well as the Distinguished Teaching Award from the

University of Lethbridge and the ASTech Award for Distinguished Science. He has received the Key to the City of Lethbridge and has honorary doctorates from Thompson Rivers University and the University of Lethbridge. His research addresses the neural basis of skilled movement and the neural basis of brain disease, and the Institute for Scientific Information includes him in its list of most cited neuroscientists. His hobby is training horses for Western performance events. G. Campbell Teskey received his Ph.D. from Western University in 1990 and then conducted postdoctoral work at McMaster University. In 1992 he relocated to the University of Calgary, where he is a professor in the Department of Cell Biology and Anatomy and at the Hotchkiss Brain Institute. His current research programs examine the development, organization, and plasticity of the motor cortex, as well as how seizures alter blood flow, brain function, and behavior. Teskey has won numerous teaching awards, has developed new courses, is a founder of the bachelor of science in neuroscience

program, served as Education Director for the Hotchkiss Brain Institute, and chaired the Education Committee of Campus Alberta Neuroscience. His hobbies include hiking, biking, kayaking, and skiing. He refuses to wear cowboy hats.

CONTENTS IN BRIEF Preface Media and Supplements CHAPTER 1 What Are the Origins of Brain and Behavior? CHAPTER 2 What Is the Nervous System’s Functional Anatomy? CHAPTER 3 What Are the Nervous System’s Functional Units? CHAPTER 4 How Do Neurons Use Electrical Signals to Transmit Information? CHAPTER 5 How Do Neurons Communicate and Adapt? CHAPTER 6 How Do Drugs and Hormones Influence Brain and Behavior? CHAPTER 7 How Do We Study the Brain’s Structures and Functions? CHAPTER 8 How Does the Nervous System Develop and Adapt? CHAPTER 9 How Do We Sense, Perceive, and See the World? CHAPTER 10 How Do We Hear, Speak, and Make Music? CHAPTER 11 How Does the Nervous System Respond to Stimulation and Produce Movement? CHAPTER 12 What Causes Emotional and Motivated Behavior? CHAPTER 13 Why Do We Sleep and Dream? CHAPTER 14 How Do We Learn and Remember? CHAPTER 15 How Does the Brain Think? 14

CHAPTER 16 What Happens When the Brain Misbehaves? Answers to Section Review Self-Tests Glossary References Name Index Subject Index

CONTENTS PREFACE MEDIA AND SUPPLEMENTS

CHAPTER 1 What Are the Origins of Brain and Behavior? CLINICAL FOCUS 1-1 Living with Traumatic Brain Injury 1-1 The Brain in the Twenty-First Century Why Study Brain and Behavior? What Is the Brain? What Is Behavior? 1-2 Perspectives on Brain and Behavior 16

Aristotle and Mentalism Descartes and Dualism COMPARATIVE FOCUS 1-2 The Speaking Brain Darwin and Materialism EXPERIMENT 1-1 Question: How do parents transmit heritable factors to offspring? Contemporary Perspectives on Brain and Behavior 1-3 Evolution of Brains and of Behavior Origin of Brain Cells and Brains Evolution of Nervous Systems in Animals Chordate Nervous System THE BASICS: Classification of Life 1-4 Evolution of the Human Brain and Behavior Humans: Members of the Primate Order Australopithecus: Our Distant Ancestor The First Humans Relating Brain Size and Behavior COMPARATIVE FOCUS 1-3 The Elephant’s Brain Why the Hominid Brain Enlarged 1-5 Modern Human Brain Size and Intelligence Meaning of Human Brain Size Comparisons Acquisition of Culture SUMMARY KEY TERMS

CHAPTER 2 What Is the Nervous System’s Functional Anatomy? RESEARCH FOCUS 2-1 Agenesis of the Cerebellum 2-1 Overview of Brain Function and Structure Plastic Patterns of Neural Organization Functional Organization of the Nervous System The Brain’s Surface Features THE BASICS: Finding Your Way Around the Brain CLINICAL FOCUS 2-2 Meningitis and Encephalitis The Brain’s Internal Features CLINICAL FOCUS 2-3 Stroke

2-2 The Conserved Pattern of Nervous System Development Comparative Brain Evolution The Nervous System and Intelligent Behavior EXPERIMENT 2-1 Question: Does intelligent behavior require a vertebrate nervous system organization? 2-3 The Central Nervous System: Mediating Behavior Spinal Cord Brainstem Forebrain Cerebral Cortex Basal Ganglia 2-4 Somatic Nervous System: Transmitting Information Cranial Nerves Spinal Nerves Somatic Nervous System Connections Integrating Spinal Functions CLINICAL FOCUS 2-4 Bell Palsy 2-5 Autonomic and Enteric Nervous Systems: Visceral Relations ANS: Regulating Internal Functions ENS: Controlling the Gut 2-6 Ten Principles of Nervous System Function

Principle 1: The Nervous System Produces Movement in a Perceptual World the Brain Constructs Principle 2: Neuroplasticity Is the Hallmark of Nervous System Functioning Principle 3: Many Brain Circuits Are Crossed Principle 4: The CNS Functions on Multiple Levels Principle 5: The Brain Is Symmetrical and Asymmetrical Principle 6: Brain Systems Are Organized Hierarchically and in Parallel Principle 7: Sensory and Motor Divisions Permeate the Nervous System Principle 8: The Brain Divides Sensory Input for Object Recognition and Movement Principle 9: Brain Functions Are Localized and Distributed Principle 10: The Nervous System Works by Juxtaposing Excitation and Inhibition SUMMARY KEY TERMS

CHAPTER 3 What Are the Nervous System’s Functional Units? RESEARCH FOCUS 3-1 A Genetic Diagnosis 3-1 Cells of the Nervous System Neurons: The Basis of Information Processing Five Types of Glial Cells EXPERIMENT 3-1 Question: Can the principles of neural excitation and inhibition control the activity of a simple robot that behaves like a cricket? CLINICAL FOCUS 3-2 Brain Tumors 3-2 Internal Structure of a Cell The Cell as a Factory Cell Membrane: Barrier and Gatekeeper THE BASICS: Chemistry Review 21

The Nucleus and Protein Synthesis The Endoplasmic Reticulum and Protein Manufacture Proteins: The Cell’s Product Golgi Bodies and Microtubules: Protein Packaging and Shipment Crossing the Cell Membrane: Channels, Gates, and Pumps 3-3 Genes, Cells, and Behavior Mendelian Genetics and the Genetic Code Applying Mendel’s Principles CLINICAL FOCUS 3-3 Huntington Disease Genetic Engineering Phenotypic Plasticity and the Epigenetic Code SUMMARY KEY TERMS

CHAPTER 4 How Do Neurons Use Electrical Signals to Transmit Information? CLINICAL FOCUS 4-1 Epilepsy 4-1 Searching for Electrical Activity in the Nervous System Early Clues That Linked Electricity and Neuronal Activity THE BASICS: Electricity and Electrical Stimulation Tools for Measuring a Neuron’s Electrical Activity How Ion Movement Produces Electrical Charges 4-2 Electrical Activity of a Membrane Resting Potential Maintaining the Resting Potential Graded Potentials Action Potential Nerve Impulse Refractory Periods and Nerve Action Saltatory Conduction and the Myelin Sheath CLINICAL FOCUS 4-2 Multiple Sclerosis 4-3 How Neurons Integrate Information Excitatory and Inhibitory Postsynaptic Potentials EXPERIMENT 4-1 Question: How does stimulating a neuron influence its excitability? Summation of Inputs Voltage-Activated Channels and the Action Potential

The Versatile Neuron RESEARCH FOCUS 4-3 Optogenetics and LightSensitive Ion Channels 4-4 Into the Nervous System and Back Out How Sensory Stimuli Produce Action Potentials How Nerve Impulses Produce Movement CLINICAL FOCUS 4-4 ALS: Amyotrophic Lateral Sclerosis SUMMARY KEY TERMS

CHAPTER 5 How Do Neurons Communicate and Adapt?

RESEARCH FOCUS 5-1 The Basis of Neural Communication in a Heartbeat 5-1 A Chemical Message EXPERIMENT 5-1 Question: How does a neuron pass on a message? Structure of Synapses CLINICAL FOCUS 5-2 Parkinson Disease Neurotransmission in Five Steps Varieties of Synapses Excitatory and Inhibitory Messages Evolution of Complex Neurotransmission Systems 5-2 Varieties of Neurotransmitters and Receptors Four Criteria for Identifying Neurotransmitters Classes of Neurotransmitters CLINICAL FOCUS 5-3 Awakening with L-Dopa Varieties of Receptors 5-3 Neurotransmitter Systems and Behavior Neurotransmission in the Somatic Nervous System (SNS) Dual Activating Systems of the Autonomic Nervous System (ANS) Enteric Nervous System (ENS) Autonomy Four Activating Systems in the Central Nervous System

CLINICAL FOCUS 5-4 The Case of the Frozen Addict 5-4 Adaptive Role of Synapses in Learning and Memory Habituation Response EXPERIMENT 5-2 Question: What happens to the gill response after repeated stimulation? Sensitization Response EXPERIMENT 5-3 Question: What happens to the gill response in sensitization? Learning as a Change in Synapse Number RESEARCH FOCUS 5-5 Dendritic Spines: Small but Mighty SUMMARY KEY TERMS

CHAPTER 6 How Do Drugs and Hormones Influence Brain and Behavior? CLINICAL FOCUS 6-1 Cognitive Enhancement? 6-1 Principles of Psychopharmacology Drug Routes into the Nervous System Drug Action at Synapses: Agonists and Antagonists An Acetylcholine Synapse: Examples of Drug Action Tolerance EXPERIMENT 6-1 Question: Will the constant consumption of alcohol produce tolerance? Sensitization EXPERIMENT 6-2 Question: Does the injection of a drug always produce the same behavior? 6-2 Psychoactive Drugs Adenosinergic Cholinergic GABAergic Glutamatergic CLINICAL FOCUS 6-2 Fetal Alcohol Spectrum Disorder Dopaminergic Serotonergic Opioidergic CLINICAL FOCUS 6-3 Major Depression Cannabinergic

6-3 Factors Influencing Individual Responses to Drugs Behavior on Drugs Addiction and Dependence Risk Factors in Addiction 6-4 Explaining and Treating Drug Abuse Wanting-and-Liking Theory Why Doesn’t Everyone Become Addicted to Drugs? Treating Drug Abuse Can Drugs Cause Brain Damage? CLINICAL FOCUS 6-4 Drug-Induced Psychosis 6-5 Hormones Hierarchical Control of Hormones Classes and Functions of Hormones Homeostatic Hormones Anabolic–Androgenic Steroids Glucocorticoids and Stress SUMMARY KEY TERMS

CHAPTER 7 How Do We Study the Brain’s Structures and Functions? RESEARCH FOCUS 7-1 Tuning In to Language 7-1 Measuring and Manipulating Brain and Behavior Early Origins of Behavioral Neuroscience RESEARCH FOCUS 7-2 Brainbow: Rainbow Neurons EXPERIMENT 7-1 Question: Do hippocampal neurons contribute to memory formation? Methods of Behavioral Neuroscience Manipulating Brain–Behavior Interactions 7-2 Measuring the Brain’s Electrical Activity Recording Action Potentials from Single Cells EEG: Recording Graded Potentials from Thousands of Cells 29

Mapping Brain Function with Event-Related Potentials CLINICAL FOCUS 7-3 Mild Head Injury and Depression Magnetoencephalography 7-3 Anatomical Imaging Techniques: CT and MRI 7-4 Functional Brain Imaging Functional Magnetic Resonance Imaging Optical Tomography Positron Emission Tomography 7-5 Chemical and Genetic Measures of Brain and Behavior Measuring Brain Chemistry Measuring Genes in Brain and Behavior Epigenetics: Measuring Gene Expression CLINICAL FOCUS 7-4 AttentionDeficit/Hyperactivity Disorder 7-6 Comparing Neuroscience Research Methods 7-7 Using Animals in Brain–Behavior Research Benefits of Animal Models of Disease Animal Welfare and Scientific Experimentation SUMMARY KEY TERMS

CHAPTER 8 How Does the Nervous System Develop and Adapt? RESEARCH FOCUS 8-1 Linking Socioeconomic Status to Cortical Development 8-1 Three Perspectives on Brain Development Correlating Emerging Brain Structures with Emerging Behaviors Correlating Emerging Behaviors with Neural Maturation Identifying Influences on Brain and Behavior 8-2 Neurobiology of Development Gross Development of the Human Nervous System Origins of Neurons and Glia Neuronal Growth and Development CLINICAL FOCUS 8-2 Autism Spectrum Disorder Glial Development 31

Unique Aspects of Frontal Lobe Development 8-3 Using Emerging Behaviors to Infer Neural Maturation Motor Behaviors Language Development Development of Problem-Solving Ability EXPERIMENT 8-1 Question: In what sequence do the forebrain structures required for learning and memory mature? A Caution about Linking Correlation to Causation 8-4 Brain Development and the Environment Experience and Cortical Organization RESEARCH FOCUS 8-3 Keeping Brains Young by Making Music Experience and Neural Connectivity Critical Periods for Experience and Brain Development Hormones and Brain Development Gut Bacteria and Brain Development 8-5 Abnormal Experience and Brain Development Early Life Experience and Brain Development CLINICAL FOCUS 8-4 Romanian Orphans Injury and Brain Development Drugs and Brain Development Other Sources of Abnormal Brain Development

CLINICAL FOCUS 8-5 Schizophrenia Developmental Disability How Do Any of Us Develop a Normal Brain? SUMMARY KEY TERMS

CHAPTER 9 How Do We Sense, Perceive, and See the World? CLINICAL FOCUS 9-1 Migraines and a Case of Blindsight 9-1 Nature of Sensation and Perception Sensory Receptors Neural Relays Sensory Coding and Representation Perception 9-2 The Visual System’s Functional Anatomy Structure of the Retina 33

THE BASICS: Visible Light and the Structure of the Eye Photoreceptors CLINICAL FOCUS 9-2 Visual Illuminance Types of Retinal Neurons CLINICAL FOCUS 9-3 Glaucoma Visual Pathways Dorsal and Ventral Visual Streams 9-3 Location in the Visual World Coding Location in the Retina Location in the Lateral Geniculate Nucleus and Region V1 Visual Corpus Callosum 9-4 Neuronal Activity Seeing Shape Seeing Color RESEARCH FOCUS 9-4 Color-Deficient Vision Neuronal Activity in the Dorsal Stream 9-5 The Visual Brain in Action Injury to the Visual Pathway Leading to the Cortex Injury to the What Pathway Injury to the How Pathway SUMMARY KEY TERMS

CHAPTER 10 How Do We Hear, Speak, and Make Music? RESEARCH FOCUS 10-1 Evolution of Language and Music 10-1 Sound Waves: Stimulus for Audition Physical Properties of Sound Waves CLINICAL FOCUS 10-2 Tinnitus Perception of Sound Properties of Spoken Language and Music as Sounds 10-2 Functional Anatomy of the Auditory System Structure of the Ear Auditory Receptors RESEARCH FOCUS 10-3 Otoacoustic Emissions Pathways to the Auditory Cortex RESEARCH FOCUS 10-4 Seeing with Sound 35

Auditory Cortex 10-3 Neural Activity and Hearing Hearing Pitch Detecting Loudness Detecting Location Detecting Patterns in Sound 10-4 Anatomy of Language and Music Processing Language CLINICAL FOCUS 10-5 Left-Hemisphere Dysfunction Processing Music RESEARCH FOCUS 10-6 The Brain’s Music System 10-5 Auditory Communication in Nonhuman Species Birdsong Whale Songs SUMMARY KEY TERMS

CHAPTER 11 How Does the Nervous System Respond to Stimulation and Produce Movement? RESEARCH FOCUS 11-1 Neuroprosthetics 11-1 Hierarchical and Parallel Movement Control THE BASICS: Relating the Somatosensory and Motor Systems Forebrain: Initiating Movement Experimental Evidence for Hierarchical and Parallel Movement Control Brainstem: Species-Typical Movement EXPERIMENT 11-1 Question: What are the effects of brainstem stimulation under different conditions? CLINICAL FOCUS 11-2 Cerebral Palsy Spinal Cord: Executing Movement CLINICAL FOCUS 11-3 Spinal Cord Injury

11-2 Motor System Organization Motor Cortex EXPERIMENT 11-2 Question: How does the motor cortex take part in the control of movement? Motor Cortex and Skilled Movement Plasticity in the Motor Cortex EXPERIMENT 11-3 Question: What is the effect of rehabilitation on the cortical representation of the forelimb after brain damage? Corticospinal Tracts Motor Neurons Control of Muscles 11-3 Basal Ganglia, Cerebellum, and Movement Basal Ganglia and the Force of Movement CLINICAL FOCUS 11-4 Tourette Syndrome Cerebellum and Movement Skill EXPERIMENT 11-4 Question: Does the cerebellum help make adjustments required to keep movements accurate? 11-4 Somatosensory System Receptors and Pathways Somatosensory Receptors and Perception Posterior Root Ganglion Neurons Somatosensory Pathways to the Brain Spinal Reflexes Feeling and Treating Pain

RESEARCH FOCUS 11-5 Phantom Limb Pain Vestibular System and Balance 11-5 Exploring the Somatosensory Cortex Somatosensory Homunculus Secondary Somatosensory Cortex RESEARCH FOCUS 11-6 Tickling Effects of Somatosensory Cortex Damage Somatosensory Cortex and Complex Movement SUMMARY KEY TERMS

CHAPTER 12 What Causes Emotional and Motivated Behavior? RESEARCH FOCUS 12-1 The Pain of Rejection 12-1 Identifying the Causes of Behavior Behavior for Brain Maintenance

Neural Circuits and Behavior Evolutionary Influences on Behavior Environmental Influences on Behavior 12-2 The Chemical Senses Olfaction Gustation 12-3 Neuroanatomy of Motivated Behavior Regulatory and Nonregulatory Behavior Activities of the Hypothalamic Circuit 12-4 Control of Regulatory Behavior Controlling Eating CLINICAL FOCUS 12-2 Diets and Rhythms EXPERIMENT 12-1 Question: Does the hypothalamus play a role in eating? Controlling Drinking 12-5 Sexual Differences and Sexual Behavior Sexual Differentiation of the Brain Effects of Sex Hormones on the Brain CLINICAL FOCUS 12-3 Androgen Insensitivity Syndrome and the Androgenital Syndrome Neural Control of Sexual Behavior Sexual Orientation, Sexual Identity, and Brain Organization Cognitive Influences on Sexual Behavior 12-6 The Neural Control of Emotion 40

Theories of Emotion Emotion and the Limbic Circuit CLINICAL FOCUS 12-4 Agenesis of the Frontal Lobes Emotional Disorders CLINICAL FOCUS 12-5 Anxiety Disorders 12-7 Reward The Reward System Mapping Pleasure in the Brain Pleasure Electrodes? SUMMARY KEY TERMS

CHAPTER 13 Why Do We Sleep and Dream?

CLINICAL FOCUS 13-1 Doing the Right Thing at the Right Time 13-1 A Clock for All Seasons Biological Rhythms The Origin of Biorhythms EXPERIMENT 13-1 Question: Is plant movement exogenous or endogenous? Free-Running Rhythms Zeitgebers CLINICAL FOCUS 13-2 Seasonal Affective Disorder 13-2 The Suprachiasmatic Biological Clock Suprachiasmatic Rhythms Keeping Time RESEARCH FOCUS 13-3 Synchronizing Biorhythms at the Molecular Level Pacemaking Circadian Rhythms Pacemaking Circannual Rhythms Chronotypes Rhythms of Cognitive and Emotional Behavior 13-3 Sleep Stages and Dreaming Measuring How Long We Sleep Measuring Sleep Stages of Waking and Sleeping A Typical Night’s Sleep

Contrasting N-Sleep and R-Sleep Dreaming CLINICAL FOCUS 13-4 Restless Legs Syndrome What We Dream about 13-4 What Does Sleep Accomplish? Sleep as a Biological Adaptation Sleep as a Restorative Process Sleep for Memory Storage 13-5 Neural Bases of Sleep Reticular Activating System and Sleep Neural Basis of the EEG Changes Associated with Waking Neural Basis of R-Sleep 13-6 Disorders of Sleep Inability to Sleep Inability to Stay Awake Narcolepsy CLINICAL FOCUS 13-5 Sleep Apnea R-Sleep Behavioral Disorder 13-7 What Does Sleep Tell Us about Consciousness? SUMMARY KEY TERMS

CHAPTER 14 How Do We Learn and Remember? CLINICAL FOCUS 14-1 Remediating Dyslexia 14-1 Connecting Learning and Memory Studying Learning and Memory in the Laboratory EXPERIMENT 14-1 Question: Does an animal learn the association between emotional experience and environmental stimuli? Two Categories of Memory What Makes Explicit and Implicit Memory Different? What Is Special about Personal Memories? 14-2 Dissociating Memory Circuits Disconnecting Explicit Memory

CLINICAL FOCUS 14-2 Patient Boswell’s Amnesia Disconnecting Implicit Memory 14-3 Neural Systems Underlying Explicit and Implicit Memories Neural Circuit for Explicit Memories CLINICAL FOCUS 14-3 Alzheimer Disease Consolidation of Explicit Memories Neural Circuit for Implicit Memories CLINICAL FOCUS 14-4 Korsakoff Syndrome Neural Circuit for Emotional Memories Evolution of Memory Systems 14-4 Structural Basis of Brain Plasticity Long-Term Potentiation Measuring Synaptic Change Enriched Experience and Plasticity Sensory or Motor Training and Plasticity EXPERIMENT 14-2 Question: Does the learning of a fine motor skill alter the cortical motor map? RESEARCH FOCUS 14-5 Movement, Learning, and Neuroplasticity Epigenetics of Memory Plasticity, Hormones, Trophic Factors, and Drugs EXPERIMENT 14-3 Question: What effect do repeated doses of amphetamine, a psychomotor stimulant, have on neurons?

Some Guiding Principles of Brain Plasticity 14-5 Recovery from Brain Injury Donna’s Experience with Traumatic Brain Injury EXPERIMENT 14-4 Question: Does nerve growth factor stimulate recovery from stroke, influence neural structure, or both? SUMMARY KEY TERMS

CHAPTER 15 How Does the Brain Think? RESEARCH FOCUS 15-1 Split Brain 15-1 The Nature of Thought Characteristics of Human Thought Neural Units of Thought COMPARATIVE FOCUS 15-2 Animal Intelligence

EXPERIMENT 15-1 Question: How do individual neurons mediate cognitive activity? 15-2 Cognition and the Association Cortex Knowledge about Objects Multisensory Integration Spatial Cognition Attention Planning Imitation and Understanding 15-3 Expanding Frontiers of Cognitive Neuroscience Mapping the Brain CLINICAL FOCUS 15-3 Neuropsychological Assessment Cognition and the Cerebellum Social Neuroscience Neuroeconomics 15-4 Cerebral Asymmetry in Thinking Anatomical Asymmetry Functional Asymmetry in Neurological Patients Functional Asymmetry in the Healthy Brain EXPERIMENT 15-2 Question: Will severing the corpus callosum affect the way in which the brain responds? Functional Asymmetry in the Split Brain

EXPERIMENT 15-3 (A) Question: How can the right hemisphere of a split-brain subject show that it knows information? (B) Question: What happens if both hemispheres are asked to respond to competing information? Explaining Cerebral Asymmetry Left Hemisphere, Language, and Thought 15-5 Variations in Cognitive Organization Sex Differences in Cognitive Organization Handedness and Cognitive Organization CLINICAL FOCUS 15-4 Sodium Amobarbital Test Synesthesia 15-6 Intelligence Concept of General Intelligence Divergent and Convergent Intelligence Intelligence, Heredity, Epigenetics, and the Synapse How Smart Brains Differ 15-7 Consciousness Why Are We Conscious? EXPERIMENT 15-4 Question: Can people alter their movements without conscious awareness? What Is the Neural Basis of Consciousness? SUMMARY KEY TERMS

CHAPTER 16 What Happens When the Brain Misbehaves? RESEARCH FOCUS 16-1 Posttraumatic Stress Disorder 16-1 Multidisciplinary Contributions to Brain and Behavior Clinical Neuroscience Behavioral Disorders 16-2 Psychiatric Disorders Schizophrenia Spectrum and Other Psychotic Disorders Mood Disorders RESEARCH FOCUS 16-2 Antidepressant Action and Brain Repair 16-3 Neurological Disorders Traumatic Brain Injury CLINICAL FOCUS 16-3 Concussion

Stroke CLINICAL FOCUS 16-4 Cerebral Aneurysms Epilepsy Multiple Sclerosis Neurocognitive Disorders Treatments for Neurocognitive Disorders RESEARCH FOCUS 16-5 Treating Behavioral Disorders with Transcranial Magnetic Stimulation 16-4 Research Challenges Organizational Complexity Systemic Complexity Neuronal Plasticity Compensatory Plasticity Technological Resolution Modeling Simplicity Modeling Limitations 16-5 Is Misbehavior Always Bad? SUMMARY KEY TERMS ANSWERS TO SECTION REVIEW SELF-TESTS GLOSSARY REFERENCES NAME INDEX SUBJECT INDEX

PREFACE As with prior editions, this sixth edition of An Introduction to Brain and Behavior incorporates the latest research and technological advancements to give students a foundation in behavioral neuroscience as it is understood and practiced today. New material on genetics and epigenetics, genetic mutations, connectomics, brain imaging, genetic engineering and transgenic techniques, and our understanding and categorization of diseases and disorders of the brain are included throughout the text. In addition to these updates, we have also made some significant changes within some sections to reflect the current understanding of the concepts and better communicate that knowledge to the student. For example, the discussion of the allocortex in Section 2-3 has been revised and expanded. The discussion of neurotransmitters in Section 5-2 has been broadened to include subsections on purines and ion transmitters. The presentation of psychoactive drugs in Section 6-2 has been revamped to emphasize the primary transmitter system that these drugs affect. The discussion of hierarchical organization in Section 11-1 has been revised to include a discussion of parallel organization. Chapter 12 has been reorganized to present a clearer picture of motivated, regulatory, nonregulatory, sexual, reward, and emotional behavior. Chapter 13 has been reorganized to incorporate the new nomenclature and understanding of sleep. Chapter 16 has also seen some significant reorganization to the discussions of psychiatric and neurological disorders and their

treatments, including an expanded discussion of the field of clinical neuroscience and the classification systems used by the DSM and RDoC. The range of updates and new coverage in the sixth edition exposition and Focus features is listed, chapter by chapter, in the margins of these Preface pages. You can easily see the breadth and scope of the revision. Yet these changes have not added to the length of the text. To keep the student focused, judicious cuts have been made throughout to compensate for the new material. Changes in each new edition are always made with the goal of maintaining the voice and style that have helped make An Introduction to Brain and Behavior successful, and this sixth edition preserves the tools and features developed in the prior editions. With encouraging feedback from readers, the book’s learning apparatus continues to feature sets of self-test questions at the end of the major sections in each chapter. These Section Reviews help students track their understanding as they progress through the text and the course. Answers appear at the back of the book. We continue to expand the popular margin notes. Beyond offering useful asides to the text narrative, these marginalia increase the reader’s ease in finding information, especially when related concepts are introduced early in the text and then elaborated on in later chapters. Readers can return quickly to an earlier discussion to refresh their knowledge or jump ahead to learn more. The margin

notes also help instructors move through the book to preview later discussions. In this edition, we’ve also highlighted with margin callouts those places where the 10 principles of nervous systems functioning, introduced in Chapter 2, correspond directly to the material in each chapter. Although this feature is by no means comprehensive, by reiterating these principles in key places where the connection is sharpest, we help to give the student a deeper understanding of these core concepts and the nervous system functioning they reflect. The illustrated Experiments, another of the book’s most popular features, show readers how researchers design experiments—that is, how they approach the study of brain–behavior relationships. The Basics features let students brush up or get up to speed on their science foundation—knowledge that helps them comprehend behavioral neuroscience. We have made some big changes, but much of the book remains familiar. In shaping content throughout, we continue to examine the nervous system with a focus on function, on how our behavior and our brain interact, by asking key questions that students and neuroscientists ask: Why do we have a brain? How is the nervous system organized—functionally as well as anatomically? How do drugs and hormones affect our behavior?

How does the brain learn? How does the brain think? Why do we sleep and dream? Every chapter’s central question highlights the brain–behavior relationship. When we first describe how neurons communicate in Chapter 5, for example, we also describe how synaptic plasticity serves as the basis of learning. Later, in Section 14-4, we expand on plasticity as we explore learning and memory. As it was when we wrote the first edition, our goal in this new edition is to bring coherence to a vast subject by helping students understand the big picture. Asking fundamental questions about the brain has another benefit: it piques students’ interest and challenges them to join us on the journey of discovery that is brain science. Scientific understanding of the human brain and human behavior continues to grow at an exponential pace. We want to communicate the excitement of recent breakthroughs in brain science as well as relate some of our own experiences from a combined 125+ years of studying brain and behavior, both to make the field’s developing core concepts and latest revelations understandable and to transport uninitiated students to the frontiers of physiological psychology.

Areas of Emphasis To convey the excitement of neuroscience as researchers understand it, we interweave evolution, genetics, and epigenetics;

psychopharmacology; and neural plasticity and connectivity, including CNS and ENS interactions, throughout the book.

EVOLUTION Our perspective—neuroscience in an evolutionary context—recurs in almost every chapter. By focusing on comparative behavior and anatomy, we address nervous system evolution in depth in Chapters 1 and 2, evolution of the synapse in Section 5-1, and evolution of visual pathways in Section 9-2. We discuss how evolution might have influenced behaviors related to aggression and mate selection in Section 12-1, the evolutionary theories of sleeping and dreaming in Section 13-4, and the evolutionary origins of memory in Section 14-3. We describe the evolution of sex differences in spatial cognition and language in Section 15-5 and links between our evolved reactions to stress and anxiety disorders in Section 16-2.

GENETICS AND EPIGENETICS We introduce the foundations of genetic and epigenetic research in Sections 1-3 and 2-1 and begin to elaborate on them in Section 3-3. Chapter 5 discusses metabotropic receptors and DNA, as well as learning and genes. The interplay of genes and drug action is integral to Chapter 6, as are the developmental roles of genes and gene methylation to Chapter 8. Section 9-4 explains the genetics of color vision, and the genetics of sleep disorders anchors Section 13-6. Section 14-4 includes the role of epigenetics in memory. Section 163 considers the roles of genetics and of prions in understanding the causes of behavioral disorders.

PSYCHOPHARMACOLOGY Chapter 6 investigates how drugs and hormones affect behavior, topics we revisit often throughout the book. You will find coverage of drugs and information transfer in Section 4-3, drugs and cellular communication in Section 5-3, and synthetic biology in Section 7-1. Section 12-6 covers drugs and emotional behavior; Section 13-6, drugs and sleep disorders; and Section 14-4, neuronal changes with drug use. Section 16-3 discusses the promise of the liposome as a delivery vehicle in pharmacological treatments, while Sections 16-2 and 16-3 explore drugs used as treatments for a range of behavioral disorders.

CONNECTIVITY Neural plasticity is a hallmark of this book. We introduce the concept in Section 1-5, define it in Section 2-1, develop it in Section 2-6, and expand on it throughout. At the conclusion of Section 14-4, we elaborate seven guiding principles of brain plasticity. In Section 1-4, we introduce the emerging field of connectomics, which we explore further throughout Chapter 15. The new field of psychobiotics, which identifies the connection between the gut microbiome and its effects on the enteric nervous system—as well as on the central nervous system—appears in Sections 2-5 and 12-5.

Scientific Background Provided We describe the journey of discovery that is neuroscience in a way that students just beginning to study the brain and behavior can understand; then they can use our clinical examples to tie its relevance to the real world. Our approach provides the background 56

students need to understand introductory brain science. Multiple illustrated Experiments in 13 chapters help them visualize the scientific method and how scientists think. The Basics features in 6 chapters address the fact that understanding brain function requires understanding information from all the basic sciences. These encounters can prove both surprising and shocking to students who come to the course without the necessary background. The Basics features in Chapters 1 and 2 address the relevant evolutionary and anatomical background. In Chapter 3, The Basics provides a short introduction to chemistry before the text describes the brain’s chemical activities. In Chapter 4, The Basics addresses electricity before exploring the brain’s electrical activity. Readers already comfortable with the material can easily skip it; less experienced readers can learn it and use it as a context for neuroscience. Students with this background can tackle brain science with greater confidence. Similarly, for students with limited knowledge of basic psychology, we review such facts as stages of behavioral development in Chapter 8 and forms of learning and memory in Chapter 14. Students in social science disciplines often remark on the amount of biology and chemistry in the book, and an equal number of students in biological sciences remark on the amount of psychology. More than half the students enrolled in the bachelor of science in neuroscience program at the University of Lethbridge switched from

an initial biochemistry or psychology major after taking this course. We must be doing something right! Chapter 7 showcases the range of methods that behavioral neuroscientists use to measure and manipulate brain and behavior— traditional methods and cutting-edge techniques such as optogenetics, optical tomography, resting-state fMRI, chemogenetics, DREADD, and CRISPR. Expanded discussions of techniques appear where appropriate, especially in Research Focus features, including Focus 4-3, Optogenetics and Light-Sensitive Ion Channels; Focus 7-2, Brainbow: Rainbow Neurons; and Focus 16-1, Posttraumatic Stress Disorder, which includes treatments based on virtual reality exposure therapies. Finally, because critical thinking is vital to progress in science, select discussions throughout the book center on relevant aspects. Section 1-2 concludes with The Separate Realms of Science and Belief. Section 15-2 discusses the rise and fall of mirror neurons, demonstrating how the media—and even scientists—can fail to question the validity of research results. Section 12-5 introduces the idea that gender identity comprises a broad spectrum rather than a female–male dichotomy. Section 7-7 considers issues of animal welfare in scientific research and the use of laboratory animal models to mimic human neurologic and psychiatric disorders.

Clinical Focus Maintained Neuroscience is a human science. Everything in this book is relevant to our lives, and everything in our lives is relevant to neuroscience.

Understanding neuroscience helps us understand how we learn, how we develop, and how we can help people with brain and behavioral disorders. Knowledge of how we learn, how we develop, and the symptoms of brain and behavioral disorders provides insights into neuroscience. Clinical material also helps make neurobiology particularly relevant to students who seek a career in psychology, social work, or another profession related to mental health, as well as to students of the biological sciences. We integrate clinical information throughout the text with Clinical Focus features, and we expand on it in Chapter 16, the book’s capstone, as well. In An Introduction to Brain and Behavior, the placement of some topics is novel relative to traditional treatments. We include brief descriptions of brain diseases close to discussions of basic associated processes, as exemplified in the integrated coverage of Parkinson disease through Chapter 5, How Do Neurons Communicate and Adapt? This strategy helps first-time students repeatedly forge close links between what they are learning and real-life issues. To provide a consistent disease nomenclature, the sixth edition follows the system advocated by the World Health Organization for diseases named after their putative discoverers. “Down syndrome,” for example, has largely replaced “Down’s syndrome” in the popular and scientific literature. We extend that convention to Parkinson disease and Alzheimer disease, among other eponymous diseases and disorders.

The nearly 150 disorders we cover are cross-referenced in the Index of Disorders inside the book’s front cover. Chapter 16 expands on the nature of neuroscience research and the multidisciplinary treatment methods for neurological and psychiatric disorders described in preceding chapters. We emphasize questions that relate to the biological bases of behavior. For us, the excitement of neuroscience lies in understanding how the brain explains what we do, whether it is talking, sleeping, seeing, or learning. Readers will therefore find nearly as many illustrations about behavior as illustrations about the brain. This emphasis on explaining the biological foundation of behavior is another reason we include a mix of Clinical, Research, and Comparative Focus features throughout the text.

Abundant Chapter Pedagogy Building on the innovative teaching devices described so far, numerous in-text pedagogical aids adorn every chapter, beginning with an outline and an opening Focus feature that draws students into the chapter’s topic. Focus features dot each chapter to connect brain and behavior to relevant clinical or research experience. Within chapters, definitions of boldface key terms introduced in the text appear in the margins as reinforcement, margin notes link topics together, and end-of-section Review self-tests help students check their grasp of major points. Each chapter ends with a Summary—several of them including summarizing tables or illustrations to help students visualize or

review big-picture concepts—and a list of Key Terms. Following this Preface, the Media and Supplements section describes the wide array of supplemental materials designed exclusively for students and teachers using the sixth edition.

Superb Visual Reinforcement Our most important learning aid appears on nearly every page in the book: an expansive and, we believe, exceptional set of illustrations. Overwhelmingly, readers agree that, hand in hand with our words, the diagrams describe and illuminate the nervous system. Important anatomical illustrations are large format to ease perusal. We have selected relevant and engaging photos that enliven and enrich the discussion, ranging from a dance class for Parkinson patients in Section 5-3 to the dress that sparked a social media controversy to illustrate color constancy in Section 9-4 to a seniors’ bridge game to illustrate the discussion of cognitively stimulating activities in Section 16-3. Illustrations are consistent from chapter to chapter in order to reinforce one another. We consistently color-code diagrams that illustrate each aspect of the neuron, depict each structural region in the brain, and demark nervous system divisions. We include many varieties of micrographic images to show what a particular neural structure actually looks like. These illustrations and images are included in our PowerPoint presentations and integrated as labeling exercises in our Study Guide and Testing materials.

Teaching Through Metaphors, Examples, and Principles If a textbook is not enjoyable, it has little chance of teaching well. We heighten students’ interest through abundant use of metaphors and examples. Students read about patients whose brain injuries offer insights into brain function, and we examine car engines, robots, and prehistoric flutes for the same purpose. Frequent illustrated Experiments, comparative biology examples, and representative Comparative Focus features help students understand how much we humans have in common with creatures as distant from us as sea slugs and as close to us as chimpanzees. We also facilitate learning by re-emphasizing main points and by distilling sets of principles about brain function that offer a framework to guide students’ thinking. Thus, Section 2-6 introduces 10 key principles that explain how the parts of the nervous system work together. Section 14-4 summarizes seven guiding principles of neuroplasticity. These sets of principles form the basis of many discussions throughout the book. Frequently, margin notes remind readers when they encounter these principles again—and where to review them in depth.

Big-Picture Emphasis One challenge in writing an introductory book on any topic is deciding what to include and what to exclude. We organize discussions to focus on the bigger picture—a focus exemplified by the 10 principles of nervous system function introduced in Section 26 and echoed throughout the book. Any set of principles may be 62

arbitrary yet nevertheless afford students a useful framework for understanding the brain’s activities. In Chapters 8 through 16, we tackle behavioral topics in a more general way than most contemporary books do. In Chapter 12, for instance, we revisit experiments and ideas from the 1960s to understand why animals behave as they do, then we consider emotional and motivated behaviors as diverse as eating and anxiety attacks in humans. In Chapter 14, the larger picture of learning and memory is presented alongside a discussion of recovery from traumatic brain injury. This broad focus helps students grasp the big picture that behavioral neuroscience paints. While broadening our focus requires us to leave out some details, our experience with students and teachers through five earlier editions confirms that discussing the larger problems and issues in brain and behavior is of greater interest to students—especially those new to this field—and is more often remembered than are myriad details without context. As in preceding editions, we are selective in our citation of the truly massive literature on the brain and behavior because we believe that too many citations can disrupt the text’s flow, distracting students from the task of mastering concepts. We provide citations to classic works by including the names of the researchers and by mentioning where the research was performed. In areas where controversy or new breakthroughs predominate, we also include detailed citations to papers (especially reviews) from the years 2013

to 2018. An end-of-book References section lists, by chapter, all the literature used in developing the book, reflecting the addition of many new citations in this edition and elimination of other, now superseded, research.

SIXTH EDITION KEY REVISIONS CHAPTER 1 REVAMPED Section 1-1, which presents PVS and MCS earlier in the chapter and is updated with a discussion of Adrian Owen’s work in this area REVISED discussion of Mendel’s experiments and Experiment 1-1 NEW subsection on brain cell connections, including an introduction of the connectome, in Section 1-4 EXPANDED discussion of the hominid genome in Section 1-4 NEW discussion of the role of cell number in relationship to brain size in mediating behavior

CHAPTER 2 EXPANDED discussion of cerebral spinal fluid in Section 2-1 REVISED and EXPANDED discussion of the allocortex in Section 2-3 UPDATED Clinical Focus 2-2, Meningitis and Encephalitis; Clinical Focus 2-3, Stroke; and Clinical Focus 2-4, Bell Palsy UPDATED discussion of Principle 9: Brain functions are localized and distributed

CHAPTER 3 REVAMPED discussion of the cells of the nervous system in Section 3-1 NEW subsection on acquired genetic mutations in Section 3-3 UPDATED discussion of transgenic techniques and NEW subsection on gene modification and CRISPR in Section 3-3

CHAPTER 4 UPDATED Clinical Focus 4-2, Multiple Sclerosis NEW discussion of optogenetic techniques in mice in Research Focus 43, Optogenetics and Light-Sensitive Ion Channels REVISED Clinical Focus 4-4, ALS: Amyotrophic Lateral Sclerosis

CHAPTER 5 REVISED and UPDATED discussion of electrical synapses (gap junctions) in Section 5-1 REVISED and UPDATED discussion of neurotransmitters, including NEW discussions of purine and ion transmitters, in Section 5-2 REVISED discussion of habituation response in Section 5-4

CHAPTER 6 REVAMPED categorization and NEW, REVISED, and UPDATED information on various recreational and medically prescribed psychoactive drugs in Section 6-2 NEW subsection on risk factors in addiction in Section 6-3 REVISED Clinical Focus 6-4, Drug-Induced Psychosis

REVISED presentation of hormones in Section 6-5

CHAPTER 7 UPDATED presentation of brain manipulation techniques, including new discussions of CRISPR, HIFU, miniscopes, and rodent touchscreen devices, in Section 7-1 UPDATED Research Focus 7-2, Brainbow: Rainbow Neurons (moved from Chapter 3)

CHAPTER 8 UPDATED discussion of astrocytes in Section 8-2 NEW Research Focus 8-3, Keeping Brains Young by Making Music UPDATED Clinical Focus 8-5, Schizophrenia NEW subsection on the adolescent brain as a critical period in Section 84 UPDATED discussion of prenatal experiences and introduction of the germline in Section 8-5

CHAPTER 9 REVISED presentation of neural relays in Section 9-1 NEW presentation of recent research on color perception in Section 9-4 NEW presentation of recent studies on the role of dorsal stream in shaping perception in Section 9-5 NEW Clinical Focus 9-3, Glaucoma

CHAPTER 10

NEW Clinical Focus 10-2, Tinnitus REVAMPED Section 10-5, including a NEW subsection on whale songs

CHAPTER 11 REVISED discussion of hierarchical organization, including NEW discussion of parallel organization, in Section 11-1 NEW discussion of position-point theory in Section 11-2 NEW subsection on the secondary somatosensory cortex in Section 11-5

CHAPTER 12 NEW Section 12-1, Identifying the Causes of Behavior, built from previous Sections 12-1 and 12-3 REVAMPED and REORGANIZED discussions of motivated, regulatory and nonregulatory, sexual, and emotional behavior in Sections 12-3, 12-4, and 12-5 NEW Clinical Focus 12-2, Diets and Rhythms EXPANDED coverage of hormones and cognitive influences in Section 12-5 NEW discussion of mapping pleasure and pleasure electrodes in Section 12-7

CHAPTER 13 UPDATED presentation, including a NEW subsection on chronotypes, in Section 13-2 REVISED presentation of the stages of waking and sleeping, including NEW classification of waking and sleep states, in Section 13-3

UPDATED discussion of sleep and memory storage in Section 13-4, including a NEW subsection on the synaptic homeostasis theory of sleep and memory REVISED and REORGANIZED presentation of sleep disorders in Section 13-5

CHAPTER 14 UPDATED Clinical Focus 14-1, Remediating Dyslexia NEW discussion of Binder’s noninvasive imaging studies looking for an engram of semantic memories, in Section 14-1 EXPANDED discussion of autobiographical memories and the hippocampus in Section 14-1 NEW subsection on the evolution of memory systems in Section 14-3

CHAPTER 15 UPDATED presentation of mirror neurons in Section 15-2 UPDATED discussion of intelligence, including a NEW subsection on the brain bases of intelligence, in Section 15-5 REVAMPED discussion of consciousness in Section 15-7

CHAPTER 16 REVAMPED Section 16-1 with EXPANDED presentation of clinical neuroscience and NEW discussion of the DSM versus RDoC REORGANIZED and UPDATED discussion of psychiatric disorders and neurological disorders and their treatments in Sections 16-2 and 16-3 REVISED Clinical Focus 16-4, Cerebral Aneurysms (moved from Chapter 10)

REVAMPED presentation of research challenges in Section 16-4

Acknowledgements We sincerely thank the many people who contributed to the development of this edition. The staff at Worth Publishers is remarkable and makes doing revisions a joy. We thank our program manager, Daniel DeBonis, more than ably assisted by Anna Munroe; our senior content project manager, Vivien Weiss; and senior workflow project manager Paul Rohloff; as well as project managers Andrea Stefanowicz and Misbah Ansari, and the composition team at Lumina. Andrew Sylvester replaced our long-time development editor Barbara Brooks, and he had big shoes to fill. He did so admirably and provided a new set of eyes that brought a fresh perspective to this edition. We thank cover design manager John Callahan for a striking cover and design manager Natasha Wolfe for a fresh, inviting, accessible new interior design. Thanks also to Cecilia Varas for coordinating photo research and to Richard Fox, who found photographs and other illustrative materials that we would not have found on our own. We are indebted to Macmillan art manager Matt McAdams and medical illustrator Eli Ensor for their excellent work in creating new illustrations. Our colleagues, too, have helped in the development of every edition. We would like to thank the following colleagues and students for making important contributions: Mike Antle, Jaideep Bains, Nicole Burma, Tim Bussey, Richard Dyck, Jonathan Epp,

Paolo Federico, Richard Frayne, Matthew Hill, Lisa Siksida, Simon Spanswick, Peter Stys, Catherine Thomas, Roger Thompson, Tuan Trang, and Alicia Zumbusch. And for their help in shaping the sixth edition, we are especially indebted to the reviewers who provided extensive comments on selected chapters and illustrations: Karen Atkinson-Leadbeater, Mount Royal University; Richard Brown, LaGuardia Community College, CUNY; Richard Conti, Kean University; Carol DeVolder, St. Ambrose University; Benjamin DeVore, Virginia Tech; Francine Dolins, University of Michigan–Dearborn; Evelyn Field, Mount Royal University; Merage Ghane, Virginia Polytechnic Institute and State University; Bradley Gruner, College of Southern Nevada; Sandra Holloway, Saint Joseph University; Adam Hutcheson, Georgia Gwinnett College; Eric Jackson, University of New Mexico; Daniel Kay, Brigham Young University; Lisa Lyons, Florida State University; Vincent Markowski, SUNY Geneseo; Michael Nadorff, Mississippi State University; Michael Neelon, University of North Carolina–Asheville; Carlos Rodriguez, The University of New Mexico; Neil Sass, Heidelberg University; Andra Smith, University of Ottawa; and Richard Straub, University of Michigan–Dearborn. Likewise, we continue to be indebted to the colleagues who provided extensive comments during the development of the fifth edition: Nancy Blum, California State University, Northridge; Kelly Bordner, Southern Connecticut State University; Benjamin Clark, University of New Mexico; Roslyn Fitch, University of Connecticut; Trevor Gilbert, University of Calgary; Nicholas Grahame, Indiana

University–Purdue University Indianapolis; Kenneth Troy Harker, University of New Brunswick; Jason Ivanoff, St. Mary’s University; Dwight Kravitz, The George Washington University; Ralph Lydic, University of Tennessee, Knoxville; Paul Meyer, The State University of New York at Buffalo; Jaime Olavarria, University of Washington; Christopher Robison, Florida State University; Claire Scavuzzo, University of Alberta; Sarah Schock, University of Ottawa; Robert Stackman, Florida Atlantic University; Sandra Trafalis, San Jose State University; Douglas Wallace, Northern Illinois University; Matthew Will, University of Missouri, Columbia; and Harris Philip Zeigler, Hunter College. We would also like to thank those reviewers who contributed to the development of the fourth edition: Mark Basham, Regis University; Pam Costa, Tacoma Community College; Russ Costa, Westminster College; Renee Countryman, Austin College; Kristen D’Anci, Salem State University; Trevor James Hamilton, Grant MacGewn University; Christian Hart, Texas Woman’s University; Matthew Holahan, Carleton University; Chris Jones, College of the Desert; Joy Kannarkat, Norfolk State University; Jennifer Koontz, Orange Coast College; Kate Makerec, William Paterson University of New Jersey; Daniel Montoya, Fayetteville State University; Barbara Oswald, Miami University of Ohio; Gabriel Radvansky, University of Notre Dame; Jackie Rose, Western Washington University; Steven Schandler, Chapman University; Maharaj Singh, Marquette University; and Manda Williamson, University of Nebraska–Lincoln.

We’d also like to thank the reviewers who contributed their thoughts to the third edition: Chana Akins, University of Kentucky; Michael Anch, Saint Louis University; Maura Mitrushina, California State University, Northridge; Paul Wellman, Texas A&M University; and Ilsun White, Morehead State University. The methods chapter was new to the third edition and posed the additional challenge of taking what easily could read like a seed catalog and making it engaging to readers. We therefore are indebted to Margaret G. Ruddy, The College of New Jersey, and Ann Voorhies, University of Washington, for providing extensive advice on the initial version of Chapter 7. In addition, we thank the reviewers who provided their thoughts on the second edition: Barry Anton, University of Puget Sound; R. Bruce Bolster, University of Winnipeg; James Canfield, University of Washington; Edward Castañeda, University of New Mexico; Darragh P. Devine, University of Florida; Kenneth Green, California State University, Long Beach; Eric Jackson, University of New Mexico; Michael Nelson, University of Missouri, Rolla; Joshua S. Rodefer, University of Iowa; Charlene Wages, Francis Marion University; Doug Wallace, Northern Illinois University; Patricia Wallace, Northern Illinois University; and Edie Woods, Madonna University. Sheri Mizumori, University of Washington, deserves special thanks for reading the entire manuscript for accuracy and providing fresh ideas that proved invaluable. Finally, we must thank our tolerant wives for putting up with sudden changes in plans as chapters returned, in manuscript or in

proof, with hopes for quick turnarounds. We also thank our colleague Robbin Gibb, who uses the book and has provided much feedback, in addition to our undergraduate and graduate students, technicians, and postdoctoral fellows, who kept our research programs moving forward when we were engaged in revising the book. Bryan Kolb, Ian Q. Whishaw, G. Campbell Teskey

MEDIA AND SUPPLEMENTS An Introduction to Brain and Behavior, Sixth Edition, features a wide array of supplemental materials designed exclusively for students and teachers of the text. For more information about any of the items, please visit the Macmillan Learning catalog at www.macmillanlearning.com.

For Students LaunchPad with LearningCurve Quizzing A comprehensive Web resource for teaching and learning psychology

LaunchPad combines Macmillan Learning’s award-winning media with an innovative platform for easy navigation. For students, it is the ultimate online study guide, with rich interactive tutorials, videos, interactive e-book, and the LearningCurve adaptive quizzing system. For instructors, LaunchPad is a full-course space where class documents can be posted, quizzes are easily assigned and graded, and students’ progress can be assessed and recorded. Whether you are looking for the most effective study tools or a robust platform for an online course, LaunchPad is a powerful way to enhance your class. LaunchPad for An Introduction to Brain and Behavior, Sixth Edition, includes the following resources: 75

NEW! NEUROSCIENCE ACTIVITIES, VOLUME I, is a brand-new collection of online activities that enables students to understand neuronal processes in action. Over a dozen new activities show in vivid animations the foundational processes that the reader can only imagine when reading the text. Students come away with a fuller understanding of topics such as the conduction of the action potential, the integration of neural inputs, synaptic transmission, and the action of neurotransmitters. A perfect accompaniment to an online or hybrid course, each activity is fully assessable with multiplechoice questions. This collection is indispensable for bringing fundamental neuroscience concepts to life. THE LEARNINGCURVE adaptive quizzing system is designed based on the latest findings from learning and memory research. It combines adaptive question selection, immediate and valuable feedback, and a gamelike interface to engage students in a learning experience that is unique to them. Students experience learning that is customized to their level of knowledge, and instructors receive state-of-the-art reporting on the progress of each student, as well as the class as a whole. PRACTICE QUIZZES provide another way for students and instructors to rehearse their knowledge. Each quiz is written on the topics discussed throughout each chapter and features a variety of multiple-choice questions presented to students randomly from question pools. Valuable to both student and instructor, these practice quizzes are fully editable and make robust assessment quick and easy to set up.

AN INTERACTIVE E-BOOK allows students to highlight, bookmark, and make notes, just as they would with a printed textbook. The search function and in-text glossary definitions make the text ready for the digital age. STUDENT VIDEO ACTIVITIES include engaging modules that instructors can easily assign for student assessment. Videos cover a variety of topics and are sure to spark discussion and encourage critical thinking. THE SCIENTIFIC AMERICAN NEWSFEED delivers weekly articles, podcasts, and news briefs on the very latest developments in psychology from the first name in popular science journalism. PSYCHOLOGY AND THE REAL WORLD: ESSAYS ILLUSTRATING FUNDAMENTAL CONTRIBUTIONS TO SOCIETY, SECOND EDITION is a superb collection of essays by major researchers describing their landmark studies. Published in association with the not-for-profit FABBS Foundation, this engaging reader includes Bruce McEwen’s work on the neurobiology of stress and adaptation, Jeremy Wolfe’s look at the importance of visual search, Elizabeth Loftus’s reflections on her study of false memories, and Daniel Wegner’s study of thought suppression. A portion of the proceeds is donated to the FABBS Foundation to support societies of cognitive, psychological, behavioral, and brain sciences.

For Instructors INSTRUCTOR’S RESOURCES This invaluable tool, for new and experienced instructors alike, was revised by Catherine Smith of Carleton University. It includes chapter-by-chapter learning objectives and chapter overviews, detailed lecture outlines, thorough chapter summaries, chapter key terms, in-class demonstrations and activities, springboard topics for discussion and debate, ideas for research and term paper projects, homework assignments and exercises, and suggested readings from journals and periodicals. Course-planning suggestions and a guide to videos and Internet resources are also included. The Instructor’s Resources can be downloaded from LaunchPad at launchpadworks.com.

Assessment Tools COMPUTERIZED TEST BANK The Test Bank includes a battery of more than 1300 multiple-choice and short-answer test questions. Each item is keyed to the page in the textbook on which the answer can be found. All the questions have been thoroughly reviewed and edited for accuracy and clarity. The Test Bank files can be downloaded from LaunchPad at launchpadworks.com.

Presentation IMAGE SLIDES AND LECTURE SLIDES Available for download from LaunchPad at launchpadworks.com, these slides can either be used as they are or customized to fit the needs of your course. There are two sets of slides for each chapter. The Image slides feature all the figures, photos, and tables. The Lecture slides feature main points of the chapter with selected figures and illustrations.

CHAPTER 1 What Are the Origins of Brain and Behavior?

1-1 The Brain in the Twenty-First Century CLINICAL FOCUS 1-1 Living with Traumatic Brain Injury Why Study Brain and Behavior? What Is the Brain? What Is Behavior?

1-2 Perspectives on Brain and Behavior Aristotle and Mentalism Descartes and Dualism Darwin and Materialism COMPARATIVE FOCUS 1-2 The Speaking Brain Experiment 1-1: Question: How do parents transmit heritable factors to offspring? Contemporary Perspectives on Brain and Behavior 1-3 Evolution of Brains and of Behavior Origin of Brain Cells and Brains THE BASICS Classification of Life Evolution of Nervous Systems in Animals Chordate Nervous System 1-4 Evolution of the Human Brain and Behavior Humans: Members of the Primate Order Australopithecus: Our Distant Ancestor The First Humans 81

Relating Brain Size and Behavior COMPARATIVE FOCUS 1-3 The Elephant’s Brain Why the Hominid Brain Enlarged 1-5 Modern Human Brain Size and Intelligence Meaning of Human Brain Size Comparisons Acquisition of Culture

CLINICAL FOCUS 1-1 Living with Traumatic Brain Injury Fred Linge, a clinical psychologist with a degree in brain research, wrote this description 12 years after his head injury occurred: In the second it took for my car to crash head-on, my life was permanently changed, and I became another statistic in what has been called “the silent epidemic.” During the next months, my family and I began to understand something of the reality of the experience of head injury. I had begun the painful task of recognizing and accepting my physical, mental, and emotional deficits. I couldn’t taste or smell. I couldn’t read even the simplest sentence without forgetting the beginning before I got to the end. I had a hair-trigger temper that could ignite instantly into rage over the most trivial incident. . . . Two years after my injury, I wrote a short article: “What Does It Feel Like to Be Brain Damaged?” At this point in my life, I began to

involve myself with other brain-damaged people. It brought me an enormous outpouring of letters, phone calls, and personal visits that continue to this day. Many were struggling as I had struggled, with no diagnosis, no planning, no rehabilitation, and most of all, no hope. . . . The catastrophic effect of my injury was such that I was shattered and then remolded by the experience, and I emerged from it a profoundly different person with a different set of convictions, values, and priorities. (Linge, 1990) Each year, between 2 and 7 million people in the United States suffer from traumatic brain injury (TBI)—a wound to the brain that results from a blow to the head or a concussion (Kisser et al., 2017). Most of these people have to cope, at least to some degree, with Linge’s forecast of “no diagnosis, no planning, no rehabilitation, and most of all, no hope.” TBI and the many other disorders of the brain that we will present in this textbook (see the index of disorders) are major challenges faced by individuals working in the field of neuroscience, the multidisciplinary study of the brain. Neuroscience looks not only at the anatomy of the brain but also at its chemistry, physics, computational processes, influences on psychological functioning, influences on sociological and economic factors, and diseases. Neuroscience can address the challenges outlined by Linge via, for example, improved diagnosis by imaging the anatomy, chemistry, and electrical activity of the brain and rehabilitation through computer-assisted training and prosthetics. Fred Linge’s life has been a journey. Before the car crash, he gave little thought to the relationship between his brain and behavior. After the crash, adapting to his injured brain and behavior dominated his life. The purpose of this book is to take you on a journey toward understanding the link between brain and behavior and how the brain is

organized to produce behavior. The knowledge that is emerging from the study of the brain and behavior is changing how we think about ourselves, how we structure our education and social interactions, and how we aid those with brain injury, disease, and disorder.

1-1 The Brain in the Twenty-First Century Illustrated Experiments throughout the book reveal how neuroscientists conduct research, beginning with Experiment 1-1 in Section 1-2.

The purpose of this chapter is to describe the relationship between brain and behavior: how the brain is organized to produce behavior. We will first present the ideas that led to our current understanding of the role of the brain in behavior. Next, we will describe the evolution of brain and behavior in diverse animal species, including humans. We will end by discussing ideas about why the human brain is special.

Why Study Brain and Behavior? The brain is a physical object, a living tissue, a body organ. Behavior is action, momentarily observable but fleeting. Brain and behavior differ greatly but are linked. They have evolved together: one is responsible for the other, which is responsible for the other, and so on. There are three reasons for linking the study of the brain to the study of behavior: 1. How the brain produces behavior is a major scientific question. Scientists and students study the brain to understand humanity. A better understanding of brain function will allow improvements

in many aspects of our world, including educational systems, economic systems, and social systems. 2. The brain is the most complex organ on Earth and is found in many groups of animals. Students of the brain want to understand its place in the biological order of our planet. This chapter describes the basic function and evolution of the brain, especially the human brain. 3. A growing list of behavioral disorders can be explained and treated as we increase our understanding of the brain. More than 2000 disorders may be in some way related to brain abnormalities. As indexed on the inside front cover of this book, we detail relationships between brain disorders and behavioral disorders in every chapter, especially in the Focus features. None of us can predict how the knowledge we gain about the brain and behavior may prove useful. A former psychology major wrote to tell us that she took our course because she was unable to register in a preferred course. She felt that, although our course was interesting, it was “biology, not psychology.” After graduating and getting a job in a social service agency, she has found to her delight that understanding the links between brain and behavior is in fact a source of insight into many of her clients’ disorders and the treatment options available for them.

What Is the Brain? Brain is the Anglo-Saxon word for the tissue found within the skull, and it describes a part of the human nervous system (Figure 1-1). The 86

human nervous system is composed of cells, as is the rest of the body. About half of these brain cells (87 billion of them) are called neurons and are specialized in that they interconnect with each other and with the muscles and organs of the body with fibers that can extend over long distances. The other half of these brain cells (86 billion) are called glial cells, and they support the function of the neurons. Through interconnections, the neurons send electrical and chemical signals to communicate with one another, with sensory receptors in the skin, with muscles, and with internal body organs. Most of the interconnections between the brain and body are made through the spinal cord, a tube of nervous tissue encased in our vertebrae. The spinal cord in turn sends nerve fibers out to our muscles and internal body organs and receives fibers from sensory receptors on many parts of our body.

FIGURE 1-1 Major Divisions of the Human Nervous System The brain and spinal cord together make up the central nervous system. All of the nerve processes radiating out beyond the brain and spinal cord and all of the neurons outside the CNS connect to sensory receptors, muscles, and internal body organs to form the peripheral nervous system.

Together, the brain and spinal cord make up the central nervous system (CNS), the part of our nervous system encased in bone. The CNS is called central because it is both the nervous system’s physical core and the core structure mediating behavior. All the processes that

radiate out beyond the brain and spinal cord constitute the peripheral nervous system (PNS). As shown in Figure 1-2, the human brain comprises two major sets of structures. The cerebrum (forebrain), shown in Figure 1-2A, has two nearly symmetrical halves, called hemispheres, one on the left and one on the right. The cerebrum is responsible for most of our conscious behaviors. It enfolds the brainstem (Figure 1-2B), a set of structures responsible for most of our unconscious behaviors. The second major brainstem structure, the cerebellum, is specialized for learning and coordinating our movements. Its conjoint evolution with the cerebrum shows that it assists the cerebrum in generating many behaviors.

FIGURE 1-2 The Human Brain (A) Shown head-on, as oriented within the human skull, are the nearly symmetrical left and right hemispheres of the cerebrum. (B) A cut through the middle of the brain from back to front reveals the right hemispheres of the cerebrum and cerebellum and the right side of the brainstem. The spinal cord (not shown) emerges from the base of the brainstem. Chapter 2 describes the brain’s functional anatomy.

So far, we have been describing the major components of the brain and nervous system, but there is more to the story. For his postgraduate research, our friend Harvey chose to study the electrical activity of the brain. He had decided that he wanted to live on as a brain in a bottle after his body died. He expected that his research would allow his bottled brain to communicate with others who could read its electrical signals. Where does Harvey’s proposed experiment lead us in understanding behavior and the brain? Harvey clearly wanted to preserve not just his brain but his self— his consciousness, those processes such as language and memory that gave him self-awareness and allowed him to interact with others. This meaning of brain refers to something other than the organ found inside the skull. It refers to the brain as the body organ that exerts control over behavior. It is what we intend when we talk of someone smart being “a brain” or when we speak of the computer that guides a spacecraft as being the vessel’s brain. The term brain, then, signifies both the organ itself and the fact that this organ produces behavior. To return to Harvey’s experiment, the effect of placing even the entire CNS in a bottle would be to separate it from the PNS and thus from the sensations and movements the PNS mediates. Could the brain remain awake and conscious without sensory information and without the ability to move? A number of fascinating experiments present us with information relevant to this question. One line of research and philosophical argument, called embodied behavior, proposes that the movements we make and the movements we perceive in others are central to our behavior (Prinz, 2008). That 90

is, we understand one another not only by listening to words but also by observing gestures and other body language. We think not only with silent language but also with overt gestures and body language. According to this view, the brain as an intelligent entity cannot be divorced from the body’s activities. In the 1920s, Edmond Jacobson wondered what would happen if our muscles completely stopped moving, a question relevant to Harvey’s experiment. Jacobson believed that, even when we think we are entirely motionless, we still make subliminal movements related to our thoughts. The muscles of the larynx subliminally move when we think in words, for instance, and we make subliminal eye movements when we imagine or visualize some action or a person, place, or thing. In Jacobson’s experiment, then, people practiced “total” relaxation and were later asked what the experience was like. They reported a condition of mental emptiness, as if the brain had gone blank (Jacobson, 1932). Note: We refer to healthy people who take part in research studies as participants and to those with brain or behavioral impairments as subjects or as patients.

Woodburn Heron took Jacobson’s investigations a step further when, in 1957, he conducted experiments on sensory deprivation, a form of torture used in the Korean War (1950–1953). How would the brain cope without sensory input? Heron examined the effects of sensory deprivation, including feedback from movement, by having student volunteers lie on a bed in a bare, soundproof room and remain

completely still. Padded tubes covered their arms so that they had no sense of touch, and translucent goggles cut off their vision. The participants reported that the experience was extremely unpleasant, not just because of the social isolation but also because they lost their focus. Some even hallucinated, as if their brain were somehow trying to create the sensory experiences that they suddenly lacked. Most asked to be released from the study before it ended. Evidence from people who have suffered nervous system injury has added further insights to the relationship between overt behavior and consciousness. When Martin Pistorius was 12 years old, his health began to deteriorate. Eventually, he lapsed into a coma, a condition in which he seemed completely unconscious. His parents placed Martin in a nursing home, where over a number of years he became conscious of his condition, although he remained completely paralyzed and unable to communicate. Martin suffered from lockedin syndrome, a condition in which the brain is intact, functioning, and sensitive to the external world but with its nerve fiber pathways that produce movement inactivated. Martin’s condition persisted until, when he was 25, a nurse noticed him making some small facial movements. He seemed to be trying to communicate. With rehabilitation, he made excellent progress toward recovering movement, including using a voice synthesizer. His 2011 book Ghost Boy describes his frustration and helplessness during years of enduring locked-in syndrome. Pistorious’s story shows that consciousness can persist in the absence of most overt movement; Pistorious was conscious of the world and could make small facial movements. 92

Another patient’s case study offers further insight into the relationship between behavior and the brain: that consciousness is important. The patient, a 38-year-old man, had lingered in a minimally conscious state (MCS) for more than 6 years after an assault. He was occasionally able to communicate with single words and occasionally able to follow simple commands. He could make a few movements but could not feed himself despite 2 years of inpatient rehabilitation and 4 years in a nursing home. Nicholas Schiff and his colleagues (Schiff & Fins, 2007) reasoned that, if they could stimulate their MCS patient’s brain by administering a small electrical current, they could improve his behavioral abilities. As part of a clinical trial (a consensual experiment directed toward developing a treatment), they implanted thin wire electrodes in his brainstem so they could administer a small electrical current. Through these electrodes, which are visible in the X-ray image shown in Figure 1-3, the investigators applied electrical stimulation for 12 hours each day—a procedure called deep brain stimulation (DBS). The researchers found dramatic improvement in the patient’s behavior and ability to follow commands. For the first time since his assault, he was able to feed himself and swallow food. He could even interact with his caregivers and watch television, and he showed further improvement in response to rehabilitation. Clearly, for someone in a minimally conscious condition, when his wakefulness was improved, so was behavior.

FIGURE 1-3 Deep Brain Stimulation X-ray image showing electrodes implanted in the thalamus, a structure deep in the brain near the tip of the brainstem, for DBS. DBS can treat disorders such as Parkinson disease and depression (see Section 16-3) and aid recovery from TBI (see Section 14-5).

Another line of inquiry indicates that consciousness can be present in the absence of all voluntary movement. Patients who have received brain injury so severe that it places them in persistent vegetative state (PVS) are alive and show signs of wakefulness, but they are unable to communicate or show signs of any cognitive function. Adrian Owen (2015) and his colleagues asked whether by imaging the brains of some of these patients they could assess the extent to which the patients were conscious. Using a magnetic resonance imaging (MRI) procedure that measures brain function in terms of oxygen use, Owen’s group discovered that some comatose patients are conscious and can communicate when given the opportunity.

These investigators devised ways to communicate with their patients by using the signals in their brains’ activity patterns. When imaging the brains of control subjects, Owen’s group asked them to imagine hitting a tennis ball with a racket. When they did so, it was observed that their brain activity changed in association with the imaginary act. When, next, Owen’s PVS patients were asked to imagine hitting a tennis ball, some patients did exhibit activity similar to that of the control participants, showing that they understood the instructions. Owen’s study demonstrates that some patients were conscious and so allowed him to proceed with further communication and rehabilitation. Taken together, these studies reveal that the brain can be conscious to a great extent in the absence of much overt behavior. They also show that in the absence of overt behavior, the brain can communicate through the signals generated by its activity, as Harvey proposed. Whether the brain can maintain consciousness with the absence of all sensory experience and movement—one of the challenges of Harvey’s brain in a bottle experiment—remains a question for further research. More research on and treatments for MCS and TBI are discussed in Sections 7-1, 14-5, and 15-7. Concussion is the topic of Clinical Focus 16-3.

Some of this future research may come from advances in artificial intelligence (AI). Contemporary AI research shows that computers can do amazing things, including beating master players at the

complex games chess and GO. Could a computer that directly experiences the world in the way we do, such as going to school, checking social media, playing sports—in short, sensing and responding in the way we do each day—be conscious in the same way that we are? The answer to the question of whether a computer can be conscious in the absence of embodied behavior is at the heart of our friend Harvey’s experiment.

What Is Behavior? Irenäus Eibl-Eibesfeldt began his classic textbook Ethology: The Biology of Behavior (1970) with the following definition: “Behavior consists of patterns in time.” These patterns can be made up of movements, vocalizations, or changes in appearance, such as the facial movements associated with smiling. The expression patterns in time includes thinking. We cannot directly observe someone’s thoughts. As we have described above, however, the changes in the brain’s electrical and biochemical activity that are associated with thought show that thinking, too, is a behavior that forms patterns in time. The behavioral patterns of animals vary enormously, and these variations indicate the diverse functions of the brain. Animals produce behavior that is described as inherited, meaning they can perform a behavior with little or no previous experience. For these behaviors, their brains come equipped with the requisite organization to produce these behaviors. Animals also produce learned behaviors, which are behaviors that require experience and practice. These behaviors depend on the brain’s plasticity, its ability to change in

response to a learning experience. Most behaviors consist of a mix of inherited and learned actions and so involve a preorganized brain that is modifiable through experience. Figure 1-4 illustrates the contributions of learning in the eating behaviors of two animal species, crossbills and roof rats. A crossbill’s beak seems awkwardly crossed at the tip, yet it is exquisitely evolved for eating pine cones. If its shape is changed even slightly, the bird is unable to eat the pine cones it prefers until its beak grows back. For crossbills, eating does not require much modification through learning. Roof rats, in contrast, are rodents with sharp incisor teeth that appear to have evolved to cut into anything. Pine cones are an unusual food for the rats, although they have been found to eat them. But roof rats can eat pine cones efficiently only if an experienced mother teaches them to do so. This eating is not only learned, it is cultural in that parents teach it to offspring. We expand on the concept of culture in Section 1-5.

FIGURE 1-4 Innate and Learned Behaviors Some animal behaviors are largely innate and fixed (top). Others are largely learned (bottom). Learning is a form of cultural transmission.

Generally, animals with smaller, simpler nervous systems exhibit a narrow range of behaviors that depend mainly on heredity. Animals with complex nervous systems have more behavioral options that are more dependent on learning. We humans believe that we are the animal species with the most complex nervous system and the greatest capacity for learning new responses. Most of our most complex behaviors, including reading, writing, mathematics, and using smartphones, were learned long after our brain evolved its present form. The lesson from the variation exhibited by different animal species with respect to learning is that, in much of its organization, the brain comes prepared to produce behavior but also prepared to change. Like other animals, humans retain many inherited ways of responding, such as the sucking response of a newborn infant. But later in life, eating is strongly influenced by learning and by culture.

1-1 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1.

and

are wounds to the brain that

result from a blow to the head.

2. The brain and spinal cord together make up the

All the nerve fibers radiating out beyond the brain and spinal cord as well as all the neurons outside the brain and spinal cord form the

3. One major set of brain structures, the

, or

, has nearly symmetrical left and right enfolding the

, which connects to the

spinal cord. 4. A simple definition of behavior is any kind of movement in a living organism. Every behavior has both a cause and a function, but behaviors vary in complexity and in the degree to which they are

, or automatic, and the degree

to which they depend on

5. Explain the concept of embodied behavior in a statement or brief paragraph.

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1-2 Perspectives on Brain and Behavior Let’s return to our central topic: how the study of brain and the study behavior are related. Many philosophers have reasoned about the causes of behavior. Their speculations can be classified into three broad approaches: mentalism, dualism, and materialism. After describing each, we explain why contemporary brain investigators subscribe to the materialist view. In reviewing these theories, you will recognize that some familiar ideas about behavior derive from these long-standing perspectives.

Aristotle and Mentalism The hypothesis that the mind (or soul or psyche) controls behavior can be traced back more than 2000 years to ancient Greco-Roman mythology. Psyche, a mortal, became the wife of the young god Cupid. Venus, Cupid’s mother, opposed his marriage, so she harassed Psyche with almost impossible tasks. Psyche performed the tasks with such dedication, intelligence, and compassion that she was made immortal, thus removing Venus’s objection to her. The ancient Greek philosopher Aristotle was alluding to this story when he suggested that all human intellectual functions are produced by a person’s psyche. The psyche, Aristotle argued, is responsible for life, and its departure from the body results in death.

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Aristotle’s account of behavior marks the beginning of modern psychology—and the brain played no role in it. Aristotle thought the brain existed to cool the blood. Even if he had thought that the brain ruled behavior, as did some other philosophers and physicians of his time, it would have made little difference in the absence of any idea of how a body organ could produce behavior (Gross, 1995). To Aristotle, the

François Gérard, Psyche and Cupid (1798)

psyche was a nonmaterial entity independent of the body but responsible for human consciousness, perceptions, and emotions and for such processes as imagination, opinion, desire, pleasure, pain, memory, and reason. In formulating the concept of a soul, Christianity adopted Aristotle’s view that a nonmaterial entity governs our behavior and that our essential consciousness survives our death.

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The word psyche was translated into English as mind, the AngloSaxon word for memory. The philosophical position that a person’s mind (psyche) is responsible for behavior is called mentalism. Mentalism has influenced modern behavioral science because many psychological terms that originated with Aristotle—consciousness, sensation, perception, attention, imagination, emotion, motivation, memory, and volition among them—survive today as descriptions of behavior. Indeed, we use these terms in this book, and they frequently appear as chapter titles in contemporary psychology and neuroscience textbooks.

Descartes and Dualism In the first book on brain and behavior, Treatise on Man, French philosopher René Descartes (1664) proposed a new explanation of behavior in which he retained the mind’s prominence but gave the brain an important role. Descartes placed the seat of the mind in the brain and linked the mind to the body. He stated in the first sentence of the book that mind and body “must be joined and united to constitute people.” Descartes’s innovation was the insight into how body organs produce their actions. He realized that mechanical and physical principles could explain most activities of body and brain—motion, digestion, and breathing, for example. Descartes was influenced by complex machines, including gears, clocks, and waterwheels, being built in Paris at the time. He saw mechanical gadgets on public display. In the water gardens in Paris, one device caused a hidden statue to approach and spray water when an unsuspecting stroller walked past it. The statue’s actions were triggered when the person stepped on a pedal hidden in the

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sidewalk. Influenced by these clever devices, Descartes developed mechanical principles to explain bodily functions. But Descartes could not imagine how consciousness could be reduced to a mechanistic explanation. He thus retained the idea that a nonmaterial mind governs rational behavior. Descartes did, however, develop a mechanical explanation for how the mind interacts with the body to produce movement, working through a small structure at the brain’s center, the pineal body (pineal gland). He concluded that the mind instructed the pineal body, which lies beside fluid-filled brain cavities called ventricles, to direct fluid from them through nerves and into muscles (Figure 1-5). When the fluid expanded the muscles, the body would move.

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FIGURE 1-5 Dualist Hypothesis To explain how the mind controls the body, Descartes suggested that the mind resides in the pineal gland, where it directs the flow of fluid through the ventricles and into the muscles to move the body. The pineal gland actually influences daily and seasonal biorhythms; see Section 13-2.

Descartes’s thesis that the mind directed the body was a serious attempt to give the brain an understandable role in controlling behavior. This idea that behavior is controlled by two entities, a mind and a body, is known as dualism (from Latin, meaning “two”). To Descartes, the mind received information from the body through the brain. The mind also directed the body through the brain. The mind, then, depended on the brain both for information and to control behavior.

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Problems plague Descartes’s dualistic theory, however. People who have a damaged pineal body or even no pineal body still display typical intelligent behavior. Today, we understand that the pineal gland’s role in behavior is relegated to biological rhythms. Experiments in Descartes’s time also showed that fluid is not pumped from the brain into muscles when they contract. Placing an arm in a bucket of water and contracting its muscles did not cause the water level in the bucket to rise, as it should if the volume of the muscle increased because fluid had been pumped into it. We now know that there is no way for a nonmaterial entity to influence the body: doing so requires the spontaneous generation of energy, which violates the physical law of conservation of matter and energy. The inability of Descartes’s theory to explain how a nonmaterial mind and a physical brain might interact is called the mind–body problem. Nevertheless, Descartes proposed tests for the presence of mind, the ability to use language and memory to reason. He proposed that nonhuman animals and machines would be unable to pass the tests because they lacked a mind. The 2014 film The Imitation Game dramatizes Turing’s efforts during World War II to crack the Nazis’ Enigma code.

The contemporary version of Descartes’s tests, the Turing test, is named for Alan Turing, an English mathematician. In 1950, Turing proposed that a machine could be judged conscious if a questioner could not distinguish its answers from a human’s. Contemporary computers are able to pass the Turing test. Experimental research also casts doubt on Descartes’s view that nonhuman animals cannot pass his

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tests. Studies of communication in apes and other animals partly seek to discover whether other species can describe and reason about things that are not present. Comparative Focus 1-2, The Speaking Brain, summarizes a contemporary approach to studying communication in animals.

COMPARATIVE FOCUS 1-2

The Speaking Brain No area of research has generated a literature as diverse and imaginative as the study of human language origins. In their book Why Only Us, Robert Berwick and Noam Chomsky (2016) argue that among animals, only humans have evolved language because of their unique ability to “merge” words and concepts to make an infinite number of concepts. In making this argument, they confront evolutionary theory that predicts it is unlikely that language appeared full-blown in modern humans. While accepting the uniqueness of human language, the study of brain and behavior can contribute to our understanding of language origins by asking how the brain plays a role in communication in diverse species of animals. Many animal species with a small cerebrum, including fishes and frogs, are capable of elaborate vocalizations, and vocalization is still more elaborate in species having a large cerebrum, such as birds, whales, and primates. In language studies with chimpanzees, humans’ closest living relatives, scientists have used three approaches: language training, analysis of spontaneous vocalizations and gestures, and study of the anatomy and function of the brain. To show that nonverbal forms of language might have preceded verbal language, Beatrice and Alan Gardner (1969) taught a version of American Sign Language (ASL) to a chimpanzee named Washoe. More recently, Sue Savage-Rumbaugh and her coworkers (1999) taught a bonobo (a chimp species thought to be an even closer relative of humans than others)

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named Kanzi the symbolic language Yerkish. Kanzi also displayed clear evidence of understanding complex human speech.

Kanzi

Recordings of Kanzi’s vocalizations when interacting with people and when eating reveal that he makes many sounds associated with their meanings, or semantic context. For example, Kanzi associates various peeps with specific foods. Chimps are also found to use a raspberry or extended grunt sound in a specific context to attract the attention of others, including people. They have even been shown to use vocalizations and facial and arm gestures, at times in combination, to signal intent. Chimps may also use one distinct call to attract others to feeding locations and another to initiate a trip. Stewart Watson and colleagues (2015) report that in two chimpanzee colonies, the animals used different referential calls (names) for apples. When the groups were combined, both modified their calls and adopted a common call, an example of gestural drift analogous to people adopting the speech patterns of those around them.

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Imaging of brain blood flow associated with the use of the chimpanzeeish language indicates that humans and chimpanzees activate the same brain regions when they communicate. Imaging studies of the pathways in the brain also show that chimpanzees that voluntarily learn to use sounds to attract human investigators show structural changes in these same brain regions compared to chimps that do not use such signals (Bianchi et al., 2016). Taken together, studies on our closest living relatives suggest that we share some key language similarities with them but that perhaps we do not share the critical aspects of language, such as the “merge” ability of humans.

Descartes’s theory of mind led to some bad results. Based on dualism, some people argued that young children and those who are insane must lack minds because they often fail to reason appropriately. We still use the expression he’s lost his mind to describe someone who is mentally ill. Some proponents of dualism also reasoned that, if someone lacked a mind, that person was simply a machine, not due respect or kindness. Cruel treatment of animals, children, and the mentally ill could be justified by Descartes’s theory. It is unlikely that Descartes himself intended these interpretations. Reportedly he was kind to his own dog, Monsieur Grat.

Darwin and Materialism By the mid-nineteenth century, another brain–behavior theory emerged. Materialism advanced the idea that the workings of the brain and the rest of the nervous system alone fully explain behavior. It came to prominence when supported by the evolutionary theory of Alfred Russel Wallace and Charles Darwin.

Evolution by Natural Selection 109

Wallace and Darwin independently arrived at the same conclusion—the idea that all living things are related. Darwin elaborated the position in his book On the Origin of Species by Means of Natural Selection, published in 1859, which is why Darwin is regarded as the founder of modern evolutionary theory. Both Darwin and Wallace were struck by the myriad anatomical and behavioral characteristics common to so many species despite their diversity. The skeleton, muscles, and body parts of humans, monkeys, and other mammals are remarkably similar. So is their behavior: many animal species reach for food with their forelimbs. More important, these same observations led Darwin to explain how the great diversity in the biological world could have evolved from common ancestry. Darwin proposed that animals have traits in common because these traits are passed from parents to their offspring. Figure 2-1 illustrates this principle of phenotypic plasticity.

Natural selection is the theory

explaining how new species evolve and how existing species change over time. A species is a group of organisms that can breed among themselves. Individual organisms of any species vary extensively in their phenotype, the characteristics we can see or measure. No two individuals of any species are exactly alike. Some are big, some are small, some are fat, some are fast, some are light-colored, and some have large teeth. Individual organisms whose characteristics best help them to survive in their environment are likely to leave more offspring than are less-fit members. This unequal ability of individual members to survive and 110

reproduce leads to a gradual change in a species’ population over time. Natural selection is nature’s blueprint for the methods of artificial selection practiced for centuries by plant and animal breeders to produce animals and crops with desirable traits.

Natural Selection and Heritable Factors Neither Darwin nor Wallace understood the basis of the great variation in plant and animal species they observed. Another scientist, the monk Gregor Mendel, discovered one principle underlying phenotypic variation and how traits pass from parents to their offspring. Through experiments he conducted on pea plants in his monastery garden beginning about 1857, Mendel deduced that heritable factors, which we now call genes, govern various physical traits displayed by the species. Members of a species that have a particular genetic makeup, or genotype, are likely to express (turn on) similar phenotypic traits, as posited in the Procedure section of Experiment 1-1. If the gene or combination of genes for a specific trait—say, flower color—is passed on to offspring, the offspring will express the same trait, as illustrated by the Results section in Experiment 1-1. EXPERIMENT 1-1

Question: How do parents transmit heritable factors to offspring? Procedure

Members of a species that have a particular genotype are likely to express similar phenotypic traits. If the gene or combination of genes for a specific trait (say, flower color) is passed on to offspring, the offspring will express the trait. Two white-flowered pea plants produce white-flowered offspring in

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the first generation, or F1 in the figure below, and purple-flowered parents produce purple-flowered offspring. Observing this result, Mendel reasoned that two alternative heritable elements govern the trait flower color. Mendel experimented with crossbreeding F1 purple and white pea plant flowers. The second-generation (F2) offspring all expressed the purple phenotype. Had the factor that expresses white flowers disappeared? To find out, Mendel crossbred the F2 purple flowers. The third generation, F3, produced flowers in the ratio of roughly one white to three purple blooms. Results

Conclusion: This result suggested to Mendel that the trait for white flowers had not disappeared but rather was hidden by the trait for purple flowers. He concluded that individuals inherit two factors, or genes, for each trait, but one may dominate and hide (suppress) the other in the individual’s phenotype.

The unequal ability of individual organisms to survive and reproduce is related to the different genes they inherit from their parents and pass on to their offspring. By the same token, similar characteristics within

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or between species are usually due to similar genes. For instance, genes that produce the nervous system in different animal species tend to be very similar.

Interplay of Genes, Environment, and Experience The principles of inheritance that Mendel demonstrated through his experiments have led to countless discoveries about genetics. We now know that new traits appear because new gene combinations are inherited from parents and that genes change or mutate. Section 3-3 explains some basic genetic and epigenetic principles, including what constitutes a gene, how genes function, and how genes can change, or mutate.

But genes alone cannot explain most traits. Even Mendel realized that the environment participates in the expression of traits; for example, planting tall peas in poor soil reduces their height. Experience likewise plays a part. The experience of children who attend a substandard school, for instance, is different from that of children who attend a model school. We now know that genes and their effects are not static; genes can be active at different times and under different conditions during our life. The field of epigenetics (meaning “beyond genes”) studies how gene expression is turned on or off at different times and how environment and experience influence our behavior through their effects on our genes.

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Epigenetic factors consist of a number of biochemical changes that influence whether a gene is active or inactive. Epigenetic factors can turn on or turn off a gene’s function so that the gene influences the function of our body or behavior, or it stops that influence. The epigenetic effects of experience that initiate epigenetic influences on genes can last long after the initial experience and, in some cases, can persist into future generations. Epigenetic factors described throughout this book revolutionize our understanding of behavior–brain relations because they offer an explanation for how our experiences, including studying, influence our brain and the behavior that it subsequently produces.

Summarizing Materialism Darwin’s theory of natural selection, Mendel’s discovery of genetic inheritance, and the reality of epigenetics have three important implications for studying the brain and behavior: 1. Because all animal species are related, their brains must be related. A large body of research confirms, first, that all animals’ brain cells are so similar that these cells must be related and, second, that all animal brains are so similar that they must be related as well. Brain researchers can study the nervous systems of animals as different as slugs, fruit flies, rats, and monkeys, knowing that they can extend their findings to the human nervous system. 2. Because all animal species are related, their behavior must be related. In his book The Expression of the Emotions in Man and Animals, Darwin (1872) argued that emotional expressions are similar in humans and other animals because all animals inherited them from a common ancestor. Figure 1-6 offers evidence. That 114

people the world over display the same behavior suggests that the trait is inherited. 3. Brains and behaviors in complex animals such as humans evolved from simpler animals’ brains and behaviors. Coming up in Section 1-3, we trace the evolution of nervous systems and their increasingly complex repertoires of actions, from a simple netlike arrangement to a multipart nervous system with a brain that controls behavior.

FIGURE 1-6 An Inherited Behavior People the world over display the same emotional expressions that they recognize in others—these smiles, for example. This evidence supports Darwin’s suggestion that emotional expression is an inherited behavior.

Section 3-1 describes the varieties of neurons and other brain cells.

More on emotions and their expression in Sections 12-6 and 14-3.

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Contemporary Perspectives on Brain and Behavior Where do modern students of the brain stand on the perspectives of mentalism, dualism, and materialism? In his influential 1949 book The Organization of Behavior, psychologist Donald O. Hebb describes the scientific acceptance of materialism in a folksy manner: Modern psychology takes completely for granted that behavior and neural function are perfectly correlated, that one is completely caused by the other. There is no separate soul or life force to stick a finger into the brain now and then and make neural cells do what they would not otherwise. (Hebb, 1949, p. iii) Hebb’s claim dovetails with his theory of how the brain produces new behavior. He suggested that learning is enabled by small groups of neurons forming new connections with one another to form a cell assembly, which is the substrate for a memory. Cell assemblies interact: one cell assembly becomes connected to another. This linking of cell assemblies is thus the linking of memories, which to Hebb is what produces our complex behavior, including our consciousness of our own and others’ actions. Hebb’s argument is materialistic and provides a way of explaining how consciousness is created in terms of the physical properties of the brain. Hebb’s explanation of consciousness espouses the philosophical position of eliminative materialism, which states that if behavior can be described adequately without recourse to the mind, then the mental explanation should be eliminated. Daniel Dennett (1978) and other philosophers argue that if attributes such as consciousness, pain, and 116

attention can be explained by physical mechanisms, it is unnecessary to appeal to mental explanations.

The Separate Realms of Science and Belief Materialists, your authors included, continue to use subjective mentalistic words such as consciousness, pain, and attention to describe complex behaviors. At the same time, they recognize that these words do not describe mental entities. Materialism argues for objective, measurable descriptions of behavior that can be referenced to brain activity. Some people may question materialism’s tenet that only the brain is responsible for behavior because they think it denies religion. But materialism is neutral with respect to religion. Many of the world’s major religions accept both evolution and the brain’s centrality in behavior as important scientific theories. Fred Linge, introduced in Clinical Focus 1-1, has strong religious beliefs, as do the other members of his family. They used their religious strength to aid in his recovery. Yet, despite their religious beliefs, they realize that Linge’s brain injury caused his changed behavior and that learning to compensate for his impairments caused his brain function to improve. The four-step experimental procedure is: (1) formulate a theory, (2) make a prediction (hypothesis), (3) test it, (4) confirm or modify the theory.

Many behavioral scientists hold religious beliefs and see no contradiction between them and their engagement with science. Science is not a belief system but rather a set of procedures designed to allow investigators to confirm answers to a question independently. As

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outlined in Experiment 1-1, this four-step procedure allows anyone to replicate, or repeat, their original conclusions—or find that they cannot.

1-2 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. The view that behavior is the product of an intangible entity called the mind (psyche) is

. The notion that the

immaterial mind acts through the material brain to produce language and rational behavior is

, the

view that brain function fully accounts for all behavior, guides contemporary research on the brain and behavior. 2. The implication that the brains and behaviors of complex animals such as humans evolved from the brains and behaviors of simpler animals draws on the theory of advanced by

3. The brain demonstrates a remarkable ability to recover, even after severe brain injury, but an injured person may linger in a , occasionally able to communicate or to follow simple commands but otherwise not conscious. Those who have such extensive brain damage that no recovery can be expected remain in a

, alive but unable to

communicate or to function independently at even the most basic level.

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4. Darwin and Mendel were nineteenth-century contemporaries. Briefly contrast the methods they used to reach their scientific conclusions.

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1-3 Evolution of Brains and of Behavior As some lineages of animals have evolved, their nervous systems and behavior have built up and changed bit by bit. We trace the evolution of the human brain and behavior by describing (1) animals that first developed a nervous system and muscles with which to move, (2) how the nervous system grew more complex as the brain evolved to mediate complex behavior, and (3) how the human brain evolved its present complexity, which we cover in the next section. The popular interpretation of human evolution is that we are descended from apes. Actually, humans are apes. Other living apes are not our ancestors, although we are related to them through a common ancestor, a forebear from which two or more lineages or family groups arise. To demonstrate the difference, consider the following story. Two people named Joan Campbell are introduced at a party, and their names provide a rich conversation starter. Although both belong to the Campbell lineage (family line), one Joan is not descended from the other. The two women live in different parts of North America, one in Texas and the other in Ontario, and both their families have been there for many generations. Nevertheless, after comparing family histories, the two Joans discover that they have ancestors in common. The Texas Campbells are descended from Jeeves Campbell, brother of Matthew Campbell, from whom the Ontario Campbells are descended. Jeeves and Matthew both 120

boarded the same fur-trading ship when it stopped for water in the Orkney Islands north of Scotland before sailing to North America in colonial times. The Joan Campbells’ common ancestors, then, were the mother and father of Jeeves and Matthew. Both the Texas and the Ontario Campbell family lines are descended from this man and woman. If the two Joan Campbells were to compare their genes, they would find similarities that correspond to their common lineage. In much the same way, humans and other apes are descended from common ancestors. But unlike the Joan Campbells, we do not know exactly who those distant relatives were. By comparing the brain and behavioral characteristics of humans and related animals and by comparing their genes, however, scientists are tracing our lineage back further and further to piece together the origins of our brain and behavior. Some living animal species display characteristics more similar to those of a common ancestor than do others. For example, in some ways chimpanzees are more similar to the common ancestor of humans and chimpanzees than are modern humans. In the following sections, we trace some major evolutionary events that led to human brains and human behavior by looking at the nervous systems of living animal species and the fossils of extinct animal species.

Origin of Brain Cells and Brains Earth formed about 4.5 billion years ago, and the first life-forms arose about a billion years later. About 700 million years ago, animals

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evolved the first brain cells, and by 250 million years ago, the first brain had evolved. A humanlike brain first developed only about 6 million years ago, and our modern human brain has been around for only the past 200,000 years or so. Although life arose early in our planet’s history, brain cells and brains evolved only recently. In evolutionary terms, large, complex brains, such as ours, appeared an eyeblink ago. If you are familiar with the principles of taxonomic classification, which names and orders living organisms according to their evolutionary relationships, read on. If you prefer a brief review before you continue, read “The Basics: Classification of Life”.

THE BASICS

Classification of Life Taxonomy is the branch of biology concerned with naming and classifying species by grouping representative organisms according to their common characteristics and their relationships to one another. As shown in the left column of the Taxonomy of Modern Humans figure, which illustrates the human lineage, the broadest unit of classification is a kingdom, with more subordinate groups being phylum, class, order, family, genus, and species. This taxonomic hierarchy is useful in helping us trace the evolution of brain cells and the brain.

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We humans belong to the animal kingdom, the chordate phylum, the mammalian class, the primate order, the great ape family, the genus Homo, and the species sapiens. Animals are usually identified by their genus and

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species names. So we humans are called Homo sapiens sapiens, meaning “wise, wise human.” The branches in the Cladogram figure, which shows the taxonomy of the animal kingdom, represent the evolutionary sequence (phylogeny) that connects all living organisms. Cladograms are read from left to right: the most recently evolved organism (animal) or trait (muscles and neurons) is farthest to the right.

Of the five kingdoms of living organisms represented in the cladogram, only the one most recently evolved, Animalia, contains species with muscles and nervous systems. It is noteworthy that muscles and nervous systems evolved together to underlie the forms of movement (behavior) that distinguish members of the animal kingdom. The Evolution of the Nervous System figure shows the taxonomy of the 15 groups, or phyla, of Animalia, classified according to increasing complexity of nervous systems and movement. In proceeding to the right from the nerve net, we find that nervous systems in somewhat more recently evolved phyla, such as flatworms, have more complex structure. These

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organisms have heads and tails, and their bodies show both bilateral symmetry (one half of the body is the mirror image of the other half) and segmentation (the body is composed of similarly organized parts). The structure of the human spinal cord resembles this segmented nervous system.

Evolution of Nervous Systems in Animals A nervous system is not essential for life. In fact, most organisms, including plants and bacteria, both past and present, have done without one. In animals that do have a nervous system, comparison of a wide variety of species broadly outlines how the nervous system has evolved. We summarize this evolution in the following general steps: 1. Neurons and muscles. Brain cells and muscles evolved together, enabling animals to move. Neurons and muscles likely have their origins in single-cell animals such as amoeba that developed numerous ways of moving about, traits that became more specialized in multicellular animals.

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2. Nerve net. The nervous system representative of evolutionarily older phyla, such as jellyfishes and sea anemones, is extremely simple. It consists of a diffuse nerve net, which has no structure that resembles a brain or spinal cord but consists entirely of neurons that receive sensory information and connect directly to other neurons that move muscles. Look again at Figure 1-1 and imagine that the brain and spinal cord have been removed. The human PNS is reminiscent of the nerve net in phylogenetically simpler animals. 3. Bilateral symmetry. In more complex animals such as flatworms, the nervous system is more organized, and it features bilateral symmetry: the nervous system on one side of the animal mirrors that on the other side. The human nervous system is also bilaterally symmetrical (see Figure 1-1). 4. Segmentation. The body of an animal such as an earthworm consists of a series of similar muscular segments. Its nervous system has similar repeating segments. The human spinal cord and brain display such segmentation: the vertebrae contain the similar repeating nervous system segments of the spinal cord. 5. Ganglia. In still more recently evolved invertebrate phyla, including clams, snails, and octopuses, are clusters of neurons called ganglia that resemble primitive brains and function somewhat like them in that they are command centers. In some phyla, encephalization (having the ganglia in the head) is distinctive. For example, insects’ ganglia are sufficiently large to merit the term brain.

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6. Spinal cord. In relatively highly evolved chordates—animals that have both a brain and a spinal cord—a single nervous system pathway connects the brain with sensory receptors and muscles. Chordates get their name from the notochord, a flexible rod that runs the length of the back. In humans, the notochord is present only in the embryo; by birth, bony vertebrae encase the spinal cord. 7. Brain. The chordate phylum, of which amphibians, reptiles, birds, and mammals are class members, displays the greatest degree of encephalization: a true brain. Of all of the chordates, humans have the largest brain relative to body size, but many other chordates have large brains as well. Although built to a common plan, the brain of each chordate species displays specializations related to the distinctive behaviors of that species. Figure 2-30 maps the human spinal cord’s segments.

Chordate Nervous System A chart called a cladogram (from the Greek word clados, meaning “branch”) displays groups of related organisms as branches on a tree. The cladogram in Figure 1-7 represents seven of the nine classes to which the approximately 38,500 extant chordate species belong. Wide variation exists among the nervous systems of chordates, but common to all is the basic structural pattern of bilateral symmetry, segmentation, and a spinal cord and brain encased in cartilage or bone.

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FIGURE 1-7 Representative Classes of Chordates This cladogram illustrates evolutionary relationships among animals that have a brain and spinal cord. Brain size increased with the evolution of limbs in Amphibia. Birds and mammals are the most recently evolved chordates, and both classes have large brains relative to body size.

As chordates evolved limbs and new forms of locomotion, their brain became larger. For example, all chordates have a brainstem, but only the birds and mammals have a large forebrain. The evolution of more complex behavior in chordates is closely related to the evolution of the cerebrum and cerebellum. Their increasing size and complexity in various classes of chordates is illustrated in Figure 1-8. These increases accommodate new behaviors, including new forms of locomotion on land, complex movements of the mouth and hands for eating, improved learning ability, and highly organized social behavior.

FIGURE 1-8 Brain Evolution The brains of representative chordate species have many structures in common, illustrating a single basic brain plan.

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Research Focus 2-1 elaborates cerebellar function by describing a man born without a cerebellum.

The cerebrum and the cerebellum are proportionately small and smooth in the earliest evolved classes (e.g., fish, amphibians, and reptiles). In later-evolved chordates, especially the birds and mammals, these structures are much more prominent. In many large-brained mammals, both structures are extensively folded, which greatly increases their surface area while allowing them to fit into a small skull, just as folding a large piece of paper enables it to occupy a small envelope. Increased size and folding are pronounced in primates, animals with large brains relative to their body size. But relatively large brains with a complex cerebrum and cerebellum have evolved in a number of animal lineages, so humans are neither unique nor special in these respects. As we will describe in the following sections, humans are distinguished in belonging to the large-brained primate lineage and are unique in having the largest, most complex brain in this lineage.

1-3 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. Because brain cells and muscles evolved only once in the animal kingdom, a similar basic pattern exists in the of all animals.

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2. Evolutionary relationships among the nervous systems of animal lineages are classified by increasing complexity, progressing from the simplest

to a

segmented nervous system to nervous systems controlled by to nervous systems in the phylum

which feature a brain and spinal cord. 3. A branching diagram that represents groups of related animals is called a

4. Given that a relatively large brain with a complex cerebrum and cerebellum has evolved in a number of animal lineages, what, if anything, makes the human brain unique?

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1-4 Evolution of the Human Brain and Behavior Anyone can see similarities among humans, apes, and monkeys. Those similarities extend to the brain as well. In this section, we consider how our brain and behaviors link to those of some of our more prominent ancestors. Then we consider the relationship between brain complexity and behavior across species, including human species. We conclude by surveying hypotheses about how the human brain evolved to become so large and the behavior that it mediates so complex. The evolutionary evidence shows that we humans are specialized in having an upright posture, making and using tools, and developing language but that we are not special because other species also shared these traits, at least to some degree.

Humans: Members of the Primate Order We humans are members of the primate order, a subcategory of mammals that includes apes, Old World monkeys, New World monkeys, tarsiers, and lemurs (Figure 1-9). We are but one of about 275 primate species. Primates have excellent color vision, with the eyes positioned at the front of the face to enhance depth perception. They use their highly developed visual sense to deftly guide their hand movements.

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FIGURE 1-9 Representatives of the Primate Order This cladogram illustrates hypothetical relationships among members of the primate order. Humans are members of the great ape family. In general, brain size increases across the groupings, with humans having the largest brain of all primates.

Australian Raymond Dart coined Australopithecus in naming the skull of a child he found among fossilized remains from a limestone quarry near Taung, South Africa, in 1924. Choosing so to represent his native land probably was no accident.

Female primates usually have only one infant per pregnancy, and they spend a great deal more time caring for their young than most other animals do. Primate brains are, on average, larger than those of animals in other mammalian orders, such as rodents (mice, rats, beavers, squirrels) and carnivores (wolves, bears, cats, weasels), and they are larger than the brains of animals in those other orders that have comparable or larger body size. Humans are members of the great ape family, which includes orangutans, gorillas, and chimpanzees. Apes are arboreal animals with limber shoulders that allow them to brachiate in trees (swing from one handhold to another), a trait retained by humans, who generally do not

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live in trees these days. Nevertheless, freeing the arms at the shoulder is handy for all sorts of human activities, from traversing monkey bars on the playground to competing in the Olympic hammer toss to raising a hand to ask a question in class. Apes are distinguished as well by their higher intelligence and very large brains—traits that humans exemplify. Among the apes, we are most closely related to the chimpanzee, having had a common ancestor between 5 million and 10 million years ago. Between that common ancestor and us over the past 5 million years, many hominids — primates that walk upright—in our lineage evolved. During most of this time, many hominid species coexisted. At present, however, we are the only surviving hominid species.

Australopithecus: Our Distant Ancestor One of our hominid ancestors is probably an Australopithecus species (from the Latin austral, meaning “southern,” and the Greek pithekos, meaning “ape”). Figure 1-10 shows reconstructions of the face and body of one such animal, Australopithecus africanus. Many species of Australopithecus lived, some at the same time, but evidence suggests that this is our common ancestor.

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FIGURE 1-10 Australopithecus africanus (A) The hominid Australopithecus walked upright with free hands, as do modern humans, but its brain was about onethird the size of ours and comparable to that of other apes. (B) Human and Australopithecus figures compared on the basis of the most complete Australopithecus skeleton yet found, a young female about 1 meter tall, popularly known as Lucy, who lived 3 million years ago.

These early hominids were among the first primates to show such human traits as walking upright and using tools. Scientists have deduced their upright posture from the shape of their back, pelvic, knee,

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and foot bones and from a set of fossilized footprints left by a family of australopiths as they walked through freshly fallen volcanic ash some 3.8 million years ago. These footprints feature impressions of a welldeveloped arch and an unrotated big toe—more like humans’ than other apes’. (Nevertheless, australopiths retained the ability to skillfully climb trees.) The bone structure of their hands evinces tool use (Pickering et al., 2011).

The First Humans The skull of the first animal to be designated as genus Homo (human) was found by Mary and Louis Leakey in the Olduvai Gorge in Tanzania in 1964. The Leakeys named the species Homo habilis (handy human) to signify that its members were toolmakers. To date, the earliest member of the genus Homo, found in Ethiopia, dates to about 2.8 million years ago. The fossils reveal a jaw and teeth much smaller than in any Australopithecus species but characteristic to humans, and their brain was slightly larger than that of Australopithecus (Villmoare et al., 2015). The first humans who spread beyond Africa migrated into Europe and Asia. This species was Homo erectus (upright human), so named because of the mistaken notion that its predecessor, H. habilis, had a stooped posture. Homo erectus first shows up in the fossil record about 1.6 million years ago. As shown in Figure 1-11, its brain was bigger than that of any preceding hominid, overlapping in size the measurements of present-day human brains. This larger brain likely contributed to its ability to travel and become widely dispersed into Europe and Asia. Because H. erectus survived for nearly 2 million years, they may have made many migrations during that time.

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FIGURE 1-11 Increases in Hominid Brain Size The brain of Australopithecus was about the same size as that of living nonhuman apes, but succeeding members of the human lineage display increased brain size. Data from Johanson & Edey, 1981.

The tools made by H. erectus were more sophisticated than those made by H. habilis, and improved tool use was no doubt enabled by their larger brain. An especially small subspecies of H. erectus, about 3 feet tall, was found on the Indonesian island of Flores. Named Homo floresiensis, these hominids lived up to about 13,000 years ago (Gordon et al., 2008), which again emphasizes the fact that it is comparatively recently that only one hominid species exists. A number of Homo sapiens species appeared within the past million

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Early humans may have followed such proposed routes out of Africa, first to Asia and Europe, eventually to Australia, and finally to the Americas.

years; these are collectively referred to as archaic humans. H. neanderthalis, named for the Neander Thal (Valley), Germany, where the first Neanderthal skulls were found, were widespread in Europe. As the first fossilized human ancestor to be discovered, Neanderthals have maintained a preeminent place in the study of modern human ancestors. Modern humans, Homo sapiens sapiens, appeared about 200,000 years ago, and in Europe where they coexisted with archaic Neanderthals, they interbred until they replaced Neanderthals about 20,000 years ago. Neanderthals had brains as large as, and perhaps a little larger than, those of modern humans, used similar tools, and wore jewelry and makeup. They lived in family groups similar to modern human ones, made music, cared for their elders, and buried their dead. From these archeological findings, we can infer that Neanderthals probably communicated using language and held religious beliefs.

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We do not know how modern humans came to completely replace archaic human species, but perhaps they had advantages in toolmaking, language use, or social organization. Contemporary genetic evidence shows that modern European humans who inherited Neanderthals’ genes acquired genes that adapted them to the cold, to novel disease, and possibly to light skin that better absorbs vitamin D (Sankararaman et al., 2014). Reconstructions like the one in Figure 1-12 show how similar to us Neanderthals really were.

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FIGURE 1-12 Neanderthal Woman A facial reconstruction by Elisabeth Daynes made from a casting of the skull. The female, whom the discoverers called Pierrette, died a violent death between the ages of 17 and 20. Her 36,000-year-old remains were discovered in western France in 1979, lying near tools from the Neanderthal

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period. Research Focus 10-1 reports on the discovery of a flute made by Neanderthals.

One possible human lineage is shown in Figure 1-13. A common ancestor gave rise to the Australopithecus lineage, and one member of this group gave rise to the Homo lineage. The bars in Figure 1-13 are not connected because many more hominid species have been discovered than are shown, and exact direct ancestors are uncertain. The bars overlap because many hominid species coexisted until quite recently.

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FIGURE 1-13 Human Origins The human lineage and a lineage of extinct Australopithecus probably arose from a common ancestor about 4 million years ago. The ancestor of the human lineage Homo was probably a hominid similar to A. africanus.

Relating Brain Size and Behavior 141

Scientists who study brain evolution often use brain size as a rough measure to explain more complex behavior. But there is more to the story. The number of brain cells is also important, as are the connections that those cells make. Unfortunately, the fossil record provides only skulls from which a measure of brain size can be estimated. In the following section, we will summarize how brain size is compared across species and how it contributes to our understanding of behavior. Then we will describe the importance of brain cell number and of brain cell connections.

Estimating Relative Brain–Body Size Harry Jerison (1973) describes an index that compares the ratio of brain size to body size across species. He calculates that as body size increases, brain size increases at about two-thirds the increase in body weight. Jerison’s underlying assumption is that even if very little is known about an animal’s behavior, its brain size could provide some clues to its behavioral complexity. The idea is that species shown to have larger brains must exhibit more complex behavior. Using the ratio of actual brain size to expected brain size, Jerison developed a quantitative measure, the encephalization quotient (EQ). He defined an average animal (a domestic cat was Jerison’s pick) as having an EQ of 1. The diagonal trend line in Figure 1-14 plots the expected brain–body size ratio of a number of animal species in relation to a trend line representing animals with an EQ of 1. Some species lie below the line: their brain size is smaller than would be expected for an animal of that size. Other species lie above the line: their brain size is larger than would be expected for an animal of that size.

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FIGURE 1-14 Ratios of Brain to Body Size in Common Mammals As represented logarithmically on this graph, average brain size relative to body weight falls along a diagonal trend line, where you find the cat. Data from Jerison, 1973.

The lower an animal’s brain falls relative to the trend line in Figure 1-14, the smaller its EQ; the higher an animal’s brain lies relative to the trend line, the larger its EQ. Notice that the rat’s brain is a little smaller (lower EQ) and the elephant’s brain a little larger (higher EQ) than the ratio predicts. Modern humans, farther above the line than any other animal, have the highest EQ.

Counting Brain Cells Jerison’s EQ provides a rough estimate of comparative brain size, but body size and brain size can vary independently (Figure 1-15, top). Some apes, such as the gorillas, are specialized in having large bodies, while others, such as ourselves, are specialized in having large brains.

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FIGURE 1-15 Comparing EQs The EQs of some familiar mammals are ranked at the top of the chart, and members of the primate lineage are ranked at the bottom. Clearly, intelligence is widespread among animals.

Counting brain cells is another way to estimate the behavioral capacity of a brain. Consider the roundworm Caenorhabditis elegans, which has 959 cells. Of these, 302 are neurons. In contrast, the blue whale—the largest animal that has ever lived, weighing as much as 200 tons—has a brain weighing 15,000 grams (33 lb). Based on EQs, we would predict that C. elegans, with one-third of its body made up of brain cells, has a more complex behavioral repertoire than a blue whale, with 0.01 percent of its body made up of brain cells. But it makes no sense to suggest that a worm’s behavior is more complex than a whale’s. Counting brain cells provides a better comparison. Karina Fonseca-Azevedo and her colleagues (Fonseca-Azevedo & Herculano-Houzel, 2012) describe a method of counting brain cells using a counting machine. Not only can they estimate the number of neurons in a brain or a part of the brain, they also can estimate the neurons’ packing density. For example, two similar-sized brains could consist of either diffusely distributed large neurons or closely packed small neurons. Using brain cell counts, a blue whale has 30 billion neurons, which is a lot more than the 302 neurons of C. elegans, numbers that provide a better explanation of their behaviors than relative size measures. Fonseca-Azevedo has found that the packing density of neurons is relatively constant in the primate lineage, so EQ and brain cell counts 145

both provide a good comparison of their brain sizes (Figure 1-15, bottom). Knowing that, Australopithecus likely had about 50 billion to 60 billion neurons, Homo habilis about 60 billion, and Homo erectus about 75 billion to 90 billion, whereas modern humans have about 86 billion neurons. If the number of brain cells is important, does the number or density of cells in different brain regions vary, and is this an additional explanation of behavior variation? It does, and counts of neurons in different regions of the brain provide an answer to a puzzle: Why is the behavior of elephants and dolphins with their very large brains not as complex as human behavior? As detailed in Comparative Focus 1-3, “The Elephant’s Brain,” pachyderms have an enormous number of neurons, but most are in the cerebellum, an area associated with motor behavior; on the other hand, the number of neurons in the elephant cerebrum, an area associated with cognitive processes, is equivalent to that of chimpanzees. These neuron counts suggest that apes and elephants should have equivalent cognitive abilities, which they do. Furthermore, the dolphin, another animal with a very large brain, has a total of 30 billion neurons, a number similar to the number in chimpanzees—and many fewer than in the smaller human brain— because dolphin neurons are not densely packed. Thus, the behavior of modern humans is complex because of a large brain size with a very large number of densely packed neurons. The utility of relating neuron number to behavioral complexity is not limited to mammals. Researchers have found that the clever behavior of birds, such as parrots and crows, is related to the larger number of

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densely packed neurons they have in their cerebrum relative to other birds.

COMPARATIVE FOCUS 1-3

The Elephant’s Brain The cerebrum and cerebellum have evolved into the human brain’s most distinct and largest structures, larger than in any other primate brain. Although the cerebellum appears smaller than the cerebrum physically, its small, tightly packed neurons are four times the number found in the cerebrum (about 68 billion vs. 16 billion), a 4:1 ratio that humans share with all other primates. Typically, the cerebrum is described as mediating cognitive functions, whereas the cerebellum mediates motor function, although in cooperative functions they do share many functions. African elephants are enormous animals. It is not surprising that they have the largest brain of all terrestrial animals—three times the size of a human’s. With such a large brain, why don’t elephants share humans’ intellectual abilities? Suzana Herculano-Houzel and her colleagues (2014) made a neuronal count of an African elephant and found that its brain contains three times as many neurons as the human brain (257 billion vs. 86 billion neurons). But remarkably, 251 billion of those neurons (97.5 percent) reside in the elephant’s cerebellum.

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An African Elephant’s Brain In this, the largest brain of all terrestrial animals, both the cerebrum (left) and the cerebellum (right) are gigantic compared to those of the human brain. But the cerebellum contains 97.5 percent of the neurons.

The elephant’s cerebellum contains nearly 45 times as many neurons as its cerebrum. What does this number tell us about the elephant’s behavior? An elephant has almost infinite degrees of freedom in the use of its trunk: it can use it to bathe, lift a tree trunk, pick up a peanut, caress a baby, or paint a picture. The vast number of neurons in its cerebellum is probably requisite to controlling the trunk’s sensory and motor abilities. In contrast, the elephant’s cerebrum, with twice the mass of that of humans, contains only 5.6 billion neurons, more neurons than most animals can boast but somewhat fewer than the chimpanzees’ cerebrum. The elephant’s cognitive ability also ranks at about that of a chimp’s. The Herculano-Houzel study offers a conclusion related to the function of the human cerebrum as well. The remarkable cognitive abilities of humans, which exceed those of all other animal species, are best explained by the

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sheer number of cerebral neurons, which exceed the number found in all other animal species, even those with much larger brains, including elephants.

Brain Cell Connections Brains become larger by the addition of neurons, and the addition of neurons adds disproportionately more connections between those neurons. Figure 1-16 illustrates one view of how the complexity of the brain evolves as more neurons are added. The first column in the figure uses different colors to illustrate the functions of neurons. Most of the cerebrum of a smaller brain (bottom), such as that of a fish, is devoted to the primary senses and movement. It has neurons for vision, hearing, touch, olfaction, and movement.

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FIGURE 1-16 Evolution of Complexity in the Cerebrum The first column provides a topographic view of how a brain might change with the addition of neurons. Each color represents a function, such as vision, touch, or hearing. Gray shading represents new areas associated with new functions of the different regions.

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The second column provides a connectome view of how connections might change as neurons are added as topographic regions separate and become larger.

The neurons with different functions do not occupy specific regions but have a “salt and pepper” organization. For animals with successively larger brains, the neurons representing the primary functions aggregate in order to keep their connections short. As their numbers increase, they also begin to form new regions (gray shading). For example, visual pathways to motor regions in a fish direct wholebody movements to guide the fish from one place to another. Visual pathways in a primate not only guide locomotion, they guide control of the arm and hand for reaching. The new function requires both a new region and new connections. Figure 1-16 also illustrates two kinds of maps that emerge as brains become larger. Topographic maps (left) represent the different functional areas—for instance, areas that control vision, hearing, touch, olfaction, and movement. Connectome maps (right) represent the connections through which each of these regions influences each other. The evolution of complexity represented by the topographic and connectome maps can be understood by analogous changes that occur as a village grows to become a large city. With growth, a downtown, an industrial area, suburbs, and so forth develop, along with more connecting streets, highways, and freeways. These two different ways of describing the brain are similar to the maps that a computer provides of a city, a scene map of buildings, and a street map of routes. Topographic and connectome descriptions of the brain will be featured throughout this book.

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Why the Hominid Brain Enlarged The evolution of modern humans—from when humanlike creatures first appeared until humans like us emerged—spans more than 4 million years. This may seem like a long time, but the brain and behavior evolution that occurred in hominids was extremely rapid, given that there was not much change for other animal species over the same time period. What caused these changes? Why did hominids evolve larger brains, and why did their behavior become more complex? Why didn’t hominids just remain apes with ape-sized brains? One hypothesis suggests that numerous drastic climate changes drove adaptation by hominids that led to more complex behavior. Another hypothesis contends that the primate lifestyle favors an increasingly complex nervous system that humans capitalize on. A third links brain growth to brain cooling. And a fourth proposes that a changed rate of maturation favors larger brains. Likely, a combination of all of these and still other factors was influential.

Climate and the Evolving Hominid Brain Climate changes have driven many physical changes in hominids, ranging from brain changes to the emergence of human culture. Evidence suggests that each new hominid species appeared after climate changes devastated old environments and led to new ones (Tattersall, 2017). About 8 million years ago, a massive tectonic event (deformation of Earth’s crust) produced the Great Rift Valley, which runs through the

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Ape species living in a wetter climate to the west of Africa’s Great Rift Valley were cut off from species that evolved into hominids and thus adapted to a drier climate to the east.

eastern part of Africa from south to north. The reshaped landmass left a wet jungle climate to the west and a much drier savannah climate to the east. To the west, the apes continued unchanged in their former habitat. But the fossil record shows that in the drier eastern region, apes evolved rapidly into upright hominids in response to the selective environmental pressures that formed their new home. Thereafter, the climate in East Africa did not remain static. It underwent a number of alterations, with some alterations isolating

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populations of hominids and others throwing different populations together. The appearance of Homo habilis 3 million years ago and the appearance of Homo erectus 1 million years ago were associated with these climatic alterations. Climatic changes also track the disappearance of other members of the human family. For instance, the warming in Europe that ended the ice age as recently as 30,000 years ago contributed to modern humans prospering and to the Neanderthal and other archaic European and Asiatic human groups disappearing. What makes Homo sapiens the sole survivor? One suggestion is that we modern humans evolved to adapt to change itself and that this adaptability has allowed us to populate every region on Earth (Grove, 2017). The caution is that modern humans have been around only a short time relative to the millions of years that other hominid species survived: our adaptability has yet to be severely tested.

The Primate Lifestyle British anthropologist Robin Dunbar (1998) argues that a primate’s social group size, a cornerstone of its lifestyle, is correlated with brain size. His conclusion: the average group size of about 150 favored by modern humans explains their large brains. He cites as evidence that 150 is the estimated group size of hunter-gatherer groups and the average group size of many contemporary institutions—a company in the military, for instance—and coincidentally, the number of people that each of us can gossip about. Consider how group size might affect the way primates forage for food. Foraging is important for all animals, but while some foraging activities are simple, others are complex. Eating grass or vegetation is

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an individual pursuit: an animal need only munch and move on. Vegetation eaters such as gorillas do not have especially large brains relative to their body size. In contrast, apes that eat fruit, such as chimpanzees and humans, have relatively large brains. Katharine Milton (2003) documented the relationship between fruit foraging and larger brains by examining the feeding behavior and brain size of two South American (New World) monkeys of the same body size. As illustrated in Figure 1-17, spider monkeys obtain nearly threequarters of their nutrients from fruit and have a brain twice as large as that of the howler monkey, which obtains less than half its nutrients from fruit.

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FIGURE 1-17 Picky Eaters Katharine Milton examined the feeding behavior and brain size of two New World monkeys that have the same body size but different brain sizes and diets.

What is so special about eating fruit? Fruit harvesting requires good sensory skills such as color vision to see it, good motor skills to reach and manipulate it, good spatial skills to find it, good memory to return to it, and having friends to help find it and ward off competitors. Having a parent who can teach fruit-finding skills and being a good learner are also useful. The payoff in eating fruit is its nutritional value for nourishing a large, energy-dependent brain that uses more than 20 percent of the body’s resources. These same skills are useful for obtaining other temporary and perishable types of food, such as those obtained through scavenging, hunting, and gathering. A neuron’s metabolic (energy) cost is estimated as relatively constant across different species but also high relative to that of other types of body cells. So any adaptive advantage to having more neurons must support that energy cost. Fonseca-Azevedo and Herculano-Houzel (2012) suggests that cooking food is a unique contribution to hominid brain development. Gorillas must spend up to 8 hours of each day foraging for vegetation and eating it. Chimps and early hominids, with a more varied diet, could support more neurons provided that they also spent most of their waking time foraging. The use of fire by Homo erectus and later hominids allowed for cooking, which predigests food and thus maximizes caloric gain to the point that much less time need be devoted to foraging. A high degree of male–male, female–female, and female–male cooperation in food

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gathering and cooking, characteristic of the hominid lifestyle, further supported the evolution of a larger brain.

Changes in Hominid Physiology Cooki ng

A small jaw distinguishes the earliest Homo fossils yet discovered.

food makes it easier to eat. This, in turn, might foster genetic mutations associated with marked size reductions in individual muscle fibers in the face and entire masticatory muscles in hominids (Stedman et al., 2004). The Stedman team speculated that smaller masticatory muscles paved the way for smaller, more delicate bones in the head. Smaller bones in turn allowed for changes in diet and access to more energyrich food. Another physiological adaptation may have given a special boost to greater brain size in our human ancestors: changes in the morphology (form) of the skull. Dean Falk (Kunz & Iliadis, 2007) developed the radiator hypothesis from her automobile mechanic’s remark that to increase the size of a car’s engine, you also have to increase the size of the radiator that cools it. Falk reasoned that if the brain’s radiator, the circulating blood, adapted into a more effective cooling system, brain size could increase. Brain cooling is important because the brain’s metabolic activity generates a great deal of heat and is at risk for overheating under conditions of exercise or heat stress. Falk argued that, unlike australopith skulls, Homo skulls contain holes through which cranial blood vessels pass. These holes suggest that, compared to earlier 157

hominids, Homo species had a much more widely dispersed blood flow from the brain, which would have greatly enhanced brain cooling.

Altered Maturation All animal species’ life history can be divided into stages. Heterochrony (from the Greek, meaning “different times”) is the study of processes that regulate the onset and end-of-life stages and their developmental speed and duration. Several proposals suggest that altered heterochronicity accounts for the large human brain and other distinctive human features. In neoteny, juvenile stages of predecessors become adult features of descendants. Neoteny is common in the animal world. Flightless birds are neotenic adult birds, domesticated dogs are neotenic wolves, and sheep are neotenic goats. Many anatomical features link us with the juvenile stages of other primates, including a small face, vaulted cranium, unrotated big toe, upright posture, and primary distribution of hair on the head, armpits, and pubic areas. Because a human infant’s head is large relative to body size, neoteny has also led to adults with proportionally larger bodies and larger skulls to house larger brains. The shape of a baby chimpanzee’s head is more similar to the shape of an adult human’s head than to an adult chimpanzee’s head (Figure 1-18). Along with this physical morphology, human adults also retain some behaviors of primate infants, including play, exploration, and intense interest in novelty and learning. The brain processes that support learning thus are retained in adulthood (Zollikofer, 2012).

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FIGURE 1-18 Neoteny The shape of an adult human’s head more closely resembles that of a juvenile chimpanzee’s head (left) than an adult chimp’s head (right). This observation leads to the hypothesis that we humans may be neotenic descendants of our more apelike common ancestors.

An alternative view is that the onset and duration of the stages of development change (Workman et al., 2013). Evidence for this idea is that each stage of human development—gestation, infancy, childhood, adulthood—is prolonged relative to such ancestral species as chimpanzees. Prolonged infancy allows the birth and development of more neurons, resulting in a bigger brain. Prolonged childhood enhances learning time; and prolonged adolescence allows for the growth of a bigger body.

The Human Genome The influences on hominid evolution described above must have been mediated by genetic changes. What were these changes? There is an incomplete data sample for investigating the origins of the hominid

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genome (a catalogue of all of a species’ genes) because only the genomes of the apes, archaic humans, and modern humans have been sequenced (i.e., all of the genes have been described). Although apes and modern humans have about 96 percent of their genes in common, each of these genes have many small differences, making it difficult to determine what each difference contributes. A different approach to understanding the origins of the hominid genome is to ask whether new genes appeared or old genes disappeared in hominids. There are a few such human-specific gene changes (Levchenko et al., 2018). One human-specific gene is SARGP2, a gene that is active when the cerebrum is developing. It plays a role in determining the number of neurons that compose the cerebrum. This gene has mutated, producing duplicate copies in the human genome, three times over the course of human evolution. The mutations are estimated to have occurred about 3.4, 2.4, and 1 million years ago. It is tempting to correlate these mutation events with the jumps in brain size that occurred in Homo habilis, erectus, and sapiens, respectively. It is unlikely the story is as simple as this, however, but the finding encourages a search for other relationships between gene changes and human evolution.

1-4 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. Modern humans share a

with the

closest living relative.

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, our

2. Modern humans evolved from a successively featured

lineage that ,

, and

, groups in which more than one species existed concurrently. 3. The

describes brain size relative to body size, but a

complete comparison of different species’ brains requires . 4. The large human brain evolved in response to a number of pressures and opportunities, including ,

, and

5. One hypothesis proposes that Homo sapiens has evolved to adapt to change itself. Explain the reasoning behind this hypothesis in a brief paragraph.

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1-5 Modern Human Brain Size and Intelligence In The Descent of Man, Charles Darwin detailed the following paradox: No one, I presume, doubts the large proportion which the size of man’s brain bears to his body, compared to the same proportion in the gorilla or orang, is closely connected with his higher mental powers. . . . On the other hand, no one supposes that the intellect of any two animals or of any two men can be accurately gauged by the cubic contents of their skulls. (Darwin, 1871, p. 37) Ignoring Darwin, many have tried to tie individual intelligence to gross brain size. If the functional unit of the brain is the brain cell and if larger human brains have more brain cells, does it not follow that brain size and intelligence are related? It depends. The evolutionary approach we have been using to explain how the large human brain evolved is based on comparisons between species. Special care attends the extension of evolutionary principles to physical comparisons within species, especially biological comparisons within or among groups of modern humans. In this section, we first illustrate the difficulty of within-species comparisons by considering the complexity of correlating human brain size with intelligence (Deary, 2000). Then we turn to another aspect of studying

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the brain and behavior in modern humans—the fact that, unlike that of other animals, so much modern human behavior is culturally learned.

Meaning of Human Brain Size Comparisons Stephen Jay Gould, in his 1981 book The Mismeasure of Man, reviews much of the early literature which suggested that brain size and intelligence are related and criticized the research on three counts: brain measurement, correlating brain size and intelligence, and what intelligence is. First, measuring a person’s brain is difficult. If a tape measure is placed around a person’s head, factoring out skull thickness is impossible. There is also no agreement about whether volume or weight is a better measure. And no matter which indicator we use, we must consider body size. The human brain varies in weight from about 1000 grams to more than 2000 grams, but people also vary in body mass. To what extent should we factor in body mass in deciding whether a particular brain is large or small? And how should we measure body mass, given that a person’s total weight can fluctuate widely over time? Large differences between the brains of individual people do exist, but the reasons for these differences are numerous and complex. Consider some examples. People may have larger or smaller brain cells. Larger people are likely to have a larger brain than smaller people because they have a larger muscle mass to control. Men have a 163

somewhat larger brain than women, but again men are also proportionately physically larger. Nevertheless, girls mature more quickly than boys, so in adolescence the brain and body size differences may be absent. As people age, they generally lose brain cells, so their brain shrinks. To find information on specific conditions, consult the Index of Disorders.

Neurological diseases associated with aging accelerate the agerelated decrease in brain size. Brain injury near the time of birth often results in a dramatic reduction in brain size, even in regions distant from the damage. Stress associated with physical or behavioral deprivation in infancy also reduces brain size (Herringa et al., 2013). Neurological disorders associated with a parent’s abuse of alcohol or other drugs are associated with conditions such as fetal alcohol spectrum disorder (FASD), in which the brain can be greatly reduced in size. Autism spectrum disorder (ASD), a largely genetic condition affecting development, produces a wide variety of brain abnormalities, including either increases or decreases in brain size in different individuals. Sections 2-1 and 2-6 elaborate on plasticity, Research Focus 8-1 and Section 8-4 on environment and brain development, Section 11-3 on skilled movement, and Section 14-1 on memory.

Brain size may also increase. For example, just as good nutrition in the early years of life can be associated with larger body size, good 164

nutrition can also be associated with an increase in brain size. The brain’s plasticity—its ability to change—in response to an enriched environment is associated with growth of existing brain cells and thus an increase in brain size. Furthermore, one way in which the brain stores new skills and memories is to form new connections among brain cells, and these connections in turn contribute to increased brain size. Finally, we must consider what is meant by intelligence. When we compare behavior across species, we are comparing species-typical behavior—behavior displayed by all members of a species. For example, lamprey eels do not have limbs and cannot walk, whereas salamanders do have limbs and can walk: the difference in brain size between the two species can be correlated with this trait. When we compare behavior within a species, however, we are usually comparing how well one individual performs a certain task in relation to others of the same species—how well one salamander walks relative to how well another salamander walks, for instance.

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Early in the twentieth century, Charles Spearman carried out the first formal performance analysis among various tests used to rate intelligence in humans. He found a positive correlation among tests and suggested that a single common factor explained them. Spearman named it g for general intelligence factor, but it turns out that g also varies. Many factors unrelated to inherent ability—among them opportunity, interest level, training, motivation, and health—influence individual performance on a task. For example, when IQ tests that were given to young adults of one generation are given to the next generation, scores increase by as much as 25 points, a phenomenon called the Flynn effect (Flynn, 2012). Taken at face value—though it shouldn’t be—the increase

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suggests that human g has risen to such a degree in two generations that most young adults fall in the superior category relative to their grandparents. Obviously, the score change has not been accompanied by a similar increase in brain size. It is more likely that education and other life experiences explain the Flynn effect. Figure 15-9 illustrates the profusion of brain networks; Section 15-6 relates network efficiency to intelligence.

Howard Gardner (2006) proposed that humans have a number of intelligences — verbal, musical, mathematical, social, and so on. Each type of intelligence is dependent on the function of a particular brain region or regions. Hampshire and colleagues (2012), who presented participants with a battery of typical intelligence assessment tests, support Gardner’s idea. As participants took the tests, their brain activity was imaged and recorded. The study identified three separate abilities—reasoning, short-term memory, and verbal ability—each associated with a different brain network. The experimenters argue that this finding provides little support for Spearman’s g. They further suggest that a wider array of assessments would reveal additional intelligence networks. Section 15-6 expands on theories of intelligence. Einstein’s brain is pictured in Figure 15-23.

If you are wondering whether having a larger brain might mean you could study a little less, consider this: the brains of people who

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are widely considered highly intelligent have been found to vary in size from the low end to the high end of the range for our species. The brain of the brilliant physicist Albert Einstein was average in size.

Acquisition of Culture The most remarkable thing that our brains have made possible is ever more complex culture—learned behaviors passed from generation to generation through teaching and experience (Stout & Hecht, 2017). Most of this culture originated long after our brains evolved. Saint Ambrose, who lived in the fourth century, is reportedly the first person who could read silently.

Cultural growth and adaptation render many contemporary human behaviors distinctly different from those of Homo sapiens living 200,000 years ago. Only 30,000 years ago, modern humans made the first artistic relics: elaborate paintings on cave walls and carved ivory and stone figurines. Agriculture appeared still more recently, about 15,000 years ago, and reading and writing were invented only about 7000 years ago. Most forms of mathematics and many of our skills in using mechanical and digital devices have still more recent origins. Computer programming languages, for example, date to the 1950s. Early H. sapiens brains certainly did not evolve to select smartphone apps or imagine traveling to distant planets. Apparently, the things

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that the human brain did evolve to do contained the elements necessary for adapting to more sophisticated skills. Al ex

Section 15-3 explores some of psychology’s expanding frontiers.

Meso udi and his colleagues (2006) suggest that cultural elements, ideas, behaviors, or styles that spread from person to person—called memes (after genes, the elements of physical evolution)—can also be studied within an evolutionary framework. They propose that individual differences in brain structure may favor the development of certain memes. Once developed, memes would in turn exert selective pressure on further brain development. For example, chance variations in individuals’ brain structure may have favored tool use in some individuals. Tool use proved so beneficial that toolmaking itself exerted selective pressure on a population to favor individuals well skilled in tool fabrication. Similar arguments can be made with respect to other memes, from language to music, from mathematics to art. Mesoudi’s reasoning supports brain science’s ongoing expansion into seemingly disparate disciplines, including linguistics, the arts, business, and economics. Studying the human brain, far from examining a body organ’s structure, means investigating how it acquires culture and fosters adaptation as the world changes and as the brain changes the world.

1-5 Review

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Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. Behavior that is displayed by all members of a species is called

2. Some modern human behavior is inherent to our nervous system, but far more is learned—passed generation to generation by

. Ideas, behaviors, or styles called

may spread from person to person and culture to culture. 3. Spearman proposed a common intelligence factor he called . Gardner supports the idea of

4. Explain the reasoning behind the statement that what is true for evolutionary comparisons across different species may not be true for comparisons within a single species.

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Summary 1-1 The Brain in the Twenty-First Century Studying the brain and behavior leads us to better understand our origins, our human nature, the causes of many behavioral disorders, and the rationale behind treatment for disorders. The human nervous system is composed of the CNS, which includes the brain and the spinal cord, and the PNS, through which the brain and spinal cord communicate with sensory receptors, with muscles and other tissues, and with the internal organs. The cerebrum and the cerebellum have undergone the most growth in large-brained animal species. We define behavior as any kind of movement, including mental processes such as thinking and imagining. In animals, behavior is caused by nervous system activity. Behavioral flexibility and complexity vary greatly across species, as does the nervous system. For some species, including humans, the brain is the organ that exerts control over behavior. The brain seems to need ongoing sensory and motor stimulation to maintain its intelligent activity.

1-2 Perspectives on Brain and Behavior

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Mentalism views behavior as a product of an intangible entity called the mind (psyche); the brain has little importance. Dualism is the notion that the immaterial mind acts through the material brain to produce language and rational behavior, whereas the brain alone is responsible for the “lower” actions that we have in common with other animal species. Materialism, the view that brain function fully accounts for all behavior—language and reasoning included—guides contemporary research on the brain and behavior. Support for the materialistic view comes from the study of natural selection—the evolutionary theory that behaviors such as human language evolved from the simpler language abilities of human ancestors —and from discoveries about how genes function. Experiments follow the process of science: (1) formulate a theory, (2) generate a question (hypothesis), (3) design a procedure to test it, and (4) evaluate the results to confirm or modify the theory. After severe TBI, the brain demonstrates a remarkable ability to recover, but after either mild or severe injury, a person can be left with a permanent disability that prevents full recovery to former levels of function. Brain imaging techniques can confirm severe disabilities such as MCS, locked-in syndrome, and PVS.

1-3 Evolution of Brains and of Behavior Behavioral neuroscientists subscribe to the evolutionary principle that all living organisms are descended from a common ancestor. Brain cells and muscles are quite recent developments 172

in the evolution of life on Earth. Because they evolved only once, a similar basic pattern exists in the nervous systems of all animals. The nervous systems of some animal lineages have become more complex, with evolution featuring first a nerve net, followed by a bilaterally symmetrical and segmented nervous system, a nervous system controlled by ganglia, and eventually, in chordates, a nervous system featuring a brain and spinal cord. Mammals are a class of chordates characterized by a large brain relative to body size. Modern humans belong to the primate order, which is distinguished by especially large brains, and to the family of great apes, whose members’ limber shoulders allow them to brachiate (hang and swing by the arms).

1-4 Evolution of the Human Brain and Behavior One of our early hominid ancestors was probably an Australopithecus, who lived in Africa several million years ago. It is from an australopith species that Homo evolved through species such as Homo habilis and Homo erectus. Modern humans, Homo sapiens sapiens, appeared about 200,000 years ago. Since Australopithecus, the hominid brain has increased in size almost threefold, as has its number of brain cells. The increases were associated with area (topography) and connection (connectome) changes. The EQ describes brain size relative to 173

body size, but a complete comparison of different species’ brains requires brain cell counts. Among the factors hypothesized to have stimulated brain evolution in human species are environmental challenges and opportunities, such as climate changes that favored the natural selection of adaptability and more complex behavior patterns. Brain and behavior changes in hominids were mediated by perhaps only a few genes that appeared de novo in hominids. Also proposed are lifestyle changes such as social cooperation and cooking food, changes in physiology, and changed maturation rate.

1-5 Modern Human Brain Size and Intelligence Evolutionary principles learned from studying the brain and behavior across species do not easily apply to the brain and behavior within a single species, such as Homo sapiens. People vary widely in body size, brain size, and, likely, the number of brain cells and the connections between brain cells. Any of these factors can contribute to varying kinds of intelligence, making a simple comparison of brain size and general intelligence unwise. Recognizing the great extent to which modern human behavior, rather than being inherent in our nervous systems, results from cultural learning and transmission is paramount to understanding how our brains function. Memes may spread from person to person and culture to culture.

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Key Terms bilateral symmetry brainstem central nervous system (CNS) cerebellum cerebrum (forebrain) chordate cladogram clinical trial common ancestor concussion connectome culture deep brain stimulation (DBS) dualism embodied behavior encephalization quotient (EQ) epigenetics ganglia genotype

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glial cell hemisphere hominid locked-in syndrome materialism meme mentalism mind–body problem minimally conscious state (MCS) natural selection neoteny nerve net neuron peripheral nervous system (PNS) persistent vegetative state (PVS) phenotype plasticity psyche segmentation species species-typical behavior

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topographic traumatic brain injury (TBI)

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CHAPTER 2 What Is the Nervous System’s Functional Anatomy?

2-1 Overview of Brain Function and Structure RESEARCH FOCUS 2-1 Agenesis of the Cerebellum Plastic Patterns of Neural Organization Functional Organization of the Nervous System The Brain’s Surface Features THE BASICS Finding Your Way Around the Brain 178

CLINICAL FOCUS 2-2 Meningitis and Encephalitis The Brain’s Internal Features CLINICAL FOCUS 2-3 Stroke 2-2 The Conserved Pattern of Nervous System Development Comparative Brain Evolution The Nervous System and Intelligent Behavior EXPERIMENT 2-1 Question: Does Intelligent Behavior Require a Vertebrate Nervous System Organization? 2-3 The Central Nervous System: Mediating Behavior Spinal Cord Brainstem Forebrain Cerebral Cortex Basal Ganglia 2-4 Somatic Nervous System: Transmitting Information Cranial Nerves Spinal Nerves

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Somatic Nervous System Connections Integrating Spinal Functions CLINICAL FOCUS 2-4 Bell Palsy 2-5 Autonomic and Enteric Nervous Systems: Visceral Relations ANS: Regulating Internal Functions ENS: Controlling the Gut 2-6 Ten Principles of Nervous System Function Principle 1: The Nervous System Produces Movement in a Perceptual World the Brain Constructs Principle 2: Neuroplasticity Is the Hallmark of Nervous System Functioning Principle 3: Many Brain Circuits Are Crossed Principle 4: The CNS Functions on Multiple Levels Principle 5: The Brain Is Symmetrical and Asymmetrical Principle 6: Brain Systems Are Organized Hierarchically and in Parallel Principle 7: Sensory and Motor Divisions Permeate the Nervous System

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Principle 8: The Brain Divides Sensory Input for Object Recognition and Movement Principle 9: Brain Functions Are Localized and Distributed Principle 10: The Nervous System Works by Juxtaposing Excitation and Inhibition Note that we are using the word function two different ways. Function can refer to the purpose of the brain—its function is to produce behavior (recall functionalism from Chapter 1)—or it can refer to how the brain works, how it functions.

Throughout this book, we examine the nervous system with a focus on function—how our brains generate behavior and how, in turn, our behavior influences our brains. In this chapter, we consider the human nervous system’s anatomical and functional organization and how its basic components work together to produce behavior. Moreover, we consider how our brains change in the context of plasticity, as illustrated in Research Focus 2-1, Agenesis of the Cerebellum. First, we emphasize the brain’s anatomy, and then we elaborate on how the brain works in concert with the rest of the nervous system to produce behavior. This focus on nervous system function and plasticity suggests 10 principles of nervous system organization. We note each principle throughout the chapter and describe all the principles in detail in Section 2-6. These big ideas apply equally to the micro and macro views of the nervous system presented in this chapter and to the broader picture of behavior that emerges in later chapters.

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RESEARCH FOCUS 2-1 Agenesis of the Cerebellum When an adult’s brain is damaged, as in traumatic brain injury, for example, we see a pattern of behavioral changes that offer insight into brain functions, as described by Fred Linge in Clinical Focus 1-1, Living with Traumatic Brain Injury. Naturally occurring brain injuries rarely remove a single structure completely, leaving the rest of the brain intact. However, agenesis, the failure of brain regions to develop, offers researchers a unique window on the brain’s organization and function because in rare cases, a complete structure is absent, yet the rest of the brain appears normal. Historically, the cerebellum was viewed as a motor structure, with the most obvious sign of damage being ataxia, a failure of muscular coordination and balance. But the cerebellum’s functions are much more extensive than movement control (e.g., Schmahmann, 2010). Adult patients with damage to the cerebellum do have motor disturbances, but they also have cognitive deficits in, for example, abstract thinking and language and in emotional control. The cerebellum contains the most neurons of any brain region, accounting for 80 percent of the neurons in humans and a whopping 97.5 percent of elephants’ neurons—believed to be related to the dexterity of the elephant’s trunk. What would happen if the cerebellum failed to develop but the rest of the brain developed apparently normally? We humans would be missing 80 percent of our neurons! The accompanying images contrast the brain of a person whose brain developed normally (A and B) to the brain of a young man born with agenesis of the cerebellum (C and D). Even lacking 80 percent of his neurons, the young man’s behavioral capacities are remarkable, but his behavior is not typical. Now in his thirties, he has an office job and lives alone. He has a distinctive speaking pattern, an awkward gait, and difficulties with balance, as well as deficits in planning and abstract thinking. His social

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skills and long-term memory are good, though, as is his mastery of routine activities.

MRI brain scans of a person with a typical cerebellum (A, B) compared to a person with cerebellar agenesis (C, D) of the same age. A and C are viewed in the coronal plane, B and D in the mid-sagittal plane. For more about this condition, see www.npr.org/blogs/health/2015/03/16/393351760.

Studies of other people with cerebellar agenesis reveal a heterogeneous set of symptoms, but neuropsychological assessments show behavioral deficits reminiscent of people with damage to frontal and parietal cortical regions (e.g., Baumann et al., 2015), even though these cerebral regions are

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intact. While people with cerebellar agenesis typically have more slowly developing language and motor functions, they show remarkable improvement over time and seem able to compensate for many of their symptoms. The individual whose brain you see in images C and D had severe visuomotor spatial disabilities as a child and adolescent, but by age 30 he showed significant improvement (Jeremy D. Schmahmann and Janet C. Sherman, personal communication). In people with cerebellar agenesis, it is thought that brain plasticity in response to early perturbations allows for compensation as regions of the cerebral cortex begin to function more efficiently. Interestingly, it has been reported that people with cerebellar agenesis appear to have some of the symptoms of autism early in life. This observation comports with evidence that dysfunction (rather than absence) of the cerebellum is related to autism (detailed in Clinical Focus 8-2, Autism Spectrum Disorder).

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2-1 Overview of Brain Function and Structure The brain’s primary function is to produce movement, and collectively this is termed behavior. To produce effective behavior, we take in sensory information—such as vision, audition, olfaction, gustation, and somatosensation—as we search, explore, and manipulate our environment. Without stimuli, the brain cannot properly orient the body and direct it to produce appropriate behaviors. The nervous system’s sensory organs gather information about the world and convert this information into biological activity that constructs perceptions—what we see, hear, smell, taste, and feel. This subjective reality is essential to carrying out any complex behavior. Principle 1: The nervous system produces movement in a perceptual world the brain constructs.

When your phone rings, for example, your brain directs your body to reach for it as the nervous system responds to vibrating air molecules by producing the subjective experience of a ringtone. We perceive this stimulus as sound and react to it as if it actually exists, when in fact the ringtone is merely a fabrication of the brain. That fabrication is produced by a chain reaction that takes place when vibrating air molecules hit the eardrum. Without the nervous system, especially the brain, perception of sound does not exist—only the movement of air molecules.

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But there is more to hearing a phone’s ringtone than vibrating air molecules. Our mental construct of reality is based not only on the sensory information we receive but also on the cognitive processes we might use to interact with that incoming information. Hearing a ringtone when we are expecting a call has a meaning vastly different from its ringing at 3 A.M., when we are not expecting a call. The subjective reality the brain constructs can be better understood by comparing the sensory realities of two different kinds of animals. You are probably aware that dogs perceive higher-pitched sounds that humans do not perceive. This difference in perception does not mean that a dog’s nervous system is better than ours or that our hearing is poorer. Rather, the perceptual world constructed by a dog brain simply differs from the world constructed by human perception. Neither experience is “correct.” The difference in subjective experience is due merely to two differently evolved systems for processing sensory stimuli. When it comes

Section 9-1 elaborates on the nature of sensation and perception.

to visual perception, our world is rich with color, whereas dogs see very little color. Human brains and dog brains construct different realities. Subjective differences in brains exist for good reason: they allow different animals to exploit different features in their environments. Dogs use their hearing to detect the movements of prey, such as mice in the grass; early hominids probably used color vision for identifying ripe fruit in trees. Evolution, then, created adaptations, equipping each species with a view of the world that helped it survive.

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Plastic Patterns of Neural Organization The brain is plastic: neural tissue has the capacity to change in response to the world by changing how it is organized. Just as the brain of the young man profiled in Research Focus 2-1 adapted to cerebellar agenesis, a person blind from birth has enhanced auditory capacities because some of the brain’s visual regions have been co-opted for hearing. The brain is also plastic in the sense that connections among neurons in a given functional system are constantly changing in response to experience. For us to learn and remember anything new, neural circuits must change to represent and store this knowledge. As we learn to play a musical instrument or speak a new language, the particular cortical regions taking part can actually increase in size as they accommodate the new skill. An important aspect of human learning and brain plasticity is related to the development of language and to the expansion of the brain regions related to language. We have learned to read, to calculate, to compose and play music, and to develop the sciences. While the human nervous system evolved long before we mastered these achievements, it is still able to learn and remember these new abilities because of brain plasticity. In turn, culture plays a dominant role in shaping our behavior. Because we drive cars and communicate electronically, we—and our nervous system—are modified in some new ways compared to those of our ancestors who did not engage in these activities. The basis for change in the nervous system is neuroplasticity, the nervous system’s

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fundamental potential to physically or chemically modify itself in response to a changing environment and to compensate for age-related changes and injury. Principle 2: Neuroplasticity is the hallmark of nervous system functioning.

Although it is tempting to see neuroplasticity as a trait unique to animals’ nervous systems, it is really part of a larger biological capacity called phenotypic plasticity, the individual’s capacity to develop a range of phenotypes—the characteristics we can see or measure. (See Gilbert & Epel, 2009, for a wonderful discussion of biological plasticity.) For instance, our skin responds to ultraviolet rays by incorporating more melanin, causing it to darken as a protective measure. Stated simply, an individual’s genotype (genetic makeup) interacts with the environment to elicit a specific phenotype. This phenotype emerges from a large genetic repertoire of possibilities, a phenomenon that in turn results from epigenetic influences. Section 1-2 introduces the genotype, phenotype, and epigenetics in an evolutionary context.

Epigenetic factors do not change genes but rather influence how genes inherited from parents express specific traits. The two mice pictured in Figure 2-1 appear very different: one is fat, one thin; one has dark fur, the other is light-colored. Yet these mice are clones, genetically identical. They appear so different because their mothers were fed different diets while pregnant. The diet supplements added

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chemical markers, or epigenetic tags, on specific genes. The tags determine whether the gene is available to influence cells, including neurons, leading to differences in body structure and eating behavior.

FIGURE 2-1 Phenotypic Plasticity These two mice are genetically identical but express very different phenotypes because their mothers were fed different supplements when pregnant.

Functional Organization of the Nervous System From an anatomical standpoint, the brain and spinal cord together make up the central nervous system. The nerve fibers radiating out beyond the

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brain and spinal cord, as well as all the neurons outside the brain and spinal cord, form the peripheral nervous system. Figure 2-2A charts this anatomical organization. PNS nerves carry sensory information into the CNS and carry motor instructions from the CNS to the body’s muscles and tissues, including those that perform such functions as blood circulation and digestion.

FIGURE 2-2 Parsing the Nervous System The nervous system can be conceptualized (A) anatomically and (B) functionally. The functional approach employed in this book focuses on how the four parts of the nervous system interact.

Now look at Figure 2-2B. In a functional organization, the focus is

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See Figure 1-1 for an anatomical illustration of the human CNS and PNS.

on how the parts of the system work together. Neurons in the somatic division of the PNS connect through the cranial and spinal nerves to receptors on the body’s surface and on its muscles. Somatic neurons gather sensory information for the CNS and convey information from the CNS to move muscles of the head, neck, face, trunk, and limbs. Similarly, the autonomic division of the PNS enables the CNS to govern the workings of your body’s internal organs—your heartbeat, urination, pupillary response, and the diaphragm movements that inflate and deflate your lungs. The enteric nervous system, which is often considered part of the autonomic nervous system, controls digestion and stomach contractions. From a functional standpoint, the major PNS divisions constitute, along with the CNS, an interacting four-part system: The CNS includes the brain and the spinal cord—the nervous system core, which mediates behavior. The somatic nervous system (SNS) includes all the spinal and cranial nerves carrying sensory information to the CNS from the muscles, joints, and skin. It also transmits outgoing motor instructions that produce movement. The autonomic nervous system (ANS) produces the rest-anddigest response through the parasympathetic (calming) nerves and its opposite, the fight-or-flight response, or vigorous activity through the sympathetic (arousing) nerves.

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The enteric nervous system (ENS), formed by a mesh of neurons embedded in the lining of the gut, controls the gut. The ENS can communicate with the CNS via the ANS but mostly operates autonomously. The directional flow of neural information is important. Afferent (incoming) information is sensory, coming into the CNS or one of its parts, whereas efferent (outgoing) information is leaving the CNS or one of its parts. When you step on a tack, the afferent sensory signals are transmitted from the body into the brain and then perceived as pain. Efferent signals from the brain cause a motor response: you lift your foot (Figure 2-3).

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FIGURE 2-3 Neural Information Flow

The Brain’s Surface Features When buying a car, people like to look under the hood and examine the engine, the part of the car responsible for its behavior. All that most of us can do is gaze at the maze of tubes, wires, boxes, and fluid reservoirs. What we see makes no sense except in the most general way. 193

We know that the engine somehow generates power to make the car move and to run the sound system, lights, and wipers. But knowing this tells us nothing about what all the many engine parts do. Spinal reflexes are discussed in detail in Section 11-4 and illustrated in Figure 11-20.

When it comes to our behavior, the brain is the engine. In many ways, examining a brain for the first time is similar to looking under the hood. We have a vague sense of what the brain does, but most of us have no sense of how its parts accomplish these tasks. We may not even be able to identify those parts. If you are familiar with the anatomical terms and orientations used in drawings and images of brains, read on. If you prefer to review this terminology before you continue, consult The Basics: Finding Your Way Around the Brain.

THE BASICS

Finding Your Way Around the Brain

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When the first anatomists began to examine the brain with the primitive tools of their time, the names they chose for brain regions often manifested their erroneous assumptions about how the brain works. They named one brain region the gyrus fornicatus because they thought that it had a role in sexual function, but most of this region actually has nothing to do with sexual activity. A Wonderland of Nomenclature

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As time went on, the assumptions and tools of brain research changed, but naming continued to be haphazard and inconsistent. Many brain structures have several names, and terms are often used interchangeably. This peculiar nomenclature arose because research on the brain and behavior spans several centuries and includes scientists of many nationalities and languages. Early investigators named structures after objects (the pulvinar, for example, was thought to look like a pillow) or ideas (the limbic system was thought to be responsible for sexuality and emotions). They used various languages, especially Latin, Greek, and English. More recently, investigators have often used numbers or letters, but even this system lacks coherence because the numbers may be Arabic or Roman and are often used in combination with Greek or Latin letters. Describing Locations in the Brain

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Many names for nervous system structures reflect their anatomical locations with respect to other anatomical structures (for example, the hypothalamus lies below the thalamus), with respect to their relative spatial locations (the lateral ventricles lie lateral to the other ventricles), and with respect to a viewer’s perspective (the anterodorsal nucleus of the thalamus is in the front and above the other thalamic nuclei):

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Brain–body orientation illustrates brain structure location from the frame of reference of the human face. Spatial orientation illustrates brain structure location in relation to other body parts and body orientation. Anatomical orientation illustrates the direction of a cut, or section, through the human brain (part A) from the perspective of a viewer (part B). These orienting terms are derived from Latin. Consult the accompanying table “Glossary of Anatomical Location and Orientation” for easy reference. It is common practice to combine orienting terms. A structure described as dorsolateral, for example, means that it lies up and to the side, as in the case of the dorsolateral prefrontal cortex. Finally, the nervous system, like the body, is bilaterally symmetrical: it has a left side and a right side. Structures that lie on the same side are ipsilateral; if they lie on opposite sides, they are contralateral to each other. Structures that occur in each hemisphere are bilateral. Structures that are close to one another are proximal; those far from one another are distal. Glossary of Anatomical Location and Orientation Term

Meaning with respect to the nervous system

Near or toward the front of the animal or the front of the head (see also frontal and rostral)

Caudal

Near or toward the tail of the animal (see also posterior)

Coronal

Cut vertically from the crown of the head down; used to reference the plane of a brain section that reveals a frontal view

Dorsal

On or toward the back of a four-legged animal (equivalent to posterior for the human spinal cord); in reference to human brain nuclei, above, and to brain sections, viewed from above

Frontal

Of the front (see also anterior and rostral); in reference to brain sections, a viewing orientation from the front

Horizontal

Cut along the horizon; used to reference the plane of a brain section that reveals a

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dorsal view Inferior

Below (see also ventral)

Lateral

Toward the side of the body or brain

Medial

Toward the middle, specifically the body’s midline; in reference to brain sections, a side view of the central structures

Posterior

Near or toward the animal’s tail (see also caudal); for the human spinal cord, at the back

Rostral

Toward the beak (front) of the animal (see also anterior and frontal)

Sagittal

Cut lengthways from front to back of the skull to reveal a medial view into the brain from the side; a cut in the midsagittal plane divides the brain into symmetrical halves

Superior

Above (see also dorsal)

Ventral

On or toward the belly of four-legged animals (see also inferior); in reference to human brain nuclei, below

Protecting the Nervous System We start our functional overview by opening the hood and observing the brain snug in its home in the skull. The first thing you encounter is not the brain but rather a tough triple-layered protective covering, the meninges (Figure 2-4). The outer dura mater (from Latin, meaning “hard mother”) is a tough durable layer of fibrous tissue that is attached to the skull and encloses the brain and spinal cord in a kind of loose sac. In the middle is the arachnoid layer (from Greek, meaning “like a spider’s web”), an ultrathin sheet of delicate connective tissue that follows the brain’s contours. The inner layer, or pia mater (from Latin, meaning “soft mother”), is a moderately tough membrane of connective tissue that clings to the brain’s surface.

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FIGURE 2-4 Cerebral Protection A triple-layered covering, the meninges, encases the brain and spinal cord, and cerebrospinal fluid (CSF) cushions them.

Between the arachnoid layer and the pia mater flows cerebrospinal fluid (CSF), a colorless solution of sodium, chloride, and other ions. CSF cushions the brain so that it can move or expand slightly without pressing on the skull. The symptoms of meningitis, an infection of the meninges and CSF, are described in Clinical Focus 2-2, Meningitis and Encephalitis.

CLINICAL FOCUS 2-2

Meningitis and Encephalitis When harmful viruses or microorganisms, such as bacteria, fungi, and protozoa, invade and multiply in the layers of the meninges, particularly the pia mater and the arachnoid layer, as well as the CSF flowing between them, this leads to meningitis (literally “inflammation of the meninges”). In response to the infection, the body produces white blood cells designed to attack and consume these invaders. This inflammatory response increases the pressure within the cranium, which in turn affects the functioning of the

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brain. Unrelieved cranial pressure can lead to delirium and, if the infection progresses, to drowsiness, stupor, coma, and even death.

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Pus, consisting of dead white blood cells, bacteria with tissue debris, and serum, is visible over the surface of this brain infected with meningitis.

Usually the earliest symptom of meningitis is severe headache and a stiff neck (cervical rigidity). Head retraction (tilting the head backward) is an extreme form of cervical rigidity. Convulsions, a common symptom in children, indicate that the inflammation is affecting the brain. Meningitis is treated with antibiotics when the cause is microorganisms and sometimes with antiviral drugs for viral infections. Survivors of meningitis can have long-term consequences, such as deafness, epilepsy, hydrocephalus, and cognitive deficits. Infection of the brain itself is called encephalitis (inflammation of the brain). Like meningitis, encephalitis is caused by a number of different invading viruses or microorganisms. Different forms of encephalitis may have different effects on the brain. For example, Rasmussen encephalitis attacks one cerebral hemisphere in children. In most cases, the only effective treatment is radical: hemispherectomy, surgical removal of the entire affected hemisphere. Surprisingly, some young children who lose a hemisphere adapt rather well. They may even complete college, literally with half a brain. But intellectual disabilities are a more common outcome of hemispherectomy as a result of encephalitis. Vaccinations have been proven highly effective as protection against certain types of encephalitis, although many vulnerable populations are still not being vaccinated. Experts estimate that encephalitis affected 4.3 million people and resulted in 150,000 deaths worldwide in 2015 (GBD 2015 Mortality and Causes of Death Collaborators, 2016).

Cerebral Geography

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After removing the meninges, we can examine the brain’s surface features, most prominently its two nearly symmetrical left and right hemispheres. Figure 2-5 diagrams the left hemisphere of a typical human forebrain oriented in the upright human skull. The outer forebrain consists of folded and layered tissue, the cerebral cortex, detailed in the frontal view in Figure 2-5. The word cortex, Latin for “bark,” is apt, considering the cortex’s heavily folded surface and its location, covering most of the rest of the brain. Unlike the bark on a tree, however, the brain’s folds are not random but rather demarcate its functional cortical zones.

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FIGURE 2-5 The Cerebral Cortex Each cerebral hemisphere is divided into four lobes: frontal, parietal, temporal, and occipital, shown at left as oriented in the head. The brain surface, or cerebral cortex, shown in the frontal view, is the layered tissue,

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heavily folded to fit inside the skull. Your right fist can map the orientation of the left hemisphere and its lobes.

Make a fist with your right hand and hold it up, as shown on the right in Figure 2-5, to represent the positions of the forebrain’s broad divisions, or lobes, in the skull. Each lobe is simply named for the skull bone it lies beneath: Immediately above your thumbnail, your fingers correspond to the location of the frontal lobe, which performs the brain’s executive functions, such as decision making, and voluntary movement. The parietal lobe is at the top of the skull, as represented by your knuckles, behind the frontal lobe. Parietal functions include directing our movements toward a goal or to perform a task, such as grasping an object. The forward-pointing temporal lobe lies at the side of the brain below the parietal lobe, in approximately the same place as the thumb on your upraised fist. The temporal lobe includes hearing, language, and musical abilities, as well as facial recognition and emotional processing. The area at the back of each hemisphere, near your wrist, constitutes the occipital lobe, where visual scene processing begins. The brain has several visual-based systems that perform different functions, such as regulating pupil size and providing input to the circadian (day/night cycle) system. Visual scene is the visual system that gives rise to our perception of the visual world.

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Examining the Brain’s Surface from All Angles As we look at the dorsal view in Figure 2-6A, the brain’s wrinkled left and right hemispheres constitute the cerebrum, which is a major forebrain structure and the most recently expanded feature of the mammalian CNS. Visible from the opposite ventral view in Figure 2-6B are the brainstem, including the wrinkly hemispheres of the smaller cerebellum (Latin for “little brain”). Both the cerebrum and the brainstem are visible in the lateral and medial views in Figure 2-6C and D.

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FIGURE 2-6 Examining the Human Brain Locations of the lobes of the cerebral hemispheres, shown in dorsal, ventral, lateral, and medial (top, bottom, side, and midline) views, as are the cerebellum, longitudinal and lateral fissures, and the central sulcus.

Much of the crinkled-up cerebral cortex is invisible from the brain’s surface. All we can see are bumps, or gyri (sing. gyrus), and cracks, or sulci (sing. sulcus). The really deep sulci are called fissures. The longitudinal fissure runs between the cerebral hemispheres and the lateral fissure along the sides of the brain. Both are shown in various views in Figure 2-6, along with the central sulcus that runs from the lateral fissures across the top of the cerebrum. Looking at the bottom of the brain, the ventral view in Figure 2-6B, we see in the midst of the wrinkled cerebrum and ventral to the cerebellum a smooth, whitish structure with little tubelike protrusions attached. This is the brainstem, the area responsible for critical functions of life, including heart rate, breathing, sleeping, and eating. The tubelike protrusions are the cranial nerves that run to and from the brain as part of the SNS.

Cerebral Circulation The brain’s surface is covered with blood vessels. As with the rest of the body, the arteries feed blood to the brain and send it back through veins to the kidneys and lungs for cleaning and oxygenation. The cerebral arteries emerge from the neck to wrap around the outside of the brainstem, cerebrum, and cerebellum, finally penetrating the brain’s surface to nourish its inner regions.

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Three major arteries send blood to the cerebrum—the anterior, middle, and posterior cerebral arteries, shown in Figure 2-7. Because the brain is highly sensitive to blood loss, a blockage or break in a cerebral artery is likely to lead to the death of the affected region. This condition, known as stroke, is the sudden appearance of neurological symptoms as a result of severely reduced blood flow. Because the three cerebral arteries supply different parts of the brain, strokes can disrupt different brain functions, depending on the artery affected.

FIGURE 2-7 Major Cerebral Arteries Each of the three major arteries that feed blood to the cerebral hemispheres branches extensively to supply the regions shaded in pink. Section 16-3 elaborates on the effects of stroke and its treatment.

Principle 3: Many brain circuits are crossed.

Because the brain’s connections are crossed, stroke in the left

hemisphere affects sensation and movement on the right side of the

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body. The opposite is true for those with strokes in the right hemisphere. Clinical Focus 2-3, Stroke, describes some disruptions that stroke can cause, both to the person who has it and to those who care for stroke survivors.

CLINICAL FOCUS 2-3

Stroke Approximately every minute in the United States, someone has a stroke with obvious visible symptoms—that adds up to more than half a million people every year. Worldwide, stroke is the second leading cause of death. Acute symptoms include facial droop, motor weakness in limbs, visual disturbance, speech difficulties, and sudden onset of severe headache. Even with the best, fastest medical attention, most stroke survivors have some residual motor, sensory, or cognitive deficit. For every 10 people who have a stroke, 2 die, 6 are disabled to varying degrees, and 2 recover to a degree but still have a diminished quality of life (Goyal et al., 2015). Of those who survive, 1 in 10 risk further stroke. The consequences of stroke are significant for those who have them, as well as for their family and lifestyle. Consider Mr. Anderson, a 45-year-old electrical engineer who took his three children to the movies one Saturday afternoon and collapsed. He had a massive stroke of the middle cerebral artery in his left hemisphere. The stroke has impaired Mr. Anderson’s language ever since, and because the brain’s connections are crossed, his right-side motor control was affected as well. Seven years after his stroke, Mr. Anderson remained unable to speak, but he understood simple conversations. Severe difficulties in moving his right leg required him to use a walker. He could not move the fingers of his right hand and so had difficulty feeding himself, among other tasks. Mr. Anderson

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will probably never return to his engineering career or drive or get around on his own. Like him, most other stroke survivors require help to perform everyday tasks. Caregivers are often female relatives who give up their own careers and other pursuits. Half of the caregivers develop emotional illness, primarily depression or anxiety or both, in a year or so. Lost income and stroke-related medical bills significantly affect the family’s living standard. We tend to speak of stroke as a single disorder, but there are two major categories of strokes. In the more common ischemic stroke, a blood vessel is blocked by either a blood clot, also known as a thrombus, or by some other obstructive material, such as fat, clumps of bacteria, or cancer, called an embolus. Ischemia refers to the failure to deliver sufficient oxygen, glucose, and other nutrients for cellular metabolism, as well as the inadequate removal of metabolic waste like carbon dioxide.

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Dorsal view of a brain with a stroke, imaged by computed tomography (CT). The dark area in the right hemisphere has been damaged by the loss of blood flow.

The more life-threatening hemorrhagic stroke results from a burst vessel bleeding into the brain. While the hemorrhage, like an ischemic stroke, also prevents sufficient delivery and removal of critical molecules, it has the added detriment of exposing neurons directly to the toxic effects of hemoglobin, the gas-carrying molecule in red blood cells that contains high levels of iron.

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The hopeful news is that ischemic stroke can be treated acutely with a medication called tissue plasminogen activator (t-PA). The body produces tPA as a natural prevention for excessive clotting. A dosage of t-PA administered within 3 hours of the onset of ischemic symptoms will boost a patient’s t-PA levels by about 1000 times above normal, which will facilitate breaking up clots and allow normal blood flow to return to an affected region. Unfortunately, there is no treatment for hemorrhagic stroke, for which the use of clot-busting t-PA would be disastrous. When patients receive t-PA, the number who make a nearly complete recovery increases by about 25 percent compared with those who receive a placebo (Hatcher & Starr, 2011). In addition, impairments are reduced in the remaining patients who survive the stroke, when the t-PA medication has some effectiveness. Unfortunately, in a small percentage of patients who do not receive any benefit from t-PA, their outcomes are worsened by the treatment. The risk of hemorrhage is about 6 percent in t-PA–treated patients relative to no risk in placebo-treated patients. Most stroke victims do not visit an emergency room until about 24 hours after symptoms appear—too late for the treatment. Apparently, most people fail to realize that having a stroke requires emergency medical attention. By taking advantage of developments in neuroimaging, research has shown that it is possible to remove clots from cerebral vessels mechanically (Goyal et al., 2015). This is achieved by using advanced radiographic imaging techniques to guide a long, thin catheter tube with a springlike mechanism on the end, which is inserted into the femoral artery near the groin. The tube is threaded through the body into the brain and right to the clot. The springlike mechanism can either grab the clot or bust it up. These new procedures have expanded the window of benefit to as long as 12 hours after the onset of stroke. There is also intense interest in developing treatments that stimulate the brain to initiate reparative processes after a patient suffers a stroke. Such

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treatments are designed to facilitate the patient’s functional improvement (see a review by Langhorne et al., 2011).

The Brain’s Internal Features The simplest way to examine the inside of something is to cut it in half. Of course, the orientation of the cut affects what we see. Consider slicing through a pear. If we cut from side to side, we cut across the core, providing a dorsal view; if we cut from top to bottom, we cut parallel to the core, providing a medial view. Our impression of the inside of a pear is clearly influenced by how we slice it. The same is true of the brain.

Macroscopic Inspection: Regions and Hemispheres We can reveal the brain’s inner features by slicing it parallel to the front of the body, downward through the middle in a coronal section (Figure 2-8A). The resulting frontal view, shown in Figure 2-8B, makes immediately apparent that the brain’s interior is not homogeneous. Both dark grayish and lighter regions of tissue are visible, and though these regions may not be as distinctive as car engine parts, they nevertheless represent different brain components.

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FIGURE 2-8 Coronal Brain Section (A) The brain is cut down the middle parallel to the front of the body; then a coronal section is viewed at a slight angle. (B) This frontal view displays white matter, gray matter, and the lateral ventricles. Visible above the ventricles, a large bundle of whitish fibers, the corpus callosum, joins the hemispheres.

The darker regions are called gray matter, largely composed of cell bodies and capillary blood vessels. Within the gray matter, neurons collect and modify information before sending it along. The lighter regions are white matter, mostly nerve fibers covered by myelin sheaths that have a high fat content. These fibers produce the white appearance, much as fat droplets in milk make it appear white. White matter fibers form longer-distance connections between and among some of the brain’s neurons. A second feature, apparent at the center of our frontal view in Figure 2-8B, are the lateral ventricles—two wing-shaped cavities that contain cerebrospinal fluid. The brain’s four ventricles, shown in place in Figure 2-9, are filled with CSF made by a network of blood vessels, called the choroid plexus, which lines the ventricles. All four ventricles are connected, so CSF flows from the two lateral ventricles to the third and fourth ventricles, which lie on the brain’s midline, and into the cerebral aqueduct, a canal that runs down the length of the spinal cord. CSF bathes the brain and circulates to the space between the lower layers of the meninges, where it is absorbed and deposited into the venous bloodstream (see Figure 2-4).

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FIGURE 2-9 Interconnected Cerebral Ventricles The lateral ventricles are symmetrical, one in each hemisphere. The third and fourth ventricles lie in the brain’s midline and connect to the cerebral aqueduct, which runs the length of the spinal cord.

The CSF performs several vital brain functions. The CSF suspends the brain, making it neutrally buoyant so that it acts like it is 1/30 of its actual mass. The CSF also acts as a shock absorber, providing the brain with important protection from mild blows to the head. The chemical content of the CSF is precisely regulated to provide a stable environment for optimal brain function. Slight changes to its chemical composition can cause dizziness and fainting. The brain also produces and distributes about 25 mL of CFS an hour, which accounts for about 1/5 of its total volume. In this way, substances are efficiently delivered to brain cells and waste products cleared away. Cutting through the brain vertically from front to back produces a sagittal section (Figure 2-10A). If we make our cut down the brain’s midline—that is, in the midsagittal plane—we divide the cerebrum into its two hemispheres, revealing several distinctive structures in the

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resulting medial view (Figure 2-10B). One feature is a long band of white matter that runs much of the length of the cerebral hemispheres. This band, the corpus callosum, contains about 200 million nerve fibers that join the two hemispheres and allow them to communicate.

FIGURE 2-10 Sagittal Brain Section (A) A section in the midsagittal plane separates the hemispheres, allowing (B) a medial view of the brain’s midline structures, including the subcortical structures that lie ventral to the corpus callosum.

Figure 2-10B clearly shows that

Principle 4: The CNS functions on multiple levels.

the neocortex covers the cerebral hemispheres above the corpus callosum; below it are various internal subcortical regions. Subcortical regions make intimate reciprocal connections with cortical areas that process sensory, perceptual, cognitive, and motor functions. In this way, when the cortical areas perceive a threat, such as an angry dog, they communicate with subcortical regions that have already begun to increase breathing and heart rate via the sympathetic nervous system. This relation between cortical and subcortical areas illuminates another principle of

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CNS organization: the concept that redundant and overlapping functions exist at many levels of the nervous system. These neocortical auditory areas are illustrated in Figure 10-13.

If you were to compare

medial views of the left and right hemispheres, you would be struck by their symmetry. The brain, in fact, has two of most structures, one on each side, and they are nearly identical. Structural asymmetry in our species can be found in the neocortical auditory areas; in right-handed people, the planum temporale, which is responsible for understanding speech, is larger in the left hemisphere, whereas Heschl’s gyrus, which is responsible for analyzing music, is larger on the right. Principle 5: The brain is symmetrical and asymmetrical.

The few one-of-a-kind structures, such

as the third and fourth ventricles, lie along the brain’s midline (see Figure 2-9B). Another one-of-a-kind structure is the pineal gland, which straddles the two hemispheres.

Microscopic Inspection: Cells and Fibers Human brains contain about 86 billion neurons and 87 billion glia. Section 3-1 examines their structures and functions in detail.

The brain’s fundamental units—its cells—are so small that they can be viewed only with the aid of a microscope. A microscope quickly reveals that the brain has two main types of cells, illustrated in Figure 2-11.

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Neurons carry out the brain’s communicative and information processing functions, whereas glial cells aid and modulate the neurons’ activities—for example, by insulating their axons. Both neurons and glia come in many forms, each marked by the work that they do.

FIGURE 2-11 Brain Cells Branches emanate from the cell bodies of a prototypical neuron (left) and a glial cell (right). This branching organization increases the cell’s surface area. This type of neuron is called a pyramidal cell because the cell body is shaped somewhat like a pyramid; the glial cell is called an astrocyte because of its star-shaped appearance.

We can see the brain’s internal structures in even greater detail by dyeing their cells with special stains (Figure 2-12). For example, if we use a dye that selectively stains cell bodies, we can see that the neurons in the cortical gray matter lie in layers, revealed by the bands of tissue in Figure 2-12A and C. Each layer contains cells that stain characteristically. Figure 2-12A and B shows that stained subcortical regions are composed of clusters, or nuclei (sing. nucleus), of similar cells.

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FIGURE 2-12 Cortical Layers and Glia Brain sections from the left hemisphere of a monkey (midline is to the left in each image), viewed through a microscope. Cells are stained with (A and C) a selective cell body stain for neurons (gray matter) and (B and D) a selective fiber stain for insulating glial cells, or myelin (white matter). The images reveal very different views of the brain at the macro (A and B) and microscopic (C and D) levels.

Although layers and nuclei appear very different, both form functional units in the brain. Whether a particular brain region has layers or nuclei is largely a random product of evolution. By using a stain that selectively dyes neuronal fibers, as shown in Figure 2-12B and D, we can see the borders of the subcortical nuclei more clearly. In

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addition, we can see that the stained cell bodies lie in regions adjacent to those with most of the fibers. A key feature of neurons is that they are connected to one another by fibers known as axons. When axons run along together, much like the wires that run from a car engine to the dashboard, they form a nerve or tract (Figure 2-13). By convention, a tract is a collection of nerve fibers in the brain and spinal cord, whereas bundles of fibers outside the CNS are typically called nerves. Thus, the pathway from the eye to the brain is the optic nerve, whereas the pathway from the cerebral cortex to the spinal cord is the corticospinal tract.

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FIGURE 2-13 Neuronal Connections

2-1 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests.

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1. The nervous system’s function is to produce movement, or , in a perceptual world constructed by the . 2. The left and right cerebral hemispheres are each divided into four lobes: , , , and . 3. The human nervous system has evolved the potential to change, for example, to adapt to changes in the world or to compensate for injury. This attribute is called . 4. Neural tissue is of two main types: (1) forms the connections among cells, and (2) collects and processes incoming (afferent) sensory or outgoing (efferent) information. 5. The nerve fibers that lie in the brain form the brain they are called .

. Outside

6. Chart the human nervous system’s functional organization.

For additional study tools, visit

launchpadworks.com

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2-2 The Conserved Pattern of Nervous System Development The nervous system’s basic structural plan is present in developing, embryonic brains, and the striking similarity of the main divisions in embryos as diverse as amphibians and mammals is evident in the earliest stages of development. Because evolution works by tinkering with the developmental programs that give rise to brain structures, simpler and evolutionarily more archaic forms have not been discarded and replaced but rather modified and added to. As a result, all anatomical and functional features of simpler nervous systems are present in and form the base for the most complex nervous systems, including ours. Section 1-3 outlines nervous system evolution, and Section 8-1 covers developmental similarities among humans and other species.

The bilaterally symmetrical nervous system of simple worms, for example, is common to complex nervous systems. Indeed, we can recognize in humans the spinal cord that constitutes most of the simplest fishes’ nervous system. The same is true of the brainstem of more complex fishes, amphibians, and reptiles. The neocortex, although particularly large and complex in humans, is clearly the same organ found in other mammals.

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Comparative Brain Evolution In a vertebrate embryo, the nervous system begins as a sheet of cells. This sheet folds into a hollow tube and develops into three regions— forebrain, midbrain, and hindbrain—which are recognizable as a series of three enlargements at the end of the embryonic spinal cord (Figure 2-14A). The adult brain of a fish, an amphibian, or a reptile is roughly equivalent to this three-part brain. The prosencephalon (front brain) is responsible for olfaction, the sense of smell; the mesencephalon (middle brain) is the seat of vision and hearing; and the rhombencephalon (hindbrain) controls movement and balance. The spinal cord is part of the hindbrain.

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FIGURE 2-14 Comparative Brain Evolution and Development As the mammalian brain has evolved, the forebrain has expanded dramatically.

In mammalian embryos (Figure 2-14B), the prosencephalon develops further to form the subcortical structures known collectively as the diencephalon (between brain) and the cerebral hemispheres and cortical areas, or telencephalon (endbrain). The mammalian hindbrain

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develops further into the metencephalon (across brain), which includes the cerebellum, and the myelencephalon (spinal brain), including the spinal cord. The human brain is particularly complex, possessing especially large cerebral hemispheres but retaining most other mammalian brain features (Figure 2-14C). Various human cerebral areas necessary to produce language—regions in the frontal, temporal, and parietal lobes —are proportionally larger compared to the brains of other primates. Language is thought to have fostered a novel worldview—in the way we think, reflect on our own thoughts, and imagine.

The Nervous System and Intelligent Behavior Most behaviors are the product not of a single locus in the brain but rather of many interacting brain areas and levels. These several nervous system regions do not simply replicate function; rather, each region adds a different dimension to the behavior. This hierarchical organization affects virtually every human behavior. Abnormalities associated with brain injury and brain disease that seem bizarre in isolation are but the normal manifestation of parts of a hierarchically organized brain. Our evolutionary history, our developmental history, and our own personal history are integrated at the various anatomical and functional levels of the nervous system. Principle 6: Brain systems are organized hierarchically and in parallel.

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Is the vertebrate nervous system the only path to evolving intelligent behavior? Invertebrate animals, such as the octopus, have traveled on an evolutionary pathway separate from that of vertebrates for over 700 million years. The octopus nervous system, while strikingly different from ours, is complex. Might the octopus learn much as vertebrate animals do? Italian biologists Graziano Fiorito and Pietro Scotto (1992) placed individuals of Octopus vulgaris (the common octopus) in separate tanks, each with an independent water supply, and allowed them to interact visually for 2 hours. As illustrated in the Procedure section of Experiment 2-1, the observer octopus watched the demonstrator octopus from an adjacent tank through a transparent wall. The demonstrator was being conditioned to learn that a red ball was associated with a reward, whereas a white ball was associated with a weak electric shock. EXPERIMENT 2-1

Question: Does intelligent behavior require a vertebrate nervous system organization? Procedure

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Results

1. The demonstrator animal quickly learned to distinguish between the colored balls. 2. When placed in isolation and tested later, the observer animals selected the same object as the demonstrators, responded faster, and performed the task correctly for 5 days without significant error. Conclusion: Invertebrates display intelligent behavior, such as learning by observation. Research from Fiorito & Scotto (1992).

As noted in the Results section, the demonstrator animals quickly learned to distinguish between the colored balls. The observers were then placed in isolation. When tested later, they selected the same object the demonstrators had, responded faster than the demonstrators did

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during their conditioning, and performed the task correctly for 5 days without significant error or further conditioning.

2-2 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. The brains of vertebrate animals have evolved into three regions: , , and . 2. The functional levels of the nervous system interact, each region contributing different aspects, or dimensions, to produce . 3. In a brief paragraph, explain how the evolution of the forebrain in mammals reinforces the principle that the CNS functions on multiple levels.

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2-3 The Central Nervous System: Mediating Behavior When we look under the hood of a car, we can make some pretty good guesses about what certain parts of a car engine do. For example, the battery must provide electrical power to run the radio and lights, and, because a battery has to be charged, the engine must contain some mechanism for charging it. We can use a similar approach to deduce how the parts of the brain function. The part connected to the optic nerve coming from each eye must have something to do with vision. Structures connected to the auditory nerve coming from each ear must have something to do with hearing. From such simple observations, we can begin to understand how the brain is organized. The real test comes when analyzing actual brain function: how this seeming jumble of parts produces experiences as complex as human thought. The place to start is the brain’s functional anatomy; learning the name of a particular CNS structure is pointless without also learning something about what it does. We focus now on the names and functions of the three major CNS components: spinal cord, brainstem, and forebrain.

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Although the brain’s principal function is to produce movement, ultimately the spinal cord, with its connections to muscles, executes most of those body movements, usually following instructions from the brain but at times acting independently via the somatic nervous system. To understand how important the spinal cord is, think of the old saying “running around like a chicken with its head cut off.” When a chicken’s head is lopped off, the chicken is still capable of running around the barnyard until it collapses from loss of blood. The chicken accomplishes this feat because the spinal cord is acting independently of the brain. Grasping the spinal cord’s complexity is easier once you realize that it is not a single structure but rather a set of segmented switching stations. As detailed in Section 2-4, each spinal segment receives information from a discrete part of the body and sends out commands to that area. Spinal nerves, which are part of the SNS, carry sensory information to the cord from the skin, muscles, and related structures and, in turn, send motor instructions to control each muscle. You can demonstrate movement controlled by the spinal cord in your own body by tapping your patellar tendon, just below your kneecap (the patella), as shown in Figure 2-15. The sensory input causes your lower leg to kick out, and try as you might, it is very hard to prevent the movement. Your brain, in other words, has trouble inhibiting this spinal reflex: it is automatic.

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FIGURE 2-15 Spinal Reflex Reflexes are explained in Section 11-4.

Brainstem Here’s a trick to help you remember the difference: alphabetically, afferent comes before efferent; sensory signals enter the brain before an outgoing signal results in a motor response.

The brainstem begins where the spinal cord enters the skull and extends upward into the lower areas of the forebrain. The brainstem receives afferent signals coming in from all of the body’s senses, and it sends efferent signals out to the spinal cord to control virtually all of the body’s movements except the most complex movements of the fingers and toes. The brainstem, then, both creates a sensory world and directs movements. In some vertebrates, such as frogs, the entire brain is largely equivalent to the mammalian or avian brainstem. And frogs get along quite well, demonstrating that the brainstem is a fairly sophisticated piece of machinery. If we had only a brainstem, we would still be able to construct a world, but it would be a far simpler sensorimotor world, more like the world a frog experiences. The brainstem, which is responsible for most life-sustaining behavior, can be divided into three regions: hindbrain, midbrain, and diencephalon (which means “between brain,” referring to the fact that it borders the brain’s upper and lower parts). In fact, the betweenbrain status of the diencephalon has been controversial: some 235

anatomists place it in the brainstem, and others place it in the forebrain. Figure 2-16A illustrates the location of these three brainstem regions under the cerebral hemispheres. Figure 2-16B compares the shape of the brainstem regions to the lower part of your arm when held upright. The hindbrain is long and thick like your forearm, the midbrain is short and compact like your wrist, and the diencephalon at the end is bulbous like a fist.

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FIGURE 2-16 Brainstem Structures (A) The medial view shows the relationship of the brainstem to the cerebral hemispheres. (B) The shapes and relative sizes of the brainstem’s three parts are analogous to your fist, wrist, and forearm.

Principle 7: Sensory and motor divisions permeate the nervous system.

The hindbrain and midbrain are essentially extensions of the spinal cord; they developed first as vertebrate animals evolved a brain at the anterior end of the body. It makes sense, therefore, that these lower brainstem regions should retain a division between structures having sensory functions and those having motor functions, with sensory structures lying dorsal and motor ones ventral, or in upright humans, posterior and anterior. Each brainstem region performs more than a single task, and each contains various groupings of nuclei that serve various purposes. In fact, all three regions have both sensory and motor functions. However, the hindbrain is especially important in motor functions, the midbrain in sensory functions, and the diencephalon in integrative sensorimotor tasks. Here, we consider the central functions of these three regions; later chapters contain more detailed information about them.

Hindbrain The hindbrain controls motor functions ranging from breathing to balance to fine movements, such as those used in dancing. Its most distinctive structure, and one of the largest in the human brain, is the

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cerebellum. Its relative size increases with the physical speed and dexterity of a species, as shown in Figure 2-17A.

FIGURE 2-17 The Cerebellum and Movement (A) Their relatively large cerebellum enables finely coordinated movements such as flying and landing in birds and pouncing on prey in cats. Slow-moving animals such as the sloth have a smaller cerebellum relative to brain size. (B) Like the cerebrum, the human

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cerebellum has left and right hemispheres, an extensively folded cortex with gray and white matter, and subcortical nuclei.

Animals that move relatively slowly (such as a sloth) have a relatively small cerebellum for their body size. Animals that can perform rapid acrobatic movements (such as a hawk or a cat) have a very large cerebellum relative to overall brain size. The human cerebellum, which resembles a cauliflower in the medial view in Figure 2-17B, likewise is important in controlling complex movements. But cerebellar size in humans is also related to cognitive capacity. Relative to other mammals, apes show an expansion of the cerebellum that correlates with increased capacity for planning and executing complex behavioral sequences, including tool use and language (see Barton, 2012). As we look beyond the cerebellum at the rest of the hindbrain, shown in Figure 2-18, we find three subparts: the reticular formation, the pons, and the medulla. Extending the length of the entire brainstem at its core, the reticular formation is a netlike mixture of neurons (gray matter) and nerve fibers (white matter). This nerve net gives the structure the mottled appearance from which its name derives (from Latin rete, meaning “net”). The reticular formation’s nuclei are localized into small patches along its length. Each has a special function in stimulating the forebrain, such as in waking from sleep.

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FIGURE 2-18 Hindbrain The principal hindbrain structures integrate voluntary and involuntary body movements. The reticular formation is sometimes called the reticular activating system.

The pons and medulla contain substructures that control many vital body movements. Nuclei in the pons receive inputs from the cerebellum and actually form a bridge from it to the rest of the brain (in Latin, pons means “bridge”). At the rostral tip of the spinal cord, the medulla’s nuclei regulate such vital functions as breathing and the cardiovascular system. For this reason, a blow to the back of the head can kill you: your breathing stops if the hindbrain control centers are injured.

Midbrain In the midbrain, a sensory component called the tectum (roof) is dorsal (posterior in upright humans), whereas a motor structure called the tegmentum (floor) is ventral (anterior in humans; Figure 2-19A).

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The tectum receives a massive amount of sensory information from the eyes and ears. The optic nerve sends a large bundle of fibers to the superior colliculus, whereas the inferior colliculus receives much of its input from auditory pathways. The colliculi function not only to process sensory information but also to produce orienting movements related to sensory inputs, such as turning your head to see a sound’s source.

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FIGURE 2-19 Midbrain (A) Structures in the midbrain are critical for producing orienting movements, species-specific behaviors, and pain perception. (B) The tegmentum in cross section, revealing various nuclei. Colliculus comes from collis, Latin for “hill.” The colliculi resemble four little hills on the midbrain’s posterior surface.

This orienting behavior is not as simple as it may seem. To produce it, the auditory and visual systems must share a map of the external world so that the ears can tell the eyes where to look. If the auditory and visual maps differed, it would be impossible to use the two together. In fact, the colliculi also have a tactile map. After all, if you want to look at what’s making your leg itch, your visual and tactile systems need a common representation of where that place is so you can scratch the itch by moving your arm and hand. Lying ventral to the tectum, the tegmentum (shown in Figure 219B in cross section) is composed of many nuclei, largely with movement-related functions. Several tegmental nuclei control eye movements. The red nucleus controls limb movements (and is absent in snakes). The substantia nigra connects to the forebrain, a connection especially important in initiating movements. (Clinical Focus 5-2 explains that the symptoms of Parkinson disease are related to the destruction of the substantia nigra.) The periaqueductal gray matter (PAG), made up of cell bodies that surround the aqueduct joining the third and fourth ventricles, contains circuits that control species-typical behaviors (e.g., female sexual behavior). These nuclei also play an important role in how opioid drugs can modulate pain.

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The diencephalon, shown in sagittal section in the center of Figure 2-20, integrates sensory and motor information on its way to the cerebral cortex. Its two principal structures are the hypothalamus and the thalamus. The thalamus—one in each hemisphere—lies just to the left of the brainstem’s tip, and the hypothalamus (in Latin, hypo means “below”) lies below the thalamus in each hemisphere.

FIGURE 2-20 Diencephalon The diencephalon (center) is composed of the epithalamus, which includes the pineal gland, the thalamus (shown at right), the hypothalamus (the posterior portion of the pituitary gland, shown at left), and the subthalamus. Thalamic regions connect to discrete cortical regions. Below the thalamus, at the base of the brain, the hypothalamus (in Latin, hypo means “below”) and pituitary lie above the roof of the mouth. The hypothalamus is composed of many nuclei, each with distinct functions.

Principle 8: The brain divides sensory input for object recognition and movement.

The hypothalamus in each hemisphere lies along the brain’s midline; it is composed of about 22 small nuclei and the nerve fiber systems that pass through it. Its critical function is to control the body’s production of hormones, accomplished via its interactions with the pituitary gland, shown at left in Figure 2-20. Although it constitutes only about 0.3 percent of the brain’s weight, the 243

hypothalamus takes part in nearly all aspects of behavior, including feeding, sleeping, temperature regulation, sexual and emotional behavior, hormone function, and movement. The hypothalamus is organized and functions more or less similarly across mammals. But sex differences have been found in the structures of some of its parts, in some species, probably due to differences between males and females in activities such as sexual behavior and parenting. We examine how thalamic sensory nuclei process incoming information in Sections 9-2, 10-2, 11-4, and 12-2 and look at memory pathways in Section 14-3.

The other principal structure of the diencephalon, the thalamus, is much larger than the hypothalamus, as are its 20-odd nuclei. Perhaps the most distinctive thalamic function is its role as an organizer and integrator of sensory information traveling to the cerebral cortex from all sensory systems. The optic tract, for example, sends information through a large fiber bundle to a thalamic region called the lateral geniculate nucleus (LGN), shown at the right tip of the thalamus in Figure 2-20. In turn, the LGN processes some of this information and then sends it to the visual region in the occipital lobe in each hemisphere. The routes to the thalamus may be indirect. For example, the route for olfaction traverses several synapses before entering the dorsomedial thalamic nucleus on its way to the forebrain. This nucleus, which projects to the frontal lobe, performs integrative tasks and thus plays a vital role in attention, planning, abstract thinking,

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and memory. Analogous sensory regions of the thalamus receive auditory and tactile information, which is subsequently relayed to the respective auditory and tactile cortical regions in each hemisphere. Other thalamic regions have motor functions, as they receive input from those regions where decisions about possible movements are made, and, in turn, relay information to movement planning areas in the neocortex.

Forebrain The largest and most recently evolved region of the mammalian brain is the forebrain. Its major internal and external structures are shown in Figure 2-21. Each of its two principal structures has multiple functions. To summarize briefly, the cerebral cortex regulates a host of mental activities ranging from perception to planning to emotions and memory; the basal ganglia control voluntary movement and also have a role in cognitive functioning.

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FIGURE 2-21 Forebrain Structures The major internal and external forebrain structures integrate sensation, motivation, emotion, and memory to enable such advanced cognitive functions as thinking, planning, and using language.

Extending our analogy between the brainstem and your forearm, imagine that the fist (the diencephalon) is thrust inside a watermelon —the forebrain, with the neocortex as the rind and the allocortex and basal ganglia as the fruit inside. Just as watermelons come in various

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sizes, so do brains, which in a sense is what evolution has done: the forebrain varies considerably in size across species.

Cerebral Cortex The forebrain contains the cerebral cortex (“bark”) which can be viewed as concentric rings of three-layered cortex, four-layered cortex, and six-layered cortex. For simplicity, we use the name allocortex (literally, “other bark”) to refer to both the three- and fourlayered cortex. Found in the brains of other chordates (including birds, reptiles, and mammals), the allocortex plays a role in controlling motivational and emotional states as well as in certain forms of memory. The six-layered neocortex (literally, “new bark”) is the tissue visible when we view the brain from the outside, as in Figure 2-5. The more recently expanded neocortex is unique to mammals; its primary function is to construct a perceptual world and respond to that world. Although the neocortex and allocortex have anatomical and functional differences, most neuroscientists usually refer to both types of tissue simply as cortex. Measured by volume, the cortex makes up most of the forebrain, constituting 80 percent of the human brain overall. It is the brain region that has expanded the most in the course of mammalian evolution. The human neocortex has a surface area as large as 2500 square centimeters but a thickness of only 2.3 to 2.8 millimeters, an area equivalent to about four printed pages of this book. By contrast, a chimpanzee has a cortical area equivalent to about one page. See Figure 2-22.

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FIGURE 2-22 Three Primate Brains The brains of a Rhesus monkey, chimpanzee, and human, shown here to scale, differ dramatically in size and in surface appearance. With an encephalization quotient of 2.0, the Rhesus monkey’s brain is just over one-quarter the size of a human’s (EQ 7.0). The chimp’s brain, EQ 2.5, is a bit more than one-third as large (see Figure 1-15).

The pattern of sulci and gyri formed by the folding of the neocortex varies across species. Smaller-brained mammals, such as rats and mice, have no sulci or gyri and thus have a smooth, or lissencephalic, brain. Larger-brained mammals, including carnivores such as cats, have gyri that form a longitudinal pattern. In primates, the sulci and gyri form a more complex pattern. These gyrencephalic brains are the result of a relatively large neocortical sheet repeatedly folded in upon itself so that it fits into the restricted space of the skull.

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The allocortex is composed of several distinct three- and four-layer structures that include the hippocampus, part of the amygdala, the cingulate cortex, several structures that make up the olfactory system, and other related areas. The hippocampus together with its dentate gyrus look astoundingly like a seahorse, and its name comes from the Greek meaning “seahorse” (see the comparison in Figure 2-23). It is involved in consolidation, the process whereby short-term memories are solidified into long-term memories. Destruction of the hippocampus leads to problems with navigation, finding our way around, as well as difficulties with word finding.

FIGURE 2-23 Hippocampi Dissected human hippocampus (left) named after a seahorse (right).

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The amygdala (meaning “almond”) plays a critical role in anxiety and fear. Removal of the amygdala produces truly startling changes in emotional behavior. A cat with its amygdala removed will wander through a colony of monkeys, completely undisturbed by their hooting and threats. No self-respecting, normally functioning cat would be caught anywhere near such bedlam. The cingulate cortex lies above the corpus callosum, close to the midline. It is involved with emotion formation and processing, learning, and memory, and it is highly influential in linking behavioral outcomes to motivation.

All sorts of behaviors can prove addictive—eating, shopping, sex, video gaming, gambling, even Twitter! How else to explain these Canadian coeds tweeting all bundled up when they could be defrosting on the beach in the Florida sun?

THE CONCEPT OF THE LIMBIC SYSTEM The concept of a limbic system has a long and controversial history in neuroscience. In the 1930s, psychiatry was dominated by the 250

theories of Sigmund Freud, who emphasized the roles of sexuality and emotion in human behavior. At the time, the brain regions controlling these behaviors had not yet been identified; coincidentally, the border, or limbus, of the brain—that area between the subcortical nuclei of the brainstem and the neocortex, which the astute reader will recognize as allocortex—had no known function. It was a simple step to thinking that perhaps the limbic structures played a central role in sexuality and emotion. For more on motivation and emotion, see Sections 12-3 and 12-4; memory, Section 14-3; and brain disorders, Research Focus 16-1 and Section 16-4.

One issue with the limbic system concept is that neuroscientists have never agreed on what anatomical structures should be considered part of it. Another issue is that the original view that the limbic system was the emotional center and the neocortex was the home of cognition doesn’t work because cognition depends on acquisition and retention of memories—and the hippocampus, an allocortical structure, plays a primary role in those functions. Thus, several neuroscientists have argued that the term limbic system be abandoned because it is obsolete. A more recent view is that specific circuits for specific functions can be traced through several allocortical, neocortical, and brainstem structures.

OLFACTORY SYSTEM At the very front of the brain lie the olfactory bulbs, the organs

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Section 12-2 considers the chemical senses smell and taste in the context of emotional and motivated behavior.

responsible for detecting odors and providing input to other brain areas responsible for our perception of smell. The olfactory system is unique among human senses, as Figure 2-24 shows, because it is almost entirely a forebrain structure. The other sensory systems project most of their inputs from the sensory receptors to the midbrain and thalamus. Olfactory input takes a less direct route: the olfactory bulb sends most of its inputs to a specialized region, the pyriform cortex, which is also part of the allocortex, on the brain’s ventral surface. From there, sensory input progresses to the amygdala and the dorsomedial thalamus (see Figure 2-20, right), which routes it to the frontal cortex.

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FIGURE 2-24 Sense of Smell Our small olfactory bulbs lie at the base of the forebrain, connect to receptor cells that lie in the nasal cavity, and send most of this input to the pyriform cortex en route to the amygdala and thalamus.

Smell is one of the first senses to have evolved in animals, yet curiously, the olfactory system lies at the front of the human brain and is considered part of the forebrain (see the ventral view in Figure 26B). The olfactory bulbs lie near the olfactory receptors in the nasal cavity. Although evolution has led to these organs sending their inputs to the pyriform cortex in mammals, their input to the brainstem is more direct in simpler brains. Compared with the olfactory bulbs of rats, cats, and dogs, which rely more heavily on smell than we do, the human olfactory bulb is 253

relatively small. Nonetheless, it is very sensitive, allowing us to distinguish a surprisingly large number of odors. Smell plays an important role in various aspects of our feeding and sexual behavior. The vomeronasal organ (VNO) contains sensory neurons that detect pheromones, molecules that carry information between individuals of the same species. The axons from these neurons project to the accessory olfactory bulb, which connects to the amygdala and in turn the hypothalamus. The VNO has an important role in reproduction and social behavior in many mammals, but its presence and functionality in humans is controversial.

Neocortical Layers In the neocortex, six layers of gray matter sit atop the corpus callosum, the white matter structure that is composed of neocortical axons and joins the two cerebral hemispheres. The six layers of the neocortex have distinct characteristics: Different layers have different types of cells. The cell density varies from layer to layer, ranging from virtually no cells in layer I (the top layer) to very dense cell packing in layer IV (Figure 2-25). Other differences in appearance are both regional and functional.

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FIGURE 2-25 Neocortical Layering Layer IV is relatively thick in the sensory cortex and relatively thin in the motor cortex. This is because abundant afferent sensory information from the thalamus connects to layer IV. Conversely, layers V and VI are relatively thick in the motor neocortex and thin in the sensory neocortex. Efferent motor information in layer V makes up the corticospinal track, connecting the motor neocortex to the spinal cord to generate movement, and layer VI connects to other cortical areas.

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These visible differences led neuroanatomists to map the neocortex a century ago. In 1909, Korbinian Brodmann published the map shown in Figure 2-26. Based on cytology, the study of cell characteristics, these maps are called cytoarchitectonic maps. For example, viewed through a microscope, sensory neocortex in the parietal lobe (shown in red in Figure 2-25) has a large layer IV, and motor cortex in the frontal lobe (shown in blue in Figure 2-25) has a large layer V. Layer IV is afferent; layer V is efferent. It makes sense that a sensory region has a large input layer, whereas a motor region has a large output layer.

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FIGURE 2-26 Early Brain Map In his cytoarchitectonic map of the neocortex, Brodmann (1909) defined areas by the organization and characteristics of the cells he examined. The regions shown in color are associated with the simplest sensory perceptions: touch (red), vision (purple), and hearing (orange). As we shall see, the neocortical areas that process sensory information are far more extensive than Brodmann’s basic areas.

Cortex is often used as shorthand for the neocortex or neocortical layers. However, cortex may refer to any and all layered structures in the forebrain. In this book, we use the terms neocortex and allocortex only when making a distinction between those structures.

Staining neocortical tissue can reveal chemical differences between cells and layers. Some regions are rich in one chemical, others rich in another. These differences presumably relate to functional specialization of different neocortical areas. The one significant difference between the organization of the neocortex and the organization of other brain parts is its range of connections. Unlike most structures, which connect only to certain brain regions, the neocortex is connected to virtually all other parts of the brain. The neocortex, in other words, is the ultimate meddler. It takes part in everything—a fact that not only makes it difficult to identify specific neocortical functions but also complicates our study of the rest of the brain because we must always consider the neocortex’s role in other brain regions. Consider your perception of clouds. You have no doubt gazed up at clouds on a summer day and imagined sailing ships, elephants, 257

faces, and countless other objects. Although a cloud does not really look like an elephant, you can concoct an image of one if you impose your frontal cortex—that is, your imagination—on the sensory inputs. This kind of cortical activity is top-down processing because the top level of the nervous system, the neocortex, is influencing how information is processed in lower regions of the hierarchy—in this case, the midbrain and hindbrain. The neocortex influences many behaviors besides object perception. It influences our cravings for foods, our lust for things (or people), and how we interpret the meaning of abstract concepts, words, and images. The neocortex ultimately creates our reality, and one reason it serves this function is that it is so well connected.

Cortical Lobes To review, the human cortex consists of the nearly symmetrical left and right hemispheres, which are separated by the longitudinal fissure, shown at left in Figure 2-27. As shown at right, each hemisphere is subdivided into four lobes corresponding to the skull bones overlying them: frontal, parietal, temporal, and occipital. Unfortunately, bone location and brain function are unrelated. As a result, the cortical lobes are rather arbitrarily defined anatomical regions that include many functional zones.

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FIGURE 2-27 Cortical Boundaries

Principle 9: Brain functions are localized and distributed.

Neverthe less, we can attach some

gross functions to each lobe. The frontal lobe is sometimes called the brain’s executive because it integrates sensory and motor functions, formulates plans of action, and contains the primary motor cortex. The three posterior lobes have sensory functions: the parietal lobe is tactile; the temporal lobe is visual, auditory, and gustatory; and the occipital lobe is visual. We can also predict some effects of injuries to each lobe: Individuals with frontal lobe injuries may have difficulty organizing and evaluating their ongoing behavior, as well as planning for the future. Injuries to the parietal lobe make it difficult to identify or locate stimulation on the skin and may contribute to deficits in moving the arms and hands to points in space.

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Temporal lobe injuries result in difficulty recognizing sounds, although, unlike people with occipital injuries, those with temporal injury can still recognize that they are hearing something. Temporal lobe injuries can also cause difficulties in processing complex visual information, such as faces. People with an injured occipital lobe have deficits in processing visual information. Although they may perceive light versus dark, for example, they may be unable to identify either the shape or the color of objects. Anatomical features presented in Section 9-2 define occipital lobe boundaries.

Fissures and sulci often establish the boundaries of cortical lobes (Figure 2-27, right). For instance, in humans, the central sulcus and lateral fissure form the boundaries of each frontal lobe, as well as the boundaries of each parietal lobe lying posterior to the central sulcus. The lateral fissure demarcates each temporal lobe, forming its dorsal boundary. The occipital lobes are not so clearly separated from the parietal and temporal lobes because no large fissure marks their boundaries.

Basal Ganglia The basal ganglia, a collection of nuclei that lie in the forebrain just below the white matter of the cortex, consist of three principal structures: the caudate nucleus, the putamen, and the globus pallidus, all shown in Figure 2-28. Together with the thalamus and two closely associated nuclei (the substantia nigra and subthalamic nucleus), the 260

basal ganglia form a system that functions primarily to control voluntary movement.

FIGURE 2-28 Basal Ganglia A coronal section through the cerebral hemispheres reveals a frontal view of the basal ganglia relative to surrounding forebrain structures. Two associated structures that are likewise instrumental in controlling and coordinating movement, the substantia nigra and subthalamic nucleus, are also shown.

We can observe the functions of the basal ganglia by analyzing the behavior resulting from the many diseases that interfere with their healthy functioning. Parkinson disease, a motor system disorder characterized by severe tremors, muscular rigidity, and a reduction in voluntary movement, is among the most common movement disorders among the elderly. People with Parkinsonism take short, shuffling steps; display bent posture; and may need a walker to get around. Many have almost continuous hand tremors and sometimes head tremors as well. Another disorder of the basal ganglia is Tourette syndrome, characterized by various motor tics; involuntary vocalizations (sometimes including curse words and grunting 261

sounds); and odd, involuntary body movements, especially of the face and head. Details on Parkinson disease appear in Clinical Focuses 5-2, 5-3, and 54, as well as Sections 11-3 and 16-3. Clinical Focus 11-4 details Tourette syndrome.

Neither Parkinsonism nor Tourette syndrome is a disorder of producing movements, as in paralysis. Rather, they are disorders of controlling movements. The basal ganglia, therefore, must play a critical role in controlling and coordinating movement patterns rather than in activating the muscles to move.

2-3 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. The three functionally distinct sections of the CNS—spinal cord, brainstem, and forebrain—represent the evolution of multiple . 2. The can perceive sensations from the skin and muscles and produce movements independent of the brain. 3. The brainstem includes three functional regions. The is an extension of the spinal cord; the is the first brain region to receive sensory inputs; and the integrates sensory and motor information on its way to the cerebral cortex. 262

4. The coordinates fine motor movements and various cognitive functions. 5. The forebrain’s subcortical regions include the which control voluntary movement, and the which controls mood, motivation, and some forms of memory.

, ,

6. The two types of cerebral cortex are the three- and fourlayered and the , which features six layers that vary in density to perform , , and functions. 7. Briefly describe the functions performed by the forebrain.

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2-4 Somatic Nervous System: Transmitting Information The SNS is monitored and controlled by the CNS—the cranial nerves by the brain and the spinal nerves by the spinal cord segments.

Cranial Nerves The linkages provided by the cranial nerves between the brain and various parts of the head and neck as well as various internal organs are illustrated and tabulated in Figure 2-29. Cranial nerves can have afferent functions, such as sensory inputs to the brain from the eyes, ears, mouth, and nose, or they can have efferent functions, such as motor control of the facial muscles, tongue, and eyes. Some cranial nerves have both sensory and motor functions, such as modulation of both sensation and movement in the face.

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FIGURE 2-29 Cranial Nerves Each of the 12 pairs of cranial nerves has a different function. A common mnemonic device for learning the order of the cranial nerves is “On Old Olympus’s Towering Top, A Finn and German View Some Hops.” The first letter of each word is, in order, the first letter of the name of each nerve.

The 12 pairs of cranial nerves are known both by their numbers and by their names, as listed in Figure 2-29. One set of 12 controls the left

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side of the head, whereas the other set controls the right side. This arrangement makes sense for innervating duplicated parts of the head (such as the eyes), but why separate nerves should control the right and left sides of a singular structure (such as the tongue) is not so clear. Yet that is how the cranial nerves work. If you have ever received lidocaine (often called Novocaine) for dental work, you know that when the dentist injects the drug into the gums on one side of your mouth, the same side of your tongue also becomes numb. The rest of the skin and muscles on each side of the head are similarly controlled by cranial nerves located on the same side. Cranial nerve

Name

Function

Olfactory

Smell

Optic

Vision

Oculomotor

Eye movement

Trochlear

Eye movement

Trigeminal

Masticatory movements and facial sensation

Abducens

Eye movement

Facial

Facial movement and sensation

Auditory vestibular

Hearing and balance

Glossopharyngeal

Tongue and pharynx movement and sensation

Vagus

Heart, blood vessels, viscera, movement of larynx and

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pharynx 11

Spinal accessory

Neck movement

Hypoglossal

Tongue movement

In later chapters, we consider many cranial nerves in detail in discussions on vision, hearing, olfaction, taste, and stress responses. For now, you simply need to know that cranial nerves form part of the SNS, providing inputs to the brain from the head’s sensory organs and muscles and controlling head and facial movements. Some cranial nerves also contribute to maintaining autonomic functions by connecting the brain and internal organs (the vagus, cranial nerve 10) and by influencing other autonomic responses, such as salivation.

Spinal Nerves For the optic nerve, see Section 9-2; auditory nerve, Section 10-2; and olfactory nerve, Section 12-2.

The spinal cord lies inside the bony spinal column, which is made up of a series of small bones called vertebrae (sing. vertebra), categorized into five anatomical regions from top to bottom: cervical, thoracic, lumbar, sacral, and coccygeal, as diagrammed in Figure 2-30A. You can think of each vertebra in these five groups as a short segment of the spinal column. The corresponding spinal cord segment in each vertebral region functions as that segment’s minibrain.

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FIGURE 2-30 Spinal Segments and Dermatomes (A) Medial view showing the five spinal cord segments: cervical (C), thoracic (T), lumbar (L), sacral (S), and coccygeal. (B) Each segment corresponds to a region of body surface (a dermatome) identified by the segment number (e.g., C5 at the base of the neck and L2 in the lower back).

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This arrangement may seem a bit odd, but it has a long evolutionary history. Think of a simpler animal, such as a snake. A snake’s body is a segmented tube. In that tube is another tube, the spinal cord, which also is segmented. Each of the snake’s nervous system segments receives nerve fibers from sensory receptors in the part of the body adjacent to it, and that nervous system segment sends back fibers to the muscles in that body part. Each segment, therefore, works independently. A complication arises in animals such as humans, whose limbs may originate at one spinal segment level, but, because we stand upright, they extend past other segments of the spinal column. Your shoulders, for example, may begin at C5 (cervical segment 5), but your arms hang down well past the sacral segments. So unlike the snake, which has spinal cord segments that connect to body segments fairly directly adjacent to them, the human body’s segments fall schematically into more of a patchwork pattern, as shown in Figure 2-30B. This arrangement makes sense if the arms are extended as they are when we walk on all fours. Sections 11-1 and 11-4 review the spinal cord’s contributions to movement and to somatosensation.

Our body segments correspond to spinal cord segments. Each of these body segments is called a dermatome (meaning “skin cut”). A dermatome has a sensory nerve to send information from the skin, joints, and muscles to the spinal cord, as well as a motor nerve to control the muscle movements in that particular body segment.

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These sensory and motor nerves, known as spinal (or peripheral) nerves, are functionally equivalent to the cranial nerves of the head. Whereas the cranial nerves receive information from sensory receptors in the eyes, ears, facial skin, and so forth, the spinal nerves receive information from sensory receptors in the rest of the body—that is, in the PNS. Similarly, whereas the cranial nerves move the muscles of the eyes, tongue, and face, the peripheral nerves move the muscles of the limbs and trunk.

Somatic Nervous System Connections Like the CNS, the SNS is bilateral (two-sided). Just as the cranial nerves control functions on the side of the head where they are found, the spinal nerves on the left side of the spinal cord control the left side of the body, and those on the right side of the spinal cord control the body’s right side. Figure 2-31A shows the spinal column in cross section. Look first at the nerve fibers entering its posterior side (in red). These posterior fibers (dorsal in four-legged animals) are afferent: they carry in information from the body’s sensory receptors. The fibers gather as they enter a spinal cord segment, and this collection of fibers is called a posterior root in humans (dorsal root in four-legged animals).

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FIGURE 2-31 Spinal Nerve Connections (A) A cross section of the human spinal cord, viewed from the front. The butterfly-shaped inner regions consist of neural cell bodies (gray matter), and the outer regions consist of nerve tracts (white matter) traveling to and from the brain. (B) A posterior view shows the intact human spinal cord exposed.

Sections 11-1 and 11-4 explore spinal cord injuries and treatments; Section 12-3 discusses the link between spinal injury and loss of emotion.

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Fibers leaving the spinal cord’s anterior side (in blue) are efferent, carrying information out from the spinal cord to the muscles. They, too, bundle together as they exit the spinal cord and so form an anterior root (ventral root in four-legged animals). The outer part of the spinal cord, pictured in Figure 2-31B, consists of white matter, or CNS nerve tracts. These tracts are arranged so that, with some exceptions, posterior tracts are sensory, and anterior tracts are motor. The inner part of the cord, which has a butterfly shape, is gray matter composed largely of cell bodies. The law of Bell and Magendie and the condition Bell palsy are both namesakes of Sir Charles Bell—surgeon, neurologist, anatomist, physiologist, artist, and philosophical theologian.

The observation that the posterior/dorsal spinal cord is sensory and the anterior/ventral side is motor in vertebrates, including humans, is one of the nervous system’s very few established laws, the law of Bell and Magendie. Combined with an understanding of the spinal cord’s segmental organization, this law enables neurologists to make accurate inferences about the location of spinal cord damage or disease on the basis of changes in sensation or movement. For instance, if a person has numbness in the fingers of the left hand but can still move the hand fairly normally, one or more of the posterior (dorsal) nerves in spinal cord segments C7 and C8 must be damaged. In contrast, if sensation in the hand is normal but the person cannot move the fingers, the anterior (ventral) roots of the same segments must be damaged. Clinical Focus 2-4, Bell Palsy, further explores the loss of motor function.

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Integrating Spinal Functions So far we have emphasized the spinal cord’s segmental organization, but the spinal cord must also somehow coordinate inputs and outputs across different segments. For example, many body movements require coordinating muscles controlled by different segments, just as many sensory experiences require coordinating sensory inputs to different parts of the spinal cord. How is this coordination accomplished? The answer is that the spinal cord segments are interconnected in such a way that adjacent segments can operate together to direct rather complex coordinated movements. Integrating spinal cord activities does not require the brain’s participation, which is why the headless chicken can run around. Still, a close working relationship must exist between the brain and the spinal cord. Otherwise, how could we consciously plan and execute our voluntary actions? Somehow, information must be relayed back and forth, and examples of this information sharing are numerous. For instance, tactile information from sensory nerves in the skin travels not just to the spinal cord but also to the cerebral cortex through the thalamus. Similarly, the cerebral cortex and other brain structures can control movements through their connections to the spinal cord’s anterior roots. So even though the brain and spinal cord can function independently, the two are intimately connected in their CNS functions.

CLINICAL FOCUS 2-4

Bell Palsy 273

C.T. woke up one morning and proceeded with his routine. He sat at the kitchen table in front of the daily newspaper and began to eat his breakfast cereal. The cereal and milk fell out of his mouth. He cleaned it up and tried again with the same result. He then looked in a mirror and discovered the left side of his face was completely paralyzed. He couldn’t move his left eyebrow or left smile muscles or any other expressive muscles on the left side of his face. He couldn’t wink with the left eye but could close both eyes. Sensation from the left side felt normal, and the sensation and movement of the right side of his face was completely normal. He immediately sought medical attention. C.T., a neuroscientist, figured he had Bell palsy, which his family doctor confirmed.

(A) Relaxed face. Strong muscles on the right side of the face pull the nose to the right, while paralyzed muscles on the left side do not pull back. (B) An attempt to smile and raise both eyebrows is achieved on the right side of the face but fails on the paralyzed left side. (C) An attempt to frown and lower both eyebrows is achieved on the right side of the face but fails on the paralyzed left side.

Bell palsy is diagnosed by exclusion. Many factors can cause facial paralysis, and they need to be ruled out one by one. C.T. underwent blood tests to rule out diabetes and Lyme disease, a neurological exam to rule out stroke, and a CT scan to rule out tumor. Bell palsy is caused by inflammation of the facial (7th) nerve, probably brought on by a virus or some other inflammatory agent. The 7th nerve travels through the longest boney canal in the body: the fallopian canal. Nerves swell when inflamed, but when constricted by the confines of a boney canal, pressure on the nerve stops them from functioning—hence the

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paralysis. If the pressure continues unabated for more than 3 weeks, the axons all die. The primary treatment is to reduce inflammation. For the first 2 weeks after the abrupt onset, C.T. had complete paralysis on the left side of his face. He taped his left eye shut at night to prevent it from drying out and damaging his cornea. His speech was slurred, and he didn’t really sound like himself. The muscles of the right side of his face pulled the left side, giving him an asymmetric look (see the accompanying photographs). Eating was a challenge. Drinking was made easy with a straw. At about the 2-week mark, to his great relief, he started to regain some minimal movement in his left eyebrow. As the weeks went by, he was able to move more and more of the left side of his face. By the sixth week, his friends and colleagues said he looked and sounded like himself again, yet he still had about 40% paralysis of the left side. Bell palsy afflicts about 1 in 65 people at some time in their life. While most people, including C.T., fully recover, a small percentage will have some permanent paralysis, which can profoundly affect their lives. Smiling is an important social signal; when it is impaired, people interpret this as disapproval. This can lead to social isolation, which itself can lead to psychological problems.

2-4 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. Two sets of SNS nerves, the and the , receive sensory information or send motor signals to muscles or both. 2. Both sets of SNS nerves are symmetrically organized, and each set controls functions on the side of the body.

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3. The cranial nerves have both sensory and motor functions, receiving and sending information to the and to the . 4. Define the law of Bell and Magendie and explain why it is important.

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2-5 Autonomic and Enteric Nervous Systems: Visceral Relations Control of the viscera (internal organs), including the heart, gut, liver, and lungs, requires complex neural systems. Yet the ANS and ENS are hidden partners, functioning in the background as the CNS controls our perceptions and behaviors. If we had to focus consciously on visceral activities, we might do little else. The ANS and ENS interact with the CNS, but each has distinctive anatomy and functions.

ANS: Regulating Internal Functions Without our conscious awareness, the ANS stays on the job to keep the heart beating, the liver releasing glucose, the pupils of the eyes adjusting to light, and so forth. Without the ANS, which regulates the internal organs and glands via connections through the SNS to the CNS, life would quickly cease. Although learning to exert some conscious control over some of these vegetative activities is possible, such conscious interference is normally unnecessary. An important reason is that the ANS must keep working during sleep, when conscious awareness is off duty. But conscious states, such as stress, can often affect ANS functions, as in the case of a racing or pounding

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heartbeat. Psychological therapies are often effective in reducing stress if such ANS symptoms persist. Section 5-3 explains CNS–ANS communication, Figure 16-22 diagrams the stress response, and Section 16-4 discusses how mood affects reactivity to stress.

It is tempting to think that the ANS’s organization must be pretty simple because it functions outside our conscious awareness. Yet, like the SNS, the ANS also has a surprisingly complex organization. The two ANS divisions work in opposition. The sympathetic division arouses the body for action, for example, by stimulating the heart to beat faster and inhibiting digestion when we exert ourselves during exercise or times of stress—the familiar fight-or-flight response. The parasympathetic division calms the body down, for example, by slowing the heartbeat and stimulating digestion to allow us to rest and digest after exertion and during quiet times. Principle 10: The nervous system works by juxtaposing excitation and inhibition.

Like the SNS, the ANS interacts with the rest of the nervous system, and like the SNS, ANS connections are ipsilateral. Activation of the sympathetic division starts in the thoracic and lumbar spinal cord regions, but the spinal nerves do not directly control the target organs. Rather, the spinal cord is connected to autonomic control centers—collections of neural cells called ganglia. The ganglia

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control the internal organs, and each acts as a minibrain for specific organs. The sympathetic ganglia are near the spinal cord on each side, forming chains that run parallel to the cord, as illustrated at left in Figure 2-32 for one set of ganglia. The parasympathetic division also is connected to the spinal cord—specifically, to the sacral region—but the greater part of it derives from three cranial nerves: the vagus nerve, which calms most of the internal organs, and the facial and oculomotor nerves, which control salivation and pupil dilation, respectively (review Figure 2-29). In contrast with the sympathetic division, the parasympathetic division connects with ganglia that are near the target organs, as shown at right in Figure 2-32.

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FIGURE 2-32 Autonomic Nervous System The two ANS pathways exert opposing effects. All fibers connect at “stops” formed by ganglia en route from the CNS to target ANS organs. Left: Arousing sympathetic fibers connect to a chain of ganglia near the spinal cord. Right: Calming parasympathetic fibers connect to individual ganglia near target organs.

ENS: Controlling the Gut The ENS is often considered part of the ANS, but it functions largely independently. Digestion is complicated, and evolution has provided this dedicated nervous system to control it. Some scientists have even

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proposed that the CNS evolved from the gut of very simple organisms. In fact, the ENS is sometimes called the second brain because, like the CNS, it contains a wide range of neuron types, the same chemical transmitters, a profusion of glial cells, and complex integrated neural circuits. Its estimated 200 million to 500 million neurons roughly equals the number in the spinal cord. The gut reacts to a range of hormones and other chemicals with exquisite neural responses. The ENS functions to control bowel motility, secretion, and blood flow to permit fluid and nutrient absorption and to support waste elimination (see Avetisyan et al., 2015). This is no simple task, given the number and balance of nutrients needed to support the body. ENS neurons are located in a sheet of tissue (plexus) lining the esophagus, stomach, small intestine, and colon. As shown in Figure 2-33, ENS neurons and glia form ganglia connected by nerve fibers found in two layers of gut tissue. The brain and ENS connect extensively through the ANS, especially via the vagus nerve. Although we are not conscious of our gut “thinking,” the ENS sends information directly to the brain—information that affects our mental state—and the brain can modify gut function. Indeed, a growing body of evidence implicates the ENS in many behavioral disorders, and stress and anxiety commonly modify gut function, leading to such symptoms as nausea and diarrhea.

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FIGURE 2-33 Enteric Nervous System The ENS is formed by a network of neurons embedded in the lining of the gastrointestinal tract. Congregations of neurons form ganglia that send projections to the ANS and CNS, in part through the vagus nerve (cranial nerve 10), to control gut function.

The ENS interacts with gut bacteria, known collectively as the 282

Section 12-4 expands on how emotions and the ENS interact, Section 12-5 on the ENS and eating.

microbiome. About 3.9 × 1013 microbiota populate the adult gut, outnumbering the host cells by a factor of 1.3 (Sender et al., 2016). The microbiota influence nutrient absorption and are a source of neurochemicals that regulate an array of physiological and psychological processes. This relationship has inspired the development of a class of compounds known as psychobiotics, live microorganisms used to treat behavioral disorders. Thus, the microbiota can influence both the CNS and ENS, leading to changes in behavior.

2-5 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. The ANS interacts with the CNS and SNS via sets of autonomic control centers called , which act as minibrains to control the internal organs. 2. The division of the ANS arouses the body for action, and the division calms the organs. The two divisions work to allow for quick defensive responses (fight or flight) or to induce a calming (rest and digest) state. 3. Why is the ANS essential to life? 283

4. The ENS is often called a second brain because of the it contains. 5. The ENS interacts with bacteria that form the which absorbs and produces regulate CNS and ENS activity.

, that can

6. What are psychobiotics?

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2-6 Ten Principles of Nervous System Function Knowing the parts of the nervous system and some general notions about what they do is only the beginning. Learning how the parts work together allows us to proceed to a closer look, in the chapters that follow, at how the brain produces behavior. A deeper appreciation of how the nervous system works also comes with an understanding of the principles of CNS organization and function. Throughout this chapter, we have identified 10 principles related to the nervous system’s functioning. Here we elaborate on each one. As you progress through the book, review these ideas regularly with an eye toward understanding the concept rather than simply memorizing the principle. Soon you will find yourself applying the principles of function as you encounter new information about the brain and behavior.

Principle 1: The Nervous System Produces Movement in a Perceptual World the Brain Constructs The nervous system’s fundamental function is to produce movements that make up behaviors. Movements are not made in a vacuum but are related to sensations, memories, and myriad other forces and factors. 285

Your mental representation of the world depends on the information sent to your brain, your previous experiences, and the neural architecture of your nervous system. People who are color-blind perceive the world very differently from those who perceive color. The perceptual world of people who have perfect pitch differs from that of people without perfect pitch. Although we tend to think that the world we perceive is what is actually there, individual realities, both between and within species, clearly are mere approximations of what is actually present. The brain of each individual develops in a particular set of environmental circumstances on a plan common to that species. The behavior that the brain produces, in other words, is directly related to the world that the brain has constructed.

Principle 2: Neuroplasticity Is the Hallmark of Nervous System Functioning Experience alters the brain’s organization, and this neuroplasticity is requisite to learning and memory. In fact, the nervous system stores information only if neural connections change. Forgetting is presumably due to a loss of the connections that represented the memory. As Experiment 2-1 demonstrates, neuroplasticity is a characteristic not just of the mammalian brain; it is found in the nervous systems of all animals, even the simplest worms. Nonetheless, larger brains have

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more capacity for change, and thus their neural organization is likely to show more plasticity. Find details on plasticity and drug addiction in Section 14-4, on feeling and treating pain in Section 11-4, and on epilepsy in Clinical Focus Box 4-1. Section 16-3 details diagnosis and treatment of epilepsy and dementias.

Plasticity can be beneficial in recovering from disorders, such as brain injuries and diseases, as well as in normal aging. Plasticity also allows the brain to compensate for developmental abnormalities, an extreme example being agenesis of brain structures, as discussed in Research Focus 2-1. Although beneficial in such circumstances, neuroplasticity can have drawbacks in the case of extreme stimulation or disease states. Brain analyses of animals given addicting doses of drugs such as cocaine or morphine reveal broad changes in neural connectivity suspected of underlying some maladaptive behaviors related to addiction. Among many other examples of pathological neuroplasticity are those associated with pain, epilepsy, and dementia.

Principle 3: Many Brain Circuits Are Crossed Most brain inputs and outputs are crossed—that is, they serve the opposite side of the body. Each hemisphere receives sensory stimulation from the opposite (contralateral) side of the body and controls muscles on the contralateral side. Crossed organization explains why people who have a stroke or other damage to the left

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cerebral hemisphere may have difficulty sensing stimulation to the right side of the body or in moving body parts on the right side. The opposite is true of people whose stroke occurs in the right cerebral hemisphere. A crossed nervous system must somehow join both sides of the perceptual world together. To do so, innumerable neural connections link the brain’s left and right sides. The most prominent connecting cable is the corpus callosum, whose roughly 200 million nerve fibers join the left and right cerebral hemispheres, allowing them to interact. Figure 9-10 illustrates how the human visual system represents the world seen through two eyes as a single perception: both eyes connect with both hemispheres.

Four important exceptions to the crossed-circuit principle are olfactory sensation and the somatic, autonomic, and enteric PNS connections. Olfactory information does not cross but rather projects directly into the same (ipsilateral) side of the brain. The cranial and spinal nerves that constitute the SNS are connected ipsilaterally, as are the sympathetic and parasympathetic ANS division connections. Likewise, ipsilateral ENS connections link to the ANS on both sides.

Principle 4: The CNS Functions on Multiple Levels In simple animals, such as worms, the nerve cord essentially constitutes the nervous system. More complex animals, such as

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fishes, have a brainstem as well, and even more complex animals, like mammals, have also evolved a forebrain. Each new addition to the CNS has added a new level of behavioral complexity without discarding previous levels of control. As animals evolved legs, for example, brain structures simultaneously evolved to move the legs. Later, the development of independent digit movements required even more brainpower. Thus, new brain areas add new levels of nervous system control. The new levels are not autonomous but rather are integrated into existing neural systems as refinements and elaborations of the control that earlier levels provided. Multiple levels of function can be seen not only in the addition of forebrain areas to refine brainstem control but also in the forebrain itself. As mammals evolved, they developed an increased capacity to represent the world in the cortex, an ability related to the addition of more maps. The new maps are related to the older ones, however, and again are simply an elaboration of the perceived sensory world that existed before.

Principle 5: The Brain Is Symmetrical and Asymmetrical The left and right hemispheres look like mirror images, but they have some dissimilar features. Cortical asymmetry is essential for integrative tasks, language and body control among them. Consider speaking. If a language zone existed in both hemispheres, each connected to one side of the mouth, we would actually be able to talk out of both sides of our mouth at once. That would make talking 289

awkward, to say the least. One solution is to locate language control of the mouth on one side of the brain. Organizing the brain in this way allows us to speak with a single voice. A similar problem arises in controlling body movements in space. We would not want the left and right hemispheres each trying to take us to a different place. Again, if a single brain area controls this sort of spatial processing, problem solved. Language control is typically situated on the left side, and spatial functions are typically on the right. The brains of many species have such symmetrical and asymmetrical features. In the bird brain, the control of singing is in one hemisphere (usually the left side), as is human language. It is likely that birds and humans evolved the same solution independently—namely, to assign the control to only one side of the brain.

Principle 6: Brain Systems Are Organized Hierarchically and in Parallel When we consider the multiple levels of CNS function, it becomes apparent that these levels are extensively interconnected to integrate their processing and produce unified perceptions or movements. The nature of neural connectivity leads to the principle that the brain has both serial (or hierarchical) and parallel circuitry.

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A hierarchical circuit hooks up a linear series of all regions concerned with a particular function. Consider vision. In a serial system, the information from the eyes goes to regions that detect the simplest properties, such as color or brightness. This information is passed along to another region that determines shape, then to another that measures movement, and so on until at the most complex level the information is understood to be, say, your grandmother. Information therefore flows sequentially from regions that make simpler discriminations to regions that make more complex discriminations in the hierarchy, as illustrated in Figure 2-34A.

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FIGURE 2-34 Models of Neural Information Processing (A) Simple hierarchical model of serial cortical processing. (B) In a distributed hierarchical processing model, each of several processing streams has multiple levels. Areas at each level interconnect.

However, functionally related brain structures are not always linked linearly. Although the brain has many serial connections, many expected connections are missing. In the visual system, not all cortical regions are connected to one another. The simplest explanation is that the unconnected regions must have widely differing functions. Parallel circuits operate on a different principle, also illustrated by the visual system. Imagine looking at a car. As we look at a car door, one set of visual pathways processes information about its nature, such as color and shape, whereas another set of pathways processes information about movements such as those necessary to open the door. These two visual systems are independent of each other, yet they must interact somehow. When you pull open the car door, you do not perceive two different representations—the door’s size, shape, and color on the one hand and the opening movements on the other. When you open the door, you have the impression of unity in your conscious experience. Figure 2-34B illustrates the information flow in such a distributed hierarchy. If you trace the flow from the primary area to levels 2, 3, and 4, you follow the parallel pathways. And while these multiple

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parallel pathways are also connected to one another, those connections are more selective than connections in a purely serial circuit. The brain’s subsystems are organized into multiple parallel pathways, yet our conscious experiences are unified. As we explore this conundrum throughout the book, keep in mind that your commonsense impressions of how the brain works might not always be correct.

Principle 7: Sensory and Motor Divisions Permeate the Nervous System The segregation of SNS sensory and motor functions described by the Bell and Magendie law exists throughout the nervous system. Spinal nerves are either sensory or motor. Some cranial nerves are exclusively sensory; some are exclusively motor; and some have two parts, one sensory and one motor, much like spinal nerves serving the skin and muscles. Review cranial nerve and spinal nerve connections in Figures 2-29 and 2-30.

The lower brainstem regions—hindbrain and midbrain—are essentially extensions of the spinal cord. They retain the spinal cord’s division, with sensory structures posterior and motor structures anterior in humans. An important midbrain function is orienting the 294

body to stimuli, which requires sensory input from the midbrain’s colliculi (posterior in the human tectum) and motor output, which the tegmentum (anterior) plays a role in controlling. Distinctions between motor and sensory functions become subtler in the forebrain. Distinct sensory

Figures 2-16 through 2-20 illustrate brainstem structures.

nuclei are present in the thalamus, too, although their positions are not segregated, as they are in lower structures. Because all sensory information reaches the forebrain through the thalamus, it is not surprising to find separate nuclei associated with vision, hearing, and touch in this structure. Separate thalamic nuclei also control movements. Other nuclei have neither sensory nor motor functions but rather connect to cortical areas, such as the frontal lobe, that perform more integrative tasks. Finally, sensory and motor functions are divided in the cortex in two ways: 1. Separate sensory and motor cortical regions process a particular set of sensory inputs, such as vision, hearing, or touch. Others control fine movements of discrete body parts, such as the fingers. 2. The entire cortex is organized around the sensory and motor distinction. As diagrammed in Figure 2-25, layer IV of the cortex always receives sensory inputs, layers V and VI always send motor outputs, and layers I, II, and III integrate sensory and motor operations.

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One should keep in mind that sensory and motor systems work together at all levels. For example, the pupil, a motor structure composed of muscles, controls the amount of light that falls on the sensory retina. Also, within muscles a sensory system called the intrafusal muscle system detects the amount and rate of change of the extrafusal muscles, which actually do the work.

Principle 8: The Brain Divides Sensory Input for Object Recognition and Movement Sensory systems evolved first for influencing movement, not for recognizing things. Simple organisms can detect stimulation such as light and move to or from it. It is not necessary to perceive an object to direct movements toward or away from it. Animals only began to represent their environment as their brains and behaviors became more complex. Animals with complex brains evolved separate systems for recognizing objects and for moving. The human visual systems for visual scene perception and for visually guided movements exemplify this separation well. Visual information in the cortical circuit travels from the eyes to the thalamus to visual regions of the occipital lobe. From the occipital cortex, the information then diverges along two separate pathways: the ventral stream, which leads to the temporal lobe for object identification, and the dorsal stream, which goes to the parietal lobe to guide movements relative to objects (Figure 2-35). People with ventral stream injuries are blind for object recognition. They cannot

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distinguish a cup from a spoon. Nevertheless, they shape their hands appropriately when asked to reach for objects that they cannot identify. In contrast, people with dorsal stream injuries can recognize objects, but they make clumsy reaching movements because they do not form appropriate hand postures until they contact objects. Only then do they shape the hand, on the basis of tactile information.

FIGURE 2-35 Neural Streams The dorsal and ventral streams mediate vision for action and recognition, respectively.

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Recognizing that perception for movement and perception for object recognition are independent processes has three important implications for understanding brain organization: 1. The dorsal and ventral visual systems also exemplify parallel information processing in the brain. 2. Although we may think we are aware of our entire sensory world, the sensory analysis required for some movements clearly is not conscious. 3. Unconscious and conscious brain processing underlies an important difference in our cognitive functions. The unconscious movement system is always acting in the present and in response to ongoing sensory input. In contrast, the conscious object recognition system allows us to escape the present and bring to bear information from the past, thus forming the neural basis of enduring memory. Sections 9-2 and 9-3 review evidence that led to understanding the visual streams’ functions and visual information processing.

Principle 9: Brain Functions Are Localized and Distributed A great debate in the early days of brain research was concerned with whether different functions are localized to specific brain regions. Some argued that specific functions are distributed, and no particular region is of prime importance. Others argued for localization, including Paul Broca and Karl Wernicke, who demonstrated

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decisively that two specific language functions are localized. Broca found that when damage occurs to the ventroposterior region of the frontal lobes, people are unable to produce spoken language. Wernicke found that when damage occurs to a different region, the left posterior superior temporal gyrus, pronounced deficits in language comprehension result. So Broca, Wernicke, and others showed us that particular functions are localized and that there are regions in the brain that are of prime importance, at least in adults. But does this mean that function is not distributed? Not at all. Consider how particular brain regions operate. Neurons in a specific region receive inputs, make a multitude of internal connections within that region, and then make outputs. Small lesions within a specific region do not necessarily produce any noticeable disruptions. That is because within a brain region, the function is distributed among the neurons that do the information processing; if some neurons are destroyed, the remaining neurons can continue carrying out the function. It is only when the majority of neurons within a specific functional region are destroyed that we see catastrophic failure for the associated function. For Alzheimer neurochemistry, see Section 5-3; for incidence and possible causes, Section 14-3; and for treatments, Section 16-4.

Because functions are both localized to specific areas and distributed within those areas, we can see paradoxical effects when certain types of brain damage occur. For instance, complete or nearly complete damage to a fairly localized region can cause irreversible

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loss of function, whereas widespread but diffuse damage may leave an individual's functional abilities intact. In fact, one characteristic of dementing diseases is that people can endure widespread deterioration of the cortex yet maintain remarkably normal language functions until late stages of the disease. Alzheimer disease is a degenerative brain disorder related to aging that first appears as progressive memory loss and only much later develops into generalized dementia.

Principle 10: The Nervous System Works by Juxtaposing Excitation and Inhibition We have emphasized the brain’s role in making movements, but we must also recognize that the brain prevents movements. To make a directed movement, such as picking up a glass of water, we must refrain from other movements, such as waving the hand back and forth. In producing movement, then, the brain uses both excitation (increased neural activity) to produce some action and inhibition (decreased neural activity) to prevent other actions. Tourette syndrome and Parkinsonism are dysfunctions of the basal ganglia, which coordinates voluntary movement.

Brain injury or disease can produce either a loss or a release of behavior by changing the balance between excitation and inhibition. A brain injury in a region that normally initiates speech may render a

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person unable to talk—a loss of behavior. A person with an abnormality in a region that inhibits inappropriate language (such as swearing) may be unable to inhibit this form of speech. Such a release of behavior can be seen in some individuals with Tourette syndrome. Patients with Parkinson disease may have uncontrollable shaking of the hands because the neural system that inhibits such movements has failed. Paradoxically, they often have difficulty initiating movements and appear frozen because they cannot generate the excitation needed to produce deliberate movements. Chapter 3 details nervous system cell structure; Chapter 4, how neurons transmit and integrate information; and Chapter 5, neuronal communication and adaptation.

The juxtaposition of excitation and inhibition, central to the way the brain produces behavior, can also be seen at the level of individual neurons. All neurons evince a spontaneous activity rate that can be either increased (excitation) or decreased (inhibition). Some neurons excite others; some inhibit. Both effects are produced by neuronal communication via specific neurochemicals. 2-6 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. Many of the brain’s input and output circuits are crossed. In the nervous system, four exceptions to this principle are the 301

, the .

, the

, and the

2. The vertebrate brain has evolved three regions—hindbrain, midbrain, and forebrain—leading to and flexibility in controlling behavior. 3. One aspect of neural activity that resembles the on–off language of digital devices is the juxtaposition of and . 4. Explain this statement: Perception is not reality.

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Summary 2-1 Overview of Brain Function and Structure The brain’s primary function is to produce movements that make up behavior in a perceptual world the brain constructs. This perceptual world is ever-changing. To adapt, the brain must also change, a property referred to as neuroplasticity. To study how the nervous system works, we abandon the anatomical divisions between the central nervous system and the peripheral nervous system to focus instead on function—on how the CNS interacts with the divisions of the PNS: the somatic, autonomic, and enteric nervous systems.

2-2 The Conserved Pattern of Nervous System Development The vertebrate nervous system evolved from a relatively simple structure mediating reflexlike behaviors to the complex human brain mediating advanced cognitive processes. To allow for more complex behavior in an increasingly sophisticated perceptual world, archaic forms have not been replaced but rather have been adapted and modified as new structures have evolved. The principles of nervous system organization and function generalize across the three vertebrate brain regions—hindbrain, midbrain, and forebrain—leading to multiple levels of

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functioning. The evolution of neural levels of control thus adds flexibility to behavioral control.

2-3 The Central Nervous System: Mediating Behavior The CNS includes the brain and the spinal cord. The spinal cord receives sensations from the skin and muscles and produces movements independent of the brain. The brain can be divided into the brainstem and forebrain, each made up of hundreds of parts. The brainstem both directs movements and constructs a sensory world through its connections with the sensory systems, spinal cord, and forebrain. The forebrain modifies and elaborates basic sensory and motor functions; regulates cognitive activity, including thought and memory; and ultimately controls movement. The most elaborate parts of the brain, the cerebral cortex and cerebellum, are relatively large in humans.

2-4 Somatic Nervous System: Transmitting Information The SNS consists of two sets of spinal nerves that enter and leave the spinal column, connecting with muscles, skin, and joints in the body, and the cranial nerves that link the facial muscles and some internal organs to the brain. Both sets of SNS nerves are symmetrical: one set controls each side of the body. Some cranial nerves are sensory, some are motor, and some combine both functions. The spinal cord acts as a minibrain for the peripheral (spinal) nerves that enter and leave its five

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segments. Each spinal segment works independently, although CNS fibers interconnect them and coordinate their activities.

2-5 Autonomic and Enteric Nervous Systems: Visceral Relations The ANS controls the body’s glands and internal organs and operates largely outside conscious awareness. Its sympathetic (arousing) and parasympathetic (calming) divisions work in opposition. The parasympathetic division directs the organs to rest and digest, whereas the sympathetic division prepares for fight or flight. The ENS controls the gut over its entire length, from the esophagus to the colon, interacting with the brain via the ANS. ENS activity can affect our behavior and mental state. In turn, the ENS is affected by the microbiome, the roughly 39 trillion bacteria that inhabit our gut.

2-6 Ten Principles of Nervous System Function Ten principles listed in the right column below form the basis for discussions throughout this book. Understanding them fully will enhance your study of brain and behavior.

Ten Principles of Nervous System Function 1

The nervous system produces movement in a perceptual world the brain constructs.

Neuroplasticity is the hallmark of nervous system functioning.

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Many brain circuits are crossed.

The CNS functions on multiple levels.

The brain is symmetrical and asymmetrical.

Brain systems are organized hierarchically and in parallel.

Sensory and motor divisions permeate the nervous system.

The brain divides sensory input for object recognition and movement.

Brain functions are localized and distributed.

The nervous system works by juxtaposing excitation and inhibition.

Key Terms adaptations afferent allocortex Alzheimer disease autonomic nervous system (ANS) basal ganglia brainstem cerebral cortex cerebrospinal fluid (CSF) corpus callosum cranial nerves cytoarchitectonic map dermatome

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diencephalon efferent enteric nervous system (ENS) excitation forebrain frontal lobe gray matter gyri (sing. gyrus) hindbrain hypothalamus inhibition law of Bell and Magendie limbic system meninges midbrain neocortex nerve neuroplasticity nuclei (sing. nucleus) occipital lobe orienting movement

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parasympathetic division parietal lobe Parkinson disease phenotypic plasticity reticular formation somatic nervous system (SNS) stroke sulci (sing. sulcus) sympathetic division tectum tegmentum temporal lobe thalamus Tourette syndrome tract ventricles vertebrae (sing. vertebra) vomeronasal organ (VNO) white matter

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CHAPTER 3 What Are the Nervous System’s Functional Units?

3-1 Cells of the Nervous System RESEARCH FOCUS 3-1 A Genetic Diagnosis Neurons: The Basis of Information Processing Five Types of Glial Cells

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EXPERIMENT 3-1 Question: Can the Principles of Neural Excitation and Inhibition Control the Activity of a Simple Robot That Behaves Like a Cricket? CLINICAL FOCUS 3-2 Brain Tumors 3-2 Internal Structure of a Cell The Cell as a Factory Cell Membrane: Barrier and Gatekeeper THE BASICS Chemistry Review The Nucleus and Protein Synthesis The Endoplasmic Reticulum and Protein Manufacture Proteins: The Cell’s Product Golgi Bodies and Microtubules: Protein Packaging and Shipment Crossing the Cell Membrane: Channels, Gates, and Pumps 3-3 Genes, Cells, and Behavior Mendelian Genetics and the Genetic Code Applying Mendel’s Principles CLINICAL FOCUS 3-3 Huntington Disease Genetic Engineering 311

Phenotypic Plasticity and the Epigenetic Code

RESEARCH FOCUS 3-1 A Genetic Diagnosis Fraternal twins Alexis and Noah Beery seemingly acquired cerebral palsy perinatally (at or near birth). They had poor muscle tone and could barely walk. Noah drooled and vomited, and Alexis had tremors. Typically, children with cerebral palsy do not get worse with age, but the twins’ condition deteriorated. In searching the literature for similar cases, their mother, Retta Beery, found a photocopy of a 1991 news report that described a child first diagnosed with cerebral palsy and then found to have a rare condition, doparesponsive dystonia. (Dystonia means “abnormal muscle tone.”) It stems from a deficiency of a neurochemical, dopamine, produced by a relatively small cluster of cells in the midbrain. When Alexis and Noah received a daily dose of L-dopa, a chemical that some brain cells convert to dopamine, they displayed remarkable improvement. “We knew that we were witnessing a miracle,” Retta recalls. A few years later, in 2005, Alexis began to have new symptoms, marked by breathing difficulties. At this time the twins’ father, Joe, worked for Life Technologies, a biotech company that makes equipment used for sequencing DNA, the genetic coding molecule found in the nucleus of every cell. Joe arranged for samples of the twins’ blood to be sent to the Baylor College of Medicine’s DNA sequencing center. The twins’ sequenced genome was compared with that of their parents and close relatives. The analysis showed that the twins had an abnormality in a gene on chromosome 2 for an enzyme that enhances not only dopamine production but also the production of serotonin, another neurochemical made by brainstem cells.

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When the twins’ doctors added tryptophan, the enzyme that is converted to serotonin, to the L-dopa, both twins showed remarkable improvement. Alexis eventually competed in junior high school track, and Noah played volleyball in the Junior Olympics; both are now in college. This is the first diagnosis established through genome sequencing that led to a treatment success, and it marks the beginning of personalized medicine, diagnosis, and treatment based on a patient’s genomic information (Hayes, 2017).

Reeta, Noah, Zach (the twins’ brother), Alexis, and Joe at an event promoting the research done by the National Institutes of Health.

The Beery twins’ remarkable story highlights how neuroscientists apply advances in genetics to treat brain disorders. Understanding genes, proteins, and cellular function allows us to understand healthy brain functioning as well.

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We begin this chapter by describing nervous system cell structure and function. Brain cells give the nervous system its structure and mediate its moment-to-moment activity, the activity that underlies our behavior. We conclude the chapter by describing Mendelian genetics and the new genetic science of epigenetics that complements Mendel’s theory.

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3-1 Cells of the Nervous System The theory that the specialized cell of the nervous system, the neuron, is the building block of the nervous system and of our behavior emerged from a controversy between the Italian Camillo Golgi and the Spaniard Santiago Ramón y Cajal. Both men were awarded the Nobel Prize for medicine in 1906, in recognition of their work on the structure of the nervous system. Golgi never revealed just how he came to develop his staining technique.

Imagine that you are Camillo Golgi, at work in your laboratory, staining and examining nervous system tissue. You immerse a thin slice of brain tissue in a solution containing silver nitrate and other chemicals, a technique used at the time to produce black-and-white photographs. A contemporary method, shown in Figure 3-1A, produces a color-enhanced microscopic image that resembles the images Golgi saw.

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FIGURE 3-1 Two Views of a Cell (A) Tissue preparation revealing human pyramidal cells stained using the Golgi technique. (B) Cajal’s drawing of a single Purkinje neuron made from Golgi-stained tissue.

The image is beautiful and intriguing, but what do you make of it? To Golgi, this structure suggested that the nervous system is an interconnected network of fibers. He thought that information flowed around this “nerve net,” like water running through pipes, and so produced behavior. Santiago Ramón y Cajal used Golgi’s stain to study chick embryos’ brain tissue and came to a different conclusion. He assumed that the chick’s developing nervous system would be simpler and easier to understand than that of an adult chicken. Figure 3-1B shows an image he rendered from the neural cells using the Golgi stain. Cajal concluded that the nervous system is made up of discrete cells, which begin life as a rather simple structure that becomes more complex with age. When mature, each cell consists of a main body with many extensions projecting from it.

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The structure looks something like a plant, with branches coming out the top and roots coming out the bottom. Cajal showed that neurons come in many shapes and sizes and can be distinguished from the glial cells that also made up a large part of brain tissue. Cajal’s neuron theory —that neurons are the nervous system’s functional units—is now accepted. The neuron theory includes the ideas that the interactions between neurons enables behavior and that the more neurons an animal has, the more complex its behavior. In the century since Golgi and Cajal’s pioneering work, scientists have developed many additional staining methods for visualizing neurons, including methods to view living cells that are cultured in a dish with nurturing fluids. They can also implant tiny microscopes, called endoscopes or microendoscopes (for small microscopes that look into tissue), in the brain to view the structure and activity of its neurons (Belykh et al., 2018). Thus, a wide variety of visualization techniques are used to investigate different problems related to how neurons produce behavior. Subsequent research has also confirmed Golgi’s nerve net, a covering called a perineuronal net that forms around neurons as they mature (Carulli, 2018). Today, investigators are examining the role of this net in stabilizing the structure of neurons once they mature, in preserving well-learned behavior, and in influencing addictions to drugs and diseases of memory loss that occur as some people age, topics that we will take up in later chapters. Figure 3-2 shows the three basic subdivisions of a neuron. The core region is called the cell body, or soma (Greek meaning “body”; the root of words such as somatic). A neuron’s branching extensions, or dendrites (from the Greek for “tree”), collect information from other cells, and its main root is the single axon (Greek for “axle”), which 317

carries messages to other neurons. A neuron has only one axon, but most neurons have many dendrites. Some neurons have so many dendrites that they look like a garden hedge, as Cajal’s drawing in Figure 3-1B illustrates.

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FIGURE 3-2 Basic Structure of a Neuron Dendrites gather information from other neurons, the cell body (soma) integrates the information, and the axon sends the information to other cells. Although a neuron may have many dendrites, it has only one axon.

The human nervous system contains 86 billion neurons and 87 billion glial cells that support their function, a ratio of about 1:1 that characterizes the brains of all animals (Herculano-Houzel et al., 2014). Neurons vary greatly in size and shape, but they have a common plan: examining how one neuron works offers insights that can generalized to other neuron types. As you learn to recognize different types of nervous system cells, you will begin to understand how their specialized structures contribute to their functions in your body.

Neurons: The Basis of Information Processing As the information-processing units of the nervous system, neurons acquire information, store it as memory, interpret it, and pass the information along to other neurons to produce behavior. In doing so, they regulate body processes such as breathing, heartbeat, and body temperature, to which we seldom give a thought. Scientists think that neurons work together in groups of many hundreds to many thousands to produce most behavior. It is important, then, to understand not only how neurons function but also how they interconnect and influence one another. The connectome is introduced in Section 1-4.

Functional groups of neurons, or neural networks, connect wide

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areas of the brain and spinal cord. The loss of a neuron or two from a network is no more noticeable than the loss of one or two voices from a cheering crowd. It is the crowd that produces the overall sound, not each person. An ongoing effort aims to map the structural connectivity—the physical wiring, or connectome—of the entire human brain. Principle 2: Neuroplasticity is the hallmark of nervous system functioning.

Each neuron’s appearance is distinctive, but neurons are also the essence of plasticity. If one views living brain tissue through a microscope, the neurons reveal themselves to be surprisingly active, producing new branches, losing old ones, and making and losing connections with each other as you watch. This dynamic activity underlies both the constancies and the changes in our behavior.

Structure and Function of the Neuron Figure 3-3 details the external and internal features common to neurons. The cell’s surface area is increased immensely by its extensions into dendrites and an axon (Figure 3-3A and B). The dendritic area is further increased by many small protrusions called dendritic spines (Figure 33C). A neuron may have up to 20 dendrites, each dendrite may have one to many branches, and the spines on the branches may number in the thousands. Dendrites collect information from other cells, and the spines are the points of contact with those neurons. The extent of a cell’s branches and its spine number correspond to its information-processing capacity.

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FIGURE 3-3 Major Parts of a Neuron (A) Typical neuron Golgi-stained to reveal its dendrites and cell body. (B) The neuron’s basic structures identified. (C) An electron micrograph captures the synapse between an axon from another neuron and a dendritic spine. (D) High-power light microscopic view inside the cell body. Note the axon hillock at the junction of the soma and axon.

Each neuron has but a single axon to carry messages to other neurons. The axon begins at one end of the cell body, at an expansion known as the axon hillock (little hill), shown in Figure 3-3D. The axon may branch out into one or many axon collaterals, which usually emerge from it at right angles, as shown at the bottom of Figure 3-3B.

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The axon collaterals may divide into multiple smaller branches (telodendria, or end branches). At the end of each telodendrion is a knob called a terminal button, or an end foot. The terminal button sits very close to but usually does not touch a dendritic spine or some other part of another cell (Figure 3-3C). This near-connection, called a synapse, includes the surfaces of the end foot and the neighboring dendritic spine as well as the space between them. Chapter 4 describes how neurons transmit information; here, we simply generalize about neuronal function by examining shape. Imagine looking down on a river system from an airplane. You see many small streams merging to make creeks, which join to form tributaries, which join to form the main river channel. As the river reaches its delta, it breaks up into many smaller channels again before discharging its contents into the sea. The general shape of a neuron suggests that it works in a broadly similar way to a river. As illustrated in Figure 3-4, the neuron collects information from many sources on its dendrites. It channels the information to its axon, which can send out only a single message over all of its collaterals and telodendria. The synapse is the information transfer site between neurons.

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FIGURE 3-4 Information Flow Through a Neuron

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Three Functions of Neurons Neurons of varying shapes and sizes are structured to perform three specialized functions. Sensory neurons (Figure 3-5A) conduct information from the sensory receptors in or on the body into the spinal cord and brain. Interneurons (Figure 3-5B) associate sensory and motor activity in the CNS, and motor neurons (Figure 3-5C) carry information from the brain and spinal cord out to the body’s muscles.

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FIGURE 3-5 Neuron Shape and Function (A) Sensory neurons of many types detect stimulation or collect information and pass it on to (B) an interneuron. The multibranched interneuron dendrites collect information from varied sources and link to (C) motor neurons, which are distinctively large and which pass on commands to muscles to move. Cells are not drawn to scale.

SENSORY NEURONS Sensory neurons are structurally the simplest of the three types of neuron. A bipolar neuron found in the retina of the eye, for example, has a single short dendrite on one side of its cell body and a single short axon on the other side. Bipolar neurons transmit afferent (incoming) sensory information from the retina’s light receptors to the neurons that carry information into the brain’s visual centers. A bit more structurally complicated is the somatosensory neuron, which brings sensory information from the body into the spinal cord, a long distance. Structurally, the somatosensory dendrite connects directly to its axon, so the cell body sits to one side of this long pathway.

INTERNEURONS Also called association cells because they link up sensory and motor neurons, interneurons branch extensively to collect information from many sources. A specific type of interneuron, the stellate (star-shaped) cell, is characteristically small, with many dendrites extending around the cell body. Its axon is difficult to see in the maze of dendrites. One of the main reasons brain sizes vary between species is that there are many more interneurons in larger brains than in smaller brains, giving a correlation between interneuron number and behavioral complexity.

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A pyramidal cell has a long axon, a pyramid-shaped cell body, and two sets of dendrites. The apical set projects from the cell body apex, the basal set from the base of its cell body. Pyramidal interneurons carry information from the cortex to the rest of the brain and spinal cord. A Purkinje cell (named for its discoverer) is a distinctive interneuron with extremely branched dendrites that form a fan shape. It carries information from the cerebellum to the rest of the brain and spinal cord.

MOTOR NEURONS To collect information from many sources, motor neurons have extensive dendritic networks, large cell bodies, and long axons that connect to muscles. Motor neurons reside in the lower brainstem and spinal cord. All efferent (outgoing) neural information must pass through them to reach the muscles.

Neuronal Networks Sensory neurons collect afferent (incoming) information from the body and connect to interneurons that process the information and pass it on to motor neurons. The motor neurons’ efferent connections move muscles and so produce behavior. These three organizational aspects of neurons are thus features of neuronal networks: input, association, and output. Neurons that project for long distances, such as somatosensory neurons, pyramidal neurons, and motor neurons, are relatively large. In general, neurons with a large cell body have long extensions, whereas neurons with a small cell body, such as stellate interneurons, have short extensions.

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Long extensions carry information to distant parts of the nervous system; short extensions are engaged in local processing. For example, the dendrite tips of some somatosensory neurons are in your big toe, whereas the target of their axons is at the base of your brain. These sensory neurons send information over as much as 2 meters—and even farther in very large animals. The axons of some pyramidal neurons must reach from the cortex as far as the lower spinal cord, a distance that can be as long as a meter. The imposing size of this pyramidal cell body therefore accords with the work it must do in providing nutrients and other cellular supplies for its axons and dendrites.

The Language of Neurons: Excitation and Inhibition Neurons are networkers with elaborate interconnections, but how do they communicate? Simply put, neurons either excite (turn on) or inhibit (turn off) other neurons. Like digital computers, neurons send yes or no signals to one another; the yes signals are excitatory, and the no signals are inhibitory. Each neuron receives up to thousands of excitatory and inhibitory signals every second. Principle 10: The nervous system works by juxtaposing excitation and inhibition.

The neuron’s response to all those inputs is reasonably democratic: it sums them. A neuron is spurred into action and sends messages to other neurons if its excitatory inputs exceed its inhibitory inputs. If the reverse occurs and inhibitory inputs exceed excitatory inputs, the neuron does not communicate.

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By exciting or inhibiting one another, a neuronal network can detect sensory information and “decide” what kind of motor response to make to that information. To confirm whether they understand how an entire neural network produces behavior, scientists might make a model, such as a robot, intended to function in the same way. Robots, after all, engage in goal-oriented actions, just as animals do. A robot’s computer must somehow sense the world, coordinate its actions in response, and perform much as an animal’s nervous system performs. Researchers construct robotic models to help confirm hypotheses about how the nervous system functions and then use the information derived from this exercise to further refine subsequent robot models to more closely function like an animal’s nervous system. Section 4-3 explains how neurons summate excitatory and inhibitory signals.

As a result of this two-way modeling, a good deal of robotic intelligence, or artificial intelligence (AI), is based on principles of nervous system function. For example, Barbara Webb’s cricket robot, constructed from Lego blocks, wires, and a motor (Figure 3-6, left), is designed to mimic a female cricket, which listens for the source of a male’s chirping song and travels to it (Reeve et al., 2007). It reflects a beginning step in constructing a more intelligent robot (Figure 3-6, right). Experiment 3-1 presents another example of the ways that inhibition and excitation might produce a cricket robot’s behavior.

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FIGURE 3-6 Nervous System Mimics Left: Barbara Webb programmed rules she developed from studying cricket behavior into her Lego cricket robot. Right: Social roboticist Heather Knight conducts research on robot body language with her companion, Marilyn Monrobot.

EXPERIMENT 3-1

Question: Can the principles of neural excitation and inhibition control the activity of a simple robot that behaves like a cricket? Procedure A

In approaching a male, a female cricket must avoid open, well-lit places where a predator could detect her. The female must often choose between competing males, preferring, for example, the male that makes the longest chirps. If we insert sensory neurons between the microphone for sound detection on each side of a hypothetical robot cricket and on the motor on the

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opposite side, we need only two rules to instruct the female robot to seek out a chirping male cricket:

Rule 1 When a microphone detects a male cricket’s song, an excitatory message is sent to the wheel’s motors, activating them so the robot moves toward the cricket. Rule 2 If the chirp is coming from the robot’s left or right side, it will be detected as being louder by the microphone on that side, which will make one wheel turn a little faster, ensuring that the robot moves directly toward the sound. Procedure B

We add two more sensory neurons, coming from photoreceptors on the robot. When activated, these light-detecting sensory neurons inhibit the motor neurons leading to the wheels and prevent the robot from moving toward a male cricket. Now the female cricket robot will move only when it is dark and “safe.”

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Result

This hypothetical arrangement mimics the functions of sensory and motor neurons and the principle of summating excitatory and inhibitory signals— but with only six neurons and each neuron connected to only one other neuron! Conclusion

Today, anthropomimetic robots, so called because their parts are constructed to mimic the parts of a human body, including its billions of neurons, are being designed to model complex behavior and act as replacements for lost or impaired limbs (Mathews et al., 2017). Entire robots are also being constructed to mimic many aspects of human behavior.

Five Types of Glial Cells Glia form the fatty coverings around neurons—the white matter in brain images such as Figures 2-12B and D.

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Glial cells (from the Greek for “glue”) are the nervous system’s support cells. Although they do not usually transmit information themselves, glial cells help neurons carry out this task, binding them together (some do act as glue) and providing support, nutrients, and protection, among other functions. Table 3-1 lists the five major types of glia, along with their characteristic structures and functions.

TABLE 3-1 Types and Functions of Glial Cells

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Glial cells are different from neurons in that most types of glial cells are produced throughout an organism’s life, and errors in their replication are a main source of abnormal growths: brain tumors. Clinical Focus 3-2, Brain Tumors, describes the results of such uncontrolled glial cell growth.

CLINICAL FOCUS 3-2

Brain Tumors One day while watching a movie in a neuropsychology class, R. J., a 19-yearold college sophomore, collapsed on the floor, displaying symptoms of a seizure. The instructor helped her to the university clinic, where she recovered except for a severe headache. She reported that she had repeated severe headaches. A few days later, a computed tomography (CT) scan showed a tumor over her left frontal lobe. The tumor was removed surgically, and R. J. returned to classes after an uneventful recovery. Her symptoms have not recurred. A tumor is an uncontrolled growth of new tissue that is independent of surrounding structures. No region of the body is immune, but the brain is a site for more than 120 kinds of tumors. They are a common cause of brain cancer in children. The incidence of brain tumors in the United States is about 20 per 100,000, according to the Central Brain Tumor Registry of the United States (Ostrom et al., 2016). In adults, brain tumors grow from glia or other supporting cells rather than from neurons, but in infants, tumors may grow from developing neurons. The rate of tumor growth depends on the type of cell affected. Some tumors are benign, as R. J.’s was, and not likely to recur after removal. Others are malignant, likely to progress and invade other tissue, and

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apt to recur after removal. Both benign and malignant tumors can pose a risk to life if they develop in sites from which removal is difficult. The earliest symptoms usually result from increased pressure on surrounding brain structures. They can include headaches, vomiting, mental dullness, changes in sensory and motor abilities, and seizures such as R. J. had. Many symptoms depend on the tumor’s location. The three major types of brain tumors are classified according to how they originate: 1. Gliomas arise from glial cells. They are slow growing, not often malignant, and relatively easy to treat if they arise from astrocytes. Gliomas that arise from the precursor blast or germinal cells that grow into glia are more often malignant, grow more quickly, and often recur after treatment. U.S. Senator Edward Kennedy was diagnosed with a malignant glioma in 2008 and died a year later. As with R. J., his first symptom was an epileptic seizure. 2. Meningiomas, such as R. J.’s, attach to the meninges and so grow entirely outside the brain, as shown in the accompanying CT scan. These tumors are usually encapsulated (contained), and if the tumor is accessible to surgery, chances of recovery are good. 3. Metastatic tumors become established when cells from one region of the body transfer to another area (which is what metastasis means). Typically, metastatic tumors are present in multiple locations, making treatment difficult. Symptoms of the underlying condition often first appear when the tumor cells reach the brain.

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The red area in this false-color CT scan is a meningioma, a noncancerous tumor arising from the meninges, which cover the brain. Large meningiomas may compress the brain but usually do not invade brain tissue.

Treatment for brain tumors is usually surgical, and surgery also remains a main diagnostic tool. Chemotherapy is less successful in treating brain tumors than tumors elsewhere in the body because the blood–brain barrier blocks the chemicals’ entry into the brain. Radiation therapy (X-ray treatment) is more

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useful for destroying brain tumor cells but can have negative effects, especially on the developing brain. Alternate treatments currently under investigation include genomic identification of a tumor and its subsequent destruction by targeting its unique genetic composition (Di Lorenzo & Ahluwalia, 2017).

Ependymal Cells Figure 2-9 shows the location of the cerebral aqueduct and the four ventricles.

On the walls of the ventricles, the fluid-filled cavities inside your brain, are ependymal cells, which produce and secrete the cerebrospinal fluid (CSF) that fills the ventricles. CSF is constantly being secreted, and it flows through the ventricles toward the base of the brain, where it is absorbed into the blood vessels. CSF serves several purposes. It acts as a shock absorber when the brain is jarred, carries away waste products, assists the brain in maintaining a constant temperature, and is a source of nutrients for parts of the brain adjacent to the ventricles. As CSF flows through the ventricles, it passes through some narrow passages, especially from the cerebral aqueduct into the fourth ventricle, which runs through the brainstem. If these passages are fully or partly blocked, fluid flow is restricted. Because CSF is continuously being produced, this blockage causes a buildup of pressure that begins to expand the ventricles, which in turn push on the surrounding brain. If such a blockage develops in a newborn infant, before the skull bones are fused, the pressure on the brain is conveyed to the skull, and

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the baby’s head swells. This condition, called hydrocephalus (literally, “water brain”), can cause severe intellectual impairment and even death. To treat it, doctors insert one end of a tube, called a shunt, into the blocked ventricle and the other end into a vein to allow excess CSF to drain into the bloodstream.

Astroglia Astrocytes (star-shaped glia, shown in Table 3-1), also called astroglia, provide structural support to the CNS. Their extensions attach to blood vessels and to the brain’s lining, forming a scaffolding that holds neurons in place. These same extensions provide pathways for certain nutrients to move between blood vessels and neurons. Astrocytes also secrete chemicals that keep neurons healthy and help them heal if injured. At the same time, astrocytes contribute to the structure of a protective partition between blood vessels and the brain, the blood–brain barrier. As shown in Figure 3-7, the ends of astrocytes attach to blood vessel cells, causing the vessels to bind tightly together. These tight junctions prevent an array of substances, including many toxins, from entering the brain through the blood vessel walls.

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FIGURE 3-7 Blood–Brain Barrier Astrocyte processes attach to neurons and to blood vessel cells to stimulate them to form tight junctions and so form the blood– brain barrier. Astrocytes also move nutrients and other chemicals between blood vessels and neurons, support brain structures, and stimulate repair of damaged brain tissue.

The molecules (smallest units) of these substances are too large to pass between the blood vessel cells unless the blood–brain barrier is somehow compromised. The downside is that many useful drugs, including antibiotics used to treat infections, cannot pass through the blood–brain barrier to enter the brain. As a result, brain infections are difficult to treat. Scientists can bypass the blood–brain barrier and

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introduce drugs into the brain by inserting small tubes that allow the delivery of a drug directly to a targeted brain region. Yet another important function of astrocytes is to enhance brain activity. When you engage in any behavior, whether it’s reading or running, the neuronal network responsible for that behavior requires more fuel in the form of oxygen and glucose. In response to neuron activity, the blood vessels that supply it expand, allowing greater oxygen- and glucose-carrying blood flow. What triggers the blood vessels to dilate? This is where astrocytes come in. They pass along signals from the neurons to the blood vessels and so contribute to increased blood flow and fuel supply (Kenny et al., 2018). Astrocytes also contribute to the healing of damaged brain tissue. If the brain is injured by a blow to the head or penetrated by some object, astrocytes form a scar to seal off the damaged area. Although the scar tissue is beneficial in healing the injury, it can also act as a barrier to the regrowth of damaged neurons. One of the many experimental approaches to repairing brain tissue seeks to get the axons and dendrites of CNS neurons to grow around or through a glial scar.

Microglia Growth factors, described in Section 8-2, are chemicals that stimulate and support brain cell growth, survival, and perhaps even plasticity (see Section 14-4).

Unlike other glial cells, which originate in the brain, microglia originate in the blood as an offshoot of the immune system and migrate

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throughout the nervous system, where they make up about 20 percent of all glial cells. The blood–brain barrier prevents most immune system cells from entering. Instead, microglia play an important part in monitoring and maintaining the health of brain tissue. They identify and attack foreign tissue, as illustrated in Figure 3-8. When brain cells are damaged, microglia invade the area to provide growth factors that aid in repair.

FIGURE 3-8 Detecting Brain Damage (A) Arrows indicate the red nucleus in a rat brain. (B) Close-up of cresyl violet–stained neurons (the large dark bodies) in the healthy red nucleus. (C) After exposure to a neurotoxin, only microglia, the small dark objects in the micrograph, survive.

There are several kinds of microglia, which take different shapes depending on the role they are performing. Microglia engulf any foreign tissue and dead brain cells, an immune process called phagocytosis. When full, they take on a distinctive appearance. The stuffed and nolonger-functioning microglia can be detected as small dark bodies, shown in Figure 3-8C, in and near damaged brain regions. Because microglia are frontline players in protecting the nervous 342

For more on understanding and treating Alzheimer disease, see Section 16-3.

system and removing its waste, considerable research is directed toward the extent to which microglia are involved in protecting the nervous system from disease. A characteristic of Alzheimer disease, a degenerative brain disorder commonly associated with aging, is the deposit of distinctive bodies called plaques in regions of damage. Microglia may also play a harmful role, consuming inflamed tissue rather than protecting it. They also interact with astrocytes in brain healing. Although small, as their name suggests, microglia play a mighty role in maintaining the brain’s health (Lannes et al., 2017).

Oligodendroglia and Schwann Cells Section 4-2 describes how myelin speeds up the neuron’s information flow.

Two kinds of glial cells insulate neuronal axons. Like the plastic insulation on electrical wires, myelin prevents adjacent neurons from short-circuiting. Myelinated neurons send information much faster than neurons without myelin. Neurons that send messages over long distances quickly, including sensory and motor neurons, are heavily myelinated to increase their messaging speed. Oligodendroglia myelinate axons in the brain and spinal cord by sending out large, flat branches that enclose and separate adjacent axons. (The prefix oligo- means “few” and here refers to the fact that

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these glia have few branches in comparison with astrocytes; see Table 31.) Schwann cells myelinate axons in the PNS. Each Schwann cell wraps itself repeatedly around a part of an axon, forming a structure somewhat like beads on a string. In addition to myelination, Schwann cells and oligodendroglia contribute to a neuron’s nutrition and functioning by absorbing chemicals that the neuron releases and releasing chemicals that the neuron absorbs.

Glial Cells, Disease, and Neuron Repair The multifaceted relationships among neurons and glia provide insights into nervous system diseases and into brain injury and recovery. The consequences of damage to oligodendroglia and Schwann cells can be as debilitating as damage to neurons themselves. For example, multiple sclerosis (MS), a degenerative nervous system disorder and the most common autoimmune disease, is associated with damage to oligodendroglia that leaves a scar (sclerosis means “scar”), rather than myelin, on neurons in nervous system pathways. As a result, information flow along affected nerves is impaired, producing impaired movement and cognitive function. Multiple sclerosis, which is caused by a loss of myelin, is discussed in depth in Clinical Focus 4-2.

Glia can also aid in nervous system repair. A deep cut on your body —on your arm or leg, for instance—may cut the axons connecting your spinal cord to muscles and to sensory receptors. Severing of motor neuron axons will render you unable to move the affected part of your body, whereas severing of sensory fibers will result in loss of sensation from that body part. Cessation of both movement and sensation is

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paralysis. Weeks to months after motor and sensory axons are severed, movement and sensation will return. What mediates this recovery? Both microglia and Schwann cells participate in repairing damage to the peripheral nervous system. When a PNS axon is cut, it degenerates back to the cell body, as shown at the top of Figure 3-9. Microglia remove all of the debris left by the dying axon. Meanwhile, the Schwann cells that provided the axon’s myelin shrink and divide to form numerous smaller glial cells along the path the axon formerly took. The cell body then sends out axon sprouts that search for and follow the path formed by the Schwann cells.

FIGURE 3-9 Neuron Repair Schwann cells aid the regrowth of axons in the somatic nervous system.

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Sections 11-1 and 11-4 detail causes of and treatments for spinal cord injury.

Eventually, one sprout reaches the intended target and becomes the new axon; all other sprouts retract. The Schwann cells envelop the new axon, forming new myelin and restoring function. In the PNS, then, Schwann cells serve as signposts to guide axons to their appropriate end points. Axons can get lost, however, as sometimes happens after surgeons reattach a severed limb. If axons destined to innervate one finger end up innervating another finger instead, the wrong finger will move when a message is sent along that axon. When the CNS is damaged—as happens, for example, when the spinal cord is cut—regrowth and repair do not occur, even though the distance that damaged fibers must bridge may be short. That recovery takes place in the PNS but not in the CNS is puzzling. Regrowth in the CNS may not occur in part because as neuronal circuits mature, they become exquisitely tuned to mediate individualized behavior and, in doing so, develop chemical strategies that prevent the proliferation of new cells or the regrowth of existing cells. The oligodendrocytes that myelinate CNS cells do not behave like PNS Schwann cells to encourage brain repair. They may actually play a role in protecting the existing structure of the CNS by inhibiting neuron regrowth (Hirokawa et al., 2017). Understanding how regrowth is inhibited is one approach to finding ways for the damaged CNS to repair itself. 3-1 Review

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Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. The two classes of nervous system cells are .

and

2. Neurons, the information-conducting units of the nervous system, act either by or one another through their connecting synapses. 3. The three types of neurons and their characteristic functions are , which ; , which ; and , which . 4. The five types of glial cells are , , and include , , neurons.

, , . Their functions , , and

5. How are robotic models being used to better understand the human nervous system?

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3-2 Internal Structure of a Cell What is it about the structure of neurons that generates the remarkable ability to receive, process, store, and send a seemingly limitless amount of information? To answer this question, we must look inside a neuron to see what its components are and understand what they do. Although neurons are minuscule, when we view them with an electron microscope, we find packed inside hundreds of interrelated parts that do the cell’s work. To a large extent, a cell’s proteins determine its characteristics and functions. Each cell can manufacture thousands of proteins, which variously take part in building the cell and in communicating with other cells. When memories are formed, proteins are involved; when a neuron malfunctions or contains errors, proteins are involved; and to restore function after brain injury, proteins are involved. In this section, we explain how the different parts of a cell contribute to protein manufacture, describe what a protein is, and detail some functions of proteins. Water, salts, and ions play prominent parts in the cell’s functions, as you will learn in this and the next few chapters. If you already understand the structure of water and you know what a salt is and what ions are, read on. If you prefer a brief chemistry review first, consult The Basics: Chemistry Review.

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THE BASICS

Chemistry Review The smallest unit of a protein or any other chemical substance is the molecule. Molecules and the even smaller atoms of elements that constitute them are the cellular factory’s raw materials. Elements, Atoms, and Ions Chemists represent each element, a substance that cannot be broken down into another substance, by a symbol—for example, O for oxygen, C for carbon, and H for hydrogen. The 10 elements listed in the Chemical Composition of the Brain table below constitute virtually the entire makeup of an average living cell. Many other elements are vital to the cell but are present only in minute quantities. The smallest quantity of an element that retains the properties of that element is an atom. Ordinarily, as shown opposite in part A of the figure Ion Formation, atoms are electrically neutral: their total positive and negative charges are equal. Atoms of chemically reactive elements such as sodium and chlorine can easily lose or gain negatively charged particles, or electrons. When an atom gives up electrons, it becomes positively charged; when it takes on extra electrons, it becomes negatively charged, as illustrated in part B of Ion Formation. Either way, the charged atom is now an ion. Ions’ positive or negative charges allow them to interact. This property is central to cell function.

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Molecules: Salts and Water Salt crystals form bonds via the electrical attraction between ions. The formula for table salt, NaCl (sodium chloride), means that this molecule consists of one sodium ion and one chloride ion. KCl, the formula for the salt potassium chloride, is composed of one potassium ion (K+) and one chloride ion (Cl−). Atoms bind together to form molecules, the smallest units of a substance that contain all of its properties. A water molecule (H2O) is the smallest unit of water that retains the properties of water. Breaking down water any further would release its component elements, the gases hydrogen and oxygen. The symbol H2O indicates that a water molecule is the union of two hydrogen atoms and one oxygen atom. Ionic bonds hold salt molecules together, but the atoms of water molecules share electrons, and electron sharing is not equal: H electrons spend more time orbiting the O atom than orbiting each H atom. As shown in part A of Chemistry of Water, this structure gives the oxygen region of the water molecule a slight negative charge and leaves the hydrogen regions with a slight positive charge. Like atoms, most molecules are electrically neutral, but water is polar: it carries opposite charges on opposite ends. Because water molecules are polar, they are attracted to other electrically charged substances and to one another. Part B of Chemistry of Water illustrates this attracting force, called a hydrogen bond. Hydrogen bonding enables water to dissolve electrically neutral salt crystals into their component ions. Salts thus cannot retain their shape in water; they dissolve. As illustrated in the figure Salty Water, the polar water molecules muscle their way into the Na+ and Cl− lattice, surrounding and separating the ions. Essentially, it is salty water that bathes our brain cells, provides the medium for their activities, supports their communications, and constitutes the brain’s CSF. Sodium chloride and many other dissolved salts, including KCl (potassium chloride) and CaCl2 (calcium chloride) are among the constituents of the brain’s salty water.

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The Cell as a Factory We began Section 3-1 by comparing a cell to a miniature factory, with work centers that cooperate to make and ship the cell’s products— proteins. To investigate the cell’s internal parts—the organelles—and how they function, we begin with a quick overview of the cell’s internal structure. Figure 3-10 displays many external and internal cellular components. A factory’s outer wall separates it from the rest of the world and affords some security. Likewise, a cell’s double-layered outer

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wall, or cell membrane, separates the cell from its surroundings and allows it to regulate what enters and leaves its domain. The cell membrane envelops the neuron’s contents and contributes to forming its cell body, its dendrites and their spines, and its axon and terminals. It thus forms the boundary around a continuous intracellular compartment.

FIGURE 3-10 Typical Nerve Cell This view of the outside and inside of a neuron reveals its overall structure and internal organelles and other components.

Very few substances can enter or leave a cell spontaneously because the cell membrane is virtually impermeable (impenetrable). Some proteins made by the cell are embedded in the cell membrane, where

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they facilitate the transport of substances into and out of the cell. These proteins thus serve as the cellular factory’s gates. Although neurons and glia appear to be packed

In the CNS, the extracellular fluid is CSF.

tightly together, like all other cells, they are separated by extracellular fluid composed mainly of water, with dissolved salts and many other chemicals. A similar intracellular fluid is found inside a cell. What is important is the cell membrane’s relative impermeability, which ensures that concentrations of substances inside and outside the cell are different. Within the cell shown in Figure 3-10 are membranes that surround its organelles, similar to the work areas demarcated by a factory’s interior walls. Each organelle membrane is also relatively impermeable and so concentrates needed chemicals while keeping out unneeded ones. The prominent nuclear membrane surrounds the cell’s nucleus. Within the nucleus, the genetic blueprints for the cell’s proteins are stored, copied, and sent to the “factory floor,” the endoplasmic reticulum (ER). The ER is an extension of the nuclear membrane; here, the cell’s protein products are assembled in accordance with instructions from the nucleus. Once those proteins are assembled, many are packaged and sent throughout the cell. The Golgi bodies are “mailrooms,” where proteins are wrapped, addressed, and shipped. Other cell components are tubules of several kinds. Some (microfilaments) reinforce the cell’s structure; others aid in the cell’s movements. Still others (microtubules) form the transportation network

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that carries proteins to their destinations, much as roads allow a factory’s trucks and forklifts to deliver goods to their destinations. Two other important parts of the cellular factory shown in Figure 310 are the mitochondria (sing. mitochondrion)—the cell’s power plants, which supply its energy needs—and lysosomes, vesicles that transport incoming nutrients and remove and store waste. Interestingly, more lysosomes are found in old cells than in young ones. Cells apparently have trouble disposing of all their garbage, just as societies do.

Cell Membrane: Barrier and Gatekeeper The cell membrane separates the intracellular from the extracellular fluid, allowing the cell to function as an independent unit. The membrane’s double-layered structure, shown in Figure 3-11A, regulates the movement of substances, including water, into and out of the cell. If too much water enters a cell, it will burst; if too much water leaves a cell, it will shrivel. The cell membrane’s structure helps ensure that neither happens.

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FIGURE 3-11 Bilayer Cell Membrane Structure (A) Double-layered cell membrane close up. (B) Detail of a phospholipid molecule’s polar head and electrically neutral tails. (C) Space-filling model shows why the phosphate head’s polar regions (positive and negative poles) are hydrophilic, whereas its nonpolar fatty acid tail is hydrophobic.

The cell membrane also regulates the differing concentrations of salts and other chemicals on its inner and outer sides. This regulation is important because, if its concentrations of chemicals are unbalanced, the cell will not function normally. What properties of a cell membrane allow it to regulate water and salt concentrations? One property is its special molecular construction. These molecules, called phospholipids, are named for their structure, shown close up in Figure 3-11B. Figure 3-11C shows a space-filling chemical model of the phospholipid molecule’s structure. The molecule has a head containing the element phosphorus (P) bound to some other atoms, and it has two tails, which are lipids, or fat molecules. The head has a polar electrical charge, with a positive charge in one location and a negative charge in another, as do water molecules. The tails consist of hydrogen and 357

carbon atoms that tightly bind to one another by their shared electrons; hence, the fatty tail has no polar regions. The polar head and the nonpolar tails are the underlying reasons a phospholipid molecule can form cell membranes. The heads are hydrophilic (from the Greek hydro, meaning “water,” and philia, meaning “love”) and so are attracted to one another and to polar water molecules. The nonpolar lipid tails have no such attraction for water. They are hydrophobic, or water hating (from the Greek word phobia, meaning “fear”). Quite literally, then, the head of a phospholipid loves water, and the tails hate it. To avoid water, the tails of phospholipid molecules point toward each other, and the hydrophilic heads align with one another and point outward to the watery intracellular and extracellular fluid. In this way, the cell membrane consists of a bilayer (two layers) of phospholipid molecules (see Figure 3-11A). The bilayer cell membrane is flexible even as it forms a formidable barrier to a wide variety of substances. It is impenetrable to intracellular and extracellular water because polar water molecules cannot pass through the hydrophobic tails on the membrane’s interior. Ions in the extracellular and intracellular fluid also cannot penetrate this membrane because they carry charges and thus cannot pass by the polar phospholipid heads. In fact, only a few small molecules, such as oxygen (O2), carbon dioxide (CO2), and the sugar glucose, can traverse a phospholipid bilayer.

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The Nucleus and Protein Synthesis In our factory analogy, the nucleus is the cell’s executive office, where the blueprints for making proteins are stored, copied, and sent to the factory floor. These blueprints are called genes, segments of DNA that encode the synthesis of particular proteins. Genes are contained within the chromosomes, the double-helix structures that hold an organism’s entire DNA library. The chromosomes have been likened to books of blueprints. Each chromosome contains thousands of genes. Each gene is the blueprint, or code, for making one protein. The location of the chromosomes in the cell nucleus, the appearance of a chromosome, and the structure of the DNA within a chromosome are shown in Figure 3-12.

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FIGURE 3-12 Chromosome The nerve cell’s nucleus contains paired chromosomes of double-stranded DNA molecules bound together by a sequence of nucleotide bases.

This static picture of chromosomes does not represent the way they look in living cells. Videos of the cell nucleus show that chromosomes are constantly changing shape and moving in relation to one another, jockeying to occupy the best locations within the nucleus. By changing shape, chromosomes expose different genes to the surrounding fluid, thus allowing the gene to begin the process of making a protein. In humans, the reproductive cells are the sperm (male) and the egg (female).

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Chromosome means “colored body”; chromosomes are so named because they can be readily stained with certain dyes.

A human somatic (body) cell has 23 pairs of chromosomes, or 46 chromosomes in all. (In contrast, there are only 23 chromosomes within a reproductive cell, and they are not paired.) Each chromosome is a double-stranded molecule of deoxyribonucleic acid (DNA). The two strands of a DNA molecule coil around each other, as shown in Figure 3-12. Each strand possesses a variable sequence of four nucleotide bases, the constituent molecules of the genetic code: adenine (A), thymine (T), guanine (G), and cytosine (C). Adenine on one strand always pairs with thymine on the other, whereas guanine on one strand always pairs with cytosine on the other. The two strands of the DNA helix are bound together by the attraction between the two bases in each pair, as illustrated in Figure 3-12. Sequences of hundreds of nucleotide bases within the chromosomes spell out the genetic code. Scientists represent this code by the letters of the nucleotide bases—for example, ATGCCG. A gene is a segment of a DNA strand. A gene’s code is its sequence of thousands of nucleotide bases. Much as a sequence of letters spells out a word, the sequence of ACTG base pairs spells out the order in which amino acids, the constituent molecules of proteins, should be assembled to construct a certain protein. To begin to make a protein, the appropriate gene segment of the DNA strand unwinds to expose its bases. The exposed sequence of nucleotide bases on the DNA strand then serves as a template to attract free-floating molecules called nucleotides. The nucleotides attach to the 361

DNA to form a complementary strand of ribonucleic acid (RNA). The single-stranded nucleic acid molecule then detaches from the DNA and leaves the cell carrying within its structure the code for protein synthesis. This process, called transcription, is shown in steps 1 and 2 of Figure 3-13. (To transcribe means “to copy,” as in copying part of a message you receive in a text.)

FIGURE 3-13 Protein Synthesis Information in a cell flows from DNA to mRNA to protein (peptide chain).

The Endoplasmic Reticulum and Protein Manufacture When RNA is produced through transcription, it forms a chain of bases much like a single strand of DNA, except that the base uracil (U) takes the place of thymine. Uracil is attracted to adenine, as is thymine in

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DNA; otherwise, the base code of RNA and DNA is similar. The transcribed strand of RNA is called messenger RNA (mRNA) because it carries the protein code (the message) out of the nucleus to the endoplasmic reticulum, where proteins are manufactured. Steps 3 and 4 in Figure 3-13 show that the ER consists of membranous sheets folded to form numerous channels. A distinguishing feature of the ER is that it may be studded with ribosomes, protein structures that act as catalysts to facilitate the building of proteins. When a mRNA molecule reaches the ER, it passes through a ribosome, where its genetic code is read. In this process of translation, a particular sequence of nucleotide bases in the mRNA is transformed into a particular sequence of amino acids. Transfer RNA (tRNA) assists in translating nucleotide bases into amino acids. As shown in Figure 3-14, each group of three consecutive nucleotide bases along an mRNA molecule encodes one particular amino acid. These sequences of three bases are called codons. For example, the codon uracil, guanine, guanine (UGG) encodes the amino acid tryptophan (Trp), whereas the codon uracil, uracil, uracil (UUU) encodes the amino acid phenylalanine (Phe). The sequence of codons on the mRNA strand determines the sequence of the resulting amino acid chain.

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FIGURE 3-14 Transcription and Translation In protein synthesis (see Figure 313), a particular sequence of nucleotide bases in a strand of DNA (top) is transcribed into mRNA (center). Each sequence of three nucleotide bases in the mRNA strand (a codon) encodes one amino acid. In translation, the amino acids, directed by the codons, link together to form a chain (bottom). The amino acids are tryptophan (Trp), phenylalanine (Phe), glycine (Gly), and serine (Ser).

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Humans utilize 20 different amino acids, all structurally similar, as illustrated in Figure 3-15A. Each amino acid consists of a central carbon atom (C) bound to a hydrogen atom (H), an amino group (NH3+), a carboxyl group (COO−), and a side chain (represented by the letter R). The side chain varies in chemical composition from one amino acid to another. Each amino group (NH3+) is bound to the carboxyl group (COO−) of the adjacent amino acid by a peptide bond, which gives the amino acid chain its alternative name, polypeptide chain (Figure 3-15B).

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FIGURE 3-15 Properties of Amino Acids (A) Each amino acid consists of a central carbon atom (C) attached to an amine group (NH3+), a carboxyl group (COO−), and a distinguishing side chain (R). (B) The amino acids are linked by peptide bonds to form a polypeptide chain.

Just as a remarkable number of words can be made from the 26 letters of the English alphabet, a remarkable number of polypeptide (meaning “many peptides”) chains can be made from the 20 amino acids. These amino acids can form 400 (20 × 20) dipeptides (twopeptide combinations), 8000 (20 × 20 × 20) tripeptides (three-peptide combinations), and almost countless polypeptides. In summary, the information flow driven by the genetic code is conceptually quite simple: a gene (a portion of a DNA strand) is transcribed into a strand of mRNA, and ribosomes translate the mRNA into a molecular chain of amino acids, a polypeptide chain, which forms a protein. Thus the sequence of events in building a protein: DNA → mRNA → protein

Proteins: The Cell’s Product A polypeptide chain and a protein are related, but they are not always the same. The relationship is analogous to the relationship between a length of ribbon and a bow that can be made from the ribbon. Long polypeptide chains have a strong tendency to twist into helices (spirals) or to form pleated sheets, which in turn have a strong tendency to fold together to form more complex shapes, as shown in Figure 3-16. A protein is a folded-up polypeptide chain; its shape is important to the function that it serves.

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FIGURE 3-16 Four Levels of Protein Structure Whether a polypeptide chain forms a pleated sheet or a helix and what its three-dimensional shape ultimately will be are determined by the amino acid sequence in the primary structure. In rare circumstances, misfolded proteins wreak havoc, as occurs with some prion proteins that are implicated in many degenerative brain diseases, including mad cow disease, wasting diseases in sheep, and possibly Alzheimer and Parkinson disease; see Section 16-3.

Any one neuron contains as many as 20,000 genes, and, in principle, these genes can produce as many as 20,000 different protein molecules. The number of proteins that can ultimately be produced by a neuron is far larger than the number of its genes, however. Although each gene codes for one protein, a protein can be cleaved into pieces—by enzymes, for example—or combined with other proteins in a variety of cellular processes to form still other proteins. A protein’s shape and its ability to change shape and to combine with other proteins are central to its function. Proteins can modify the length, shape, and behavior of other proteins and so act as enzymes, proteins that enhance chemical reactions. Proteins embedded in a cell membrane can regulate the flow of substances across the membrane. And proteins can be exported from one cell to another and so act as messenger molecules.

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Golgi Bodies and Microtubules: Protein Packaging and Shipment Getting proteins to the right destination is the task of cellular components that package, label, and ship them. These components operate much like a postal or shipping service. To reach their appropriate destinations, protein molecules that have been synthesized in the cell are wrapped in membranes and marked with addresses to indicate where they are to go. This wrapping and labeling take place in the organelles called Golgi bodies. The packaged proteins are then loaded onto motor molecules that move along the many microtubules radiating through the cell, carrying each protein to its destination. Protein export is illustrated in Figure 3-17.

FIGURE 3-17 Protein Export Exporting a protein entails packaging, transporting, and assigning its fate at the destination.

If a protein is destined to remain within the cell, it is unloaded into the intracellular fluid. If it is to be incorporated into the cell membrane, it is carried to the membrane, where it inserts itself. If it is to be exported from the cell, it is usually transferred out in a process called

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exocytosis (meaning “out of the cell”). The membrane, or vesicle, in which the protein is wrapped fuses with the cell membrane, and the protein is excreted into the extracellular fluid.

Crossing the Cell Membrane: Channels, Gates, and Pumps Some proteins are embedded in the cell membrane. These proteins serve many functions, including transporting small molecules, such as salts, sugar, and other chemicals, across the membrane. We now consider how three such membrane proteins—channels, gates, and pumps—perform the transport function. In each case, the particular protein’s function is an emergent property of its shape. A protein’s shape and its ability to change shape derive from the precise amino acid sequence that composes the protein molecule. Some proteins change shape when other chemicals bind to them; others change shape as a function of temperature; and still others change shape in response to changes in electrical charge. The protein molecule’s ability to change shape is analogous to a lock in a door. When a key of the appropriate size and shape is inserted into the lock and turned, the locking device activates and changes shape, allowing the door to be closed or opened. Such a shape-changing protein is illustrated in Figure 3-18. The surface of this protein molecule has a groove, called a receptor, analogous to a keyhole. Small molecules, such as glucose, or other proteins can bind to a protein’s receptors and cause the protein to change shape. Changes in shape allow the proteins to serve some new function. 370

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FIGURE 3-18 Receptor Binding When substances bind to a protein’s receptors, the protein changes shape, which may change its function.

Some membrane proteins form channels through which substances can pass. Different-sized channels regulate the passage of differentsized substances. Figure 3-19A illustrates a protein with a particular shape forming a channel large enough to pass potassium (K+) but not other ions. Other protein channels allow sodium ions or chloride ions to pass into or out of the cell. Still others allow the passage of various other substances.

FIGURE 3-19 Transmembrane Proteins Channels, gates, and pumps are proteins embedded in the cell membrane.

Figure 3-19B shows a protein molecule that acts as a gate to regulate the passage of substances. Like the protein in Figure 3-18, gates change their shape in response to some trigger. The protein allows substances to pass through when its shape forms a channel and prevents passage when its shape leaves the channel closed.

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Changes in protein’s shape can also allow it to act as a pump. Figure 3-19C shows a protein that changes its shape to pump Na+ and K+ across the membrane, exchanging the Na+ on one side for the K+ on the other. Channels, gates, and pumps play an important role in allowing substances to enter and leave a cell. Again, this passage of substances is critical in explaining how neurons send messages. Chapter 4 explores how neurons use electrical activity to communicate. 3-2 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. The constituent parts of the cell include the , , , .

, , and

2. Proteins in the cell membrane serve many functions, including acting at the cell membrane as , , and to regulate movement of substances across the membrane. 3. The basic sequence of events in building a protein is that makes , which in turn makes . 4. Once proteins are formed in the , they are wrapped in membranes by and transported by to their designated sites in the neuron or its membrane or exported from the cell by .

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5. Briefly explain how the production of proteins in a cell contributes to behavior.

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3-3 Genes, Cells, and Behavior Your genotype (genetic makeup) influences your physical and behavioral traits, which combine to form your phenotype (individual characteristics, including behavioral characteristics). Genetic analysis conducted by the Human Genome Project cataloged the human genome —all 20,000 or so genes in our species—and today individual genomes are routinely sequenced. (Recall the Beery twins in Research Focus 31.) James Watson, the co-discoverer of DNA, was the first person to have his genome sequenced. Res earcher

Figure 1-12 shows how a Neanderthal woman might have looked.

s have sequencing the genomes of some of our extinct ancestors, including the Neanderthal genome. The genomes of James Watson and the Neanderthal are surprisingly similar, as you’d expect for close hominid relatives. You can have your genome sequenced to reveal many aspects of its coding functions, including your relationship to Neanderthals, if you have European ancestry. The cost is about $100. (Before you decide, you may want to check on any required information sharing with employers and insurers.) Studying how genes influence our traits is the objective of Mendelian genetics, named for Gregor Mendel, whose research led to the concept of the gene. Studying how the environment influences gene

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expression is the objective of epigenetics. In this section, we describe how both factors influence our phenotypes.

Mendelian Genetics and the Genetic Code The nucleus of each human somatic cell contains 23 pairs of chromosomes, or 46 in all. One member of each pair comes from the mother, and the other member comes from the father. The chromosome pairs are numbered from 1 to 23, roughly according to size, with chromosome 1 being the largest (Figure 3-20).

FIGURE 3-20 Human Chromosomes The nucleus of a human cell contains 23 chromosomes derived from the father and 23 from the mother. Sexual characteristics are determined by the twenty-third pair, the X and Y (sex) chromosomes.

Chromosome pairs 1 through 22 are called autosomes, and they contain the genes that contribute most to our physical appearance and behavior. The twenty-third pair are the sex chromosomes, which contribute to our physical and behavioral sexual characteristics. The two mammalian sex chromosomes are referred to as X and Y, shown at the right in Figure 3-20. Ordinarily, female mammals have two X 376

chromosomes, whereas males have an X and a Y. The Y chromosome contains the SRY (sex determining region) gene that makes the SRY protein, which triggers testes development and hence the male phenotype. Because all but your sex chromosomes are matched pairs, each cell contains two copies of every gene, one inherited from your mother, the other from your father. These two copies of a gene are called alleles. The term matched here does not necessarily mean identical. The nucleotide sequences in a pair of alleles may be either identical or different. If they are identical, the two alleles are homozygous (homomeans “the same”). If they are different, the two alleles are heterozygous (hetero- means “different”). The nucleotide sequence most common in a population is called the wild-type allele, whereas a less frequently occurring sequence is called a mutation. Any wild-type allele may have a number of mutations— some beneficial, some neutral, and some harmful.

Dominant and Recessive Alleles If both alleles in a gene pair are homozygous, the two encode the same protein, but if the two alleles in a pair are heterozygous, they encode somewhat different proteins. Three possible outcomes attend the heterozygous condition when these proteins express a physical or behavioral trait: (1) only the allele from the mother may be expressed, (2) only the allele from the father may be expressed, or (3) both alleles may be expressed simultaneously. A member of a gene pair that is routinely expressed as a trait is called a dominant allele; an unexpressed allele is recessive. Alleles can 377

vary considerably in their dominance. In complete dominance, only the allele’s own trait is expressed in the phenotype. In incomplete dominance, the allele’s own trait is expressed only partially. In codominance, both the allele’s own trait and that of the other allele in the gene pair are expressed completely. Each gene makes an independent contribution to the offspring’s inheritance, even though the contribution may not always be visible in the offspring’s phenotype. When paired with a dominant allele, a recessive allele is often not expressed. Still, it can be passed on to future generations and influence their phenotypes when not masked by the influence of some dominant trait.

Genetic Mutations The mechanism described in Section 3-2 for reproducing genes and passing them on to offspring is fallible. Errors can arise in the nucleotide sequence when reproductive cells make gene copies. The altered alleles are mutations. A mutation may be as small as a change in a single nucleotide base, called a single nucleotide polymorphism (SNP, pronounced “snip”). This one base change results in a change in a codon and a resulting change in one amino acid in a protein. A single amino acid change is a mutation and is often sufficient to alter the protein’s function. Because the average gene has more than 1200 nucleotide bases, an enormous number of SNPs as well as more Complex Losses and changes in bases can occur on a single gene. For example, the BRCA1 (BReast CAncer) gene, found on chromosome 17, is a caretaker gene that contributes to preventing breast cancer and other cancers in both 378

men and women. More than 1000 mutations of this gene have already been found. Thus, in principle, there are more than 1000 ways in which to have a predisposition to, or increased resistance to, a cancer just from this gene. A mutation in a nucleotide or the addition of a nucleotide to a gene sequence In this micrograph, a sickle cell is surrounded by healthy blood cells.

can be beneficial or

disruptive or both. For example, a SNP in which a T base is substituted for an A base in the HBB (hemoglobin) gene on chromosome 11 causes sickle-cell anemia, a condition in which blood cells take on an abnormal sickle shape. The sickle shape offers some protection against malaria, but sickle cells also have poor oxygen-carrying capacity, which weakens the person who possesses them. Sickle-cell anemia is the most common genetic blood disease, affecting millions of people worldwide, including 80,000 people in the United States. Neuroscientists cannot yet explain human behavior in relation to genes, but we know the severe behavioral consequences of about 2000

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genetic abnormalities that affect the nervous system. For example, an error in a gene could produce a protein that should be an ion channel but will not allow the appropriate substance to pass. It may produce a pump that will not pump or a protein that the cell’s transportation system refuses to transport.

ACQUIRED GENETIC MUTATIONS The genetic mutations just described may be inherited by offspring from their parents. However, each of us also acquires a surprisingly large number of genetic mutations during our lifetime. These acquired mutations are not inheritable, but they have the potential to affect the behavior of the individual carrier. Some mutations are due to mitotic (cell division) errors that occur during our development, and others occur as a cell’s DNA engages in its routine activity of producing proteins. Different mutations may be localized in different parts of the body or brain, or even in individual brain cells. Given that the human brain consists of 86 billion neurons and 87 billion glial cells, all of which arose by cell division from a single cell, it is not surprising that mutations occur. And because most neurons are with us for life and are metabolically active for life, it is not surprising that they can accumulate mutations. Self-generated mutations can feature SNPs or even larger pieces of DNA that escape the mechanisms that normally repair DNA. One analysis of the DNA of single human neurons finds that errors in each neuron accumulate at the rate of one per week. At 1 year of age, a neuron may have up to 300–900 mutations; by 80 years of age, a neuron may have as many as 2000 mutations (Lodato et al.,

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2018). Do the math: 173 billion brain cells multiplied by up to 2000 mutations per cell is a lot of mutations in a lifetime. The accumulation of mutations in the brain immediately raises the question of their effects on behavior. While mutations may be beneficial or seemingly neutral to the functioning of the organism that carries them, most mutations likely have negative effects. DNA mutations may contribute to childhood development disorders and could also influence diseases of aging. In short, we are accustomed to hearing that our genome is inherited from our parents, but it actually gets modified a lot as we develop and age.

Applying Mendel’s Principles Gregor Mendel introduced the

Experiment 1-1 describes one of Mendel’s experiments.

concept of dominant and recessive alleles in the nineteenth century, when he studied pea plants. Today, scientists study genetic variation to gain insight into how genes, neurons, and behaviors are linked. This knowledge is directed toward explaining healthy behavior and helping reduce the negative effects of genetic abnormalities, perhaps someday even eliminating them.

Allele Disorders That Affect the Brain Som e

Scientists Warren Tay and Bernard Sachs first described the disorder.

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diso rders caused by mutant genes illustrate Mendel’s principles of dominant and recessive alleles. One is Tay-Sachs disease, caused by a dysfunction in a gene that produces HexA (hexosaminidase A). HexA breaks down a class of lipids (fats) in brain cells. If HexA is nonfunctional, the lipids accumulate in brain cells, resulting in cell damage. Symptoms usually appear a few months after birth. The baby begins to have seizures, deteriorating eyesight, and degenerating motor and mental abilities. Inevitably, the child dies within a few years. Tay-Sachs mutations appear with high frequency among certain ethnic groups, including Jews of European origin and French Canadians, but the mutation in different populations can be different. The dysfunctional Tay-Sachs HexA enzyme is caused by a recessive (nonfunctioning) allele of the HEXA gene on chromosome 15. Distinctive inheritance patterns result from recessive alleles because two copies (one from the mother and one from the father) are needed for the disorder to develop. A baby can inherit Tay-Sachs disease only when both parents pass on the recessive allele. Because both parents have survived to adulthood, both must also possess a corresponding dominant wild-type HEXA allele for that particular gene pair. The egg and sperm cells produced by this man and woman will therefore contain a copy of the wild type, or the mutation of these two alleles. Which allele is passed on is determined completely by chance.

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In any child born of two Tay-Sachs carriers, then, this situation gives rise to three possible gene combinations, as shown in Figure 3-21A. The child may have two wild-type alleles, in which case he or she will be spared the disorder and cannot pass it on. The child may have one normal and one Tay-Sachs allele, in which case he or she, like the parents, will be a carrier. Or the child may have two Tay-Sachs alleles, in which case he or she will develop the disease.

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FIGURE 3-21 Inheritance Patterns (A) Recessive condition: If a parent has one mutant allele, the parent will not show symptoms of the disease but will be a carrier. If both parents carry a mutant allele, each of their offspring stands a 25 percent chance of developing the disease. (B) Dominant condition: A person with a single allele will develop the disease. If this person mates with a noncarrier, offspring have a 50–50 chance of developing the disease. If both parents are carriers, both will develop the disease, and offspring have a 75 percent chance of developing it.

The chance of a child of two carriers being normal is 25 percent, the chance of being a carrier is 50 percent, and the chance of having TaySachs disease is 25 percent. If one parent is a Tay-Sachs carrier and the other is normal, any child has a 50–50 chance of being normal or a carrier. Such a couple has no chance of conceiving a baby with TaySachs disease. The Tay-Sachs allele operates independently of the dominant allele. As a result, it still produces the defective HexA enzyme, so the person who carries it has a higher-than-normal lipid accumulation in the brain. Because this person also has a normal allele that produces a functional enzyme, the abnormal lipid accumulation is not enough to cause TaySachs disease. A blood test can detect whether a person carries the Tay-Sachs allele. People who find that they are carriers can make informed decisions about conceiving children. If they avoid having children with another Tay-Sachs carrier, none of their children will have the disorder, although some will probably be carriers. Where genetic counseling has been effective, the disease has been eliminated.

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The normal dominant allele that a carrier of Tay-Sachs possesses produces enough functional enzyme to enable the brain to operate in a satisfactory way. That would not be the case if the abnormal allele were dominant, however, as happens with the genetic disorder Huntington disease. Here, the buildup of an abnormal version of the huntingtin protein kills brain cells, especially in the basal ganglia and the cortex. Huntington disease is a landmark disease for neuroscience because it has revealed much about the relationship between a single gene and the nervous system and, perhaps more importantly, because this knowledge can in principle lead to a cure for the disease. Symptoms can begin at any time from infancy to old age, but they most often start in midlife and include abnormal involuntary movements—which is why the disorder was once called a chorea (from the Greek word for “dance”). Other symptoms are memory loss and eventually a complete deterioration of behavior, followed by death. The abnormal HTT (huntingtin) allele is dominant, and the recessive allele is normal, so only one defective allele is needed to cause the disease. Figure 3-21B illustrates the inheritance patterns associated with a dominant allele on chromosome 4 that produces Huntington disease. If one parent carries the defective allele, offspring have a 50 percent chance of inheriting the disorder. If both parents have the defective allele, the chance of inheritance increases to 75 percent. As discussed further in Clinical Focus 3-3, Huntington Disease, because the abnormal huntingtin allele usually is not expressed until midlife—that is, usually after the people who possess it have already had children—it is unwittingly passed down even though it is lethal.

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CLINICAL FOCUS 3-3

Huntington Disease Woody Guthrie, whose protest songs made him a spokesperson for farm workers during the Great Depression of the 1930s, is revered as one of the founders of American folk music. His best-known song is “This Land Is Your Land.” Singer, songwriter, and recent Nobel Prize winner Bob Dylan was instrumental in reviving Guthrie’s popularity in the 1960s. Guthrie’s case illustrates much of the history of Huntington disease. Guthrie died in 1967, after struggling with what was eventually diagnosed as Huntington disease. His mother had died of a similar condition, although her illness was never diagnosed. Two of Guthrie’s five children from two marriages developed the disease, and his second wife, Marjorie, became active in promoting its study.

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Woody Guthrie, whose unpublished lyrics and artwork are archived at woodyguthrie.org.

Huntington disease is devastating, characterized by memory impairment; choreas (abnormal, uncontrollable movements); and marked changes in personality, eventually leading to nearly total loss of healthy behavioral, emotional, and intellectual functioning. Even before the onset of motor

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symptoms, Huntington disease impairs theory of mind, a person’s ability to assess the behavior of others (Eddy & Rickards, 2015). The symptoms of Huntington disease result from neuronal degeneration in the basal ganglia and cortex. Symptoms can appear at any age but typically start in midlife. In 1983, the HTT (huntingtin) gene responsible for forming the abnormal huntingtin protein was found on chromosome 4. The HTT gene has been a source of insights into the transmission of genetic disorders. Part of the gene contains repeats of the base sequence CAG. The CAG codon encodes the amino acid glutamine. If the number of CAG repeats exceeds about 40, then the carrier, with 40 or more glutamine amino acids in the huntingtin protein, has an increased likelihood of Huntington symptoms. As the number of CAG repeats increases, the onset of symptoms occurs earlier in life, and the disease progresses more rapidly. Typically, nonEuropeans have fewer repeats than do Europeans, among whom the disease is more common. The number of repeats can also increase with transmission from the father but not from the mother. Investigations into why brain cells change in Huntington disease and into potential treatments use transgenic animal models. Mice, rats, and monkeys that have received the HTT gene feature the abnormal huntingtin protein and display symptoms of Huntington disease (Stricker-Shaver et al., 2018). Modification of the HTT gene using modern genetic engineering is in principle a cure for the disease (Yapijakis, 2017).

As with the allele that causes Tay-Sachs disease, a genetic test can determine whether a person carries the allele that causes Huntington disease. If so, the person can elect not to procreate. A decision not to have children in this case will reduce the incidence of the abnormal huntingtin allele in the human gene pool.

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Chromosome Abnormalities Genetic disorders are not caused solely by single defective alleles. Some nervous system disorders are caused by copy number variations —that is, aberrations in a part of a chromosome or even an entire chromosome. Copy number variations are related to a variety of disorders, including autism, schizophrenia, and learning disabilities. Often, though, copy number variation has little obvious consequence or is even beneficial. For example, humans average about 6 copies of the AMY1 (amylase) gene but may have as many as 15 copies. The gene is an adaptation that improves the ability to digest starchy foods (Mimori et al., 2015). One condition due to a change in chromosome number in humans is Down syndrome, which affects approximately 1 in 700 children. Down syndrome is usually the result of an extra copy of chromosome 21. One parent (usually the mother) passes on to the child two copies of chromosome 21 rather than the normal single chromosome. Combining these two with one chromosome from the other parent yields three chromosome 21s, an abnormal number called a trisomy (Figure 3-22).

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FIGURE 3-22 Chromosome Aberration Left: Down syndrome, also known as trisomy 21, is caused by an extra chromosome 21 (colored red, bottom row at left). Right: Chris Burke, the first person with Down syndrome to play a leading role on a television series—Life Goes On, in the 1990s—is now in his fifties and remains an advocate for individuals with Down syndrome. He performs as a lead singer in a band.

Although chromosome 21 is the smallest human chromosome, its trisomy can dramatically alter a person’s phenotype. People with Down syndrome have characteristic facial features and short stature. They are susceptible to heart defects, respiratory infections, and intellectual impairment. They are prone to developing leukemia and Alzheimer disease. Although people with Down syndrome usually have a shorterthan-normal life span, some live to middle age or beyond. Improved educational opportunities enrich the lives of children with Down syndrome.

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Genetic Engineering Despite advances in understanding gene structure and function, the gap in understanding how genes produce behavior remains wide. To investigate gene structure and behavior relationships, geneticists have invented methods to influence the traits that genes express. This approach collectively defines the science of genetic engineering. In its simplest forms, genetic engineering entails manipulating a genome, removing a gene from a genome, or modifying or adding a gene to the genome. Its techniques include selective breeding, cloning, and transgenics.

Selective Breeding The oldest means of influencing genetic traits is the selective breeding of animals and plants. Beginning with the domestication of wolves into dogs more than 30,000 years ago, humans have domesticated many animal species by selectively breeding males and females that display particular traits. The selective breeding of dogs, for example, has produced the species with the most diverse traits of all animal species: breeds that can run fast, haul heavy loads, retrieve prey, dig for burrowing animals, climb rocky cliffs in search of sea birds, herd sheep and cattle, or sit on an owner’s lap and cuddle. Selective breeding has influenced the dog brain by making it smaller than a wolf’s brain but also by giving it a comparatively large number of cortical neurons for a carnivore of its size, which may account for its sociability with humans (Jardim-Messeder et al., 2017). Maintaining spontaneous mutations is one objective of selective breeding. Using this method, researchers produce whole populations of animals possessing some unusual trait that originally arose as an 392

unexpected mutation in only one individual or in a few animals. In laboratory colonies of mice, for example, multiple spontaneous mutations have been discovered and maintained to produce more than 450 different mouse strains. Unlike other animals, humans can consent to experimental procedures. Section 7-7 frames debates on the benefits and ethics of conducting research using nonhuman animals.

Some strains of mice make abnormal movements, such as reeling, staggering, and jumping. Other strains have diseases of the immune system; others are blind or cannot hear. Some mice are smart, some mice are not; some have big brains, some small; and many display distinctive behavioral traits. Some mice are also designed to have neurons that incorporate proteins that produce specialized channels and fluorescent proteins. Some of these fluorescent proteins are so bright that they can be visualized through the skull. If the fluorescence is activated by a metabolic change in a single cell, this cell’s activity can be observed through the skull (Iwano et al., 2018). As a result, the neural and genetic bases of the altered behavior in the mice can be studied systematically to understand and treat human disorders.

Cloning Sections 7-1 and 7-5 review genetic methods used in neuroscience research.

More direct approaches to manipulating the expression of genetic traits include altering early embryonic development. One such method is 393

cloning—producing an offspring that is genetically identical to another animal. To clone an animal, scientists begin with a cell nucleus that contains DNA (usually from a living animal donor), place it in an egg cell from which the nucleus has been removed, and, after stimulating the egg to start dividing, implant the new embryo in the uterus of a female. Because each individual animal that develops from these cells is genetically identical to the donor, clones can be used to preserve valuable traits, to study the relative influences of heredity and environment, or to produce new tissue or organs for transplant to the donor. Dolly, a female sheep, was the first cloned mammal. A team of researchers in Scotland cloned Dolly in 1996. As an adult, she mated and bore a lamb.

Cloning has matured from an experimental manipulation to a commercial enterprise to produce better strains of domestic animals, preserve rare animal species, and even bring back extinct species. The first horse to be cloned was Charmayne James’s horse Scamper, the mount she rode to 11 world championships in barrel racing. The first cat to be cloned, shown in Figure 3-23, was called Copycat. The first rare species cloned was an Asian gaur, an animal related to the cow. Investigators interested in de-extinction propose using preserved cells from species such as the extinct passenger pigeon or from frozen carcasses of the extinct mastodon to clone those animals. (An enclosure to house a de-extinct mastodon has in fact been prepared in Russia.)

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FIGURE 3-23 A Clone and Her Mom Copycat (left) and Rainbow (right), the cat that donated the cell nucleus for cloning. Although the cats’ genomes are identical, their phenotypes, including fur color, differ. One copy of the X chromosome is randomly inactivated in each cell, which explains the color differences. Even clones are subject to phenotypic plasticity: they retain the capacity to develop into more than one phenotype.

Transgenic Techniques Transgenic technology enables scientists to introduce genes into an embryo or to remove genes from it. In knock-in technology, a number of genes or a single gene from one species is added to the genome of another species, passed along, and expressed in subsequent generations of transgenic animals. For instance, researchers have introduced into lines of mice, rats, and Rhesus monkeys the human HTT gene that causes Huntington disease (Stricker-Shaver et al., 2018). The animals

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express the abnormal allele and display humanlike Huntington symptoms, allowing investigations into potential treatments for the disease (see Clinical Focus 3-3). Knockout technology can be used to inactivate a gene, for example, so that a line of laboratory animals fails to express it. The line can then be examined to determine whether the targeted gene is responsible for a specific function or a human disorder and to examine possible therapies. Knockout technology has been used to produce a line of rats that display the emotional and cognitive symptoms of human childhood attention-deficit/hyperactivity disorder in order to explore methods of treatment (Adinolfi et al., 2018).

Gene Modification A number of new methods for modifying genes involve altering its code, its base pairs. CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat, pronounced “crisper”) is a new technology that allows for faster and easier modifications of genes. The CRISPR machinery was discovered as part of the immune system of bacteria. A CRISPR RNA base sequence in the bacteria seeks out a matching DNA sequence in the invading virus and cuts the virus DNA, thus inactivating the virus. The molecular mechanism that identifies an invading virus by its unique DNA sequences can be modified in the laboratory to produce an RNA sequence that can identify specific parts of the DNA in any gene. Using the CRISPR method, the identified gene can be cut, a portion of it deleted, and the deleted portion replaced by another DNA base sequence. This type of gene editing is similar to the way that you edit a

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sentence with your word processor to delete words, add words, or correct spelling mistakes. For more information on the CRISPR method, see Section 7-1.

Applic ations of the

CRISPR technology include making plants or animals resistant to viral or bacterial infections, identifying cancer cells (including brain cancer) to kill them, and making animal models to study almost any aspect of behavior, including emotion, memory, and motor behavior. CRISPR technology can in principle also be used to identify genes that are implicated in various diseases, such as the HTT gene that causes Huntington disease, and fix the gene. CRISPR technology has been used to study the olfactory behavior of mosquitoes and ants, and it is possible that the genes of these insects can be modified so that they do not identify humans as targets to bite (Vinauger et al., 2018).

Phenotypic Plasticity and the Epigenetic Code Our genotype is not sufficient to explain our phenotype. We all know that if we expose ourselves to the sun, our skin darkens; if we exercise, our muscles enlarge; if we study, we learn. Our phenotype also changes with our diet and as we age. In short, the extent of phenotypic variation, given the same genotype, is remarkable. Every individual has a capacity to develop into more than one phenotype. This phenotypic plasticity is due in part to the genome’s capacity to express a large number of phenotypes and in part to

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epigenetics, the influence of environment and experience on phenotypic expression. Seemingly puzzling features in the expression of genomes in relation to phenotypes are illustrated in strains of genetically identical mice, some of which develop a brain with no corpus callosum (Figure 3-24). The absence of this hemispheric connector results from an epigenetic influence on whether the trait is expressed in a particular mouse. It occurs in the embryo at about the time the corpus callosum should form. This lack of concordance (incidence of similar behavioral traits) is also observed in patterns of disease incidence in human identical twins, who share the same genome.

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FIGURE 3-24 Gene Expression Identical coronal sections through the brains of mice with identical genotypes reveal frontal views of distinctly different phenotypes. (A) This mouse had a corpus callosum. (B) This mouse did not.

The concordance rate between identical twins for a vast array of diseases—including schizophrenia, Alzheimer disease, multiple sclerosis, Crohn disease (a form of inflammatory bowel disease), asthma, diabetes, and prostate cancer—is between 30 and 60 percent. For cleft palate and breast cancer, identical twins’ concordance rate is about 10 percent. The expectation from Mendelian genetics is 100 percent concordance. These less-than-perfect concordance rates point to epigenetic factors. The cloned mice shown in Figure 2-1 exemplify phenotypic plasticity.

Phenotypic plasticity is in evidence not only in adult organisms but also in cells. In Section 3-1, we described the variety of neurons and glia found in the nervous system. Each of these cells usually has the same genotype. So do the 248 other cell types of our body. How then do they become so different?

Applying the Epigenetic Code The genes expressed in a cell are influenced by factors within the cell and in the cell’s environment. Once a fertilized egg begins to divide, each new cell finds itself in a somewhat different environment from that of its parent cell. The cell’s environment will determine which genes are expressed and so what kind of tissue it becomes, including what kind of nervous system cell it becomes. Environmental influences do not end at

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birth, of course. Our environment changes daily throughout our lives, as does its influence on our genes. The International Human Epigenome Consortium (IHEC) mandate is to describe the epigenetic code, as the Human Genome Project has described the genetic code.

Epigenetic mechanisms create phenotypic variation without altering the base pair nucleotide sequence of the genes. Through these mechanisms, experience and the environment can allow a gene to be expressed or prevent its expression. Epigenetics is viewed as a second code; the first code is the genome. Epigenetics describes how a single genetic code produces each somatic cell type, explains how a single genome can code for many phenotypes, and describes how cell functions go astray to produce diseases ranging from cancer to brain dysfunction. Epigenetic mechanisms can influence protein production either by blocking a gene to prevent transcription or by unlocking a gene so that it can be transcribed. This is where experiential and environmental influences come into play. To review, each of your chromosomes consists of a long, double-stranded chain of nucleotide bases that forms your DNA. Each gene on a chromosome is a segment of DNA that encodes the synthesis of a particular protein (see Figure 3-13). Chromosomes are wrapped around supporting molecules of a protein called histone. Histone wrapping allows the many yards of a chromosome to be packaged in a small space, as yards of thread are wrapped around a spool. For any gene to be transcribed into messenger

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RNA, its DNA must be unspooled from the histone. Once unspooled, each gene must be instructed to transcribe mRNA. Then the mRNA must be translated into an amino acid chain that forms the protein. Figure 3-25 illustrates some ways that each step can be either enabled or blocked: 1. Histone modification. DNA may unwrap or be stopped from unwrapping from the histone. At the top of Figure 3-25, a methyl group (CH3) or other molecule binds to the tails of histones to block DNA from unspooling. The DNA’s genes cannot be exposed for transcription with the block in place (left), but the DNA’s genes can be opened for transcription (right) if the block is absent or removed. 2. Gene (DNA) methylation. Transcription of DNA into mRNA may be enabled or blocked. In Figure 3-25 at center, one or more methyl groups bind to CG base pairs to block transcription. 3. mRNA modification. mRNA translation may be enabled or blocked. In Figure 3-25, bottom, noncoding RNA (ncRNA) binds to mRNA, blocking translation.

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FIGURE 3-25 Epigenetic Mechanisms

Methylation dramatically alters gene expression during brain development (see Sections 8-2 and 12-5) and can affect memory and brain plasticity (see Section 14-4).

An environmental influence can either induce or remove one or more blocks, thus allowing the environment to regulate gene expression and influence behavior (Rogers, 2018). It is through these epigenetic mechanisms that cells are instructed to differentiate into various body

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tissues and that our unique environment and experience induce changes in our brain that make us unique individuals and allow us to learn. Some experientially induced events can also be passed from one generation to the next, as the following classic case study illustrates.

A Case of Inheriting Experience The idea that traits are passed from parent to child through genes is a cornerstone of Mendelian genetics. Mendel’s theory also predicts that individual life experience cannot be inherited. In a now classic report, Lars Olov Bygren and colleagues (Kaati et al., 2007) found, however, that individuals’ nutritional experiences can affect their offspring’s health. The investigators focused on Norrbotten, a sparsely populated northern Swedish region. In the nineteenth century, Norrbotten was virtually isolated from the outside world. If the harvest there was bad, people starved. According to historical records, the years 1800, 1812, 1821, 1836, and 1856 saw total crop failure. The years 1801, 1822, 1828, 1844, and 1863 brought good harvests and abundance. Bygren and colleagues identified at random individuals who had been subjected to famine or to plenty in the years just before they entered puberty. Then the researchers examined the health records and longevity of these people’s children and grandchildren. The findings seem to defy logic. The descendants of the plenty group had higher rates of cardiovascular disease and diabetes and had a life expectancy more than 7 years shorter than that of the famine group! Notably, these effects were found only in male offspring of males and female offspring of females. 404

Bygren and colleagues propose that diet during a critical period can modify the genetic expression of sex chromosomes—the Y chromosome in males and the X chromosome in females. Furthermore, this change can be passed on to subsequent generations. Dietary experience in the prepubertal period, just before the onset of sexual maturity, is important: this is the time at which gene expression on the sex chromosomes begins. Section 8-4 examines critical periods, limited time spans during which events have long-lasting influences on development.

Many other studies support the seminal findings of Bygren and his colleagues. Together, this body of research makes a strong argument for epigenetics and for the idea that some epigenetic influences can be passed on for at least a few generations. Evidence that epigenetic influences play a demonstrable role in determining gene expression is highlighting how our experiences shape our brains to influence the individuals we become and how our current environment might influence our descendants’ epigenetic inheritance (Guerrero-Bosagna, 2017). 3-3 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. Each of our chromosome pairs contains thousands of genes, and each gene contains the code for one .

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2. The genes we receive from our parents may include slightly different of particular genes, which will be expressed in slightly different . 3. Abnormalities in a gene, caused by a(n) , can result in an abnormally formed protein, hence in abnormal cell function. Chromosome abnormality can result in abnormal functioning of many genes. , for example, is caused by an extra copy of chromosome 21, a(n) . 4. Tay-Sachs disease results from a(n) allele being expressed; Huntington disease results from the expression of a(n) allele. 5.

is a new technology that allows for faster and easier gene modification. Using this method, researchers can identify specific parts of the in any gene, cut it, and replace it with another .

is an epigenetic mechanism that either enables or blocks transcription.

7. What distinguishes Mendelian genetics from epigenetics?

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Summary 3-1 Cells of the Nervous System The nervous system is composed of two kinds of cells: neurons, which transmit information, and glia, which support neuronal function. Sensory neurons may act as receptors to convey information from the body to the brain, motor neurons command muscles to move, and interneurons link up sensory and motor neuron activities. Like neurons, glial cells can be grouped by structure and function. Ependymal cells produce CSF. Astrocytes structurally support neurons, help to form the blood–brain barrier, and seal off damaged brain tissue. Microglia aid in brain cell repair and waste removal. Oligodendroglia and Schwann cells myelinate axons in the CNS and in the somatic division of the PNS, respectively. A neuron is composed of three parts: a cell body, or soma; multiple branching extensions called dendrites, designed to receive information; and a single axon that passes information along to other neurons. Numerous dendritic spines greatly increase a dendrite’s surface area. An axon may have branches (axon collaterals), which further divide into telodendria, each ending at a terminal button (end foot). A synapse is the almostconnection between a terminal button and another cell’s membrane. 407

3-2 Internal Structure of a Cell A surrounding cell membrane protects the cell and regulates what enters and leaves it. Within the cell are a number of organelles, also enclosed in membranes. These compartments include the nucleus (containing the cell’s chromosomes and genes), the endoplasmic reticulum (where proteins are manufactured), the mitochondria (where energy is gathered and stored), the Golgi bodies (where protein molecules are packaged for transport), and lysosomes (which break down wastes). A cell also contains a system of tubules (microfilaments) that aid its movements, provide structural support, and act as highways for transporting substances. To a large extent, the work of cells is carried out by proteins. The nucleus contains chromosomes—long chains of genes, each encoding a specific protein the cell needs. Proteins perform diverse tasks by virtue of their diverse shapes. Some act as enzymes to facilitate chemical reactions; others serve as membrane channels, gates, and pumps; still others are exported for use in other parts of the body. A gene is a segment of a DNA molecule made up of a sequence of nucleotide bases. Through transcription, a copy of a gene is produced in a strand of messenger RNA. The mRNA travels to the endoplasmic reticulum, where a ribosome moves along the mRNA molecule, translating it into a sequence of amino acids. The resulting amino acid chain is a polypeptide. 408

Polypeptides fold and combine to form protein molecules with distinctive shapes that serve specific purposes in the body.

3-3 Genes, Cells, and Behavior From each parent, we inherit one of each chromosome in the 23 chromosome pairs that constitute the human genotype. Because all but the sex chromosomes are matched pairs, a cell contains two alleles of every gene. Sometimes the paired alleles are homozygous (the same), and sometimes they are heterozygous (different). An allele may be dominant and expressed as a trait, recessive and not expressed, or codominant and expressed along with the other allele in the organism’s phenotype. One allele of each gene is designated the wild type—the most common in a population— whereas the other alleles are called mutations. A person might inherit any of these alleles from a parent, depending on the parent’s genotype. Genes have the potential to undergo many mutations—of a single base pair, of part of the chromosome, or of the entire chromosome. Mutations can be inherited by offspring from parents, or they can be acquired as we develop and age. Acquired mutations can be localized to different parts of the body, organs (including the brain), or even individual cells. Mutations can be beneficial, harmful, or neutral in their effects on nervous system structure and behavioral function. Genetic research seeks to

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prevent the expression of genetic and chromosomal abnormalities and to find cures for those that are expressed. Selective breeding is the oldest form of genetic manipulation. In genetic engineering, an animal’s genome is artificially altered. The genetic composition of a cloned animal is identical to that of a parent or sibling. In transgenic animals, a new or altered gene may be added or a gene removed. CRISPR is a relatively new technology in gene modification, faster and easier than previous methods, that allows researchers to identify, cut, and replace specific DNA sequences in the genome. The genome encodes a range of phenotypes. The phenotype that is eventually produced is determined by epigenetics and further influenced by experience and the environment. Epigenetic mechanisms such as DNA methylation can influence whether genes are transcribed or transcription is blocked without changing the genetic code itself.

Key Terms allele astrocyte axon axon collateral axon hillock

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bipolar neuron blood–brain barrier cell body (soma) channel dendrite dendritic spine Down syndrome ependymal cell gate gene gene (DNA) methylation glial cell heterozygous homozygous Huntington disease hydrocephalus interneuron microglia motor neuron mutation myelin

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neural network oligodendroglia paralysis protein pump Purkinje cell pyramidal cell Schwann cell sensory neuron somatosensory neuron synapse Tay-Sachs disease terminal button (end foot) transgenic animal tumor wild type

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CHAPTER 4 How Do Neurons Use Electrical Signals to Transmit Information?

4-1 Searching for Electrical Activity in the Nervous System CLINICAL FOCUS 4-1 Epilepsy Early Clues That Linked Electricity and Neuronal Activity THE BASICS Electricity and Electrical Stimulation Tools for Measuring a Neuron’s Electrical Activity

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How Ion Movement Produces Electrical Charges 4-2 Electrical Activity at a Membrane Resting Potential Maintaining the Resting Potential Graded Potentials Action Potential Nerve Impulse Refractory Periods and Nerve Action Saltatory Conduction and the Myelin Sheath CLINICAL FOCUS 4-2 Multiple Sclerosis 4-3 How Neurons Integrate Information Excitatory and Inhibitory Postsynaptic Potentials EXPERIMENT 4-1 Question: How Does Stimulating a Neuron Influence Its Excitability? Summation of Inputs Voltage-Activated Channels and the Action Potential The Versatile Neuron

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RESEARCH FOCUS 4-3 Optogenetics and Light-Sensitive Ion Channels 4-4 Into the Nervous System and Back Out How Sensory Stimuli Produce Action Potentials How Nerve Impulses Produce Movement CLINICAL FOCUS 4-4 ALS: Amyotropic Lateral Sclerosis

CLINICAL FOCUS 4-1 Epilepsy J. D. worked as a disc jockey for a radio station and at parties in his offhours. One evening, he set up on the back of a truck at a rugby field to emcee a jovial and raucous rugby party. Between musical sets, he made introductions, told jokes, and exchanged toasts. At about 1 A.M., J. D. suddenly collapsed, making unusual jerky motions, then passed out. He was rushed to a hospital emergency room, where he gradually recovered. The attending physician noted that he was not intoxicated, released him to his friends, and recommended that a series of neurological tests be run the next day. Neuroimaging with state-of-the-art brain scans can usually reveal brain abnormalities (Cendes et al., 2016), but it did not do so in J. D.’s case. When the electrical activity in J. D.’s brain was recorded while a strobe light was flashed before his eyes, an electroencephalogram, or EEG, displayed a series of abnormal electrical patterns characteristic of epilepsy. The doctor prescribed Dilantin (diphenylhydantoin), an antiseizure drug, and advised J. D. to refrain from drinking alcohol. He was required to give up his

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driver’s license to prevent the possibility of an attack while driving. And he lost his job at the radio station.

The EEG detects electrical signals given off by the brain in various states of consciousness, as explained in Sections 7-2 and 13-3, Section 16-3 details the diagnosis and treatment of epilepsy.

After 3 uneventful months, medication was stopped, and J. D.’s driver’s license was restored. J. D. convinced the radio station that he could resume work, and subsequently he has remained seizure free. Epilepsy is a common neurological disease marked by periods of excessive neural synchrony called electrographic seizures. The disease is electrical in nature. The brain is normally electrically active; if this activity becomes abnormal, even infrequently, the consequences, including loss of conscious awareness, can be severe. Electrographic seizures often follow innocuous stimuli—events that would not typically cause seizures in people who do not have epilepsy. The

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core concept is that the brain of a person with epilepsy has a chronically low seizure threshold and so is subject to recurrent seizures. About 4 in 10 cases of epilepsy have been linked to specific neural causes, among them infections, trauma, tumors, structural abnormalities, or genetic mutations in the proteins that make up ion channels (Bhalla et al., 2011). But that leaves the remaining 60 percent without a clear cause. If seizures occur repeatedly and cannot be controlled by drug treatment, as occurs in about 30 percent of people with epilepsy, other options may include the high-fat/low-carbohydrate ketogenic diet, deep brain stimulation, and surgical resection of the seizure focus (Rho et al., 2010). Removing this small area of brain tissue may prevent seizures and keep them from spreading to other brain regions.

The most reproduced drawing in behavioral neuroscience is nearly 350 years old, predating our understanding of the electrical basis of epilepsy by centuries. Taken from René Descartes’s book Treatise on Man (1664) and reproduced in Figure 4-1, it illustrates the first serious attempt to explain how information travels through the nervous system. Descartes proposed that the carrier of information is cerebrospinal fluid flowing through nerve tubes.

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FIGURE 4-1 Descartes’s Theory of Information Flow

Descartes proposed the idea behind dualism–that the nonmaterial mind controls body mechanics; see Section 1-2.

Descartes reasoned that when the fire burns the man’s toe, it stretches the skin, which tugs on a nerve tube leading to the brain. In response to the tug, a valve in a brain ventricle opens, and cerebral spinal fluid (CSF) flows down the tube, filling the leg muscles and causing them to contract and pull the toe back from the fire. The flow of fluid through other tubes to other muscles of the body (not shown in Figure 4-1) causes the head to turn toward the painful stimulus and the hand to rub the injured toe. Descartes’s theory was incorrect, yet it is remarkable because he isolated the three basic questions that underlie a behavioral response to stimulation:

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1. How do our nerves detect a sensory stimulus and inform the brain about it? 2. How does the brain decide what response to make? 3. How does the brain command muscles to move? Descartes was trying to explain the very same things that scientists have sought to explain in the intervening centuries. If not by stretched skin tugging on a nerve tube initiating the message, the message must still be initiated somehow. If not by opening valves to initiate the flow of CSF to convey information, the information must still be sent. If not by filling the muscles with fluid that produces movements, the muscles must contract by some other mechanism. These mechanisms are the subject of this chapter. We examine how neurons convey information from the environment throughout the nervous system and ultimately activate muscles to produce movement. We begin by describing the clues and tools that were first used to explain the nervous system’s electrical activity.

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4-1 Searching for Electrical Activity in the Nervous System The first hints about how the nervous system conveys its messages came in the eighteenth century, following the discovery of electricity. Early discoveries about the nature of electricity quickly led to proposals that it plays a role in conducting information in the nervous system. We describe a few milestones that led from this idea to an understanding of how the nervous system really conveys information. If you have a basic understanding of how electricity works and how it is used to stimulate neural tissue, read on. If you prefer to brush up on electricity and electrical stimulation first, turn to The Basics: Electricity and Electrical Stimulation.

THE BASICS

Electricity and Electrical Stimulation Electricity powers the lights in your home and the batteries that run so many electronic gadgets, from smartphones to electric cars. Electricity is the flow of electrons from a body that contains a higher charge (more electrons) to a body that contains a lower charge (fewer electrons). This electron flow can perform work—lighting an unlit bulb, for instance. When biological tissue contains an electrical charge, the charge can be recorded; if living tissue is sensitive to an electrical charge, the tissue can be stimulated.

How Electricity Works

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In the Power Source diagram, negatively charged electrons are attracted to the positive pole because opposite charges attract. The electrons on the negative pole have the potential to flow to the positive pole. This electrical potential, or electrical charge, is the ability to do work using stored electrical energy.

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Electrical potential is measured in volts, the difference in charge between the positive and negative poles. These poles are separated by an insulator. Thus, when not connected, the positive and negative poles in a battery, like the poles in each wall socket in your home, hold voltage between the poles.

Electrical Activity in Cells If the bare tip of an insulated wire, or electrode, from each pole of a battery comes into contact with biological tissue, current will flow from the electrode connected to the negative pole into the tissue and from the tissue into the electrode connected to the positive pole. The stimulation comes from the electrode’s uninsulated tip. Microelectrodes can record from or stimulate tissue as small as parts of a single living cell. Electrical stimulation, illustrated in part A of the Studying Electrical Activity in Animal Tissue diagram below, is most effective when administered in brief pulses. A timer in the stimulator turns the current on and off to produce the pulses. In electrical recording, voltage can be displayed by the dial on a voltmeter, a recording device that measures the voltage of a battery or of biological tissue (part B).

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Early Clues That Linked Electricity and Neuronal Activity Gray’s experiment resembles accumulating electrons by combing your hair. Hold a piece of paper near the comb, and the paper bends toward it. Negative charges on the comb push negative charges on the paper to its backside, leaving the front side positively charged. Because opposite charges attract, the paper bends toward the comb.

In a dramatic demonstration in 1731, Stephen Gray, an amateur scientist, rubbed a rod with a piece of cloth to accumulate electrons on the rod. Then he touched the charged rod to the feet of a boy suspended on a rope and raised a piece of metal foil to the boy’s nose. The foil was attracted to the boy’s nose, causing it to bend on its approach; as foil and nose touched, electricity passed from the rod through the boy to the foil. Gray speculated that electricity might be the messenger that spreads information through the nervous system. Two other lines of evidence, drawn from electrical stimulation and electrical recording studies, implicated electrical activity in the nervous system’s flow of information.

Electrical Stimulation Studies When the Italian scientist Luigi Galvani, a contemporary of Gray, observed that frogs’ legs hanging on a wire in a market twitched during a lightning storm, he surmised that sparks of electricity from the storm were activating the leg muscles. Investigating this possibility, he found

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that if an electrical current is applied to an exposed nerve, the muscle connected to that nerve contracts. While it was unclear how the process worked, Galvani had discovered electrical stimulation: passing an electrical current from the uninsulated tip of an electrode onto a nerve to produce behavior—a muscular contraction. Among the many researchers who used Galvani’s technique to produce muscle contraction, two mid-nineteenth-century scientists, Gustav Theodor Fritsch and Eduard Hitzig, demonstrated that electrical stimulation of the neocortex causes movement. They studied several animal species, including rabbits and dogs, and may even have stimulated the neocortex of a person whom they were treating for head injuries sustained on a Prussian battlefield. They observed their subjects’ arm and leg movements in response to the stimulation of specific parts of the neocortex. In 1874, Roberts Bartholow, a Cincinnati physician, first described the effects of human brain stimulation. His patient, Mary Rafferty, had a skull defect that exposed part of her neocortex. Bartholow stimulated her exposed brain tissue to examine the effects. In one of his observations, he wrote: Passed an insulated needle into the left posterior lobe so that the non-insulated portion rested entirely in the substance of the brain. The reference was placed in contact with the dura mater. When the circuit was closed, muscular contraction in the right upper and lower extremities ensued. Faint but visible contraction of the left eyelid, and dilation of the pupils, also ensued. Mary complained of a very strong and unpleasant feeling of tingling in both right extremities, especially in the right arm, which she seized with the 426

opposite hand and rubbed vigorously. Notwithstanding the very evident pain from which she suffered, she smiled as if much amused. (Bartholow, 1874) As you might imagine, Bartholow’s report was not well received! The uproar after its publication forced him to leave Cincinnati. Despite his unethical experiment, Bartholow had demonstrated that the brain of a conscious person could be stimulated electrically to produce movement of the body. By the 1960s, the scientific community had established ethical standards for research on human and nonhuman subjects (see Section 7-7). Today, lowintensity and non-damaging brain stimulation is standard in many neurosurgical procedures (see Section 16-3).

Electrical Recording Studies A less invasive line of evidence that information flow in the brain is partly electrical came from the results of electrical recording experiments. Richard Caton, a physician who lived a century ago, was the first to measure the brain’s electrical currents with a sensitive voltmeter, a device that measures the flow and the strength of electrical voltage by recording the difference in electrical potential between two bodies. When he placed electrodes on a human subject’s skull, Caton reported fluctuations in his voltmeter recordings. Today, this type of brain recording, the electroencephalogram (EEG), is a standard tool used for, among other things, monitoring sleep stages and detecting the excessive neural synchrony that characterizes electrographic seizures, as described in Clinical Focus 4-1, Epilepsy.

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Details on these EEG applications appear in Sections 7-2, 13-3, and 16-3.

These pioneering studies provided evidence that neurons send electrical messages, but it would be incorrect to conclude that nerves and tracts carry the kind of electrical current that powers your phone. Hermann von Helmholtz, a nineteenth-century scientist, stimulated a nerve leading to a muscle and measured the time the muscle took to contract. The nerve conducted information at only 30 to 40 meters per second, whereas electricity flows along a wire about a million times faster. Information flow in the nervous system, then, is much too slow to be a flow of electricity (based on electrons). To explain the electrical signals of a neuron, Julius Bernstein suggested in 1886 that neuronal chemistry (based on ions) produces an electrical charge. He also proposed that the charge could change and thus could act as a signal. Bernstein’s idea was that successive waves of electrical change constitute the message conveyed by the neuron. Moreover, it is not the ions themselves that travel along the axon but rather a wave of charge. To understand the difference, consider other kinds of waves. If you drop a stone into a pool of still water, the contact produces a wave that travels away from the site of impact, as shown in Figure 4-2. The water itself moves up and down and does not travel away from the impact site. Only the change in pressure moves, shifting the height of the water surface and producing the wave effect.

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FIGURE 4-2 Wave Effect Waves formed by dropping stones into still water do not entail the water’s forward movement but rather pressure differences that change the height of the water surface.

Similarly, when you speak, you induce pressure waves in air, and these waves carry your voice to a listener. If you flick a towel, a wave travels to the other end of the towel. Just as waves through the air send a spoken message, Bernstein’s idea was that waves of chemical change travel along an axon to deliver a neuron’s message.

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Waves that carry messages in the nervous system are minute and are restricted to the surfaces of neurons. Still, we can produce these waves using conventional electrical stimulation and measure them using electrical recording techniques to determine how they are produced. When a single axon is stimulated, it produces a wave of excitation. If an electrode connected to a voltmeter is placed on a single axon, as illustrated in Figure 4-3, the electrode can detect a change in electrical charge on that axon’s membrane as the wave passes.

FIGURE 4-3 Wave of Information Neurons can convey information as a wave, induced by stimulation on the cell body, traveling down the axon to its terminal. A voltmeter detects the wave’s passage.

As simple as this process may seem, recording a wave and determining how it is produced requires a neuron large enough to record, a recording device sensitive enough to detect a tiny electrical impulse, and an electrode small enough to be placed on the surface of a single neuron. The fortuitous discovery of the giant axon of the squid, the invention of the oscilloscope, and the development of microelectrodes met all these requirements.

Giant Axon of the Squid The neurons of most animals, including humans, are tiny, on the order of 1 to 20 micrometers (μm) in diameter—too small to be seen by the naked eye. The zoologist J. Z. Young, when dissecting the North

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Atlantic squid Loligo vulgaris, noticed that it has giant axons, as large as a millimeter (1000 μm, or about 1/25 inch) in diameter. Figure 4-4 illustrates Loligo and the giant axons leading to its body wall, or mantle, which contracts to propel the squid through the water.

FIGURE 4-4 Laboratory Specimen (A) The North Atlantic squid propels itself both with fins and by contracting its mantle to force water out for propulsion. (B) The stellate ganglion projects giant axons to contract the squid’s mantle.

1 micrometer (also called a micron) (μm) = one-millionth of a meter, or one-thousandth of a millimeter (mm).

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Measuring only about 1 foot long, Loligo is not a giant squid. But its axons are giant, as axons go. Each is formed by the fusion of many smaller axons. Because larger axons send messages faster than smaller axons do, these giant axons allow the squid to jet-propel away from predators. In 1936, Young suggested to Alan Hodgkin and Andrew Huxley, neuroscientists at Cambridge University in England, that Loligo’s axons were large enough to be used for electrical recording studies. They dissected a giant axon out of the squid and kept it alive and functioning in a bath of salty liquid that approximated the squid’s body fluids. In this way, Hodgkin and Huxley (1939) determined the neuron’s ionically based electrical activity. In 1963, they received the Nobel Prize for their accomplishment.

Oscilloscope Hodgkin and Huxley’s experiments were made possible by the invention of the oscilloscope, a voltmeter with a screen sensitive enough to display the minuscule electrical signals emanating from a nerve or neuron over time (Figure 4-5A). As graphed in Figure 4-5B, the units used when recording the electrical charge from a nerve or neuron are millivolts (mV; 1 mV is one-thousandth of a volt) and milliseconds (ms; 1 ms is one-thousandth of a second). Computers interfaced with recording equipment have largely replaced oscilloscopes.

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FIGURE 4-5 Oscilloscope Recording (A) Basic wave shapes are displayed on a digital oscilloscope, a versatile electronic instrument used to visualize and measure electrical signals as they change. (B) On the graph of a trace produced by an oscilloscope, S stands for stimulation. The horizontal axis measures time, and the vertical axis measures voltage. By convention, the axon voltage is represented as negative, in millivolts (mV). On the right, one trace of two action potentials from an individual neuron as displayed on a digital oscilloscope screen.

Microelectrodes The final device needed to measure a neuron’s electrical activity is an electrode small enough to place on or in an axon—a microelectrode. A microelectrode can deliver electrical current to a single neuron as well as record from it. One way to create a microelectrode is to etch the tip of a piece of thin wire to a fine point about 1 mm in size and insulate the rest of the wire with a synthetic polymer, like plastic. The tip is placed on or in the neuron, as shown in the left-hand image in Figure 46A.

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FIGURE 4-6 Uses of Microelectrodes (A) A squid axon is larger than the tip of either a wire (left) or a glass (right) microelectrode. Both can be placed on an axon or in it. (Drawings are not to scale.) (B) A glass microelectrode can record from only a small area of an axon by suctioning the membrane up onto its tip.

A microelectrode can also be made from a thin glass tube tapered to a very fine tip (Figure 4-6A, right image). The tip of a hollow glass microelectrode can be as small as 1 mm. When the glass tube is filled with salty water, a conducting medium through which electrical current can travel, it acts as an electrode. A wire in the salt solution connects the electrode to either a stimulating device or a recording device. Microelectrodes can record from axons in many ways. The tip of a microelectrode placed on an axon provides an extracellular measure of the electrical current from a tiny part of the axon. The tip of one electrode can be placed on the surface of the axon, and the tip of a

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second electrode can be inserted into the axon. This technique can be used to measure voltage across the cell membrane. A still more refined use of a glass microelectrode is to place its tip on the neuron’s membrane and apply a little suction until the tip is sealed to a patch of the membrane, as shown in Figure 4-6B. This technique, analogous to placing the end of a soda straw against a piece of plastic wrap and sucking, allows a recording to be made from only the small patch of membrane sealed to the microelectrode tip. Using the giant axon of the squid, an oscilloscope, and microelectrodes, Hodgkin and Huxley recorded the electrical voltage on an axon’s membrane and learned that the nerve impulse is a change in the concentration of specific ions across the cell membrane. The basis of electrical activity in nerves is the movement of intracellular and extracellular ions, which carry positive and negative charges across the cell membrane. We discuss the role of electrical activity in cell functioning in the next section, but first, to understand Hodgkin and Huxley’s results, you first need to understand the principles underlying the movement of ions.

How Ion Movement Produces Electrical Charges The intracellular fluid within a neuron and the extracellular fluid surrounding it contain various ions, including Na+ (sodium) and K+ (potassium)—positively charged, as the plus signs indicate—and negatively charged Cl− (chloride). These fluids also contain numerous protein molecules, most of which hold an overall negative charge (A−). Positively charged ions are called cations, and negatively charged ions, 435

including protein molecules, are called anions. Three factors influence the movement of anions and cations into and out of cells: diffusion, concentration gradient, and voltage gradient. Because molecules move constantly, they tend to spread out from a point of high concentration. This spreading out is diffusion. Requiring no additional energy, diffusion results from the random motion of molecules as they move and bounce off one another to gradually disperse in a solution. Diffusion results in a dynamic equilibrium, with a relatively equal number of molecules everywhere in the solution. Smoke, for example, gradually diffuses through the air in a room until every bit of air contains the same number of smoke molecules. Dye poured into water diffuses in the same way—from its point of contact to every part of the water in the container. Salts placed in water dissolve; their individual ions dissociate and become surrounded by water molecules. The ions and their associated water molecules then diffuse throughout the solution to equilibrium, at which point every part of the container has the same ion concentration. The Basics covers ions. The Salty Water illustration shows how water molecules dissolve salt crystals.

Concentration gradient describes the relative abundance of a substance in a space. Ions are initially highly concentrated where they enter at the top of a beaker of water, as illustrated in Figure 4-7, compared to the bottom of the beaker. As time passes, concentration gradients flow down due to diffusion.

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FIGURE 4-7 Moving to Equilibrium

Because ions carry an electrical charge and because like charges repel one another, ion movement can be described by a concentration gradient, the difference in the number of ions between two regions, and a voltage gradient, the difference in charge between two regions. Ions move down a voltage gradient from an area of higher charge to an area of lower charge, just as they move down a concentration gradient from an area of higher concentration to an area of lower concentration. Figure 4-7B illustrates this process. When salt is dissolved in water, the diffusion of its ions can be described either as movement down a concentration gradient (for sodium and chloride ions) or movement down a voltage gradient (for the positive and negative charges). In a container that allows unimpeded movement of ions, the positive and negative charges eventually balance. The cell membrane is an insulator impermeable to salty solutions: dissolved ions, surrounded by water molecules, do not pass through the membrane’s hydrophobic tails (review Figure 3-11).

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A thought experiment will illustrate how a cell membrane influences ion movement. Figure 4-8A shows a container of water divided in half by a solid membrane that is impermeable to water and ions. If we place a few grains of table salt (NaCl) in the left half of the container, the salt dissolves. The ions diffuse down their concentration and voltage gradients until the water in the left compartment is in equilibrium.

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FIGURE 4-8 Modeling the Cell Membrane

In the left side of the container, there is no longer a gradient for either sodium or chloride ions because they occur everywhere with the same relative abundance. There are no gradients for these ions on the

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other side of the container either because the solid membrane prevents the ions from entering that side. But there are concentration and voltage gradients for both sodium and chloride ions across the membrane—that is, from the salty side to the freshwater side. Transmembrane protein molecules embedded in a cell membrane form channels, some with gates, and pumps that allow specific kinds of ions to pass through the membrane. Returning to our thought experiment, we insert a few chloride channels into the membrane that divides the container of water, making the membrane semipermeable— that is, permeable to chloride but not to sodium, as illustrated at the left in Figure 4-8B. Chloride ions will now diffuse through the channels and cross the membrane by moving down their concentration gradient to the side of the container that previously had no chloride ions, shown in the middle of Figure 4-8B. The sodium ions, in contrast, cannot pass through the chloride channels and remain on one side of the cell membrane. Even though dissolved sodium ions are smaller than chloride ions, they hold water molecules more strongly and thus act like they are bulkier and cannot pass through a narrow chloride channel.

If the only factor affecting the movement of chloride ions were the chloride concentration gradient, the efflux (outflow) of chloride from the salty side to the freshwater side of the container would continue until chloride ions were in equilibrium on both sides. But this is not what happens. Remember that opposite charges attract, so the chloride ions, which carry a negative charge, are attracted to the positively charged sodium ions they left behind. Because they are pulled back

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toward the sodium ions, the chloride ions cannot diffuse completely. Consequently, the concentration of chloride ions remains somewhat higher in the left side of the container than in the right, as illustrated at the right in Figure 4-8B. In other words, the efflux of chloride ions down the chloride concentration gradient is counteracted by the influx (inflow) of chloride ions down the chloride voltage gradient. At some point, an equilibrium is reached: the chloride concentration gradient on the right side of the beaker is balanced by the chloride voltage gradient on the left. In brief: concentration gradient = voltage gradient At this equilibrium, the differential concentration of the chloride ions on the two sides of the membrane produces a difference in charge— voltage. The left side of the container is more positively charged because some chloride ions have migrated, leaving a preponderance of positive (Na+) charges. The right side of the container is more negatively charged because some chloride ions have entered that chamber, where none were before. The charge is highest on the surface of the semipermeable membrane, the area at which positive and negative ions accumulate. Much the same process happens at the semipermeable membranes of real cells.

4-1 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests.

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1. Although he was incorrect, was the first to seriously attempt to explain how information travels through the nervous system. 2. Experimental results obtained over hundreds of years from electrical and more recently from electrical implicated electrical activity in the nervous system’s flow of information. 3. By the mid-twentieth century, scientists had solved three technical problems in measuring the changes in electrical charge that travel like a wave along an axon’s membrane: , , and . 4. The electrical activity of neuronal axons entails the diffusion of ions. Ions may move down a(n) and down a(n) . 5. In what three ways does the semipermeable cell membrane affect the movement of ions in the nervous system?

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4-2 Electrical Activity at a Membrane Most biological membranes are semipermeable because they have ion channels embedded within them; we will refer to them simply as membranes. Electrical activity in neurons is the movement of specific ions through channels across neuronal membranes. It is this process which allows the waves of electrical activity moving along membranes to convey information throughout the nervous system. So how are changes in the movement of ions across neuronal membranes achieved?

Resting Potential Figure 4-9 shows how the voltage difference is recorded when one microelectrode is placed on the outer surface of an axon’s membrane and another is placed on its inner surface. In the absence of stimulation, the difference is about 70 mV. Although the charge on the outside of the membrane is actually positive, by convention it is given a charge of zero. Therefore, the inside of the membrane at rest is −70 mV relative to the extracellular side.

FIGURE 4-9 Resting Potential The electrical charge across a resting cell membrane stores potential energy.

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Why zero? We are interested in the relative difference, not the actual charge.

If we were to continue to record for a long time, the charge across the unstimulated membrane would remain much the same. The charge can change, given certain changes in the membrane, but at rest the difference in charge on the inside and outside of the membrane produces an electrical potential—the ability to use its stored power, analogous to a charged battery. The charge is thus a store of potential energy called the membrane’s resting potential. We might use the term potential in the same way to talk about the financial potential of someone who has money in the bank; the person can spend the money at some future time. The resting potential, then, is a store of energy that can be used later. Most of your body’s cells have a resting potential, but it is not identical on every axon. Resting potentials vary from −40 to −90 mV, depending on neuronal type and animal species. Four charged particles take part in producing the resting potential: ions of sodium (Na+), potassium (K+), chloride (Cl−), and large negatively charged protein molecules (A−). These are the cations and anions, respectively, defined in Section 4-1. As Figure 4-10 shows, these charged particles are distributed unequally across the axon’s membrane, with more protein anions and potassium ions in the intracellular fluid and more sodium and chloride ions in the extracellular fluid. How do the unequal concentrations arise, and how does each contribute to the resting potential?

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FIGURE 4-10 Ion Distribution Across the Resting Membrane The number of ions distributed across the resting cell membrane is unequal. Protein anions are represented by the label A−.

Use this mnemonic to remember which ions are on which side: we put table salt—sodium chloride—on the outside of our food.

Maintaining the Resting Potential The cell membrane’s channels, gates, and pumps maintain the resting potential. Figure 4-11, which shows the resting membrane close up, details how these three features contribute to the cell membrane’s resting charge: 1. Because the membrane is relatively impermeable to large molecules, the negatively charged proteins (A−) remain inside the cell. 2. Ungated potassium and chloride channels allow potassium (K+) and chloride (Cl−) ions to pass more freely, but gates on sodium channels keep out positively charged sodium ions (Na+).

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3. Na+−K+ pumps extrude Na+ from the intracellular fluid and inject K+.

FIGURE 4-11 Maintaining the Resting Potential Channels, gates, and pumps in the cell membrane contribute to the transmembrane charge.

Inside the Cell Large protein anions are manufactured inside cells. No membrane channels are large enough to allow these proteins to leave the cell, and their negative charge alone is sufficient to produce transmembrane voltage, or a resting potential. Because most cells in the body manufacture these large, negatively charged protein molecules, most cells have a charge across the cell membrane. To balance the negative charge produced by large protein anions in the intracellular fluid, cells accumulate positively charged potassium ions to the extent that about 20 times as many potassium ions cluster inside the cell as outside it. Potassium ions cross the cell membrane

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through open potassium channels, as shown in Figure 4-11. With this high concentration of potassium ions inside the cell, however, the potassium concentration gradient across the membrane limits the number of potassium ions entering the cell. In other words, not all the potassium ions that could enter do enter. Because the internal concentration of potassium ions is much higher than the external potassium concentration, potassium ions are drawn out of the cell by the potassium concentration gradient. A few residual potassium ions on the outside of the membrane are enough to contribute to the charge across the membrane. They add to the net negative charge on the intracellular side of the membrane relative to the extracellular side. You may be wondering whether you read the last sentence correctly. If there are 20 times as many potassium ions inside the cell as there are outside, why should the inside of the membrane have a negative charge? Should not all those potassium ions in the intracellular fluid give the inside of the cell a positive charge instead? No, because not quite enough potassium ions are able to enter the cell to balance the negative charge of the protein anions. Think of it this way: if the number of potassium ions that could accumulate on the intracellular side of the membrane were unrestricted, the positively charged potassium ions inside would exactly match the negative charges on the intracellular protein anions. There would be no charge across the membrane at all. But the number of potassium ions that accumulate inside the cell is limited because when the intracellular K+ concentration becomes higher than the extracellular concentration, further potassium ion influx is opposed by its concentration gradient.

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Outside the Cell The equilibrium of the potassium voltage and concentration gradients results in some potassium ions remaining outside the cell. It is necessary to have only a few positively charged potassium ions outside the cell to maintain a negative charge inside the cell. As a result, potassium ions contribute to the charge across the membrane. Sodium (Na+) and chloride (Cl−) ions also take part in producing the resting potential. If positively charged sodium ions were free to move across the membrane, they would diffuse into the cell and eliminate the transmembrane charge produced by the unequal distribution of potassium ions inside and outside the cell. This diffusion does not happen because a gate on the sodium ion channels in the cell membrane is ordinarily closed (see Figure 4-11), blocking the entry of most sodium ions. Still, given enough time, sufficient sodium ions could leak into the cell to neutralize its membrane potential. The cell membrane has a different mechanism to prevent this neutralization. When sodium ions do leak into the neuron, they are immediately escorted out again by the action of a sodium–potassium pump, a protein molecule embedded in the cell membrane. A membrane’s many thousands of pumps continually exchange three intracellular sodium ions for two potassium ions, as shown in Figure 4-11. The potassium ions are free to leave the cell through open potassium channels, but closed sodium channels slow the reentry of the sodium ions. In this way, sodium ions are kept out to the extent that about 10 times as many sodium ions reside on the outside of the axon membrane as on its inside. The difference in sodium concentrations also contributes to the membrane’s resting potential.

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Now consider the chloride ions. Unlike sodium ions, chloride ions move in and out of the cell through open channels in the membrane. The equilibrium point, at which the chloride’s concentration gradient equals its voltage gradient, is approximately the same as the membrane’s resting potential, so chloride ions ordinarily contribute little to the resting potential. At this equilibrium point, there are about 12 times as many chloride ions outside the cell as inside it. The cell membrane’s semipermeability and the actions of its channels, gates, and pumps thus produce voltage across the cell membrane: its resting potential (Figure 4-12).

FIGURE 4-12 Resting Transmembrane Charge

Graded Potentials The resting potential provides an energy store that can be used somewhat like the water in a dam: small amounts can be released by opening gates for irrigation or to generate electricity. If the concentration of any of the ions across the unstimulated cell membrane

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changes, the membrane voltage changes. These graded potentials are small voltage fluctuations across the cell membrane. Stimulating a membrane electrically through a microelectrode mimics the way the membrane’s voltage changes to produce a graded potential in the living cell. If the voltage applied to the inside of the membrane is negative, the membrane potential increases in negative charge by a few millivolts. As illustrated in Figure 4-13A, it may change from a resting potential of −70 mV to a slightly greater potential of −73 mV.

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FIGURE 4-13 Graded Potentials (A) Stimulation (S) that increases relative membrane voltage produces a hyperpolarizing graded potential. (B) Stimulation that decreases relative membrane voltage produces a depolarizing graded potential.

This change is a hyperpolarization because the charge (polarity) of the membrane increases. Conversely, if positive voltage is applied inside the membrane, its potential decreases by a few millivolts. As illustrated in Figure 4-13B, it may change from, say, a resting potential of −70 mV to a slightly lower potential of −65 mV. This change is a depolarization because the membrane charge decreases. Graded potentials usually last only a few milliseconds. Hyperpolarization and depolarization typically take place on the soma (cell body) membrane and on neuronal dendrites. These areas contain gated channels that can open and close, thereby changing the membrane potential, as illustrated in Figure 4-13. Three channels—for potassium, chloride, and sodium ions—underlie graded potentials: 1. Potassium channels. For the membrane to become hyperpolarized, its extracellular side must become more positive, which can be accomplished with an outward movement, or efflux, of potassium ions. But if potassium channels are ordinarily open, how can the efflux of potassium ions increase? Apparently, even though potassium channels are open, some resistance to the outward flow of potassium ions remains. Reducing this resistance enables hyperpolarization. 2. Chloride channels. The membrane can also become hyperpolarized if an influx of chloride ions occurs. Even though chloride ions can pass through the membrane, more ions remain on the outside than

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on the inside, so a decreased resistance to Cl− flow can result in brief increases of Cl− inside the cell. 3. Sodium channels. Depolarization can be produced if normally closed sodium channel gates open to allow an influx of sodium ions. Evidence that potassium channels have a role in hyperpolarization comes from the fact that the chemical tetraethylammonium (TEA), which blocks potassium channels, also blocks hyperpolarization. The involvement of sodium channels in depolarization is Puffer Fish

indicated by the fact that the chemical

tetrodotoxin (TTX), which blocks sodium channels, also blocks depolarization. The puffer fish, considered a delicacy in some countries, especially Japan, secretes TTX—a potentially deadly poison—to fend off would-be predators. Skill is required to prepare this fish for human consumption. It can be lethal to the guests of careless cooks because its toxin impedes the electrical activity of neurons.

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Table 6-2 lists a variety of neurotoxins and their sources and summarizes some of their effects.

Action Potential Electrical stimulation of the cell membrane at resting potential produces local graded potentials. An action potential, on the other hand, is a brief but very large reversal in an axon membrane’s polarity (Figure 414A) that lasts about 1 ms. The voltage across the membrane suddenly reverses, making the intracellular side positive relative to the extracellular side, then abruptly reverses again to restore the resting potential. Because the action potential is brief, many action potentials can occur within a second, as illustrated in Figures 4-14B and C, where the time scales are compressed.

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FIGURE 4-14 Measuring Action Potentials (A) Phases of a single action potential. The time scales on the horizontal axes are compressed to chart (B) each action potential as a discrete event, (C) the ability of a membrane to produce many action potentials in a short time, (D) and the series of action potentials over the course of 1 second (1000 ms).

An action potential occurs when a large concentration of first Na+ and then K+ crosses the membrane rapidly. The depolarizing phase of the action potential is due to Na+ influx, and the hyperpolarizing phase is due to K+ efflux. Sodium rushes in and then potassium rushes out. As shown in Figure 4-15, the combined flow of sodium and potassium ions underlies the action potential.

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FIGURE 4-15 Triggering an Action Potential

An action potential is triggered when the cell membrane is depolarized to about –50 mV. At this threshold potential, the membrane charge undergoes a remarkable further change with no additional stimulation. The relative voltage of the membrane drops to zero and continues to depolarize until the charge on the inside of the membrane is as great as +30 mV—a total voltage change of 100 mV. Then the membrane potential reverses again, becoming slightly hyperpolarized—a reversal of a little more than 100 mV. After this

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second reversal, the membrane slowly returns to its resting potential at –70 mV. The action potential normally consists of the summed current changes caused first by the inflow of sodium and then by the outflow of potassium on an axon. Experimental results reveal that if an axon membrane is stimulated electrically while the solution surrounding the axon contains the chemical TEA (to block potassium channels), the result is a smaller-than-normal ion flow due entirely to an Na+ influx. Similarly, if an axon’s membrane is stimulated electrically while the solution surrounding the axon contains TTX (to block sodium channels), a slightly different ion flow due entirely to the efflux of K+ is recorded. Figure 4-16 illustrates these experimental results, in which the graphs represent ion flow rather than voltage change.

FIGURE 4-16 Blocking an Action Potential

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What cellular mechanisms underlie the movement of sodium and potassium ions to produce an action potential? The answer is the behavior of a class of gated sodium and potassium channels sensitive to the membrane’s voltage (Figure 4-17). These voltageactivated channels are closed when an axon’s membrane is at its resting potential: ions cannot pass through them. When the membrane reaches threshold voltage, the configuration of the voltage-activated channels alters: they open briefly,

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enabling ions to pass

FIGURE 4-17 Voltage-Activated Potassium Channel

through, then close again to restrict ion flow. The sequence of actions is as follows: 1. Both sodium and potassium voltage-activated channels are attuned to the threshold voltage of about –50 mV. If the cell membrane changes to reach this voltage, both types of channels open to allow ion flow across the membrane. 2. The voltage-activated sodium channels respond more quickly than the potassium channels. As a result, the voltage change due to Na+ influx takes place slightly before the voltage change due to K+ efflux can begin. 3. Sodium channels have two gates. Once the membrane depolarizes to about +30 mV, one of the gates closes. Thus, Na+ influx begins quickly and ends quickly. 4. The potassium channels open more slowly than the sodium channels, and they remain open longer. Thus, the efflux of K+ reverses the depolarization produced by Na+ influx and even hyperpolarizes the membrane.

Action Potentials and Refractory Periods There is an upper limit to how frequently action potentials occur, and sodium and potassium channels are responsible for it. Stimulation of the axon membrane during the depolarizing phase of the action potential will not produce another action potential. Nor is the axon able to produce another action potential when it is repolarizing. During these times, the membrane is described as being absolutely refractory.

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Exceptions do exist: some CNS neurons discharge during the repolarizing phase.

If, on the other hand, the axon membrane is stimulated during hyperpolarization, another action potential can be induced, but the second stimulation must be more intense than the first. During this phase, the membrane is relatively refractory. Refractory periods result from the way gates of the voltage-activated sodium and potassium channels open and close. A sodium channel has two gates, and a potassium channel has one gate. Figure 4-18 illustrates the position of these gates before, during, and after the phases of the action potential. We describe changes first in the sodium channels and then in the potassium channels.

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FIGURE 4-18 Phases of an Action Potential Initiated by changes in voltageactivated sodium and potassium channels, an action potential begins with a depolarization: gate 1 of the sodium channel opens, and then gate 2 closes. The slower-opening potassium channel gate contributes to repolarization and hyperpolarization until the resting membrane potential is restored.

During the resting potential, gate 1 of the sodium channel depicted in Figure 4-18 is closed; only gate 2 is open. At the threshold level of stimulation, gate 1 also opens. Gate 2, however, closes very quickly after gate 1 opens. This sequence produces a brief period during which both sodium gates are open. When both gates are open and when gate 2 is closed, the membrane is absolutely refractory.

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The opening of the potassium channels repolarizes and eventually hyperpolarizes the cell membrane. The potassium channels open and close more slowly than the sodium channels do. The hyperpolarization produced by a continuing efflux of potassium ions makes it more difficult to depolarize the membrane to the threshold that reopens the gates underlying an action potential. While the membrane is hyperpolarizing, it is relatively refractory. The changes in polarity that take place during an action potential are analogous to the action of a lever-activated toilet. Pushing the lever slightly produces a slight water flow that stops when the lever is released. This activity is analogous to a graded potential. A harder lever press brings the toilet to threshold and initiates flushing, a response that is out of all proportion to the lever press. This activity is analogous to the action potential. During the flush, the toilet is absolutely refractory: another flush cannot be induced at this time. During the refilling of the bowl, in contrast, the toilet is relatively refractory, meaning that flushing again is possible but harder. Only after the cycle is over and the toilet is once again at rest can a full flush be produced again.

Nerve Impulse Suppose you place two recording electrodes at a distance from one another on an axon membrane and then electrically stimulate an area adjacent to one electrode. That electrode would immediately record an action potential. A similar recording would register on the second electrode in a flash. An action potential has arisen near this second

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electrode also, even though it is some distance from the original point of stimulation. Is this second action potential simply an echo of the first that passes down the axon? No, it cannot be because the action potential’s size and shape are exactly the same at the two electrodes. The second is not just a faint, degraded version of the first but is equal in magnitude. Somehow the full action potential has moved along the axon. This propagation of an action potential along an axon is called a nerve impulse. Why does an action potential move? Remember that the total voltage change during an action potential is 100 mV, far beyond the 20-mV change needed to bring the membrane from its resting state of –70 mV to the action potential threshold level of –50 mV. Consequently, the voltage change on the part of the membrane where an action potential first occurs is large enough to bring adjacent parts of the membrane to a threshold of –50 mV. When the membrane at an adjacent part of the axon reaches –50 mV, the voltage-activated channels at that location pop open to produce an action potential there as well. This second occurrence, in turn, induces a change in the membrane voltage still farther along the axon, and so on and on, down the axon’s length. Figure 4-19 illustrates this process. The nerve impulse occurs because each action potential propagates another action potential on an adjacent part of the axon membrane. The word propagate means “to give birth,” and that is exactly what happens. Each successive action potential gives birth to another down the length of the axon.

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FIGURE 4-19 Propagating an Action Potential Voltage sufficient to open Na+ and K+ channels spreads to adjacent sites of the axon membrane, inducing voltageactivated gates to open. Here, voltage changes are shown on only one side of the membrane.

Because they are propagated by gated ion channels acting on the membrane in their own vicinity, action potentials on a nerve or tract are the same magnitude wherever they occur. An action potential depends on energy expended where it occurs, and the same amount of energy is typically expended at every site along the membrane as a nerve impulse is propagated. As a result, action potentials do not dissipate: an action potential is either generated completely or not generated at all. Action potentials are all-or-none events. As the nerve’s impulse, or message, the action potential maintains a constant size and arrives unchanged to every terminal on the nerve that receives it. Think of the voltage-activated channels along the axon as a series of dominoes. When one falls, it knocks over its neighbor, and so on down the line. There is no decrement in the size of the fall. The last domino travels exactly the same distance and falls just as hard as the first one did. Essentially, the domino effect happens when voltage-activated channels open. The opening of one channel produces a voltage change that triggers its neighbor to open, just as one domino knocks over the next. The channel-opening response does not grow any weaker as it moves along the axon, and the last channel opens exactly like the first, just as the domino action stays constant to the end of the line. 464

The Domino Effect

Refractory Periods and Nerve Action Refractory periods are determined by the position of the gates that mediate ion flow in the voltage-activated channels. This limits the frequency of action potentials to about one every 5 ms. The action potential’s refractory phase thus has two practical uses for nerves that are conducting information. First, the maximum rate at which action potentials can occur is about 200 per second (1 s, or 1000 ms/5 ms limit = 200 action potentials in 1

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s). The sensitivity of voltage-activated channels, which varies among kinds of neurons, likewise affects firing frequency. Second, although an action potential can travel in either direction on an axon, refractory periods prevent it from reversing direction and returning to its point of origin. Refractory periods thus produce a single, discrete impulse that travels away from the initial point of stimulation. When an action potential begins near the cell body, it usually travels down the axon to the terminals. To return to our domino analogy, once a domino falls, setting it up again takes time. This is its refractory period. Because each domino falls as it knocks down its neighbor, the sequence cannot reverse until the domino is set upright again: the dominos can fall in only one direction. The same principle determines the action potential’s direction.

Saltatory Conduction and the Myelin Sheath Because the giant axons of squid are so large, they can transmit nerve impulses very quickly, much as a large-diameter pipe can rapidly deliver a lot of water. But large axons take up substantial space: a squid cannot accommodate many of them, or its body would be too bulky. For mammals, with our many axons innervating a substantial number of muscles, giant axons are out of the question. Our axons must be extremely slender because our complex movements require a great many of them.

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Our largest axons, which run to and from our muscles, are only about 30 μm wide, so the speed with which they convey information should not be especially fast. And yet, like most other vertebrate species, we humans are hardly sluggish creatures. We process information and generate responses with impressive speed. How do we manage to do so if our axons are so thin? The vertebrate nervous system has evolved a solution that has nothing to do with axon size. Glial cells play a role in speeding nerve impulses in the vertebrate nervous system. Schwann cells in the human peripheral nervous system and oligodendroglia in the central nervous system wrap around some axons, forming the myelin sheath that insulates it (Figure 4-20). Action potentials cannot occur where myelin is wrapped around an axon. For one thing, the myelin is an insulating barrier to ionic current flow. For another, axonal regions that lie under myelin have few channels through which ions can flow, and ion channels are essential to generating an action potential.

FIGURE 4-20 Myelination An axon is insulated by (A) oligodendroglia in the CNS and (B) Schwann cells in the PNS. Each glial cell is separated by a gap, or node of

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Ranvier.

But axons are not totally encased in myelin. Unmyelinated gaps between successive glial cell wrappings are richly endowed with voltage-activated channels. These tiny gaps in the myelin sheath, the nodes of Ranvier, are sufficiently close to one another that an action potential at one node can open voltage-activated gates at an adjacent node. In this way, a relatively slow action potential jumps quickly from node to node, as shown in Figure 4-21. This flow of energy is called saltatory conduction (from the Latin verb saltare, meaning “to leap”).

FIGURE 4-21 Saltatory Conduction Myelinated stretches of axons are interrupted by nodes of Ranvier, rich in voltage-activated channels. In saltatory conduction, the action potential jumps rapidly from node to node.

M yelin

To review glial cell types, appearance, and functions, see Table 3-1.

has two important consequences for propagating action potentials. First, 468

propagation becomes energetically cheaper, since action potentials regenerate only at the nodes of Ranvier, not along the axon’s entire length. Action potential conduction in unmyelinated axons, by contrast, has a significant metabolic energy cost (Crotty et al., 2006). The second consequence is that myelin improves the action potential’s conduction speed. Jumping from node to node speeds the rate at which an action potential can travel along an axon because the current flowing within the axon beneath the myelin sheath travels very fast. While the current moves speedily, the voltage drops quickly over distance. But the nodes of Ranvier are spaced ideally to ensure sufficient voltage at the next node to supersede the threshold potential and thus regenerate the action potential. On larger, myelinated mammalian axons, nerve impulses can travel at a rate as high as 120 meters per second. On smaller, uninsulated axons, they travel only about 30 meters per second. Spectators at sporting events sometimes initiate a wave that travels around a stadium. Just as one person rises, the next person begins to rise, producing the wave effect. This human wave is like conduction along an unmyelinated axon. Now think of how much faster the wave would complete its circuit around the field if only spectators in the corners rose to produce it. This is analogous to a nerve impulse that travels by jumping from one node of Ranvier to the next. The quick reactions that humans and other mammals are capable of are due in part to this saltatory conduction in their nervous system. Neurons that send messages over long distances quickly, including sensory and motor neurons, are heavily myelinated. If myelin is damaged, a neuron may be unable to send any messages over its axons. 469

In multiple sclerosis (MS), the myelin formed by oligodendroglia is damaged, which disrupts the functioning of neurons whose axons it encases. Clinical Focus 4-2, Multiple Sclerosis, describes the course of the disease.

CLINICAL FOCUS 4-2

Multiple Sclerosis One day, J. O., who had just finished university requirements to begin work as an accountant, noticed a slight cloudiness in her right eye. It did not go away when she wiped her eye. Rather, the area grew over the next few days. Her optometrist suggested that she see a neurologist, who diagnosed optic neuritis, an indication that can be a flag for multiple sclerosis (MS). MS results from a loss of myelin produced by oligodendroglia cells in the CNS (see illustration). It disrupts the affected neurons’ ability to propagate action potentials via saltatory conduction. This loss of myelin occurs in patches, and scarring frequently results in the affected areas.

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Eventually, a hard scar, or plaque, forms at the site of myelin loss, which can be visualized with magnetic resonance imaging (MRI). (MS is called a sclerosis from the Greek word meaning “hardness.”) Associated with the loss of myelin is impairment of neuron function, which causes the characteristic MS symptoms sensory loss and difficulty in moving. Fatigue, pain, and depression are commonly associated with MS. Bladder dysfunction, constipation, and sexual dysfunction all complicate it. MS, about twice as common in women as in men, greatly affects a person’s emotional, social, and vocational functioning. Multiple sclerosis is the most common of nearly 80 autoimmune diseases, conditions in which the immune system makes antibodies to a person’s own body (Rezania et al., 2012). The FDA has approved 15 medications for modifying the course of multiple sclerosis, but it is doubtful that the disease can be fully arrested with current therapies (Reich et al., 2018).

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J. O.’s eye cleared over the next few months, and she had no further symptoms until after the birth of her first child 3 years later, when she felt a tingling in her right hand. The tingling spread up her arm, until gradually she lost movement in the arm for 5 months. Then J. O.’s arm movement returned. But 5 years later, after her second child was born, she felt a tingling in her left big toe that spread along the sole of her foot and then up her leg, eventually leading again to loss of movement. J. O. received corticosteroid treatment, which helped, but the condition rebounded when she stopped treatment. Then it subsided and eventually disappeared. Since then, J. O. has had no major outbreaks of motor impairment, but she reports enormous fatigue, takes long naps daily, and is ready for bed early in the evening. Her sister and a female cousin have experienced similar symptoms, and recently a third sister began to display similar symptoms in middle age, as has J.O.’s daughter, who is in her mid-20s. Furthermore, one of J. O.’s grandmothers had been confined to a wheelchair, but the source of her problem was never determined. MS is difficult to diagnose. Symptoms usually appear in adulthood; their onset is quite sudden, and their effects can be swift. Initial symptoms may be loss of sensation in the face, limbs, or body or loss of control over movements or loss of both sensation and control. Motor symptoms usually appear first in the hands or feet. Early symptoms often go into remission and do not appear again for years. In some forms, however, MS progresses rapidly over just a few years until the person is bedridden. MS is common in the northern-most and southern-most latitudes, so it may be related to a lack of vitamin D, which is produced by the action of sunlight on the skin. The disease may also be related to genetic susceptibility, as is likely in J. O.’s case. Many MS patients take vitamin D3 and vitamin B12. While MS is the most prevalent chronic inflammatory disease of the CNS, affecting more than 2 million people worldwide (Reich et al., 2018), the underlying cause for the inflammation and loss of myelin is still

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unknown. It has been suggested that multiple sclerosis may primarily be a degenerative disease that secondarily elicits an autoimmune response (Stys, 2013). Research aimed at solving this problem is important because the answer would likely influence therapeutic approaches.

4-2 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. The

results from the unequal distribution of inside and outside the cell membrane.

2. Because it is , the cell membrane prevents the efflux of large protein anions and pumps sodium ions out of the cell to maintain a slightly charge in the intracellular fluid relative to the extracellular fluid. 3. For a graded potential to arise, a membrane must be stimulated to the point that the transmembrane charge increases slightly to cause a(n) or decreases slightly to cause a(n) . 4. The voltage change associated with a(n) is sufficiently large to stimulate adjacent parts of the axon membrane to the threshold for propagating it along the length of an axon as a(n) . 5. Briefly explain why nerve impulses travel faster on myelinated axons than on unmyelinated axons.

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4-3 How Neurons Integrate Information A neuron’s extensive dendritic tree is covered with spines, and through them it can establish more than 50,000 connections from other neurons. A neuron’s body, which sits between its dendritic tree and axon, can also receive multiple connections. Nerve impulses traveling from other neurons to each of these synaptic locations bombard the receiving neuron with excitatory and inhibitory inputs. In the 1950s and 1960s, John C. Eccles (1965) and his students performed experiments that helped answer the question of how the neuron integrates such an enormous array of inputs into a nerve impulse. Rather than record from the giant axon of a squid, Eccles recorded from the cell bodies of large motor neurons in the vertebrate spinal cord. In doing so, he refined the electrical stimulating and recording techniques first developed for studying squid axons (see Section 4-1). Eccles received the Nobel Prize in Physiology or Medicine for his work. Motor neurons, for example, receive input from multiple sources. A spinal cord motor neuron has an extensive dendritic tree with as many as 20 main branches that subdivide numerous times and are covered with dendritic spines. Input from the skin, joints, muscles, spinal cord, and brain make motor cells ideal for studying how a neuron responds to diverse inputs. Each motor neuron sends its axon directly to a muscle. The motor neuron is the final common pathway the nervous system uses to produce behavior.

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Excitatory and Inhibitory Postsynaptic Potentials To study motor neuron activity, Eccles inserted a microelectrode into a vertebrate’s spinal cord until the tip was in or right beside a motor neuron’s cell body. He then placed stimulating electrodes on sensory nerve fiber axons entering the spinal cord. By teasing apart the many incoming sensory fibers, he was able to stimulate one nerve fiber at a time. Experim ent 4-1

Figure 2-30A diagrams the human spinal cord in cross section.

diagrams the experimental setup Eccles used. As shown at the left in the Procedures section, stimulating some incoming sensory fibers produced a depolarizing graded potential (reduced the charge) on the membrane of the motor neuron to which these fibers were connected. Eccles called these graded potentials excitatory postsynaptic potentials (EPSPs). As graphed on the left side of the Results section, EPSPs reduce (depolarize) the charge on the membrane toward the threshold level and increase the likelihood that an action potential will result. EXPERIMENT 4-1

Question: How does stimulating a neuron influence its excitability? Procedure

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Results

Conclusion: EPSPs increase the likelihood that an action potential will result. IPSPs decrease the likelihood that an action potential will result.

You can find several videos online that describe how the initial segment initiates an action potential.

When Eccles stimulated other incoming sensory fibers, as graphed at the right of the Procedures section, he produced a hyperpolarizing graded potential (increased the charge) on the receiving motor neuron membrane. Eccles called these graded potentials inhibitory postsynaptic potentials (IPSPs). As graphed at the right in the Results section, IPSPs increase the

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charge on the membrane away from the threshold level and decrease the likelihood that an action potential will result. Both EPSPs and IPSPs last only a few milliseconds before they decay and the neuron’s resting potential is restored. EPSPs are associated with the opening of sodium channels, which allows an influx of sodium ions. IPSPs are associated with the opening of potassium channels, which allows an efflux of potassium ions (or with the opening of chloride channels, which allows an influx of chloride ions). Although the size of a graded potential is proportional to the intensity of stimulation, an action potential is not produced on the motor neuron’s cell body membrane even when an EPSP is strongly excitatory. The reason is simple: the cell body membrane of most neurons does not contain voltage-activated channels. The stimulation must reach the initial segment, an area rich in voltage-gated channels, the area near or overlapping the axon hillock, where the action potential begins (Bender & Trussel, 2012).

Summation of Inputs Neurons typically receive both excitatory and inhibitory signals simultaneously and, on a moment-to-moment basis, sum up the information they get.

A motor neuron’s myriad dendritic spines can each contribute to membrane voltage, via either an EPSP or an IPSP. How do these incoming graded potentials interact at its membrane? What happens if two EPSPs occur in succession? Does it matter if the time between them increases or decreases? What happens when an EPSP and an IPSP arrive together?

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Temporal Summation If one excitatory pulse is followed some time later by a second excitatory pulse, one EPSP is recorded and then, after a delay, a second identical EPSP is recorded, as shown at the top left in Figure 4-22. These two widely spaced EPSPs are independent and do not interact. If the delay between them is shortened so that the two occur in rapid succession, however, a single large EPSP is produced, as shown in the left-center panel of Figure 4-22.

FIGURE 4-22 Temporal Summation Stimulation (S1 and S2) of two depolarizing pulses separated in time produce two EPSPs similar in size. Pulses close together in time partly sum. Simultaneous EPSPs sum as one large EPSP. Two hyperpolarizing pulses (S1 and S2) widely separated in time produce two IPSPs similar in size. Pulses coming fast partly sum. Simultaneous IPSPs sum as one large IPSP.

Here, the two excitatory pulses at the same location are summed— added together to produce a larger depolarization of the membrane than either would induce alone. This relationship between two EPSPs occurring close together or even at the same time (bottom-left panel) is called temporal summation. The right side of Figure 4-22 illustrates that

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equivalent results are obtained with IPSPs. Therefore, temporal summation is a property of both EPSPs and IPSPs.

Spatial Summation How does physical spacing affect inputs to the cell body membrane? By using two recording electrodes (R1 and R2), we can see the effects of spatial relations on the summation of inputs. If two EPSPs are recorded at the same time but on widely separated parts of the membrane (Figure 4-23A), they do not influence one another. If two EPSPs occurring close together in time are also close together on the membrane, however, they sum to form a larger EPSP (Figure 4-23B). This spatial summation occurs when two separate inputs are very close to one another both on the cell membrane and in time. Similarly, two IPSPs produced at the same time sum if they occur at approximately the same place and time on the cell body membrane but not if they are widely separated.

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FIGURE 4-23 Spatial Summation The process for IPSPs is equivalent to the process for EPSPs.

Role of Ions in Summation Summation is a property of both EPSPs and IPSPs in any combination. These interactions make sense when you consider that ion influx and efflux are being summed. The influx of sodium ions accompanying one EPSP is added to the influx of sodium ions accompanying a second EPSP if the two occur close together in time and space. If the two influxes are remote in time or in space or in both, no summation is possible. The same is true regarding effluxes of potassium ions. When they occur close together in time and space, they sum; when they are far apart in either or both ways, there is no summation. The patterns are identical for an EPSP and an IPSP. The influx of sodium ions associated with the EPSP is added to the efflux of potassium ions associated with the IPSP, and the difference between them is recorded as long as they are spatially and temporally close together. If, on the other hand, they are widely separated in time or in space or in both, they do not interact, and there is no summation. A neuron with thousands of inputs responds no differently from one with only a few inputs; it sums all inputs that are close together in time and space. The cell body membrane, therefore, always indicates the summed influences of multiple temporal and spatial inputs. Therefore, a neuron can be said to analyze its inputs before deciding what to do. The ultimate decision is made at the initial segment, the region on the axon that initiates the action potential.

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Voltage-Activated Channels and the Action Potential Unlike the cell body membrane, the axon is rich in voltage-activated channels, beginning at the initial segment (Figure 4-24). These channels, like those on the squid axon, open at a particular membrane voltage. The actual threshold voltage varies with the type of neuron, but to keep things simple, we will stay with a threshold level of −50 mV.

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FIGURE 4-24 Triggering an Action Potential If the summated graded potentials—the EPSPs and IPSPs—on the dendritic tree and cell body of a neuron charge the membrane to threshold level at the initial segment, an action potential is initiated, and it travels down the axon membrane.

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To produce an action potential, the summed graded potentials—the IPSPs and EPSPs—on the cell body membrane must depolarize the membrane at the initial segment to −50 mV. If that threshold voltage is obtained only briefly, voltage-activated channels open, and just one or a few action potentials may occur. If the threshold level is maintained for a longer period, however, action potentials will follow one another in rapid succession, just as quickly as the gates on the voltage-activated channels can reset. Each action potential is then repeatedly propagated to produce a nerve impulse that travels from the initial segment down the length of the axon. Many neurons have extensive dendritic trees, but dendrites and dendritic branches do not have many voltage-activated channels and ordinarily do not produce action potentials. And distant branches of dendrites may have less influence in producing action potentials initiated at the initial segment than do the more proximal branches of the dendrites. Consequently, inputs close to the initial segment are usually much more influential than those occurring some distance away, and those close to the initial segment are usually inhibitory, creating IPSPs. As in all governments, some inputs have more say than others (Höfflin et al., 2017).

The Versatile Neuron Dendrites collect information as graded potentials (EPSPs and IPSPs), and the initial segment initiates discrete action potentials delivered to other target cells via the axon. Exceptions to this picture of how a neuron works do exist. For example, some cells in the developing hippocampus can produce additional action potentials, called giant depolarizing potentials, when the cell would ordinarily be refractory. It is thought that giant

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depolarizing potentials aid in developing the brain’s neural circuitry (Khalilov et al., 2015). Principle 2: Neuroplasticity is the hallmark of nervous system functioning.

Because the cell body membrane does not contain voltage-activated channels, a typical neuron does not initiate action potentials on its dendrites. In some neurons, however, voltage-activated channels on dendrites do enable action potentials. The reverse movement of an action potential from the initial segment into the dendritic field of a neuron is called back propagation. Back propagation, which signals to the dendritic field that the neuron is sending an action potential over its axon, may play a role in plastic changes in the neuron that underlie learning. For example, back propagation may make the dendritic field refractory to incoming inputs, set the dendritic field to an electrically neutral baseline, or reinforce signals coming in to certain dendrites (Schiess et al., 2016). We explore the neuronal basis of learning in Sections 5-4 and 14-4.

Section 7-1 describes the promise of optogenetics for neuroscience research and for clinical applications.

The neurons of some nonmammalian species have no dendritic branches. And some ion channels, rather than responding to voltage, respond to light by opening and allowing ions to pass. The many differences among neurons suggest that the nervous system capitalizes on structural and functional modifications to produce adaptive behavior in each species. In research to determine the neuron’s specific functions,

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neuroscientists have incorporated into certain types of neurons ion channels that respond to light, as described in Research Focus 4-3, Optogenetics and Light-Sensitive Ion Channels.

RESEARCH FOCUS 4-3

Optogenetics and Light-Sensitive Ion Channels Membrane channels that are responsive to light have been discovered in nonmammalian animal species. Using the transgenic technique of optogenetics, researchers have successfully introduced light-sensitive channels into a variety of species including worms, fruit flies, and mice. Optogenetics combines genetics and light to control targeted cells in living tissue. Here, we examine how introducing different light-sensitive channels into a species changes the organism’s behavior with one wavelength and reverses them with another wavelength. One class of light-activated ion channels in the green alga Chlamydomonas reinhardtii is channelrhodopsin-2 (ChR2). The ChR2 light-activated channel absorbs blue light and, in doing so, opens briefly to allow the passage of Na+ and K+. The resulting depolarization excites the cell to generate action potentials. Halorhodopsin (NpHR) is a light-driven ion pump, specific for chloride ions and found in phylogenetically ancient bacteria (archaea) known as halobacteria. When illuminated with green-yellow light, the NpHR pumps chloride anions into the cell, hyperpolarizing it and thereby inhibiting its activity. The behavior of animals with genetically introduced light-sensitive channels has been controlled when their nervous system cells were illuminated with appropriate wavelengths of light. Using optogenetic techniques, light-sensitive channels can be incorporated into specific neural circuits so that light stimulation controls only a subset of neurons.

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Stress has both behavioral and hormonal consequences for individuals, which can be transmitted socially to others. Using optogenetic techniques in mice, Sterley and colleagues (2018) silenced a specific collection of neurons in the hypothalamus during stress, thus preventing changes to the brain that would normally occur after stress. They then took it one step further and silenced the neurons in a partner mouse of a stressed individual, and the stress did not transfer to the partner. The group next performed the opposite experiment: in the absence of stress, they optogenetically activated the same hypothalamic neurons, causing the same changes in the brain as actual stress. They also observed that the partner mouse interacted with the light-activated-stressed individual in the same fashion as they would approach a naturally stressed mouse (Sterley et al., 2018). The experimental power of optogenetics is unprecedented because we can learn the contribution of specific neuronal types to a behavior or in a disease state. But can optogenetics become a clinical tool to be used in people suffering from a CNS malady such as depression? One major hurdle is that specific viruses are used to transfer the light-activated channels to neurons in localized brain regions, and the usage of viruses in human populations is still fraught with difficulties. There are studies suggesting that impaired vision due to the loss of the light-sensitive cells of the eye could be restored with light-activated channels in surviving retinal neurons (Pan et al., 2015).

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4-3 Review 488

Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. Graded potentials that decrease the charge on the cell membrane, moving it toward the threshold level, are called because they increase the likelihood that an action potential will occur. Graded potentials that increase the charge on the cell membrane, moving it away from the threshold level, are called because they decrease the likelihood that an action potential will result. 2. EPSPs and IPSPs that occur close together in both and are summed. This is how a neuron the information it receives from other neurons. 3. The membrane of the does not contain voltageactivated ion channels, but if summed inputs excite the to a threshold level, action potentials are triggered and then propagated as they travel along the cell’s as a nerve impulse. 4. Explain what happens during back propagation.

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4-4 Into the Nervous System and Back Out The nervous system allows us to respond to afferent (incoming) sensory stimuli by detecting them and sending messages about them to the brain. The brain interprets the information, triggering efferent (outgoing) responses that contract muscles and produce behavior. Until now, we have been dealing only with the middle of this process—how neurons convey information to one another, integrate the information, and generate action potentials. Now we explore the beginning and end of the journey. To fill in the missing pieces, we explain how a sensory stimulus initiates a nerve impulse and how a nerve impulse produces a muscular contraction. Once again, ion channels are vitally important, but, in muscles, the channels are different from those described so far.

How Sensory Stimuli Produce Action Potentials We receive information about the world through bodily sensations (touch and balance), auditory sensations (hearing), visual sensations (sight), and chemical sensations (taste and olfaction). Each sensory modality has one or more separate functions. In addition to touch, for example, the body senses include pressure, joint sense, pain, temperature, and itch. Receptors for audition and balance are modified touch receptors. The visual system has receptors for light and for colors.

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And taste and olfactory senses respond to a plethora of chemical compounds.

For detail on how sensory receptors transduce external energy into action potentials: Hearing, Section 10-1 Sensation and perception, Section 9-1 Smell and taste, Section 12-2 Touch, pain, and balance, Section 11-4 Vision, Section 9-2

Processing all these varied sensory inputs requires a remarkable array of sensory receptors. But in all our sensory systems, the neurons related to these diverse receptors have one thing in common: conduction of information begins at ion channels. Ion channels initiate the chain of events that produces a nerve impulse. An example is touch. Each hair on the human body allows an individual to detect even a very slight displacement. You can demonstrate this sensitivity yourself by selecting a single hair on your arm and bending it. If you are patient and precise in your experimentation, you will discover that some hairs are sensitive to displacement in one direction only, whereas others respond to displacement in any direction. What enables this finely tuned sensitivity? The base of each hair is wrapped in a dendrite of a touch neuron. When you bend a hair or otherwise mechanically displace it, the encircling dendrite is stretched (Figure 4-25).

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FIGURE 4-25 Tactile Stimulation A hair’s touch receptor activated by a feather results in a nerve impulse heading to the brain.

The displacement opens stretch-activated channels in the dendrite’s membrane. When open, these channels allow an influx of sodium ions sufficient to depolarize the dendrite to threshold. At threshold, the voltage-activated sodium and potassium channels initiate a nerve impulse that conveys touch information to your brain. Other kinds of sensory receptors have similar mechanisms for transducing (transforming) the energy of a sensory stimulus into nervous system activity. When displaced, the hair receptors that provide information about hearing and balance likewise open stretchactivated channels. In the visual system, photons (light particles) strike 492

opsin proteins in receptors within specialized cells in the eye. The resulting chemical change activates ion channels in relay neuron membranes. An odorous molecule in the air that lands on an olfactory receptor and fits itself into a specially shaped compartment opens chemical-activated ion channels. When tissue is damaged, injured cells release chemicals that activate channels on a pain nerve. The point here is that ion channels originate conduction of information in all our sensory systems.

How Nerve Impulses Produce Movement Principle 1: The nervous system produces movement in a perceptual world the brain constructs.

What happens at the end of the neural journey? After sensory information has traveled to the brain and been interpreted, how does the brain generate output—muscular contractions—as a behavioral response? Behavior, after all, is movement, and for movement to take place, muscles must contract. Motor neurons in the spinal cord are responsible for activating muscles. Without them, movement becomes impossible and muscles atrophy, as described in Clinical Focus 4-4, ALS: Amyotrophic Lateral Sclerosis.

CLINICAL FOCUS 4-4

ALS: Amyotrophic Lateral Sclerosis

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In 1869, French physician Jean-Martin Charcot first described ALS, amyotrophic lateral sclerosis. Amyotrophic means “muscle weakness”; lateral sclerosis means “hardening of the lateral spinal cord.” In North America, ALS is also known as Lou Gehrig disease. A baseball legend who played for the New York Yankees from 1923 until 1939, Gehrig had set a host of individual records. He was an outstanding hitter, and his incredible durability earned him the nickname The Iron Horse. Gehrig played on many World Series championship teams, but ALS sapped his strength, forcing him to retire from baseball at age 36. His condition deteriorated rapidly, and he died just 2 years later. ALS is due primarily to the death of spinal motor neurons, but it can affect brain neurons as well in some instances. It strikes most commonly at age 50 to 75, although its onset can be as early as the teenage years. About 5000 new cases are reported in the United States each year, and roughly 10 percent of people with ALS have a family history of the disorder. While death often occurs within 5 years of diagnosis, internationally renowned theoretical physicist and cosmologist Stephen Hawking was a notable exception. Diagnosed at age 21, Hawking had a rare early-onset and slowly progressing form of ALS. As a doctoral student at Oxford, he grew increasingly clumsy, and his speech was slightly slurred. In his late twenties, he began to use crutches. In his thirties, his speech deteriorated to the point that only his family and close friends could understand him. In his seventies, and confined to a wheelchair, Hawking, pictured below, was still able to communicate by using a single cheek muscle attached to a speech-generating device.

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ALS typically begins with general weakness, at first in the throat or upper chest and in the arms and legs. Gradually, walking becomes difficult and falling common. ALS does not usually affect any sensory systems, cognitive functions, bowel or bladder control, or even sexual function. Even as his motor neurons continued to die, Stephen Hawking’s mind-blowing advancements continued to enrich our understanding of the universe. Sadly, we lost Stephen Hawking in March 2018. At present, no cure for ALS exists, although some newly developed drugs appear to slow its progression and offer some hope for future treatments. In 2014, the ALS Ice Bucket Challenge first appeared on YouTube to promote

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awareness of ALS and encourage donations to research. The Challenge went viral and has been revived every summer since.

Motor neurons send nerve impulses to synapses on muscle cells. These synapses are instrumental in making the muscle contract. Each motor neuron axon contacts one or a few synapses with its target muscle (Figure 4-26A). The axon terminal contacts a specialized area of the muscle membrane called an end plate, where the axon terminal releases the chemical transmitter acetylcholine.

FIGURE 4-26 Muscle Contraction (A) When a motor neuron’s axon collaterals contact a muscle fiber end plate, (B) acetylcholine attaches to receptor sites on the end plate’s transmitter-activated channels, opening them. These large membrane channels allow simultaneous influx of Na+ and efflux of K+, generating current

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sufficient to activate voltage-activated channels, triggering action potentials, and causing the muscle to contract.

Acetylcholine does not enter the muscle but rather attaches to transmitter-activated channels on the end plate (Figure 4-26B). When these channels open in response, they allow a flow of Na+ and K+ across the muscle membrane sufficient to depolarize the muscle to the threshold for its action potential. Yes, to contract, muscles generate action potentials. At this threshold, adjacent voltage-activated channels open. They in turn produce an action potential on the muscle fiber, as they do in a neuron. The transmitter-activated channels on muscle end plates are somewhat different from the channels on axons and dendrites. A single end plate channel is larger than two sodium and two potassium channels on a neuron combined. So when its transmitter-activated channels open, they allow both Na+ influx and K+ efflux through the same pore. Generating a sufficient depolarization on the end plate to activate neighboring voltage-activated channels on the muscle membrane requires the release of an appropriate amount of acetylcholine. Sections 5-2 and 5-3 describe the varieties of chemical transmitters and how they function.

If the acetylcholine receptors on muscle end plates are blocked, acetylcholine released from the motor neuron cannot properly exert its depolarizing effect. This prevents muscular contraction in conditions such as the autoimmune disease myasthenia gravis. In affected individuals, the thymus, an immune system gland that normally

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produces antibodies that bind to foreign material like viruses, makes antibodies that bind to the acetylcholine receptors on muscles, causing weakness and fatigue (see Figure 4-27).

FIGURE 4-27 Myasthenia Gravis When this patient follows the direction to look up (1), her eyelids quickly become fatigued and droop (2, 3). After a few minutes of rest, her eyelids open normally (4).

Unlike MS, another autoimmune disease, myasthenia gravis is usually well controlled with treatment, including drugs that suppress the immune system or inhibit acetylcholine breakdown, extending the time the transmitter can act, or by removal of the thymus gland (thymectomy).

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The actions of membrane channels can explain a wide range of neural events. Some channels generate the transmembrane charge. Others mediate graded potentials. Still others trigger the action potential. Sensory stimuli activate channels on neurons to initiate a nerve impulse, and the nerve impulse eventually activates channels on motor neurons to produce muscle contractions. These various channels and their different functions evolved over a long time as new species of animals and their behaviors evolved. We have not described all the different ion channels that neural membranes possess, but you will learn about some additional ones in subsequent chapters.

4-4 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. Across all sensory systems, the conduction of sensory information that occurs within the neuron begins at the . 2. A(n) membrane contains a mechanism for transducing sensory energy into changes in ion channels. In turn, the channels allow ion flow to alter the membrane voltage to the point that channels open, initiating a nerve impulse. 3. Sensory stimuli activate ion channels to initiate a nerve impulse that activates channels on neurons, which in turn contract .

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4. In myasthenia gravis, a(n) gland produces antibodies to causing weakness and fatigue.

disease, the thymus receptors on muscles,

5. Why have so many kinds of ion channels evolved on cell membranes?

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Summary 4-1 Searching for Electrical Activity in the Nervous System Electrical stimulation studies dating as far back as the eighteenth century show that stimulating a nerve with electrical current induces a muscle contraction. In more recent recording studies, the brain’s electrical current, measured using an oscilloscope, shows that electrical activity in the nervous system is continuous. In the twentieth century, researchers used giant axons of the squid to measure the electrical activity of a single neuron. Using microelectrodes that they could place on or in the cell, they recorded small, rapid electrical changes with an oscilloscope. Today, digital oscilloscopes and computers record these measurements. A neuron’s electrical activity is generated by ions flowing across the cell membrane. Ions flow down a concentration gradient (from an area of relatively high concentration to an area of lower concentration) as well as down a voltage gradient (from an area of relatively high voltage to an area of lower voltage). The opening, closing, and pumping of ion channels in neural cell membranes also affect ion distribution.

4-2 Electrical Activity at a Membrane

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Unequal ion distribution on a cell membrane’s two sides generates the neuron’s resting potential. At rest, the intracellular membrane registers about −70 mV relative to the extracellular side. Negatively charged protein anions are too large to leave the neuron, and the cell membrane actively pumps out positively charged sodium ions. Unequal distributions of potassium cations and chloride anions contribute to the resting potential as well. Graded potentials, which are short-lived small increases or decreases in transmembrane voltage, result when the neuron is stimulated. Voltage changes affect the membrane’s ion channels and in turn change the cross-membrane ion distribution. An increase in transmembrane voltage causes hyperpolarization; a decrease causes depolarization. An action potential is a brief but large change in axon membrane polarity triggered when the transmembrane voltage drops to a threshold level of about –50 mV. During an action potential, transmembrane voltage suddenly reverses—the intracellular side becomes positive relative to the extracellular side—and abruptly reverses again. Gradually, the resting potential is restored. These membrane changes result from voltage-activated channels—sodium and potassium channels sensitive to the membrane’s voltage. When an action potential is triggered at the initial segment, it can propagate along the axon as a nerve impulse. Nerve impulses travel more rapidly on myelinated axons because of saltatory

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conduction: the action potentials leap rapidly between the nodes separating the glial cells that form the axon’s myelin sheath.

4-3 How Neurons Integrate Information Inputs to neurons from other cells can produce both excitatory postsynaptic potentials and inhibitory postsynaptic potentials. The membrane sums their voltages both temporally and spatially to integrate the incoming information. If the summed EPSPs and IPSPs move the membrane voltage at the initial segment to threshold, the axon generates an action potential. The neuron is a versatile kind of cell. Some species’ ion channels respond to light rather than to voltage changes, an attribute that genetic engineers are exploiting. Most of our neurons do not initiate action potentials on the cell body because the cell body membrane does not contain voltage-activated channels. But some voltage-activated channels on dendrites do enable action potentials. Back propagation, the reverse movement of an action potential from the initial segment into the dendritic field of a neuron, may play a role in plastic changes that underlie learning.

4-4 Into the Nervous System and Back Out Sensory receptor cells convert sensory energy to graded potentials. These changes, in turn, alter transmembrane voltage to trigger an action potential and propagate a nerve impulse that

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transmits sensory information to relevant parts of the nervous system. Ion channels come into play to activate muscles as well because the chemical transmitter acetylcholine, released at the axon terminal of a motor neuron, activates channels on the end plate of a muscle cell membrane. The subsequent ion flow depolarizes the muscle cell membrane to the threshold for its action potential. In turn, this depolarization opens voltageactivated channels, producing an action potential on the muscle fiber—hence the muscle contractions that enable movement. In myasthenia gravis, antibodies to the acetylcholine receptor prevent muscle depolarization, which is the basis of weakness and fatigue.

Key Terms absolutely refractory action potential autoimmune disease back propagation concentration gradient depolarization diffusion electrical stimulation

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electroencephalogram (EEG) electrographic seizures end plate excitatory postsynaptic potential (EPSP) graded potential hyperpolarization inhibitory postsynaptic potential (IPSP) initial segment microelectrode multiple sclerosis (MS) nerve impulse node of Ranvier optogenetics oscilloscope relatively refractory resting potential saltatory conduction spatial summation stretch-activated channel temporal summation threshold potential

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transmitter-activated channel voltage-activated channel voltage gradient voltmeter

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CHAPTER 5 How Do Neurons Communicate and Adapt?

5-1 A Chemical Message RESEARCH FOCUS 5-1 The Basis of Neural Communication in a Heartbeat EXPERIMENT 5-1 Question: How Does a Neuron Pass on a Message? CLINICAL FOCUS 5-2 Parkinson Disease

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Structure of Synapses Neurotransmission in Five Steps Varieties of Synapses Excitatory and Inhibitory Messages Evolution of Complex Neurotransmission Systems 5-2 Varieties of Neurotransmitters and Receptors Four Criteria for Identifying Neurotransmitters Classes of Neurotransmitters CLINICAL FOCUS 5-3 Awakening with L-Dopa Varieties of Receptors 5-3 Neurotransmitter Systems and Behavior Neurotransmission in the Somatic Nervous System (SNS) Dual Activating Systems of the Autonomic Nervous System (ANS) Enteric Nervous System (ENS) Autonomy Four Activating Systems in the Central Nervous System CLINICAL FOCUS 5-4 The Case of the Frozen Addict 5-4 Adaptive Role of Synapses in Learning and Memory

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Habituation Response EXPERIMENT 5-2 Question: What Happens to the Gill Response After Repeated Stimulation? Sensitization Response EXPERIMENT 5-3 Question: What Happens to the Gill Response in Sensitization? Learning as a Change in Synapse Number RESEARCH FOCUS 5-5 Dendritic Spines: Small but Mighty

RESEARCH FOCUS 5-1 The Basis of Neural Communication in a Heartbeat Discoveries about how neurons communicate stem from experiments designed to study what controls an animal’s heart rate. As happens with any animal, your heartbeat quickens if you are excited or exercising; if you are resting, it slows. Heart rate changes to match energy expenditure—that is, to meet the body’s nutrient and oxygen needs. Your heartbeat undergoes a dramatic change when you dive beneath water: it slows almost to stopping. This drastic slowing, called diving bradycardia, conserves the body’s oxygen when you are not breathing. Bradycardia (brady, meaning “slow,” and cardia, meaning “heart”) is a useful survival strategy. This energy-conserving response under water is common to many animals. But what controls your heartbeat? Otto Loewi, a great storyteller, recounted that his classic experiment, which earned him a Nobel Prize in 1936, came to him in a dream. As shown

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in the Procedure section of Experiment 5-1, Loewi first maintained a frog’s heart in a mild saline bath, then electrically stimulated the vagus nerve—the cranial nerve that leads from the brain to the heart. At the same time, he channeled some of the fluid bath from the vessel containing the stimulated heart through a tube to another vessel in which a second heart was immersed but not electrically stimulated. Loewi recorded both heart rates. His findings are represented in the Results section of Experiment 5-1. The electrical stimulation decreased the rate of the first heart, but more important, the second heartbeat also slowed. This result indicated that the fluid transferred from the first container to the second container carried instructions to slow down. Where did the message come from originally? Loewi reasoned that a chemical released from the stimulated vagus nerve must have diffused into the fluid bath to influence the second heart. His experiment therefore demonstrated that the vagus nerve contains a chemical that tells the heart to slow its rate. Loewi subsequently identified the messenger chemical. Later, he also identified a chemical that tells the heart to speed up. The heart adjusts its rate in response to at least two different messages: an excitatory message that says speed up and an inhibitory message that says slow down.

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Puffins fish by diving underwater, propelling themselves by flapping their short, stubby wings as if flying. During these dives, their heart displays the diving bradycardia response, just as our heart does.

In the preceding chapter, we learned how neurons transmit information as electrical signals: first an action potential is generated and then that impulse flows down an axon to the synapse. In this chapter, first we explain how neurons communicate with one another using excitatory and inhibitory signals. Next, we describe how chemicals carried by one neuron signal receptors on receiving neurons to produce a response. We conclude the chapter by exploring the neural bases of learning—that is, how neural synapses adapt physically as a result of an organism’s experience.

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5-1 A Chemical Message Otto Loewi’s successful heartbeat experiment, discussed in Research Focus 5-1, The Basis of Neural Communication in a Heartbeat and diagrammed in Experiment 5-1, marked the beginning of research into how chemicals carry information from one neuron to another in the nervous system. Loewi was the first to isolate a chemical messenger. We now know that chemical as acetylcholine (ACh), the same transmitter that activates skeletal muscles, as described in Section 4-4. Yet in Loewi’s experiment, ACh acts to inhibit heartbeat, to slow it down. It turns out that ACh excites skeletal muscles in the somatic nervous system, causing them to contract, and may either excite or inhibit various internal organs in the autonomic system. How can the same chemical messenger do both? It turns out that the ion channel and its associated receptor, not the molecule itself, determine whether the messenger will be excitatory or inhibitory, which we explore in Section 5-2. And, yes, acetylcholine is the chemical messenger associated with the slowed heartbeat in diving bradycardia.

EXPERIMENT 5-1

Question: How does a neuron pass on a message?

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Conclusion: The message is a chemical released by the nerve.

In further experiments modeled on his procedure in Experiment 5-1, Loewi stimulated another nerve to the heart, the accelerator nerve, and heart rate increased. The fluid that bathed the accelerated heart also speeded the beat of a second heart that was not electrically stimulated. Loewi identified the chemical that carries the message to speed up heart rate in frogs as epinephrine (EP; epi-, “above,” and nephron, “kidney”), also known as adrenaline. Adrenaline (Latin) and epinephrine (Greek) are the same substance, produced by the adrenal glands located atop the kidneys. Adrenaline is the name more people

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know, in part because a drug company used it as a trade name, but epinephrine is common parlance in the science community. Further experimentation eventually demonstrated that in mammals, the chemical that accelerates heart rate is norepinephrine (NE; also called noradrenaline), a chemical closely related to epinephrine (EP). The results of Loewi’s complementary experiments showed that acetylcholine from the vagus nerve inhibits heartbeat, and epinephrine from the accelerator nerve excites it. ACh, EP, and NE molecules are structurally different from each other, as can be seen in Figure 5-1, which allows each of them to interact with a specific receptor.

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FIGURE 5-1 ACh, EP, and NE Three-dimensional space-filling models contrast the molecular structure of ACh, which inhibits heartbeat, to the structures of EP and NE, which excite the heart in frogs and humans, respectively.

The vagus nerve influences the heart and other internal body processes; see Figure 2-29.

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Chemical messengers released by a neuron onto a target to cause an excitatory or inhibitory effect are neurotransmitters. Outside the central nervous system, many of the same chemicals, epinephrine among them, circulate in the bloodstream as hormones. Under control of the hypothalamus, the pituitary gland releases hormones into the bloodstream to excite or inhibit targets, such as the organs and glands in the autonomic and enteric nervous systems. In part because hormones travel throughout the body to distant targets, their actions are slower than those of CNS neurotransmitters prodded by the lightning-quick nerve impulse. But the real difference between neurotransmitters and hormones is the distances they travel, within the same body, before they encounter their receptors. The role of hormones in the regulation of behavior is explored further in Section 12-4.

Section 6-5 explains how hormones influence the brain and behavior.

L oew i’s

discoveries led to the search for more neurotransmitters and their functions. The actual number of transmitters is an open question, with 100 posited as the maximum. The confirmed number is 60, with most of the work being done by 10. Whether a chemical is accepted as a neurotransmitter depends on the extent to which it meets certain criteria. As this chapter unfolds, you will learn those criteria, along with the names and functions of many neurotransmitters. You will also learn how groups of neurons form neurotransmitter systems throughout the brain to modulate, or temper, aspects of behavior. The three Clinical

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Focus boxes in this chapter tell the fascinating story of how one such neurotransmitter, dopamine, has yielded deep insight into brain function. When depleted in a particular brain area, this neurotransmitter is associated with a specific neurological disorder. The story begins with Clinical Focus 5-2, Parkinson Disease.

CLINICAL FOCUS 5-2

Parkinson Disease Case VI: The gentleman . . . is seventy-two years of age. . . . About eleven or twelve, or perhaps more, years ago, he first perceived weakness in the left hand and arm, and soon after found the trembling to commence. In about three years afterwards, the right arm became affected in a similar manner: and soon afterwards the convulsive motions affected the whole body and began to interrupt speech. In about three years from that time the legs became affected. (James Parkinson, 1817) In the 1817 essay from which this case study is taken, British physician James Parkinson reported similar symptoms in six patients, some of whom he had observed only in the streets near his clinic. Shaking was usually the first symptom, and it typically began in a hand. Over a span of years, the shaking spread to include the arm and then other parts of the body. As the disease progressed, patients had a propensity to lean forward and walk on the balls of their feet. They also tended to run forward to prevent themselves from falling. In the later stages, patients had difficulty eating and swallowing. They drooled, and their bowel movements slowed. Eventually, the patients lost all muscular control and were unable to sleep because of the disruptive tremors. More than 50 years after James Parkinson’s descriptions, French neurologist Jean-Martin Charcot named the condition Parkinson’s disease,

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known today as Parkinson disease. Three findings have helped researchers understand its neural basis: 1. In 1919, Constantin Tréatikoff (1974) studied the brains of nine Parkinson patients on autopsy and found that the substantia nigra, a small midbrain nucleus, had degenerated. In the brain of one patient who had Parkinsonlike symptoms on only one side of the body, the substantia nigra had degenerated on the side opposite that of the symptoms. 2. Chemical examination of the brains of Parkinson patients showed that disease symptoms appear when the level of dopamine (DA), then a proposed neurotransmitter, was reduced to less than 10 percent of normal in the basal ganglia (Ehringer & Hornykiewicz, 1960/1974). 3. Confirming the role of dopamine in a neural pathway connecting the substantia nigra to the basal ganglia, Urban Ungerstedt found in 1971 that injecting a neurotoxin called 6-hydroxydopamine into rats selectively destroyed these dopamine-containing neurons and produced symptoms of Parkinson disease.

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Michael J. Fox gained wide fame as an actor before being diagnosed in 1991, at age 30, with young-onset Parkinson disease. His first book, Lucky Man, discusses his first 7 years with the disease, why he went public with his condition, and how he started The Michael J. Fox Foundation and became a leading advocate for research to cure Parkinson disease. His second book, Always Looking Up: The Adventures of an Incurable Optimist, describes how he campaigned for stem-cell research as a potential cure.

Loss of dopamine-containing substantia nigra neurons has been linked to environmental factors such as insecticides, herbicides, fungicides, flu virus, and toxic drugs. About 10% of people with Parkinson disease have a mutation in one of several specific genes, and it may also be the case that people who are susceptible to environmental influences also have a genetic predisposition. Dopamine itself in other brain areas has been linked not only to motor behavior but also to some forms of learning and to neural structures that mediate reward and addiction. Some Parkinson patients who receive

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dopaminergic drugs as therapy have become shopaholics or compulsive gamblers, despite showing no such tendencies before treatment. Treatments for neurological diseases are usually much more effective the earlier they are started, so early detection is important. Joy Milne has an incredible sense of smell that is able to recognize Parkinson disease on the human body. She perceives a “thick musk smell” on people who have Parkinson disease and those yet to be diagnosed—even 10 years before diagnosis. Scientists are working with Joy to help create a diagnostic test for Parkinson disease.

Structure of Synapses Loewi’s discovery about the chemical messengers that regulate heart rate was the first of two seminal findings that form the foundation for current understanding of how neurons communicate. The second discovery had to wait until the invention of the electron microscope nearly 30 years later, which allowed researchers to determine that neurotransmitters are packaged into vesicles at the end terminals of axons. When tissue is stained with a substance that reflects electrons, ultrastructural details emerge.

Chemical Synapses Synaptic structure was first revealed in the 1950s, using electron microscopy. In the center of the micrograph in Figure 5-2A, the upper part of the synapse is the axon terminal, or end foot; the lower part is the receiving dendrite. The round granular substances in the terminal are the synaptic vesicles, which contain neurotransmitter molecules.

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FIGURE 5-2 Chemical Synapse (A) Surrounding the central synapse in this electron micrograph are astrocytes, a type of glial cell, axons, dendrites, other synapses, and a synaptic cleft. (B) Within a chemical synapse, storage granules hold vesicles containing neurotransmitter that travel to the presynaptic membrane in preparation for release. Neurotransmitter is expelled into the synaptic cleft by exocytosis, crosses the cleft, and binds to receptor proteins on the postsynaptic membrane.

Dark patches on the axon terminal membrane are proteins that serve largely as ion channels to signal the release of the transmitters or as pumps to recapture the transmitter after its release. The dark patches on the dendrite consist mainly of receptor molecules also made up of proteins that receive chemical messages. The terminal and the dendrite are separated by a small space, the synaptic cleft. The synaptic cleft is central to synapse function because neurotransmitter chemicals must bridge this gap to carry a message from one neuron to the next. You can also see in the micrograph that the synapse is sandwiched by many surrounding structures, including an astrocyte, other axons and dendritic processes, and other synapses. The surrounding astrocyte contributes to chemical neurotransmission in several ways—by supplying the building blocks for neurotransmitter synthesis, by confining the movement of neurotransmitters to the synapse, and by mopping up excess neurotransmitter molecules, for example. This functional integration and physical proximity of the presynaptic membrane, postsynaptic membrane, and their intimate association with surrounding astrocytes make up what is known as the tripartite synapse.

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Figure 5-2B details the process of neurotransmission at a chemical synapse, the junction where messenger molecules are released from one neuron to interact with the next neuron. Here, the presynaptic membrane forms the axon terminal, the postsynaptic membrane forms the dendritic spine, and the space between the two is the synaptic cleft. Within the axon terminal are specialized structures, including mitochondria, the organelles that supply the cell’s energy needs; storage granules, large compartments that hold several synaptic vesicles; and microtubules, which transport substances, including neurotransmitter, to the terminal.

Neurotransmission in Five Steps Anterograde synaptic transmission is the five-step process of transmitting information across a chemical synapse from the presynaptic side to the postsynaptic neuron (see Figure 5-3). In brief: 1. The neurotransmitter is synthesized somewhere inside the neuron. 2. It is packaged and stored within vesicles at the axon terminal. 3. It is transported to the presynaptic membrane and released into the cleft in response to an action potential. 4. It binds to and activates receptors on the postsynaptic membrane. 5. It is degraded or removed, so it will not continue to interact with a receptor and work indefinitely.

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FIGURE 5-3 Anterograde Synaptic Transmission

Steps 1 and 2: Neurotransmitter Synthesis, Packaging, and Storage There are several main classes of transmitters, and they are derived in different ways. The small-molecule transmitters are synthesized in the axon terminal from building blocks that are often derived from food. Transporters are protein molecules that move substances across cell membranes, and they are responsible for packaging some neurotransmitter classes into vesicles. Mitochondria in the axon terminal provide the energy needed both to synthesize precursor chemicals into the transmitter and to power transporters. Peptide transmitters are synthesized in the cell body according to

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The main classes of transmitters aresmall-molecule, peptide, lipid, gaseous, and ion. We describe each in the next section.

instructions in the neuron’s DNA, packaged in membranes on the Golgi bodies, and transported on microtubules to the axon terminal. Peptide transmitters may also be manufactured within the presynaptic terminal by ribosomes using mRNA transported to the terminal. Lipid transmitters cannot be packaged and stored in vesicles, which are composed of lipids, but are rather synthesized “on demand” when an action potential reaches the axon terminal. Gaseous transmitters are also generated within the cells by enzymes, but they differ from classical signaling molecules in many ways. Although their production is regulated, gaseous transmitters are able to permeate cell membranes and thus are not stored within the cell. Ion transmitters are not biochemically synthesized. Instead, like all other atoms heavier than helium, they are made in the hearts of dying stars. However, ion transmitters can be packaged and stored in vesicles, usually along with other transmitter types, and then released into the synaptic cleft. For a refresher on protein export, review Figure 3-17.

Regardless of their origin, neurotransmitters

that are packaged into vesicles can be found in three locations at the axon terminal. Some vesicles are warehoused in granules, some are attached to microfilaments (a type of microtubule; see Figure 5-2B) in 525

the terminal, and still others are attached to the presynaptic membrane. These sites correspond to the steps by which a transmitter is transported from a granule to the membrane, ready to be released into the synaptic cleft.

Step 3: Neurotransmitter Release Synaptic vesicles loaded with neurotransmitters must dock near release sites on the presynaptic membrane. Then the vesicles are primed to prepare them to fuse rapidly in response to calcium (Ca2+) influx. When an action potential reaches the presynaptic membrane, voltage changes on the membrane set the release process in motion. Calcium cations play a critical role. The presynaptic membrane is rich in voltageactivated calcium channels, and the surrounding extracellular fluid is rich in Ca2+. As illustrated in Figure 5-4, the action potential’s arrival opens these calcium channels, allowing an influx of calcium ions into the axon terminal.

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FIGURE 5-4 Neurotransmitter Release

Primed vesicles quickly fuse with the presynaptic membrane in response to the calcium influx and empty their contents into the synaptic cleft by exocytosis. The vesicles from storage granules and on filaments then move up to replace the vesicles that just emptied their contents.

Step 4: Receptor-Site Activation After its release from vesicles on the presynaptic membrane, the neurotransmitter diffuses across the synaptic cleft and binds to specialized protein molecules embedded in the postsynaptic membrane. These transmitter-activated receptors have binding sites for the transmitter, which we elaborate on in Section 5-3. The properties of the receptors on the postsynaptic membrane determine the effect on the

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postsynaptic cell. Ionotropic receptors are associated with a pore that can open to allow ions to pass through the membrane, rapidly changing membrane voltagein one of two possible ways. These ion channels may allow Na+ to enter the neuron, depolarizing the postsynaptic membrane, and so have an excitatory action on the postsynaptic neuron. Or they may allow K+ to leave the neuron or Cl− to enter the neuron, hyperpolarizing the postsynaptic membrane, and so typically have an inhibitory action on the postsynaptic neuron. When bound by a transmitter, a second type of receptor, called a metabotropic receptor, may initiate intracellular messenger systems; this, in turn, may open an ion channel, thus modulating either excitation or inhibition or influencing other functions of the receiving neuron. (This process is discussed in more detail in Section 5-2.) In addition to interacting with the postsynaptic membrane’s receptors, a neurotransmitter may interact with receptors on the presynaptic membrane: it may influence the cell that just released it. That is, a neurotransmitter may activate presynaptic receptors called autoreceptors (self-receptors) to receive messages from their own axon terminals. Autoreceptors serve a critical function as part of a negative feedback loop, providing information about whether adjustment to synaptic communication should be made. How much neurotransmitter is needed to send a message? Bernard Katz was awarded a Nobel Prize in 1970 for providing an answer to this question. While recording electrical activity from the postsynaptic membranes of muscles, he detected small, spontaneous depolarizations now called miniature postsynaptic potentials. The potentials varied in size, but each size appeared to be a multiple of the smallest potential. 528

Katz concluded that the smallest postsynaptic potential is produced by the release of the contents of just one synaptic vesicle. This number of neurotransmitter molecules is called a quantum (pl. quanta). Producing a postsynaptic potential large enough to initiate a postsynaptic action potential requires the simultaneous release of many quanta from the presynaptic cell. The results of subsequent experiments show that the number of quanta released from the presynaptic membrane in response to a single action potential depends on two factors: (1) the amount of Ca2+ that enters the axon terminal in response to the action potential and (2) the number of vesicles docked at the membrane, waiting to be released. Both factors are relevant to synaptic activity during learning, which we consider in Section 5-4.

Step 5: Neurotransmitter Inactivation Chemical transmission would not be an effective messenger system if a neurotransmitter lingered within the synaptic cleft, continuing to occupy and stimulate receptors. If this happened, the postsynaptic cell could not respond to other messages sent by the presynaptic neuron. Thus, after a neurotransmitter has done its work, it is quickly removed from receptor sites and from the synaptic cleft. Inactivation is accomplished in at least four ways: 1. Diffusion. Some of the neurotransmitter simply diffuses away from the synaptic cleft and is no longer available to bind to receptors. 2. Degradation. Enzymes in the synaptic cleft break down the transmitter.

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3. Reuptake. Membrane transporters specific to that transmitter may bring it back into the presynaptic axon terminal for reuse. The byproducts of degradation by enzymes also may be taken back into the terminal to be used again in the cell. 4. Astrocyte uptake. Some neurotransmitters are taken up by neighboring astrocytes. Astrocytes can also store certain transmitters for re-export to the axon terminal. Table 3-1 describes astrocytes and other types of glial cells and their functions.

Highlighting the flexibility of synaptic function, an axon terminal has chemical mechanisms that enable it to respond to the frequency of its own use. If the terminal is very active, the amount of neurotransmitter made and stored there increases. If the terminal is not often used, however, enzymes within the terminal buttons may break down excess transmitter. The by-products are then reused or excreted from the neuron. Axon terminals may even send messages to the neuron’s cell body, requesting increased supplies of the neurotransmitter or the molecules with which to make it.

Varieties of Synapses So far, we have considered a generic chemical synapse, with features possessed by most synapses. Synapses vary widely in the nervous system. Each type is specialized in location, structure, function, and target. Figure 5-5 illustrates this diversity on a single hypothetical neuron.

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FIGURE 5-5 The Versatile Synapse

You have already encountered two kinds of chemical synapses. One is the axomuscular synapse, in which an axon synapses with a muscle end plate, releasing acetylcholine. The other synapse familiar to you is the axodendritic synapse, detailed in Figure 5-2B, in which the axon terminal of a neuron synapses with a dendrite or dendritic spine of another neuron. Figure 4-26 shows a schematic view of an axomuscular synapse.

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Figur e 5-5

diagram s axon terminals at the axodendritic synapse, as well as the axosomatic synapse, at a cell body; the axoaxonic synapse, on another axon; and the axosynaptic synapse, on another presynaptic terminal (that is, at the synapse between some other axon and its target). Axoextracellular synapses have no specific targets but instead secrete their transmitter chemicals into the extracellular fluid. In the axosecretory synapse, a terminal synapses with a tiny blood vessel, a capillary, and secretes its transmitter directly into the blood. Finally, synapses are not limited to axon terminals. Dendrites also may send messages to other dendrites through dendrodendritic synapses. This wide variety of connections makes the synapse a versatile chemical delivery system. Synapses can deliver transmitters to highly specific sites or diffuse locales. Through connections to the dendrites, cell body, or axon of a neuron, transmitters can control the neuron’s actions in different ways. Through axosynaptic connections, they can also exert precise control over another neuron’s input to a cell. By excreting transmitters into extracellular fluid or into the blood, axoextracellular and axosecretory synapses can modulate the function of large areas of tissue or even the entire body. Many transmitters secreted by neurons act as hormones circulating in your blood, with widespread influences on your body.

Electrical Synapses Chemical synapses are the most common synapses in mammalian nervous systems, but they are not the only kind of synapse. Some neurons influence each other electrically through an electrical synapse,

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or gap junction, where two neurons’ intracellular fluids or cytoplasm can come into direct contact (Figure 5-6). A gap junction is formed when connexin proteins in one cell membrane make a hemichannel that connects to a hemichannel in an adjacent cell's membrane, allowing ions to pass from one neuron to the other in both directions. Gap junctions constitute a regulated gate between cells because they can either be open or closed.

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FIGURE 5-6 Gap Junction The connexin proteins on adjacent cell membranes connect to form hemichannels, which allow ions to pass between the two neurons.

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Gap junctions eliminate the brief delay in information flow—about 5 milliseconds per synapse—of chemical transmission (note the space between the presynaptic terminal and the dendritic spine in Figure 5-2B compared with Figure 5-3). For example, the crayfish’s gap junctions activate its tail flick, a response that provides quick escape from a predator. Gap junctions are found in the mammalian brain as well, where in some regions they allow groups of interneurons to synchronize their firing rhythmically. Gap junctions also allow glial cells and neurons to exchange substances (Dere & Zlomuzica, 2012). Gap junctions also come with some variety. There are different connexin subunits that give rise to different pore sizes, which allows selectivity for specific small molecules. Large biomolecules such as nucleic acids and proteins cannot fit through gap junctions. Gap junctions further increase the signaling diversity between neurons. Such interneuronal communication may occur via dendrodendritic and axoaxonic gap junctions. Interestingly, gap junctions at axon terminals synapsing on dendrites and cell bodies allow for dual chemical and electrical synaptic transmission. These “mixed synapses” have only recently been discovered, and their functional properties have yet to be determined in the mammalian CNS (Nagy et al., 2017). If chemical synapses transmit messages more slowly, why do mammals rely on them more than on gap junctions? The answer is that chemical synapses can show plasticity; they can amplify or diminish a signal sent from one neuron to the next; and they can change with experience to alter their signals and thus mediate learning. Gap

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junctions themselves allow no such plasticity and are built for speed and efficient communication.

Excitatory and Inhibitory Messages A neurotransmitter can influence a neuron’s functioning through a remarkable variety of mechanisms. In its direct actions in influencing a neuron’s electrical activity, however, a neurotransmitter acting through its receptors has only one of two immediate effects. It influences transmembrane ion flow either to increase or to decrease the likelihood that the cell with which it comes in contact will produce an action potential. Thus, despite the wide variety of synapses, they all convey messages of only these two types, excitatory or inhibitory. To be precise, neurotransmitters themselves do not determine excitation or inhibition. As noted at the beginning of this section, the ion channel associated with the receptor makes the call. Each neuron receives thousands of excitatory and inhibitory signals every second. As indicated in Principle 10: The nervous system works by juxtaposing excitation and inhibition.

Excitatory and inhibitory synapses differ in their appearance and are generally located on different parts of the neuron. As shown in Figure 5-7, excitatory synapses are typically on the shafts or spines of dendrites, whereas inhibitory synapses are typically on the cell body. Excitatory synapses have round synaptic vesicles; the vesicles in inhibitory synapses are flattened. The material on the presynaptic and postsynaptic membranes is denser in an excitatory synapse than it is in

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an inhibitory synapse, and the excitatory synaptic cleft is wider. Finally, the active zone on an excitatory synapse is larger than that on an inhibitory synapse.

FIGURE 5-7 Excitatory and Inhibitory Zones Excitatory synapses typically occupy spines and dendritic shafts on a neuron. Inhibitory synapses are typically found on the cell body.

Behaviors are lost when a disorder prevents excitatory instructions, and they are uncontrollably expressed, or “released,” when a disorder prevents inhibitory instructions.

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The differing locations of excitatory and inhibitory synapses divide a neuron into two zones: an excitatory dendritic tree and an inhibitory cell body. Think of excitatory and inhibitory messages as interacting from these two different perspectives. Viewed from an inhibitory perspective, you can picture excitation coming in over the dendrites and spreading past the axon hillock to trigger an action potential at the initial segment. If the message is to be stopped, it is best stopped by inhibiting the cell body close to the initial segment. In this model of excitatory–inhibitory interaction, inhibition blocks excitation by using a “cut ’em off at the pass” strategy. Another way to conceptualize excitatory–inhibitory interaction is to picture excitation overcoming inhibition. In fact, excitatory synaptic inputs that are farther away from the soma are larger, to counteract the loss of signal that occurs over distance (Magee & Cook, 2000). If the cell body is typically in an inhibited state, the only way to generate an action potential is to reduce cell body inhibition. In this “open the gates” strategy, the excitatory message is like a racehorse ready to run down the track, but first the inhibitory starting gate must be removed.

Evolution of Complex Neurotransmission Systems Considering all the biochemical steps required to get a message across a synapse and the variety of synapses, you might well wonder why—and how—such a complex communication system ever evolved. How did chemical transmitters originate?

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To make the origin of chemical secretions for neuronal communication easier to imagine, think about the feeding behaviors of simple single-celled creatures. The earliest unicellular creatures secreted juices onto bacteria to immobilize and prepare them for ingestion. These digestive juices were probably expelled from the cell body by exocytosis: a vacuole or vesicle attached itself to the cell membrane and then opened into the extracellular fluid to discharge its contents. The prey, thus immobilized, was captured through the reverse process of endocytosis. The exocytosis mechanism for digestion in a single-celled organism is parallel to the release of a neurotransmitter for communication in more complex creatures. Quite possibly, evolution long ago adapted these primordial digestive processes into processes of neural communication in more complex organisms.

5-1 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. In mammals, the principal form of communication between neurons occurs via , even though this structure is slower and more complex than the fused . 2. The principal benefit of chemical synapses over electrical synapses is that they can change with to alter their signals and so mediate . 3. The nervous system has evolved a variety of synapses: between axon terminals and dendrites,

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between axon terminals and cell bodies, between axon terminals and muscles, between axon terminals and other axons, between axon terminals and other synapses. A(n) synapse releases chemical transmitters into extracellular fluid, a(n) synapse releases transmitter into the bloodstream as hormones, and a(n) synapse connects dendrites to other dendrites. 4. Excitatory synapses are usually located on a(n) whereas inhibitory synapses are usually located on a(n) . 5. Describe the five steps in chemical neurotransmission.

For additional study tools, visit

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5-2 Varieties of Neurotransmitters and Receptors Subsequent to Otto Loewi’s 1921 discovery that excitatory and inhibitory chemicals control heart rate, many researchers thought that the brain must work under much the same type of dual control. They reasoned that norepinephrine and acetylcholine are the transmitters through which excitatory and inhibitory brain cells worked. They did not imagine what we know today: the human brain employs a dazzling variety of neurotransmitters and receptors. The neurotransmitters operate in even more versatile ways: some may be excitatory at one location and inhibitory at another, for example, and two or more may team up in a single synapse so that one makes the other more potent. Moreover, each neurotransmitter may interact with several varieties of receptors, each with a somewhat different function. In this section, you will learn how neurotransmitters are identified and how they fit within broad categories on the basis of their chemical structure. The functional aspects of neurotransmitters interrelate and are intricate, and there is not a simple one-to-one relation between a single neurotransmitter and a single behavior. Furthermore, receptor variety is achieved by the unique combination of protein molecules coming together to form a functional receptor.

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Four Criteria for Identifying Neurotransmitters Among the many thousands of chemicals in the nervous system, which are neurotransmitters? Figure 5-8 presents four identifying criteria: 1. The transmitter must be synthesized in the neuron or otherwise be present in it. 2. When the neuron is active, the transmitter must be released and produce a response in some target. 3. The same response must be obtained when the transmitter is experimentally placed on the target. 4. A mechanism must exist for removing the transmitter from its site of action after its work is done.

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FIGURE 5-8 Criteria for Identifying Neurotransmitters

These identifying criteria are fairly easy to apply for examining the somatic nervous system, especially at an accessible nerve–muscle junction with only one main neurotransmitter, acetylcholine. But identifying chemical transmitters in the CNS is not so easy. In the brain and spinal cord, thousands of synapses are packed around every neuron, preventing easy access to any single synapse and its activities.

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Consequently, multiple techniques, including staining, stimulating, and collecting, are used to identify substances thought to be CNS neurotransmitters. A suspect chemical that has not yet been shown to meet all the criteria is called a putative (supposed) transmitter. Researchers trying to identify new CNS neurotransmitters can use microelectrodes to stimulate and record from single neurons. A glass microelectrode is small enough to be placed on specific neuronal targets. It can be filled with a chemical of interest, and when a current is passed through the electrode, the chemical can be ejected into or onto the neuron to mimic neurotransmitter release onto the cell. Figure 4-6 illustrates the use of a glass microelectrode.

Many staining techniques can identify specific

chemicals inside the cell. Methods have also been developed for preserving nervous system tissue in a saline bath while experimenters determine how the neurons in the tissue communicate. The use of such living tissue slices simplifies the investigation by allowing the researcher to view a single neuron through a microscope while stimulating it or recording from it. Acetylcholine was not only the first substance identified as a neurotransmitter but also the first substance identified as a CNS neurotransmitter. A logical argument that predicted its presence even before experimental evidence was gathered greatly facilitated the process. All motor neuron axons leaving the spinal cord use acetylcholine as a transmitter. Each axon has an axon collateral within the spinal cord that synapses on a nearby CNS interneuron. The interneuron, in turn, synapses on the motor neuron’s cell body. This 544

circular set of connections, called a Renshaw loop (after the researcher who first described it), is shown in Figure 5-9.

FIGURE 5-9 Renshaw Loop Left: Some spinal cord motor neurons project to the rat’s forelimb muscles. Right: In a Renshaw loop, the main motor axon (green) projects to a muscle, and its axon collateral remains in the spinal cord to synapse with a Renshaw interneuron (red). The Renshaw interneuron contains the inhibitory transmitter glycine, which acts to prevent motor neuron overexcitation. Both the main motor axon and its collateral terminals contain acetylcholine. When the motor

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neuron is highly excited, it can modulate its activity level through the Renshaw loop (plus and minus signs).

Because the main axon to the muscle releases acetylcholine, investigators suspected that its axon collateral also might release acetylcholine. For two terminals of the same axon to use different transmitters seemed unlikely. Knowing what chemical to look for made it easier to find and obtain the required evidence that ACh is in fact a neurotransmitter in both locations. The loop made by the axon collateral and the interneuron in the spinal cord forms a feedback circuit that enables the motor neuron to inhibit itself from overexcitation, should it receive a great many excitatory inputs from other parts of the CNS. Follow the positive and negative signs in Figure 5-9 to see how the Renshaw loop works. If the loop is blocked, as can be done with the toxin strychnine, motor neurons become overactive, producing convulsions that can choke off respiration and so cause death. The term neurotransmitter is used much more broadly now than it was when researchers began to identify these chemicals. Today, the term applies to chemicals that Carry a message from the presynaptic membrane of one neuron to another by influencing postsynaptic membrane voltage. Change the structure of a synapse. Communicate by sending messages in the opposite direction. These retrograde (reverse-direction) messages influence the release or reuptake of transmitters on the presynaptic side.

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Classes of Neurotransmitters We impose some order on the diversity of neurotransmitters by classifying them into groups based on their chemical composition: small-molecule transmitters, peptide transmitters, lipid transmitters, gaseous transmitters, and ion transmitter.

Small-Molecule Transmitters The quick-acting small-molecule transmitters, such as acetylcholine, are typically synthesized from dietary nutrients and packaged ready for use in axon terminals. When a small-molecule transmitter has been released from a terminal button, it can quickly be replaced at the presynaptic membrane. Because small-molecule transmitters or their main components are derived from the food we eat, diet can influence their abundance and activity in our bodies. This fact is important in the design of drugs that act on the nervous system. Many neuroactive drugs are designed to reach the brain by the same route that small-molecule transmitters or their precursor chemicals follow: the digestive tract. Taking drugs orally is easy and comparatively safe, but not all drugs can traverse the digestive tract. Section 6-1 explains.

Table 5-1 lists some of the best-known and most extensively studied small-molecule transmitters. In addition to acetylcholine, four amines (related by a chemical structure that contains an NH group, or amine), four amino acids, and two purines are included in this list.

TABLE 5-1 Best-Known and Well-Studied Small547

Molecule Neurotransmitters Acetylcholine (ACh) Amines Dopamine (DA) Norepinephrine (NE, or noradrenaline [NA]) Epinephrine (EP, or adrenaline) Serotonin (5-HT) Amino acids Glutamate (Glu) Gamma-aminobutyric acid (GABA) Glycine (Gly) Histamine (H) Purines Adenosine Adenosine triphosphate (ATP)

ACETYLCHOLINE SYNTHESIS Acetylcholine is present at the junction of neurons and muscles, including the heart, as well as in the CNS. Figure 5-10 illustrates how ACh molecules are synthesized from choline and acetate by two enzymes and then broken down. Choline is among the breakdown products of fats in foods such as egg yolk, avocado, salmon, and olive oil; acetate is a compound found in acidic foods, such as vinegar and lemon juice.

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FIGURE 5-10 Chemistry of Acetylcholine Two enzymes combine the dietary precursors of ACh within the cell, and a third breaks them down in the synapse for reuptake.

As depicted in Figure 5-10, inside the cell, acetyl coenzyme A (acetyl CoA) carries acetate to the synthesis site, and a second enzyme, choline acetyltransferase (ChAT), transfers the acetate to choline to synthesize acetylcholine. After ACh has been released into the synaptic cleft and diffuses to receptor sites on the postsynaptic membrane, a 549

third enzyme, acetylcholinesterase (AChE), reverses the process, breaking down the transmitter by detaching acetate from choline. The breakdown products can then be taken back into the presynaptic terminal for reuse.

AMINE SYNTHESIS Some transmitters grouped together in Table 5-1 have common biochemical pathways to synthesis and so are related. You are familiar with the amines dopamine (DA), norepinephrine (NE), and epinephrine (EP). To review, DA loss figures in Parkinson disease, EP is the excitatory transmitter at the amphibian heart, and NE is the excitatory transmitter at the mammalian heart. Figure 5-11 charts the biochemical sequence in which these amines are synthesized. The precursor chemical is tyrosine, an amino acid abundant in food. (Hard cheese and bananas are good sources.) The enzyme tyrosine hydroxylase (enzyme 1 in Figure 5-11) changes tyrosine into L-dopa, which other enzymes convert into dopamine, then norepinephrine, and, finally, epinephrine.

FIGURE 5-11 Sequential Synthesis of Three Amines A different enzyme is responsible for each successive molecular modification in this biochemical sequence of amine neurotransmitters. The twins featured in Research Focus 3-1 lack an enzyme that enhances DA production.

Interestingly, the supply of the enzyme tyrosine hydroxylase is limited. Consequently, so is the rate at which dopamine,

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norepinephrine, and epinephrine can be produced, regardless of how much tyrosine is present or ingested. This rate-limiting factor can be bypassed by the oral administration of L-dopa, which is why L-dopa is a medication used in treating Parkinson disease, as described in Clinical Focus 5-3, Awakening with L-Dopa.

CLINICAL FOCUS 5-3

Awakening with L-Dopa He was started on L-dopa in March 1969. The dose was slowly raised to 4.0 mg a day over a period of three weeks without apparently producing any effect. I first discovered that Mr. E. was responding to L-dopa by accident, chancing to go past his room at an unaccustomed time and hearing regular footsteps inside the room. I went in and found Mr. E., who had been chair bound since 1966, walking up and down his room, swinging his arms with considerable vigor, and showing erectness of posture and a brightness of expression completely new to him. When I asked him about the effect, he said with some embarrassment: “Yes! I felt the L-dopa beginning to work three days ago—it was like a wave of energy and strength sweeping through me. I found I could stand and walk by myself, and that I could do everything I needed for myself—but I was afraid that you would see how well I was and discharge me from the hospital.” (Sacks, 1976) In this case history, neurologist Oliver Sacks describes administering Ldopa to a patient who had acquired Parkinsonism as an aftereffect of severe influenza in the 1920s. The relationship between the influenza and the Parkinsonlike symptoms suggests that the flu virus had entered the brain and selectively attacked dopamine neurons in the substantia nigra. By increasing the amount of DA in remaining synapses, L-dopa relieved the patient’s symptoms.

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The movie Awakenings recounts the L-dopa trials conducted by Oliver Sacks and described in his book of the same title.

Two separate groups of investigators independently gave L-dopa to Parkinson patients beginning in 1961 (Barbeau et al., 1961; Birkmayer & Hornykiewicz, 1961). Both research teams knew that the chemical is catalyzed into dopamine at DA synapses (see Figure 5-11). The L-dopa, it turned out, reduced the patients’ muscular rigidity. This work provided the first demonstration that a neurological condition can be relieved by a drug that aids in increasing the amount of a neurotransmitter. L-Dopa has since become a standard treatment for Parkinson disease. Its effects have been improved by the administration of drugs that prevent L-dopa from being converted to dopamine in the body before it passes through the blood–brain barrier and gets to dopamine neurons in the brain. L-Dopa

is not a cure, however. Parkinson disease still progresses during

treatment, and as more and more dopamine synapses are lost, the treatment becomes less and less effective. L-dopa can also produce dyskinesias— involuntary, unwanted movements, such as ballistic (throwinglike) or choreic

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(dancelike) movements. When these side effects eventually become severe, the treatment must be discontinued.

SEROTONIN SYNTHESIS The amine transmitter serotonin (5-HT, for 5-hydroxy-tryptamine) is synthesized from the amino acid L-tryptophan. Tryptophan is abundant in pork, turkey, milk, and bananas, among other foods. Serotonin plays a role in regulating mood and aggression, appetite and arousal, respiration, and pain perception.

AMINO ACID SYNTHESIS Two amino acid transmitters, glutamate (Glu) and gammaaminobutyric acid (GABA), are closely related. GABA is formed by a simple modification of the glutamate molecule, as shown in Figure 512. These two transmitters are the workhorses of the brain because so many synapses use them.

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FIGURE 5-12 Amino Acid Transmitters Top: Removal of a carboxyl (COOH) group from the bottom of the glutamate molecule produces GABA. Bottom: Their different shapes, illustrated by three-dimensional space-filling models, thus allow these amino acid transmitters to bind to different receptors.

In the forebrain and cerebellum, glutamate is the main excitatory transmitter, and GABA is the main inhibitory transmitter. Thus, glutamate is a neurotransmitter in excitatory synapses, and GABA is a neurotransmitter in inhibitory synapses. Interestingly, glutamate is widely distributed in CNS neurons, but it becomes a neurotransmitter only if it is appropriately packaged in vesicles in the axon terminal. The amino acid transmitter glycine (Gly) is a much more common inhibitory transmitter in the brainstem and spinal cord, where it acts within the Renshaw loop, for example (review Figure 5-9).

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Histidine is an amino acid that serves as the primary biological source of the transmitter histamine (H). Histidine is converted by the enzyme histidine decarboxylase into histamine. Among its many functions, which include control of arousal and of waking, histamine can also cause the constriction of smooth muscles. When activated in allergic reactions, histamine contributes to asthma, a constriction of the airways. You are probably familiar with antihistamine drugs used to treat allergies.

PURINES The purines are synthesized as nucleotides—the kind of molecules that make up DNA and RNA. The purine adenosine triphosphate (ATP) consists of a molecule of adenine attached to a ribose sugar molecule and three phosphate groups. Removal of the three phosphate groups leaves adenosine, a molecule that plays a central role in promoting sleep, suppressing arousal, and regulating blood flow to various organs through vasodilation (the dilation of blood vessels).

Peptide Transmitters More than 50 short amino acid chains of various lengths (fewer than 100 amino acids) form the families of peptide transmitters, or neuropeptides, listed in Table 5-2. Synthesized through the translation of mRNA from instructions contained in the neuron’s DNA, neuropeptides are multifunctional chains of amino acids that act as neurotransmitters.

TABLE 5-2 Peptide Neurotransmitters Family

Examples

Opioids

Met-enkephalin, dynorphin, beta-endorphin

Neurohypophyseals

Vasopressin, oxytocin

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Secretins

Secretin, motilin, glucagon, growth hormone–releasing factor

Insulins

Insulin, insulin growth factors

Gastrins

Gastrin, cholecystokinin

Somatostatins

Somatostatin

Tachykinins

Neurokinin A, neurokinin B, substance P

Section 3-2 includes a detailed description of DNA and RNA and the process of protein synthesis. Figure 3-15 diagrams peptide bonding, and Figure 3-17 diagrams protein export.

In some neurons, peptide transmitters are made in the axon terminal, but most are assembled on the neuron’s ribosomes, packaged in a membrane by Golgi bodies, and transported by the microtubules to the axon terminals. The entire process of neuropeptide synthesis and transport is relatively slow compared with the nearly ready-made smallmolecule neurotransmitters. Consequently, peptide transmitters act slowly and are not replaced quickly. Neuropeptides, however, perform an enormous range of functions in the nervous system, as might be expected from their large numbers. They act as hormones that respond to stress, enable a mother to bond with her infant, regulate eating and drinking and pleasure and pain, and probably contribute to learning. Opium, morphine, and related synthetic chemicals such as heroin— long known both to produce euphoria and to reduce pain—mimic the actions of endogenous brain opioid neuropeptides: enkephalins, dynorphins, and endorphins. (The term enkephalin derives from the phrase in the cephalon, meaning “in the brain or head,” whereas the term endorphin is a shortened form of “endogenous morphine.”)

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A part of the amino acid chain in each of these naturally occurring opioid peptides is structurally similar to the others, as illustrated for two of them in Figure 5-13. Morphine mimics this part of the chain. The discovery of naturally occurring morphine-like neuropeptides suggested that one or more of them might have analgesic properties and may take part in pain perception. It turns out that beta-endorphin, released in response to exercise and thought to be responsible for runner’s high, has many times the analgesic potency of morphine.

FIGURE 5-13 Opioid Peptides Parts of the amino acid chains of some neuropeptides that act on brain centers for pleasure and pain are structurally similar and also share similarities to drugs such as morphine, which mimic their functions (see Section 6-2).

Some CNS peptides take part in specific periodic behaviors, each month or each year perhaps. For instance, in a female deer, neuropeptide transmitters act as hormones (luteinizing hormone) that prepare her for the fall mating season. Come winter, a different set of

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biochemicals facilitates the developing deer fetus. When the mother gives birth in the spring, yet other highly specific neuropeptide hormones—such as oxytocin, which enables her to bond to her fawn, and prolactin, which enables her to nurse—take control. Sections 12-3 and 12-6 explain hormonal influence over human motivated and emotional behavior.

The same neuropeptides serve similar specific hormonal functions in humans. Others, such as neuropeptide growth hormones, perform far more general functions in regulating growth. Unlike many transmitters that bind to receptors associated with ion channels, neuropeptides are metabotropic and have no direct effects on postsynaptic membrane voltage. Instead, peptide transmitters activate synaptic receptors that indirectly influence cell structure and function. Digestive processes degrade neuropeptide amino acid chains, so they generally cannot be taken orally as drugs, whereas some small-molecule transmitters can.

Lipid Transmitters Predominant among the lipid neurotransmitters are the endocannabinoids (endogenous cannabinoids), a class of lipid neurotransmitters synthesized at the postsynaptic membrane to act on receptors at the presynaptic membrane. The endocannabinoids include anandamide and 2-AG (2-arachidonoylglycerol), both derived from arachidonic acid, an unsaturated fatty acid. Poultry and eggs are especially good sources. Endocannabinoids participate in a diverse set of physiological and psychological processes that affect appetite, pain, sleep, mood, memory, anxiety, and the stress response. Their scientific

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history is brief but illustrates how science can progress, punctuated by short steps. Because endocannabinoids are lipophilic (fat-loving) molecules, they are not soluble in water and are not stored in vesicles. Rather, investigators hypothesize that endocannabinoids are synthesized on demand after a neuron has depolarized and calcium has entered. Calcium activates the enzyme transacylase, the first step in producing anandamide. Once anandamide or 2-AG is synthesized, it diffuses across the synaptic cleft and interacts with its receptor on the presynaptic membrane. Thus, both molecules act as retrograde neurotransmitters, for a time reducing the amount of small-molecule transmitter being released. In this way, the postsynaptic neuron reduces the amount of incoming neural signal. Fatty acid molecules that contribute to forming the cell membrane likewise are hydrophobic. See Figure 3-11.

The CB1 receptor is the target of all cannabinoids, whether generated by the body (endocannabinoids), from plants (phytocannabinoids), or synthetically. Yes, your body is teeming with weed receptors (Scudellari, 2017). CB1 receptors are found at both glutamate and GABA synapses, so cannabinoids act as neuromodulators to inhibit release of glutamate and GABA. Cannabinoids thus dampen both neuronal excitation and inhibition. Phyto cannabin

Cannabis contains a psychotropic drug discussed in Section 6-2.

oids are

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obtained from the hemp plants Cannabis sativa and Cannabis indica. These plants have been used medically and recreationally for thousands of years, but only recently was an extract from cannabis synthesized. Early in the last century, many constituents of cannabis, including tetrahydrocannabinol (THC) and cannabidiol (CBD), were isolated and their chemical structure determined. In 1967, Yehiel Gaoni and Raphael Mechoulam reported the structure of the THC molecule, the main psychoactive constituent in cannabis. Next, investigators determined how THC is metabolized. (The process is quite slow, which explains why THC can be detected in urine for weeks after cannabis use.) Research on the physiological and psychological effects of THC in animals and people, which began after its isolation and purification, is ongoing. Twenty-four years after the structure of the THC molecule was determined, the first cannabinoid receptor (CB1) was found. Typically, receptors are activated by endogenous molecules, which motivated researchers to look for endogenous cannabinoids. Four years later, in 1992, anandamide was isolated and its structure determined, but it took another couple decades to figure out that endocannabinoids act as retrograde transmitters (Mechoulam et al., 2014).

Gaseous Transmitters The gases nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) further expand the biochemical strategies that transmitter substances display. As water-soluble gases, they are neither stored in synaptic vesicles nor released from them; instead, the cell synthesizes them on demand. After synthesis, each gas diffuses away, easily crossing the cell membrane and immediately becoming active. Both NO and CO activate metabolic (energy-expending) processes in cells,

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including processes modulating the production of other neurotransmitters. H2S prevents oxygen from binding in the mitochondria and thus functions to slow down metabolism. All three gaseous transmitters serve as chemical messengers in many parts of the body. NO and H2S control intestinal wall muscles and dilate blood vessels in active brain regions, allowing these regions to receive more blood. Because NO and H2S also dilate blood vessels in the sexual organs, both are active in producing penile erections. Drugs used to treat erectile dysfunction in men, such as Viagra and Cialis, act by enhancing the chemical pathways influenced by NO. NO does not of itself produce sexual arousal.

Ion Transmitter Recent evidence has led researchers to classify zinc (Zn2+) as a transmitter. As a charged atom, zinc is not biologically synthesized but rather, like all other atoms, was formed by fusion reactions in stars. It is actively transported, packaged into vesicles—usually with another transmitter like glutamate—and released into the synaptic cleft. Zinc interacts with several different receptors to cause biological change. When vesicular zinc becomes dysregulated, cognitive decline associated with age and Alzheimer disease occurs, whereas maintaining zinc homeostasis or correcting it with drug treatment protects cognitive ability (McAllister & Dyck, 2017).

Varieties of Receptors Each of the two general classes of receptor proteins produces a different effect: one directly changes the postsynaptic membrane’s electrical potential, and the other induces cellular change indirectly. A dazzling

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array of receptor subtypes allows for subtle differences in receptor function.

Two Classes of Receptors When a neurotransmitter is released from any of the wide varieties of synapses onto a wide variety of targets, as illustrated in Figure 5-6, it crosses the synaptic cleft and binds to a receptor. What happens next depends on the receptor type. Ionotropic receptors allow ions such as Na+, K+, Cl−, and Ca2+ to move across a membrane (the suffix -tropic means “moving toward”). As Figure 5-14 illustrates, an ionotropic receptor has two parts: (1) a binding site for a neurotransmitter and (2) a pore, or channel. When the neurotransmitter attaches to the binding site, the receptor quickly changes shape, either opening the pore and allowing ions to flow through it or closing the pore and blocking the ion flow. Thus, ionotropic receptors bring about rapid changes in membrane voltage and are usually excitatory: they trigger an action potential.

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FIGURE 5-14 Ionotropic Receptor When activated, embedded transmitter proteins bring about direct, rapid changes in membrane voltage.

Structurally, ionotropic receptors resemble voltage-activated channels, which propagate the action potential. See Figure 4-17.

In contrast, a metabotropic receptor has a binding site for a neurotransmitter but lacks its own pore through which ions can flow. Through a series of steps, activated metabotropic receptors indirectly produce changes in nearby membrane-bound ion channels or in the cell’s metabolic activity. Figure 5-15A shows the first of these two indirect effects. The metabotropic receptor consists of a single protein that spans the cell membrane, its binding site facing the synaptic cleft.

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Each receptor is coupled to one of a family of guanyl nucleotide– binding proteins, G proteins for short, shown on the inner side of the cell membrane in Figure 5-15A. When activated, a G protein binds to other proteins.

FIGURE 5-15 Metabotropic Receptors When activated by a neurotransmitter, embedded membrane receptor proteins trigger associated G proteins, exerting indirect effects (A) on nearby ion channels or (B) in the cell’s metabolic activity.

A G protein consists of three subunits: alpha, beta, and gamma. (A subunit is a protein that assembles with other proteins.) The alpha subunit detaches when a neurotransmitter binds to the G protein’s 564

associated metabotropic receptor. The detached alpha subunit can then bind to other proteins within the cell’s membrane or its intracellular fluid. If the alpha subunit binds to a nearby ion channel in the membrane, as shown at the bottom of Figure 5-15A, the channel structure changes, modifying the flow of ions through it. If the channel is open, the alpha subunit may close it or, if closed, it may open. Changes in the channel and the ion flow across the membrane influence the membrane’s electrical potential. The binding of a neurotransmitter to a metabotropic receptor can also trigger more complicated cellular reactions, summarized in Figure 515B. All these reactions begin when the detached alpha subunit binds to an enzyme. The enzyme in turn activates a second messenger (the neurotransmitter being the first messenger) that carries instructions to other cellular structures. As illustrated at the bottom of Figure 5-15B, the second messenger can Bind to a membrane-bound channel, causing the channel to change its structure and thus alter ion flow through the membrane Initiate a reaction that incorporates intracellular (within the cell) protein molecules into the cell membrane, resulting, for example, in the formation of new ion channels Bind to sites on the cell’s DNA to initiate or cease the production of specific proteins Metabotropic receptors also allow for the possibility that a single neurotransmitter’s binding to a receptor can activate an escalating sequence of events called an amplification cascade. The cascade effect results in many downstream proteins (second messengers or channels or

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both) being either activated or deactivated. Ionotropic receptors do not have such a widespread amplifying effect. Recall that acetylcholine has an excitatory effect on skeletal muscles, where it activates an ionotropic receptor. Conversely, acetylcholine has an inhibitory effect on the heart rate, where it activates a metabotropic receptor. Furthermore, each transmitter may bind with several different kinds of ionotropic or metabotropic receptors. Elsewhere in the nervous system, for example, ACh activates a wide variety of receptors of either type.

Receptor Subtypes While there are two general classes of receptors, ionotropic and metabotropic, each neurotransmitter may interact with a number of receptor subtypes specific to that neurotransmitter. Serotonin (5-HT), for instance, has 1 ionotropic receptor subtype (5-HT3) and 12 subtypes of metabotropic receptors. Table 5-3 lists the variety of small-molecule neurotransmitter receptor subtypes.

TABLE 5-3 Small-Molecule Transmitter Receptors Neurotransmitter

Ionotropic receptors

Metabotropic receptors

Acetylcholine (ACh)

Nicotinic

5 muscarinic*

Dopamine (DA)

—

5 dopamine

GABA

GABAA

GABAB

Glutamate (Glu)

NMDA, AMPA, kainate

7 mGluRs, NMDA

Glycine (Gly)

Glycine, NMDA

—

Histamine (H)

—

3 histamine

Norepinephrine (NE)

—

8 NE alpha and 3 NE beta

Serotonin (5-HT)

5-HT3

12 5-HT

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Peptide neurotransmitters and the lipid neurotransmitters anandamide and 2-AG have specific metabotropic-class receptors. Gaseous neurotransmitters do not have a specific receptor. The ion neurotransmitter zinc has binding sites on several receptor types. *

All metabotropic cholinergic receptors are muscarinic.

How is this variety achieved? Alternative forms of each subunit can assemble in unique combinations to make a functional receptor. For instance, the functional NMDA receptor, that can act as an ionotropic receptor for glutamate, is always composed of 4 subunits, but a total of 12 distinct subunits are available to come together in various combinations to form the functional receptor. The NMDA receptor can also act as a metabotropic receptor further broadening its function (Weilinger et al., 2016). Figure 14-18 diagrams how glutamate and the NMDA receptor function in associative learning.

Why does the brain contain so many receptor subtypes for each neurotransmitter? The answer seems to be that each subtype has slightly different properties, which confer different activities. These activities can include the presence or absence of binding sites for other molecules, how long a channel remains open or closed, and the ability to interact with intracellular signaling molecules. It should not be surprising that a brain such as ours, with its incredible complexity, is built on a vast array of units, including copious neurotransmitter types and even more copious receptor types. All this, and more, allows the human brain to function successfully.

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5-2 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. Neurotransmitters are identified using four experimental criteria: , , , and . 2. The broad classes of chemically related neurotransmitters are , , , , and . 3. Acetylcholine is composed of and . After release into the synaptic cleft, ACh is broken down by , and the products can be recycled. 4. Endocannabinoids are demand and released from the

neurotransmitters, made on membrane.

5. Contrast the major characteristics of ionotropic and metabotropic receptors.

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5-3 Neurotransmitter Systems and Behavior When researchers began to study neurotransmission, they reasoned that any given neuron would contain only one transmitter at all its axon terminals. Newer methods of analysis have revealed that this hypothesis is not strictly accurate. A single neuron may use one transmitter at one synapse and a different transmitter at another synapse. Moreover, different transmitters may coexist in the same terminal or synapse. Neuropeptides have been found to coexist in terminals with smallmolecule transmitters, and more than one small-molecule transmitter may be found in a single synapse. In some cases, more than one transmitter is packaged within a single vesicle. All these findings allow for multiple combinations of neurotransmitters and receptors for them. They caution as well against assuming a simple cause-and-effect relation between a neurotransmitter and a behavior. What are the functions of so many combinations? The answer will likely vary, depending on the behavior that is controlled. Historically, researchers focused on the most abundant transmitter within any given axon terminal and then associated that neurotransmitter with a function or behavior. We now consider some links between neurotransmitters and behavior. We begin by exploring the three peripheral nervous system divisions: SNS, ANS, and ENS. Then we investigate neurotransmission in the central nervous system.

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Neurotransmission in the Somatic Nervous System (SNS) Motor neurons in the brain and spinal cord send their axons to the body’s skeletal muscles, including the muscles of the eyes and face, trunk, limbs, fingers, and toes. Without these SNS neurons, movement would not be possible. Motor neurons are also called cholinergic neurons because acetylcholine is their main neurotransmitter. At a skeletal muscle, cholinergic neurons are excitatory, producing muscular contractions. Just as a single main neurotransmitter serves the SNS, so does a single main receptor, a transmitter-activated ionotropic channel called a nicotinic acetylcholine receptor (nAChr). As shown in Figure 5-16, when ACh binds to this receptor, its pore opens to permit ion flow, thus depolarizing the muscle fiber. The nicotinic receptor pore is large enough to permit the simultaneous efflux of K+ and influx of Na+. The molecular structure of nicotine, a chemical found in tobacco, activates the nAChr in the same way that acetylcholine does, which is how this receptor got its name. The molecular structure of nicotine is sufficiently similar to that of ACh that nicotine acts as a mimic, fitting into acetylcholine receptor binding sites.

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FIGURE 5-16 Nicotinic ACh Receptor Research from Heuser & Reese, 1977.

Acetylcholine is the primary neurotransmitter at skeletal muscles, but other neurotransmitters also occupy these cholinergic axon terminals and are released onto the muscle along with ACh. One is a neuropeptide called calcitonin gene–related peptide (CGRP), which acts

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through CGRP metabotropic receptors to increase the force with which a muscle contracts.

Dual Activating Systems of the Autonomic Nervous System (ANS) The complementary ANS divisions, sympathetic and parasympathetic, regulate the body’s internal environment. The sympathetic division rouses the body for action, producing the fight-or-flight response. Heart rate ramps up, and digestive functions ramp down. The parasympathetic division calms the body down, producing an essentially opposite restand-digest response. Digestive functions ramp up, heart rate ramps down, and the body is ready to relax. Figure 5-17 shows the neurochemical organization of the ANS. Both divisions are controlled by acetylcholine neurons that emanate from the CNS at two levels of the spinal cord. The CNS neurons synapse with parasympathetic neurons that also contain acetylcholine and with sympathetic neurons that contain norepinephrine. In other words, cholinergic neurons in the CNS synapse with sympathetic NE neurons to prepare the body’s organs for fight or flight. Cholinergic neurons in the CNS synapse with autonomic ACh neurons in the parasympathetic division to prepare the body’s organs to rest and digest.

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FIGURE 5-17 Controlling Biological Functions in the Autonomic Nervous System The neurotransmitter in all the neurons leaving the spinal cord is acetylcholine. Left: In the sympathetic division, ACh neurons activate autonomic norepinephrine neurons in the sympathetic ganglia. NE stimulates organs required for fight or flight and suppresses activity in organs used to rest and digest. Right: In the parasympathetic division, ACh neurons from the spinal cord activate ACh neurons in the parasympathetic ganglia near their target organs to suppress activity in organs used for fight or flight and to stimulate organs used to rest and digest. To review the ANS divisions and connections in detail, see Figure 2-32.

Which type of synapse is excitatory and which inhibitory depends on the particular body organ’s receptors. During sympathetic arousal, norepinephrine turns up heart rate and turns down digestive functions because NE receptors on the heart are excitatory, whereas NE receptors

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on the gut are inhibitory. Similarly, acetylcholine turns down heart rate and turns up digestive functions because its receptors on these organs are reversed: on the heart, inhibitory; on the gut, excitatory. Neurotransmitter activity, excitatory in one location and inhibitory in another, mediates the sympathetic and parasympathetic divisions, forming a complementary autonomic regulating system that maintains the body’s internal environment under varying circumstances.

Enteric Nervous System (ENS) Autonomy The ENS can act without input from the CNS, which is why it has been called the second brain. It uses the main classes of neurotransmitters— more than 30 transmitters in total. Most of these neurotransmitters are identical to those employed by the CNS. Chief among the smallmolecule neurotransmitters used by the enteric nervous system are serotonin and dopamine. See Section 2-5 for a detailed discussion of the ENS.

Sensory ENS neurons detect mechanical and

chemical conditions in the gastrointestinal system. Via intestinal muscles, motor neurons in the ENS control the mixing of intestinal contents. Secretion of digestive enzymes is also under ENS control. Principle 7: Sensory and motor divisions permeate the nervous system.

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Four Activating Systems in the Central Nervous System Just as there is an organization to the neurochemical systems of the PNS, there is an organization of neurochemical systems in the CNS. These systems are remarkably similar across a wide range of animal species, allowing for their identification first in the rat brain and then in the human brain (Hamilton et al., 2010). For each of the four activating systems described here, a relatively small number of neurons grouped together in one or a few brainstem nuclei send axons to widespread CNS regions, suggesting that these nuclei and their terminals help synchronize activity throughout the brain and spinal cord. You can envision an activating system as being analogous to the power supply in a house. The fuse box or breaker box is the source of the power, and from it transmission lines go to each room. Just as in the ANS, the precise action of the CNS transmitter depends on the brain region that is innervated and on the types of receptors the transmitter acts on at that region. To continue our analogy, the precise activating effect of the power in each room depends on the electrical devices in that room. Each of four small-molecule transmitters participates in its own neural activating system—the cholinergic, dopaminergic, noradrenergic, and serotonergic systems. Figure 5-18 locates each system’s nuclei, with arrow shafts mapping the axon pathways and arrowheads indicating axon terminal locales.

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FIGURE 5-18 Major Activating Systems Each system’s cell bodies are gathered into nuclei (shown as ovals) in the brainstem. Their axons project diffusely through the CNS and synapse on target structures. Each activating system is associated with one or more behaviors or diseases.

As summarized on the right in Figure 5-18, each CNS activating system is associated with numerous behaviors. Associations among activating systems, behavior, and brain disorders are far less certain. All these relations are subjects of ongoing research. Making definitive correlations between activating systems and behavior or activating systems and a disorder is difficult because the axons of these systems connect to almost every part of the brain and spinal cord. They likely have both specific functions and modulatory roles. We detail some of the documented relationships between the systems and behavior and disorders here and in many subsequent chapters.

Cholinergic System Figure 5-19 shows in cross section a rat brain stained for the enzyme acetylcholinesterase (AChE), which breaks down ACh in synapses, as diagrammed earlier in Figure 5-10. The darkly stained areas have high AChE concentrations, indicating the presence of cholinergic terminals. AChE permeates the cortex and is especially dense in the basal ganglia. Many of these cholinergic synapses are connections from ACh nuclei in the brainstem, as illustrated in the top panel of Figure 5-18.

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FIGURE 5-19 Cholinergic Activation Drawing at left shows the cortical location of the micrograph at right, stained to reveal AChE. Cholinergic neurons in the rat’s basal forebrain project to the neocortex, and the darkly stained bands in the cortex show areas rich in cholinergic synapses. The darker central parts of the section, also rich in cholinergic neurons, are the basal ganglia.

The cholinergic system participates in typical waking behavior, attention, and memory. For example, cholinergic neurons take part in producing one form of waking EEG activity. People affected by the degenerative Alzheimer disease, which begins with minor forgetfulness, progresses to major memory dysfunction, and later develops into generalized dementia, show a profound loss of cholinergic neurons at autopsy. Two treatment strategies for Alzheimer disease are drugs that either inhibit the enzyme acetylcholinesterase, thereby elevating levels of ACh, or raise the number of nicotinic receptors (Anand et al., 2017). Recall that ACh is synthesized from nutrients in food; thus, the role of diet in maintaining acetylcholine levels also is being investigated. The EEG detects electrical signals the brain emits during various conscious states; see Sections 7-2 and 13-3.

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The brain abnormalities associated with Alzheimer disease are not limited to the cholinergic neurons, however. Autopsies reveal extensive damage to the neocortex and other brain regions. As a result, what role, if any, the cholinergic neurons play in the progress of the disorder is not yet clear. Perhaps their destruction causes degeneration in the cortex or perhaps the cause-and-effect relation is the other way around, with cortical degeneration causing cholinergic cell death. Then, too, the loss of cholinergic neurons is just one of many neural symptoms of Alzheimer disease. This is why drug treatments that prevent cell death are also being developed to slow the progression of Alzheimer disease (Anand et al., 2017). Focus 14-3 details research on Alzheimer disease. Section 16-3 reviews various causes of and treatments for dementia.

Dopaminergic System Figure 5-17 maps the dopaminergic activating system’s two distinct pathways. The nigrostriatal dopaminergic system plays a major role in coordinating movement. As described throughout this chapter in relation to Parkinsonism, when dopamine neurons in the substantia nigra are lost, the result is a condition of extreme muscular rigidity. Opposing muscles contract at the same time, making it difficult for an affected person to move. Parkinson patients also exhibit rhythmic tremors, especially of the limbs, which signals a release of formerly inhibited movement. Although the causes of Parkinson disease are not fully known, it can actually be triggered by the ingestion of certain toxic drugs, as

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described in Clinical Focus 5-4, The Case of the Frozen Addict. Those drugs may act as selective neurotoxins that specifically kill dopamine neurons in the substantia nigra.

Rhythmic movement helps Parkinson patients restore the balance between neural excitation and inhibition—between the loss and the release of behavior. Some patients participate in a specially designed dance class for people with Parkinson. Participants enjoy the activity and report several benefits.

CLINICAL FOCUS 5-4

The Case of the Frozen Addict Patient 1: During the first 4 days of July 1982, a 42-year-old man used 4½ grams of a “new synthetic heroin” . . . injected intravenously three or four times daily. . . . The immediate effects were different from heroin, producing an unusual “spacey” high as well as transient visual distortions and hallucinations. (Ballard et al., 1985, p. 949)

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Patient 1 was one of seven young adults hospitalized at about the same time in California. All showed symptoms of Parkinson disease that appeared very suddenly after drug injection. They would awake to find themselves “frozen”—only able to move in “slow motion.” According to Patient 1, he had to deliberately think through every movement, and described himself as stiff, slow, almost mute, and catatonic. These symptom are extremely unusual in this age group. All who were affected reportedly injected a synthetic heroin that was being sold on the streets in the summer of 1982. J. William Langston (2008) has recounted when he and colleagues found that the “synthetic heroin” contained a contaminant called MPTP (1-methyl4-phenyl-1,2,3,6-tetrahydropyridine) that resulted from poor technique during the drug’s synthesis. The results of experimental studies in rodents showed that MPTP was not itself responsible for the patients’ symptoms but was metabolized into MPP+ (1-methyl-4-phenylpyridinium), a neurotoxin. The autopsy of one individual who was suspected of having died of MPTP poisoning showed that the brain had selectively lost dopamine neurons in the substantia nigra. The rest of the brain appeared healthy. Injecting MPTP into monkeys, rats, and mice produced similar symptoms and a similar selective loss of dopaminergic neurons in the substantia nigra. Thus, the combined clinical and experimental evidence indicates that a toxin can selectively kill dopamine neurons and that the die-off can induce Parkinson disease. In 1988, Patient 1 received an experimental treatment at University Hospital in Lund, Sweden. Living dopamine neurons taken from human fetal brains at autopsy were implanted into the caudate nucleus and putamen (Widner et al., 1992). Extensive work with rodents and nonhuman primates in a number of laboratories had demonstrated that fetal neurons, before they develop dendrites and axons, can survive transplantation, mature, and secrete neurotransmitters. Patient 1 had no serious postoperative complications and was much improved 24 months after the surgery. He could dress and feed himself, visit

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the bathroom with help, and make trips outside his home. He also responded much better to medication. The accompanying diagrams contrast DA levels in the brain of a Parkinson patient before (left) and 2 years, 4 months after implantation (right).

These diagrams represent PET scans that contrast DA levels in a Parkinson patient’s brain before and 28 months after implantation. Research from Widner et al., 1992.

Transplantation of fetal neurons to treat Parkinson disease typically does not work. Unlike in the case of the frozen addict, Parkinson disease is associated with a continuing, active process that destroys dopaminergic neurons, including transplanted neurons, in the substantia nigra. Because Parkinson disease can affect as many as 20 people per 100,000, scientists continue to experiment with new approaches to transplantation and with genetic approaches for modifying remaining dopamine neurons (Lane et al., 2010).

Dopamine in the mesolimbic dopaminergic system may be the neurotransmitter most affected in addiction—to food, to drugs, and to other behaviors that involve a loss of impulse control. A common 582

feature of addictive behaviors is that stimulating the mesolimbic dopaminergic system enhances responses to environmental stimuli, thus making those stimuli attractive and rewarding. Indeed, some Parkinson patients who take dopamine receptor agonists as medications show a loss of impulse control that manifests in such behaviors as pathological gambling, hypersexuality, and compulsive shopping (Moore et al., 2014). Sections 6-3, 6-4, and 12-1 describe drug effects on the mesolimbic DA system. Sections 6-2 and 7-4 discuss possible causes of schizophrenia, and Section 16-2 discusses its neurobiology.

Excessive mesolimbic dopaminergic activity has also been proposed to play a role in schizophrenia, a behavioral disorder characterized by delusions, hallucinations, disorganized speech, blunted emotion, agitation or immobility, and a host of associated symptoms. Schizophrenia is one of the most common and most debilitating psychiatric disorders, affecting about 1 in 100 people.

Noradrenergic System Norepinephrine (noradrenaline) may play a part in learning by stimulating neurons to change their structure. Norepinephrine may also facilitate healthy brain development and contribute to organizing movements. A neuron that uses norepinephrine as its transmitter is termed a noradrenergic neuron (derived from adrenaline, the Latin name for epinephrine). Behaviors and disorders related to the noradrenergic system concern emotions. Some symptoms of major depression—a mood disorder

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characterized by prolonged feelings of worthlessness and guilt, the disruption of typical eating habits, sleep disturbances, a general slowing of behavior, and frequent thoughts of suicide—may be related to decreased activity of noradrenergic neurons. Conversely, some symptoms of mania (excessive excitability) may be related to increased activity in these same neurons. Decreased NE activity has also been associated both with hyperactivity and attention-deficit/hyperactivity disorder (ADHD).

Serotonergic System The serotonergic activating system maintains a waking EEG in the forebrain when we move and thus participates in wakefulness, as does the cholinergic system. Like norepinephrine, serotonin plays a role in learning, as described in Section 5-4. Some symptoms of depression may be related to decreased activity in serotonin neurons, and drugs commonly used to treat depression act on 5-HT neurons. Consequently, two forms of depression may exist, one related to norepinephrine and another related to serotonin. Consult the Index of Disorders inside the book’s front cover for more information on major depression, mania, ADHD, OCD, sleep apnea, and SIDS.

Likewise, some research results suggest that various symptoms of schizophrenia also may be related to increases in serotonin activity, which implies that different forms of schizophrenia may exist. Decreased serotonergic activity is related to symptoms observed in obsessive-compulsive disorder (OCD), in which a person has repetitive and often unpleasant thoughts (obsessions) and compulsively

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repeats acts (such as hand washing). Evidence also points to a link between abnormalities in serotonergic nuclei and conditions such as sleep apnea and sudden infant death syndrome (SIDS).

5-3 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. Although neurons can contain more than one are usually identified by the principal terminals.

, they in their axon

2. In the peripheral nervous system, the neurotransmitter at somatic muscles is ; in the autonomic nervous system, neurons from the spinal cord connect with neurons for parasympathetic activity and with neurons for sympathetic activity. 3. The two principal small-molecule transmitters used by the enteric nervous system are and . 4. The four main activating systems of the CNS are , , and . 5. How would you respond to the comment that a behavior is caused solely by a chemical imbalance in the brain?

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5-4 Adaptive Role of Synapses in Learning and Memory Among our most cherished abilities are learning and remembering. Neuroplasticity is a requirement for learning and memory and a characteristic of the mammalian brain. In fact, it is a trait of the nervous systems of all animals, even the simplest worms. Larger brains with more synapses are more plastic, however, and thus likely to show more alterations in neural organization. Experiment 2-1 demonstrates observational learning in the octopus and the ubiquity of neuroplasticity.

Alterations in neural organization happen because experience can alter the synapse. Not only are synapses versatile in structure and function, they are plastic: they can change. The synapse, therefore, is the site for the neural basis of learning, a relatively persistent or even permanent change in behavior that results from experience. Principle 2: Neuroplasticity is the hallmark of nervous system functioning.

Donald O. Hebb was not the first to suggest that learning is mediated by structural changes in synapses, but the change that he envisioned in his book The Organization of Behavior was novel 70 years ago. Hebb 586

theorized, “When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased” (Hebb, 1949, p. 62). Simply put, cells that fire together wire together. A synapse that physically adapts in this way is called a Hebb synapse. Eri c

Hebb’s “cell-assembly” diagram appears at the end of Section 15-1.

Kand el was awarded a Nobel Prize in 2000 for his descriptions of the synaptic basis of learning in a way that Hebb envisaged: learning in which the conjoint activity of nerve cells serves to link them. Kandel’s subject, the marine slug Aplysia californica, is an ideal subject for learning experiments. Slightly larger than a softball and lacking a shell, Aplysia has roughly 20,000 neurons. Some are quite accessible to researchers, who can isolate and study circuits having relatively few synapses. When threatened, Aplysia defensively withdraws its more vulnerable body parts—the gill (through which it extracts oxygen from the water to breathe) and the siphon (a spout above the gill that excretes seawater and waste). By stroking or shocking the slug’s appendages, Kandel and his coworkers (Bailey et al., 2015) produced enduring changes in its defensive behaviors. They used these behavioral responses to study underlying changes in Aplysia’s nervous system. We illustrate the role of synapses in two kinds of learning that Kandel has studied: habituation and sensitization. For humans, both are called unconscious because they do not depend on a person’s knowing 587

Section 14-4 investigates the neural bases of brain plasticity in conscious learning and in memory.

precisely when and how they occur.

Habituation Response In habituation, the response to a stimulus weakens with repeated stimulus presentations. If you are accustomed to living in the country and then move to a city, you might at first find the sounds of traffic and people extremely loud and annoying. With time, however, you stop noticing most of the noise most of the time. You have habituated to it. Habituation develops with all our senses. We simply become insensitive to the customary background sensations of sound, touch, smell, taste, and even vision. We cease to notice the feel of our clothes 588

sometime after donning them. Most of us aren’t aware of the smell of our houseplants (a phenomenon called nose blindness), but people who have recently returned from Antarctica report being nearly overwhelmed by it for some time. Tastes can fade over the course of a meal. And if we record the response from photoreceptors to a newly presented light stimulus, they increase their firing rate for some time and then eventually cease firing altogether. In fact, to prevent this form of habituation, our eyes make small, fast random movements, call saccades, which continually change the light falling on individual photoreceptors, allowing us to continue to see. Aplysia habituates to waves in the shallow tidal zone where it lives. These slugs are constantly buffeted by the flow of waves against their body, and they learn that waves are just the background sensations of daily life. They do not flinch and withdraw every time a wave passes over them. They habituate to this stimulus. A sea slug that is habituated to waves nevertheless remains sensitive to other touch sensations. Prodded with a novel object, it responds by withdrawing its siphon and gill. The animal’s reaction to repeated presentations of the same novel stimulus forms the basis for Experiment 5-2, studying its habituation response.

Neural Basis of Habituation The Procedure section of Experiment 5-2 shows the setup for studying what happens to the withdrawal response of Aplysia’s gill after repeated stimulation. A gentle jet of water is sprayed on the siphon while gill movement is recorded. If the water jet is presented to Aplysia’s siphon as many as 10 times, the gill withdrawal response is weaker some

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minutes later, when the animal is again tested. The decrement in the strength of the withdrawal is habituation, which can last as long as 30 minutes in this case. EXPERIMENT 5-2

Question: What happens to the gill response after repeated stimulation? Procedure

Results

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Conclusion: The withdrawal response weakens with repeated presentation of water jet (habituation) due to decreased Ca2+ influx and subsequently less

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neurotransmitter release from the presynaptic axon terminal.

The Results section of Experiment 5-2 starts by showing a simple representation of the pathway that mediates Aplysia’s gill withdrawal response. For purposes of illustration, only 1 sensory neuron, 1 motor neuron, and 1 synapse are shown; in actuality, about 300 neurons may take part in this response. The water jet stimulates the sensory neuron, which in turn stimulates the motor neuron responsible for the gill withdrawal. But exactly where do the changes associated with habituation take place? In the sensory neuron? In the motor neuron? In the synapse between the two? Habituation does not result from an inability of either the sensory neuron or the motor neuron to produce action potentials. In response to direct electrical stimulation, both the sensory neuron and the motor neuron retain the ability to generate action potentials even after habituation. Electrical recordings from the motor neuron show that as habituation develops, the excitatory postsynaptic potentials (EPSPs) in the motor neuron become smaller. The most likely way in which these EPSPs decrease in size is that the motor neuron is receiving less neurotransmitter from the sensory neuron across the synapse. And if less neurotransmitter is being received, then the changes accompanying habituation must be taking place in the presynaptic axon terminal of the sensory neuron.

Reduced Sensitivity of Calcium Channels Underlies Habituation

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Kandel and his coworkers measured neurotransmitter output from a sensory neuron and verified that less neurotransmitter is in fact released from a habituated neuron than from a nonhabituated one. Recall from Figure 5-4 that neurotransmitter release in response to an action potential requires an influx of calcium ions across the presynaptic membrane. As habituation takes place, that Ca2+ influx decreases in response to the voltage changes associated with an action potential. Presumably, with repeated use, voltage-activated calcium channels become less responsive to voltage changes and more resistant to the passage of calcium ions. The neural basis of habituation lies in the change in presynaptic calcium channels. Its mechanism, which is summarized up close in the Results section of Experiment 5-2, is a reduced sensitivity of calcium channels and a consequent decrease in neurotransmitter release. Thus, habituation can be linked to a specific molecular change, as summarized in the experiment’s Conclusion.

Sensitization Response A sprinter crouched in her starting blocks is often hyperresponsive to the starter’s gun: its firing triggers in her a rapid reaction. The stressful, competitive context of the race helps sensitize the sprinter to this sound. Sensitization, an enhanced response to some stimulus, is the opposite of habituation. The organism becomes hyperresponsive to a stimulus rather than accustomed to it. Sensitization occurs within a context. Sudden, novel stimulation heightens our general awareness and often results in larger-than-typical responses to all kinds of stimulation. If a loud noise startles you

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suddenly, you become much more responsive to other stimuli in your surroundings, including some to which you previously were habituated. In posttraumatic stress disorder (PTSD), physiological arousal related to recurring memories and dreams surrounding a traumatic event persist for months or years after the event. One characteristic of PTSD is a heightened response to stimuli, suggesting that the disorder is in part related to sensitization. Stress can foster and prolong the effects of PTSD. See Sections 6-5 and 12-6. Section 16-2 covers treatment strategies.

The same thing happens to Aplysia. Sudden, novel stimuli can heighten the slug’s responsiveness to familiar stimulation. When attacked by a predator, for example, the slug displays heightened responses to many other stimuli in its environment. In the laboratory, a small electric shock to Aplysia’s tail mimics a predatory attack and effects sensitization, as illustrated in the Procedure section of Experiment 5-3. A single electric shock to the slug’s tail enhances its gill withdrawal response for a period that lasts for minutes to hours. EXPERIMENT 5-3

Question: What happens to the gill response in sensitization? Procedure

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Results

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Conclusion: Enhancement of the withdrawal response after a shock (sensitization) is due to increased Ca2+ influx and subsequently more neurotransmitter release from the presynaptic axon terminal.

Neural Basis of Sensitization The neural circuits participating in sensitization differ from those that take part in a habituation response. The Results section of Experiment 5-3 shows the sensory and motor neurons that produce the gill withdrawal response and adds an interneuron that is responsible for sensitization. An interneuron that receives input from a sensory neuron in Aplysia’s tail (and so carries information about the shock) makes an axoaxonic synapse with a sensory neuron in the siphon. The interneuron’s axon terminal contains serotonin. Consequently, in response to a tail shock, the tail sensory neuron activates the interneuron, which in turn releases 5-HT onto the axon of the siphon sensory neuron. Information from the siphon still comes through the sensory neuron to activate the motor neuron leading to the gill muscle, but the interneuron’s action in releasing 5-HT onto the sensory neuron’s presynaptic membrane amplifies the gill withdrawal response. At the molecular level, shown close up in the Results section of Experiment 5-3, the serotonin released from the interneuron binds to a metabotropic serotonin receptor on the siphon’s sensory neuron axon. This binding activates second messengers in the sensory neuron. Specifically, the serotonin receptor is coupled through its G protein to the enzyme adenyl cyclase. This enzyme increases the concentration of

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second messenger cyclic adenosine monophosphate (cAMP) in the presynaptic membrane of the siphon’s sensory neuron. Through several chemical reactions, cAMP attaches a phosphate molecule (PO4) to potassium channels, rendering them less responsive. The close-up in Experiment 5-3 sums it up. In response to an action potential traveling down the axon of the siphon’s sensory neuron (such as one generated by a touch to the siphon), the potassium channels on that neuron are slower to open. Consequently, K+ ions cannot repolarize the membrane as quickly as normal, so the action potential lasts longer than it usually would.

Less-Responsive Potassium Channels Underlie Sensitization The longer-lasting action potential that occurs because potassium channels are slower to open prolongs Ca2+ inflow. Ca2+ influx is necessary for neurotransmitter release. Thus, greater Ca2+ influx results in more neurotransmitter being released from the sensory synapse onto the motor neuron. This increased neurotransmitter release produces greater activation of the motor neuron and thus a larger-than-normal gill withdrawal response. If the second messenger cAMP mobilizes more synaptic vesicles, making more neurotransmitter ready for release into the sensory–motor synapse, gill withdrawal may also be enhanced. Sensitization, then, is the opposite of habituation at the molecular level as well as at the behavioral level. In sensitization, more Ca2+ influx results in more transmitter being released, whereas in habituation, less Ca2+ influx results in less neurotransmitter being 598

released. The structural basis of cellular memory in these two forms of learning is different, however. In sensitization, the change takes place in potassium channels, whereas in habituation, the change takes place in calcium channels.

Learning as a Change in Synapse Number Neural changes associated with learning must last long enough to account for a relatively permanent change in an organism’s behavior. The changes at synapses described in the preceding sections develop quite quickly, but they do not last indefinitely, as memories often do. How, then, can synapses be responsible for the long-term changes associated with learning and memory? Repeated stimulation produces habituation and sensitization that can persist for months. Brief training produces short-term learning; longer training periods produce more enduring learning. If you cram for an exam the night before you take it, you might forget the material quickly, but if you study a little each day for a week, your learning may tend to endure. What underlies this more persistent form of learning? Researchers working with Eric Kandel (Bailey et al., 2015) found that the number and size of sensory synapses change in well-trained, habituated, and sensitized Aplysia. Relative to a control neuron, the number and size of synapses decrease in habituated animals and increase in sensitized animals, as represented in Figure 5-20. Apparently, synaptic events associated with habituation and sensitization can also trigger processes in the sensory cell that result in the loss or formation of new synapses. 599

FIGURE 5-20 Physical Basis of Memory Relative to a control neuronal connection (left), the number of synapses between Aplysia’s sensory neuron and a motor neuron decline as a result of habituation (center) and increase as a result of sensitization (right). Such structural changes may underlie enduring memories.

A mechanism through which these processes can take place begins with calcium ions that mobilize second messengers to send instructions to nuclear DNA. The transcription and translation of nuclear DNA in turn initiate structural changes at synapses, including the formation of new synapses and new dendritic spines. Research Focus 5-5, Dendritic Spines: Small but Mighty, summarizes experimental evidence about structural changes in dendritic spines.

RESEARCH FOCUS 5-5

Dendritic Spines: Small but Mighty Dendritic spines, which protrude from the dendrite’s shaft, measure about 1 to 3 micrometers (µm, one-millionth of a meter) long and less than 1 μm in diameter. Each neuron can have many thousands of spines. The number of dendritic spines in the human cerebral cortex is estimated at 1014. Dendritic spines originate in filopodia (from the Latin file, for “thread,” and the Greek podium, for “foot”) that bud out of neurons, especially at

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dendrites. Microscopic observation of dendrites shows that filopodia are constantly emerging and retracting over several seconds. This budding of filopodia is much more pronounced in developing neurons and in the developing brain (see Figure 8-13). Because filopodia can grow into dendritic spines, their budding suggests that they are searching for contacts from axon terminals to form synapses. When contact is made, some new synapses may have only a short life; others will endure. A permanent dendritic spine tends to have a large, mushroom-shaped head, giving it a large contact area with a terminal button, and a long stem, giving it an identity apart from that of its dendrite. The heads of spines and the terminals of presynaptic connections form functional compartments that can generate huge electrical potentials and so influence the neuron’s electrical messages.

Synaptic structures that may subserve learning.

Dendritic spines mediate learning that lasts, including habituation and sensitization. To mediate learning, each spine must be able to act

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independently, undergoing changes that its neighbors do not undergo. Examination of dendritic spines in the nervous system shows that some are simple and others complex. The cellular mechanisms that allow synapses to appear on spines and to change shape include microfilaments linked to the membrane receptors, protein transport from the cell body, and the incorporation of nutrients from the extracellular space. The variety suggests that all this activity changes the appearance of both presynaptic and postsynaptic structures. The illustration summarizes synaptic structures that can be measured and related to learning and behavior and to structural changes that may subserve learning. Dendritic spines provide the structural basis for our behavior, our individual skills, and our memories (Bosch & Hayashi, 2012). Impairments in forming spines characterize some kinds of mental disability, and the loss of spines is associated with the dementia of Alzheimer disease.

The second messenger cAMP plays an important role in carrying instructions regarding these structural changes to nuclear DNA. The evidence for cAMP’s involvement comes from studies of the fruit fly Drosophila. Two genetic mutations in the fruit fly can produce similar learning deficiencies. Both render the second messenger cAMP inoperative—but in opposite ways. One mutation, called dunce, lacks the enzymes necessary to degrade cAMP, so the fruit fly has abnormally high cAMP levels. The other mutation, called rutabaga, reduces levels of cAMP below the normal range for Drosophila neurons. Significantly, fruit flies with either mutation are impaired in acquiring habituated and sensitized responses because their levels of cAMP cannot be regulated. New synapses seem to be required for learning to take place, and the second messenger cAMP seems to carry

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instructions to form them. Figure 5-21 summarizes these research findings.

FIGURE 5-21 Genetic Disruption of Learning Either of two mutations in the fruit fly Drosophila inactivates the second messenger cAMP by moving its level either above or below the concentration range the cell can regulate, thus disrupting learning.

More lasting habituation and sensitization are mediated by relatively permanent changes in neuronal structure—by fewer or more synaptic connections—and the effects can be difficult to alter. As a result of sensitization, for example, symptoms of PTSD can persist indefinitely.

5-4 Review

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Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. Experience alters the , the site of the neural basis of , a relatively persistent or permanent change in behavior that results from experience. 2. Aplysia’s synaptic function mediates two basic forms of learning: and . 3. Changes that accompany habituation take place within the of the neuron, mediated by channels that grow sensitive with use. 4. The sensitization response is amplified by that release serotonin onto the presynaptic membrane of the sensory neuron, changing the sensitivity of presynaptic channels and increasing the influx of . 5. One characteristic of , defined as physiological arousal related to recurring memories and dreams surrounding a traumatic event that persist for months or years after the event, is a heightened response to stimuli. This suggests that the disorder is in part related to . 6. Describe the benefits and/or drawbacks of permanent habituation and sensitization.

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Summary 5-1 A Chemical Message In the 1920s, Otto Loewi suspected that nerves to the heart secrete a chemical that regulates its beat rate. His subsequent experiments with frogs showed that acetylcholine slows heart rate, whereas epinephrine increases it. This observation proved key to understanding the basis of chemical neurotransmission. The systems for chemically synthesizing an excitatory or inhibitory neurotransmitter are in the presynaptic neuron’s axon terminal or its soma, whereas the systems for neurotransmitter storage are in its axon terminal. The receptor systems on which that neurotransmitter acts typically are on the postsynaptic membrane. Such anterograde chemical neurotransmission is dominant in the human nervous system. Nevertheless, neurons also make direct connections with each other through gap junctions, channel-forming proteins that allow direct sharing of ions or nutrients. The five major stages in the life of a neurotransmitter are (1) synthesis, (2) packaging and storage, (3) release from the axon terminal, (4) action on postsynaptic receptors, and (5) inactivation. After synthesis, the neurotransmitter is transported into synaptic vesicles that are stored near the axon terminal. When an action potential is propagated on the presynaptic membrane, voltage changes set in motion the vesicles’ 605

attachment to the presynaptic membrane and neurotransmitter release by exocytosis. One synaptic vesicle releases a quantum of neurotransmitter into the synaptic cleft, producing a miniature potential on the postsynaptic membrane. Generating an action potential on the postsynaptic cell requires simultaneous release of many quanta of transmitter. After a transmitter has done its work, it is inactivated by such processes as diffusion out of the synaptic cleft, breakdown by enzymes, and reuptake of the transmitter or its components into the axon terminal (or sometimes uptake into astrocytes).

5-2 Varieties of Neurotransmitters and Receptors Small-molecule transmitters, peptide transmitters, lipid transmitters, gaseous transmitters, and ion transmitters are broad classes for ordering the roughly 100 neurotransmitters that investigators propose might exist. Neurons containing these transmitters make a variety of connections with other neurons, as well as with muscles, blood vessels, and extracellular fluid. Functionally, neurons can be both excitatory and inhibitory, and they can participate in local circuits or in general brain networks. Excitatory synapses are usually on a dendritic tree, whereas inhibitory synapses are usually on a cell body. Some neurotransmitters are associated with both ionotropic and metabotropic receptors. An ionotropic receptor quickly and 606

directly induces voltage changes on the postsynaptic cell membrane. Slower-acting metabotropic receptors activate second messengers to indirectly produce changes in the cell’s function and structure. A plethora of receptors, formed from combinations of multiple types of proteins called subunits, exist for most transmitters.

5-3 Neurotransmitter Systems and Behavior Because neurotransmitters are multifunctional, scientists find it impossible to isolate relationships between a single neurotransmitter and a single behavior. Rather, activating systems of neurons that employ the same principal neurotransmitter influence various general aspects of behavior. For instance, acetylcholine, the main neurotransmitter in the SNS, controls movement of the skeletal muscles, whereas acetylcholine and norepinephrine, the main neurotransmitters in the ANS, control the body’s internal organs. In the ENS, dopamine and serotonin serve as the main neurotransmitters that regulate the gut’s functioning. The CNS contains not only widely dispersed glutamate and GABA neurons—its main neurotransmitters—but also neural activating systems that employ acetylcholine, norepinephrine, dopamine, or serotonin. All these systems ensure that wide areas of the brain act in concert, and each is associated with various classes of behaviors and disorders.

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5-4 Adaptive Role of Synapses in Learning and Memory Changes in synapses underlie the neural basis of learning and memory. In habituation, a form of learning in which a response weakens as a result of repeated stimulation, calcium channels become less responsive to an action potential. Consequently, less neurotransmitter is released when an action potential is propagated. In sensitization, a form of learning in which a response strengthens as a result of stimulation, changes in potassium channels prolong the action potential’s duration; this results in an increased influx of calcium ions and, consequently, release of more neurotransmitter. With repeated training, new synapses can develop, and both forms of learning can become relatively permanent. In Aplysia, the number of synapses connecting sensory neurons and motor neurons decreases in response to repeated sessions of habituation. Conversely, the number of synapses connecting sensory and motor neurons increases in response to repeated sensitization sessions. These changes in the numbers of synapses and dendritic spines are related to long-term learning.

Key Terms acetylcholine (ACh) activating system

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Alzheimer disease anterograde synaptic transmission autoreceptor carbon monoxide (CO) chemical synapse cholinergic neuron dopamine (DA) endocannabinoid epinephrine (EP) G protein gamma-aminobutyric acid (GABA) gap junction glutamate (Glu) habituation histamine (H) hydrogen sulfide (H2S) ionotropic receptor learning major depression mania metabotropic receptor

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neuropeptide neurotransmitter nitric oxide (NO) noradrenergic neuron norepinephrine (NE) obsessive-compulsive disorder (OCD) Parkinson disease postsynaptic membrane posttraumatic stress disorder (PTSD) presynaptic membrane quantum (pl. quanta) rate-limiting factor reuptake saccades schizophrenia second messenger sensitization serotonin (5-HT) small-molecule transmitter storage granule subunit

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synaptic cleft synaptic vesicle transmitter-activated receptor transporter tripartite synapse zinc

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CHAPTER 6 How Do Drugs and Hormones Influence Brain and Behavior?

6-1 Principles of Psychopharmacology CLINICAL FOCUS 6-1 Cognitive Enhancement? Drug Routes into the Nervous System Drug Action at Synapses: Agonists and Antagonists An Acetylcholine Synapse: Examples of Drug Action

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Tolerance EXPERIMENT 6-1 Question: Will the Constant Consumption of Alcohol Produce Tolerance? Sensitization EXPERIMENT 6-2 Question: Does the Injection of a Drug Always Produce the Same Behavior? 6-2 Psychoactive Drugs Adenosinergic Cholinergic GABAergic Glutamatergic CLINICAL FOCUS 6-2 Fetal Alcohol Spectrum Disorder Dopaminergic Serotonergic Opioidergic CLINICAL FOCUS 6-3 Major Depression Cannabinergic 6-3 Factors Influencing Individual Responses to Drugs 613

Behavior on Drugs Addiction and Dependence Risk Factors in Addiction 6-4 Explaining and Treating Drug Abuse Wanting-and-Liking Theory Why Doesn’t Everyone Become Addicted to Drugs? Treating Drug Abuse Can Drugs Cause Brain Damage? CLINICAL FOCUS 6-4 Drug-Induced Psychosis 6-5 Hormones Hierarchical Control of Hormones Classes and Functions of Hormones Homeostatic Hormones Anabolic–Androgenic Steroids Glucocorticoids and Stress

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Some university and college students take certain psychoactive drugs without a prescription—for example, Adderall obtained through friends or family—to remain alert and focused for extended periods while studying for exams. Indeed, the number of prescriptions for Adderall has fallen, and yet there is an increase in medical problems related to Adderall abuse because the drug is being diverted to those for whom it is not legitimately prescribed. Many college students think stimulants like Adderall and Ritalin are harmless study aids, but misuse can carry serious health risks, including mental health problems, depression, bipolar disorder, incidents of aggressive or hostile behavior, and addiction (Han et al., 2016).

Both Adderall (mainly dextroamphetamine) and Ritalin (methylphenidate) are prescribed as a treatment for attentiondeficit/hyperactivity disorder (ADHD), a developmental disorder characterized by core behaviors including impulsivity, hyperactivity, and/or inattention. Methylphenidate and dextroamphetamine are Schedule II drugs, signifying that they carry the potential for abuse and require a prescription when used medically. Their main illicit source is through falsified

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prescriptions or purchase from someone who has a prescription. Both drugs share the pharmacological properties of amphetamine: prolonging and increasing dopamine levels in the synapse by reversing its transporter (see Section 6-2). The use of cognitive enhancers is not new. In his classic paper on cocaine, Viennese psychoanalyst Sigmund Freud stated in 1884, “The main use of coca [cocaine] will undoubtedly remain that which the Indians [of Peru] have made of it for centuries . . . to increase the physical capacity of the body.” Freud later withdrew his endorsement when he realized that cocaine is addictive. In 1937, an article in the American Journal of Psychiatry reported that a form of amphetamine called Benzedrine improved performance on mental efficiency tests (Bradley, 1937). This information was quickly disseminated among students, who began using the drug as a study aid for examinations. In the 1950s, dextroamphetamine, marketed as Dexedrine, was similarly prescribed for narcolepsy, a sleep disorder, and used illicitly by students as a study aid. The complex neural effects of amphetamine stimulants center on learning at the synapse by means of habituation and sensitization. With repeated use for nonmedicinal purposes, the drugs can also begin to produce side effects, including sleep disruption, loss of appetite, and headaches. Some people develop cardiovascular abnormalities and/or become addicted to amphetamine. Treating ADHD with prescription drugs is itself controversial, despite their widespread use for this purpose. According to Aagaard and Hansen (2011), assessing the adverse effects of cognitive enhancement medication is hampered because many participants drop out of studies, and the duration of the studies is short. Despite the contention that stimulant drugs can improve school and work performance by improving brain function in otherwise healthy individuals,

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evidence for their effectiveness, other than a transient improvement in motivation, is weak.

Psychopharmacology, the study of how drugs affect the nervous system and behavior, is the subject of this chapter. We begin by looking at the most common ways drugs are administered, the routes they take to reach the central nervous system, and how they are eliminated from the body. We then examine psychoactive drugs based on the primary neurotransmitter system that they interact with. Next, we consider why different people may respond differently to the same dose of a drug and why people may become addicted to drugs. Many principles related to drugs also apply to the action of hormones, the chapter’s final topic, which includes a discussion of synthetic steroids that act as hormones. Before we examine how drugs produce their effects on the brain for good or for ill, we must raise a caution: the sheer number of neurotransmitters, receptors, and possible sites of drug action is astounding. Every drug acts at many sites in the body and brain and affects more than one neurotransmitter system. In other words, every drug has a primary or intended action as well as secondary or unintended actions. Moreover, individual differences—genetic makeup, adverse childhood experiences, sex, age, height, and weight—all influence how drugs affect people. Considering all the variables, psychopharmacological research has made important advances in understanding drug action, but neuroscientists do not know everything there is to know about every drug.

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6-1 Principles of Psychopharmacology Drugs are simply chemical compounds that are administered to bring about some desired change in the body and brain. Drugs are usually used to diagnose, treat, or prevent illness; to relieve mental or physical pain and suffering; or to improve some adverse physiological condition. In this chapter, we focus on psychoactive drugs—substances that alter mood, thought, or behavior; are used to manage neuropsychological illness; and may be taken recreationally. We also consider psychoactive drugs that, depending on dose and repeated usage, can act as toxins, producing alterations in behavior, brain damage, or even death.

Drug Routes into the Nervous System To be effective, a psychoactive drug has to reach its target in the nervous system. The way a drug enters and passes through the body to reach its target is called its route of administration. Drugs can be administered orally, inhaled into the lungs, administered rectally in a suppository, absorbed from patches applied to the skin or mucous membranes; or injected into the bloodstream, into a muscle, or even directly into the brain. Figure 6-1 illustrates some of these routes of drug administration and summarizes the characteristics of drugs that allow them to pass through various barriers to reach their targets.

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FIGURE 6-1 Routes of Drug Administration

Oral administration is easy and convenient but is nonetheless a complex route. To reach the bloodstream, an ingested drug must first be absorbed through the lining of the stomach or small intestine. Drugs in liquid form are absorbed more readily. Drugs taken in solid form are not absorbed unless the stomach’s gastric juices can dissolve them. Some drugs may be destroyed or altered by enzymes in the gastrointestinal tract’s microbiome. Whether a drug is an acid or a base also influences its absorption. Once absorbed by the stomach or intestine, the drug must enter the bloodstream. This leg of the journey requires that the drug have additional properties. Because blood has a high water concentration, the drug must be water-soluble. It is then diluted by the approximately 6

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liters of blood that circulate through an adult body. When the drug leaves the bloodstream, the body’s roughly 35 liters of extracellular fluid further dilute it. Our largest organ, the skin, has three cell layers designed to be a protective body coat. Some small-molecule drugs (for example, nicotine in a patch) easily penetrate the skin barrier. Drugs administered as gases or aerosols penetrate the cell linings of the respiratory tract very easily and are absorbed across these membranes into the bloodstream almost immediately after they are inhaled. Thus, they reach the bloodstream by circumventing the barriers in the digestive system or skin. When administered as a gas or in smoke, drugs like nicotine, cocaine, and tetrahydrocannabinol (THC), are similarly absorbed. Still fewer obstacles confront a drug destined for the brain if that drug is injected directly into the bloodstream. And the fewest obstacles are encountered if a psychoactive drug is injected directly into the brain. This route of administration is normally carried out only by medical professionals in a sterile setting. With each obstacle eliminated en route to the brain, a drug’s dosage can

1000 μg = 1 mg (milligram)

be reduced by a factor of 10. For example, 1 milligram or 1000 micrograms (μg; 1 μg is equal to onethousandth of a milligram) of amphetamine, a psychomotor stimulant and major component of the drugs described in Clinical Focus 6-1, Cognitive Enhancement? produces a noticeable behavioral change when ingested orally. If inhaled into the lungs or injected into the blood, circumventing the stomach, a dose of just 100 μg yields the same results. If amphetamine is injected into the cerebrospinal fluid, 620

bypassing both the stomach and the blood, 10 μg is enough to produce an identical outcome, as is merely 1 μg if, rather than being diluted in the cerebrospinal fluid, the drug is applied directly to target neurons. Drugs that are prepared for inhalation or intravenous injection are much cheaper per dose because the amount required is so much smaller than that needed for an effective oral dose. On the other hand, there are increased risks associated with intravenous injections and direct brain applications under non-sterile conditions, as happens when needles are shared among drug users, because small amounts of blood potentially containing viruses and microorganisms can be passed from one user to another.

Revisiting the Blood–Brain Barrier Figures 4-7 and 4-8 illustrate ion diffusion and concentration and voltage gradients.

The body presents barriers to the internal movement of drugs: cell membranes, capillary walls, and the placenta. The passage of drugs across capillaries in the brain is difficult because the blood–brain barrier, the tight junctions between the cells of blood vessels found in the brain, blocks passage of most water-soluble substances. The blood– brain barrier protects the brain’s ionic balance and denies many neurochemicals passage into the brain, where they can disrupt communication between neurons. It protects the brain from the effects of many circulating hormones and from toxic and infectious substances. Injury or disease can sometimes compromise the integrity of the blood–

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brain barrier, letting pathogens through. For the most part, however, the brain is protected from harmful substances. The brain has a rich capillary network. None of its neurons is farther than about 50 micrometers (μm; 1 μm is equal to one-millionth of a meter) from a capillary. As shown at the left in Figure 6-2, brain capillaries (like all other capillaries) are composed of a single layer of endothelial cells. In most parts of the body, endothelial cells in capillary walls are not fused, so substances can pass through the clefts between the cells. In most parts of the brain, by contrast, endothelial cell walls are fused to form tight junctions, so molecules of most substances cannot squeeze between them.

FIGURE 6-2 Blood–Brain Barrier Capillaries in most of the body allow for substances to pass between capillary cell membranes, but those in the brain, stimulated by the actions of astrocytes, form the tight junctions of the blood–brain barrier.

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Figure 6-2 also shows that the endothelial cells of brain capillaries are surrounded by the end feet of astrocytes attached to and covering most of the capillary wall. Astrocytes provide a route for the exchange of food and waste between capillaries and the brain’s extracellular fluid, as well as from there to other cells, shown at the right in Figure 6-2. Section 13-2 details the pineal gland’s pacemaking function.

The cells of capillary walls in

three brain regions, shown in Figure 6-3, lack a blood–brain barrier. The pituitary is a source of many hormones secreted into the blood, and their release is triggered in part by other hormones carried to the pituitary by the blood. The absence of a blood–brain barrier in the brainstem’s area postrema allows toxic substances in the blood to enter that area and be detected by those neurons, which triggers vomiting to expel any ingested toxins that remain in the stomach. The pineal gland also lacks a blood–brain barrier, enabling hormones to reach it and modulate the day–night cycles it controls.

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FIGURE 6-3 Barrier-Free Brain Sites The pituitary gland is a target for many blood-borne hormones; the pineal gland is a target for hormones that affect circadian rhythms. The area postrema detects and initiates vomiting of noxious substances.

To carry out its work, the brain needs, among other substances, oxygen and glucose for fuel and amino acids to build proteins. Fuel molecules reach brain cells from the blood, just as carbon dioxide and other waste products are excreted from brain cells and are carried away

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by the blood. Molecules of these vital substances cross the blood–brain barrier in two ways: 1. Small molecules, such as oxygen and carbon dioxide, and lipidsoluble molecules can pass through the endothelial membranes. 2. Complex molecules of glucose, amino acids, and other food components are carried across the membrane by active transport systems or ion pumps (transporter proteins specialized to convey a particular substance). A few psychoactive drug molecules are sufficiently small or have the correct chemical structure to gain access to the CNS. An important property possessed by those few drugs that have CNS effects, then, is an ability to cross the blood–brain barrier.

How the Body Eliminates Drugs Drugs developed for therapeutic purposes are usually designed not only to have an increased chance of reaching their targets but also to have extended time in the body. Drugs are diluted throughout the body and are often sequestered in fat cells and then released slowly. After a drug is administered, the body begins to break it down through catabolism, a process that takes place in several areas of the body, including the kidneys, liver, and the intestines. The body excretes drugs and their metabolites in urine, feces, sweat, breast milk, and exhaled air. The liver is

Catabolic processes break down; anabolic processes build up.

especially active in catabolizing drugs. This organ houses a family of enzymes involved in drug catabolism, called the cytochrome P450 enzyme family 625

(some of which are also present in the gastrointestinal tract microbiome); the liver is capable of breaking down many different drugs into forms more easily excreted from the body. Substances that cannot be catabolized or excreted can build up in the body and become toxic. The metal mercury, for instance, is not easily eliminated and can produce severe neurological effects. Humans living in modern, industrialized societies consume a large number and enormous quantities of active drugs, which are eliminated from the body, along with their metabolites, and discharged into the environment, usually into water. This situation is highly problematic, as these substances are often reingested by many other animals, including other humans (Brown et al., 2015). Some may affect fertility, development in high-risk groups such as embryos and juveniles, and even the physiology and behavior of adult organisms. The solution is redesigning waste management systems to remove by-products eliminated by humans as well as by other animals (Berninger et al., 2016).

Drug Action at Synapses: Agonists and Antagonists Most drugs that produce psychoactive effects work by influencing chemical reactions at synapses. To understand how drugs work, we must explore the ways they modify synaptic actions. Figure 6-4 summarizes the major steps in neurotransmission at a synapse—each a potential site of drug action: 1. Synthesis of the neurotransmitter in the cell body, the axon, or the terminal

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2. Packaging and storage of the neurotransmitter in vesicles 3. Release of the transmitter from the terminal’s presynaptic membrane into the synapse 4. Receptor interaction in the postsynaptic membrane, as the transmitter acts on an embedded receptor 5. a. Inactivation by reuptake into the presynaptic terminal for reuse OR b. Inactivation by enzymatic degradation of excess neurotransmitter

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FIGURE 6-4 Points of Influence In principle, a drug can modify major chemical processes, any of which result in enhanced or reduced synaptic transmission, depending on the drug’s action as an agonist or antagonist.

Ultimately, a drug that affects any of these synaptic functions either increases or diminishes neurotransmission. Drugs that increase neurotransmission are classified as agonists; drugs that decrease neurotransmission are classified as antagonists. To illustrate, consider a

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typical synapse: the acetylcholine synapse between motor neurons and muscles.

An Acetylcholine Synapse: Examples of Drug Action Figure 4-26 details the structure and action of ACh at a neuromuscular synapse.

Figure 6-5 shows how some drugs and toxins act as agonists or antagonists at the acetylcholine (ACh) synapse on skeletal muscles. ACh agonists excite muscles, increasing muscle tone, whereas ACh antagonists inhibit muscles, decreasing muscle tone. Some of these substances may be new to you, but you have probably heard of others. If you know their effects at the ACh synapse, you can understand the relationships between these substances’ neurochemical actions and their behavioral effects.

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FIGURE 6-5 Acetylcholine Agonists and Antagonists Drugs and nutrients can affect ACh transmission by altering its synthesis or release or by binding to the postsynaptic receptor and affecting its breakdown or inactivation.

Figure 6-5 includes two toxins that influence ACh release from the axon terminal. Black widow spider venom acts as an agonist by promoting ACh release to excess. A black widow spider bite does not inject enough drug to paralyze a person, though a victim may feel some muscle weakness. Botulinum toxin, or botulin, is the poisonous agent in improperly processed canned goods. An antagonist, it blocks ACh release, and the effect can last for weeks to months. Severe poisoning can paralyze both movement and breathing and so cause death. Botulin has medical uses, however. Injected into a muscle, it can selectively paralyze the muscle, making it useful for blocking excessive 630

Clinical Focus 11-2 describes the causes and range of outcomes for cerebral palsy.

and enduring muscular twitches or contractions, including the spasms that make movement difficult—such as in people with cerebral palsy. Under the trade name Botox, botulin is also used cosmetically to paralyze facial muscles that cause wrinkling. As illustrated in Section 5-3, a single main receptor serves the sympathetic nervous system: the nicotinic ACh receptor (nAChR).

Figure 6-5 also shows two drugs that act on ACh receptors. Nicotine’s molecular structure is similar enough to that of ACh to allow nicotine to fit into ACh receptors’ binding sites, where it causes the associated ion channel to open and therefore acts as an agonist. Curare acts as an ACh antagonist by occupying cholinergic receptors, but it does not cause the ion channel to open, and it also prevents ACh from binding to the receptor. Once introduced into the body, curare acts quickly and is cleared from the body in a few minutes. Large doses, however, arrest movement and breathing for a period sufficient to result in death. Early European explorers of South America discovered that the indigenous peoples living along the Amazon River in South America killed small animals using arrowheads coated with curare prepared from the seeds of a plant. The hunters did not poison themselves when eating the animals because ingested curare cannot pass from the gut into the body. Many curarelike drugs have been synthesized. Some were used to 631

briefly paralyze large animals for examination or tagging for identification. You have probably seen these drugs in action in wildlife videos. Skeletal muscles are more sensitive to curarelike drugs than are respiratory muscles; an appropriate dose paralyzes an animal’s movement temporarily but allows it to breathe. T he

Figure 5-10 illustrates ACh synthesis and how AChE breaks it down.

final drug action shown in Figure 6-5 is that of physostigmine and organophosphate agonists that inhibit acetylcholinesterase (AChE), the enzyme that breaks down ACh, thus increasing the amount available in the synapse. Physostigmine, obtained from an African bean, is also used as a poison by hunters. In myasthenia gravis, muscle receptors lose their sensitivity to motor neuron messages, as illustrated in Section 4-4.

Large doses of physostigmine can be toxic because they produce excessive excitation of the neuromuscular synapse, disrupting movement and breathing. In small doses, however, physostigmine is used to treat myasthenia gravis, a condition of muscular weakness in which muscle receptors are less than normally responsive to ACh. Physostigmine’s action is short lived, lasting only a few minutes or at most a half hour. Organophosphates bind irreversibly to AChE and consequently allow a toxic buildup of ACh in the synaptic cleft. Many insecticides and chemical weapons are organophosphates. Insects use glutamate as a

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neurotransmitter at the nerve–muscle junction, but elsewhere in their nervous system, they have nicotinic receptors. Thus, organophosphates poison insects by acting centrally, but they poison chordates by acting peripherally as well. The Chemical Weapons Convention of 1993 banned one potent organophosphate agent, the lethal nerve gas Sarin. That international ban, however, did not restrain the government of Syria, in 2013 and again in 2017, from using Sarin against its own citizens. The Basics: Classification of Life in Section 1-3 charts nervous system evolution in the animal kingdom.

Does a drug or toxin that affects neuromuscular synapses also affect ACh synapses in the brain? It depends on whether the substance can cross the blood–brain barrier. Physostigmine and nicotine readily pass the barrier; curare cannot. Nicotine is the psychoactive ingredient in cigarette smoke, and its actions on the brain account for its addictive properties (see Section 6-4). Physostigminelike drugs reportedly have some beneficial effects for memory disorders.

Tolerance In tolerance, as in habituation, learning takes place when the response to a stimulus weakens with repeated presentations (see Experiment 5-2).

Tolerance is a decreased response to a drug with repeated exposure. Harris Isbell and colleagues (1955) conducted an experiment that, while unethical by today’s standards, did suggest how tolerance comes about.

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The researchers gave volunteers in a prison enough alcohol to initially induce a state of intoxication and then administered additional doses daily over a 13-week period. Yet they found that the participants did not remain drunk for that entire period and had to have their dosage increased. When the experiment began, the participants showed rapidly rising blood alcohol levels and behavioral signs of intoxication, as shown in the Results section of Experiment 6-1. Between the twelfth and twentieth days of alcohol consumption, however, blood alcohol and the signs of intoxication fell, even though the participants increased their alcohol intake. Thereafter, blood alcohol levels and signs of intoxication fluctuated; one did not always correspond to the other. A relatively high blood alcohol level was sometimes associated with a low outward appearance of intoxication. Why? EXPERIMENT 6-1

Question: Will the constant consumption of alcohol produce tolerance? Procedure

Results

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Conclusion: Because of tolerance, as the study progressed, much more alcohol was required to obtain the same level of intoxication that was produced at the beginning. Information from Isbell et al., 1955.

The three results were the products of three kinds of tolerance, each much more likely to develop with repeated drug use: 635

1. In metabolic tolerance, the number of enzymes needed to break down alcohol in the liver, blood, and brain increases. As a result, any alcohol consumed is metabolized more quickly, so blood alcohol levels fall. 2. In cellular tolerance, brain cell activities adjust to minimize the effects of alcohol in the blood. Cellular tolerance can help explain why the behavioral signs of intoxication may be so low despite a relatively high blood alcohol level. 3. Learned tolerance explains a drop in outward signs of intoxication. As people learn to cope with the demands of living under the influence of alcohol, they may no longer appear intoxicated. Does it surprise you that learning plays a role in alcohol tolerance? It has been confirmed in many studies, including a description of the effect first reported by John Wenger and his colleagues (1981). They trained rats to prevent electric foot shocks as they walked on a narrow conveyor belt sliding over an electrified grid. One group of rats received alcohol after training in walking the belt; another group received alcohol before training. A third group received training only, and a fourth group received alcohol only. Experiment 5-3 describes sensitization at the level of neurons and synapses. Section 14-4 relates sensitization to neuroplasticity and learned addictions.

After several days’ exposure to their respective conditions, all groups received alcohol before a walking test. The rats that had received alcohol before training performed well, whereas those that had received training and alcohol separately performed just as poorly as those that 636

had never had alcohol or those that had not been trained. Despite alcohol intoxication, then, animals can acquire the motor skills needed to balance on a narrow belt. With motor experience, they can learn to compensate for being intoxicated.

Sensitization Drug tolerance is much more likely to develop with repeated use than with intermittent use, but tolerance does not always follow repeated exposure to a drug. Tolerance resembles habituation in that the response to the drug weakens with repeated presentations. The drug user may have the opposite reaction, sensitization—increased responsiveness to successive equal doses. Whereas tolerance generally develops with repeated drug use, sensitization is much more likely to develop with intermittent use. To demonstrate drug sensitization, Terry Robinson and Jill Becker (1986) isolated rats in observation boxes and recorded their reactions to an injection of amphetamine, which is a dopaminergic agonist. Every 3 or 4 days, the investigators injected the rats and found their motor activities—sniffing, rearing, and walking—more vigorous with each administration of the same drug dose, as graphed in Results 1 of Experiment 6-2. EXPERIMENT 6-2

Question: Does the injection of a drug always produce the same behavior? Procedure 1

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Results 1

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Conclusion 1: Sensitization indicated by increased rearing develops with periodic repeated injections. Information from Robinson & Becker, 1986. Procedure 2

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Results 2

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Conclusion 2: Sensitization depends on the occurrence of a behavior: the swimming speed decreased over time. Information from Whishaw et al., 1989.

The increased motor activity on successive tests was not due to the animals becoming comfortable with the test situation. Control animals that received no drug failed to display a similar escalation. Administering the drug to rats in their home cages did not affect activity in subsequent tests, either. Moreover, the sensitization to amphetamine was enduring. Even when two injections were administered months apart, the animals still showed an escalation of motor behavior. Even a single exposure to amphetamine produced sensitization. Sensitization is not always characterized by an increase in an elicited behavior but may also manifest as a progressive decrease in behavior. Ian Whishaw and his colleagues (1989) administered flupentixol, a drug that blocks dopamine receptors, to rats that had been well trained in a swimming task. As illustrated in Results 2 of Experiment 6-2, the rats’ swimming speeds slowed significantly with each successive trial, and eventually the rats stopped swimming altogether. The trial-dependent

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decrease in swimming was similar whether the trials were massed on the same day or spaced over days or weeks. The neural basis of sensitization lies in part in changes at the synapse. Studies on the dopamine synapse after sensitization to amphetamine show more dopamine in the synaptic cleft in sensitized animals. Sensitization can be associated with changes in receptor numbers on the postsynaptic membrane, in the rate of transmitter metabolism in the synaptic space, in transmitter reuptake by the presynaptic membrane, and in the number and size of synapses. Sensitization also has a learned basis. Animals show a change in learned responses to environmental cues as sensitization progresses. Consequently, sensitization is difficult to achieve in an animal tested in its home cage. In the Whishaw group’s experiment, administering flupentixol to rats left in their home environment did not influence their performance in subsequent swim tests. In another study, Sabina Fraioli and her coworkers (1999) gave amphetamine to two groups of rats and recorded the behavioral responses to successive injections. One group of rats lived in the test apparatus, so for that group, home was the test box. The other group was taken out of their home cage and placed in the test box for each day’s experimentation. The home group showed no sensitization to amphetamine, whereas the out group displayed robust sensitization. At least part of the explanation of the home–out effect is that the animals are accustomed to engaging in a certain behavioral repertoire in their home environment, so it is difficult to get them to change their response to home cues even when influenced by a drug. When subjects

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are away from home, they receive novel out cues, which favor conditioning of new responses. Sensitization is relevant to understanding some psychopharmacological effects of drugs: 1. Many drug therapies, including those for the psychiatric disorder schizophrenia, must be taken for several weeks before they produce beneficial effects. Possibly sensitization underlies the development of these beneficial effects. 2. Sensitization is related to drug dependence. Before a person becomes dependent on or addicted to a drug, he or she must be sensitized by numerous experiences with the drug away from the home environment. Clinical Focus 8-5 relates the possible origin of schizophrenia and its progress.

3. Life experiences, especially stressful ones, can produce effects resembling sensitization that prime the nervous system for addiction (Roberts et al., 2015).

6-1 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1.

, substances that produce changes in behavior by acting on the nervous system, are one subject of , the study of

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how drugs affect the nervous system and behavior. 2. Perhaps the most important obstacle on a psychoactive drug’s journey between its entry into the body and its action at a target is the

, which generally allows only substances

needed for nourishment to pass from the capillaries into the . 3. Most drugs that have psychoactive effects influence chemical reactions at neuronal

. Drugs that influence

communication between neurons do so by acting either as (increasing the effectiveness of neurotransmission) or as

(decreasing the effectiveness of

neurotransmission). 4. Behavior may change with the repeated use of a psychoactive drug. These changes include

and

, in

which the effect of the drug decreases or increases, respectively, with repeated use. 5. The body eliminates drugs through ,

, and

6. Describe briefly how tolerance and sensitization might affect someone who uses cognitive enhancers occasionally (a) at home or (b) at work.

For additional study tools, visit

launchpadworks.com

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6-2 Psychoactive Drugs People have been using drugs for therapeutic and recreational reasons likely for as long as there have been, well, people. In fact, our closest relatives, including chimpanzees, bonobos, and gorillas, appear to select and ingest, or topically apply, substances to prevent or reduce the harmful effects of pathogens and toxins—a behavior known as zoopharmacognosy (for “animal” + “drug” + “knowing”) (Kapadia et al., 2014). Humans have taken this practice a step further by cultivating particular plants and fungi, then extracting, purifying, studying, and synthesizing their psychoactive ingredients—and making a great deal of profit from the enterprise. Over time, we have amassed an enormous catalogue of psychoactive drugs, and there is no question that the templates for these drugs come from the natural world (Campbell, 1996). Finding a universally acceptable grouping for... the psychoactive drugs is virtually impossible. Any system will have a unique set of limitations because drugs with similar chemical structure can have different effects, while drugs with different structure can have similar effects. Furthermore, a single drug acts on many neurochemical systems and has many effects. A full appreciation of any drug’s action requires a multifaceted description, such as can be found in medical compendia. Behavioral descriptions undergo constant review, as illustrated by continuing revisions of the Diagnostic and Statistical Manual of Mental Disorders (DSM). Published by the American Psychiatric Association and

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currently in its fifth edition, the DSM offers a classification system for diagnosing neurological and behavioral disorders, including those caused by drug use. For our purposes, we group psychoactive drugs based on the primary neurotransmitter system that they are known to affect, similarly to the way we organized transmitter systems in Chapter 5. Of course, our grouping system also has limitations. The vast majority of medically prescribed drugs were not created to act on specific neurotransmitter systems; rather, drugs were tested on different patient groups, and specific uses in medical treatments were approved based on analysis of their effectiveness. Table 6-1 categorizes psychoactive drugs based on their primary neurotransmitter system of action. Each category may contain a few to thousands of chemicals in its subcategories. In the following sections, we highlight drug actions, both on neurochemical systems in the brain and on synaptic function, and provide some examples. Note that many medically prescribed psychoactive drugs are also recreationally used and abused.

TABLE 6-1 Psychoactive Drugs Primary transmitter system

Recreationally used

Medically prescribed (for psychoactive conditions)

Adenosinergic antagonist

caffeine

Cholinergic agonist

nicotine

tacrine (Cognex)

GABAergic agonists

alcohol

diazepam (Valium), alprazolam (Xanax), clonazepam (Klonopin)

Glutamatergic antagonists

phencyclidine/PCP (angel dust), ketamine (Special K)

memantine (Namenda)

Dopaminergic

cocaine, amphetamine, methamphetamine

dextroamphetamine (Adderall),

agonists

methylphenidate (Ritalin), L-dopa

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Dopaminergic

phenothiazines: chlorpromazine

antagonists (Thorazine); butyrophenones: haloperidol (Haldol) clozapine (Clozaril), aripiprazole (Abilify, Aripiprex) Serotonergic agonists

mescaline (peyote), DMT, psilocybin, lysergic acid diethylamide (LSD), MDMA (Ecstasy)

sertraline (Zoloft), fluoxetine (Prozac), imipramine (Tofranil)

Opioidergic agonists

opium, morphine, heroin

morphine, codeine, oxycodone (Percocet), fentanyl, methadone

Cannabinergic agonists

tetrahydrocannabinol (THC)

THC (Sativex)

Most psychoactive drugs have three names: chemical, generic, and branded. The chemical name describes a drug’s structure; the generic name is nonproprietary and is spelled lowercase; and the proprietary, or brand, name, given by the pharmaceutical company that sells it, is capitalized. Some psychoactive drugs also sport street or club names.

Adenosinergic We begin with the world’s most widely consumed psychoactive drug: caffeine. Caffeine-containing drinks, such as coffee, tea, soft drinks, and “energy drinks,” are consumed daily by about 85 percent of adults in the United States. A cup of coffee contains about 100 mg of caffeine; many common soft drinks contain almost as much; and some energy drinks pack as much as 500 mg. You may be using more caffeine than you realize. Caffeine has a very similar structure to adenosine and binds to adenosine receptors without activating them, thereby blocking the effect of adenosine and thus acting as an adenosine antagonist. Endogenous

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adenosine induces drowsiness, and caffeine works in opposition to this, making us feel more alert and peppy. Excessive levels can lead to the jitters. But caffeine has other mechanisms of action as well; it inhibits an enzyme that ordinarily breaks down the second messenger, cyclic adenosine monophosphate (cAMP). The resulting increase in cAMP leads to increased glucose production, making more energy available and allowing higher rates of cellular activity. Caffeine also promotes the release of other neurotransmitters, such as dopamine and acetylcholine, which endows caffeine with its stimulant effects that improve reaction time, wakefulness, concentration, and motor coordination (Nehlig, 2010). Repeated daily intake of caffeine produces a mild form of drug dependence. When the individual stops using caffeine, he or she experiences sleepiness, headache, and irritability. These withdrawal symptoms are avoided by continuing to consume caffeine daily but will fade with time (about 4 to 7 days) if the individual gives up caffeine altogether. The most well-known source of caffeine is the coffee seed (not a bean) of Coffea plants. But caffeine is also found in the seeds, nuts, leaves, and nectar of a number of other plants native to East Asia and South America. Why do some plants incorporate caffeine into their tissues? To properly answer this question, we need to consider life from the plants’ perspective. Plants face several challenges, such as herbivores, pathogens (like fungi), and attracting pollinators. All of these selective forces, and many others, have shaped plant adaptations; one such adaptation is incorporating toxins such as caffeine into its tissues. 649

Caffeine acts as a natural pesticide, discouraging or killing herbivorous insects and inhibiting the invasion and colonization of pathogenic fungi. Nectar containing caffeine may enhance the rewarding properties of pollinators, such as honeybees, and improve distribution of pollen (Wright et al., 2013). We humans have contributed massively to the success of coffee and tea plants by distributing them widely over our planet, at the expense of native plant and animal species and the local ecology.

Cholinergic Nicotine is found in the leaves of the tobacco plant, Nicotiana tabacum. Like caffeine, it functions as an antiherbivore chemical and was at one time widely used as an insecticide. Nicotine is also found in small amounts in potatoes, tomatoes, and eggplant. Nicotine’s mood-altering effects are unusual in comparison to most drugs. At low doses, nicotine is a stimulant, but at very high doses, it dampens neuronal activity (Wadgave & Nagesh, 2016). Tobacco smokers report feelings of relaxation, sharpness, calmness, and alertness. When smoke from a tobacco cigarette is inhaled, within a few seconds nicotine stimulates acetylcholine nicotinic receptors, which then indirectly causes the release of acetylcholine and several other neurotransmitters, including norepinephrine, epinephrine, arginine vasopressin, serotonin, endorphins, and dopamine. It is the release of dopamine that provides the reinforcing aspect of nicotine. Nicotine dependence involves both psychological and physical aspects. Smoking cessation leads to heightened anxiety, irritability, craving, inability to feel pleasure, and tremors.

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Nicotine is a potentially lethal poison; in fact, the total amount of nicotine in one cigarette, if injected, can be lethal to an inexperienced person. Tolerance develops rapidly, however, and experienced users can withstand much higher levels of the drug. Respiratory diseases, lung cancer, and related negative effects are caused by the harmful chemicals found in tobacco smoke rather than in nicotine itself. This fact has propelled the popularity of vaping, in which nicotine can be inhaled without tobacco smoke. The long-term health effects of e-cigarettes are likely less serious than those of tobacco smoke but are not known. While smoking is a risk factor for Alzheimer disease, cholinergic agonists are medically prescribed to treat it. Acetylcholinesterase inhibitors, such as tacrine (Cognex), raise ACh levels and may provide a small benefit (Birks et al., 2015), although no medication has been clearly shown to delay or halt the progression of Alzheimer disease.

GABAergic At low doses, GABAergic agonists reduce anxiety; at medium doses, they sedate; at high doses, they anesthetize or induce coma. At very high doses, they can kill (Figure 6-6).

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FIGURE 6-6 Behavioral Continuum of Sedation Increasing doses of GABAergic agonists affect behavior: low doses reduce anxiety, and very high doses result in death.

In order

GABA is an amino acid. Figure 5-12 shows its chemical structure.

to understand how GABAergic agonists work, we must consider the binding sites and channel associated with the GABAA receptor complex. The GABAA receptor, illustrated in Figure 6-7, contains a site where GABA binds, another separate site where alcohol binds, and still another site where benzodiazepines bind, as well as a chloride ion (Cl−) channel.

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FIGURE 6-7 Drug Effects at the GABAA Receptor These receptors have a binding site for alcohol (left) and a different binding site for benzodiazepines (center). When taken together (right), these two types of drugs can be lethal.

Principle 10: The nervous system works by juxtaposing excitation and inhibition.

Excitation of the GABAA receptor produces an influx of Cl− through its pore. An influx of Cl− increases the concentration of negative charges inside the cell membrane, hyper-polarizing it and making it less likely to propagate an action potential. GABA therefore produces its inhibitory effect by decreasing a neuron’s firing rate. Widespread reduction of neuronal firing underlies the behavioral effects of drugs that affect the GABAA synapse. Benzodiazepines are a class of chemicals that include diazepam (Valium), alprozolam (Xanax), and clonazepam (Klonopin) and are medically prescribed to reduce anxiety. Benzodiazepines are often used

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by people who are having trouble coping with significant physical or mental stress, such as a traumatic accident or a death in the family. They are also used as presurgical relaxation agents and can terminate seizures. Because the GABAA receptor has different binding sites for GABA, alcohol, and benzodiazepines, activation of each site promotes an influx of Cl−, but in different ways. The effects of actions at these three sites summate, which is why alcohol and benzodiazepine drugs should not be consumed together. In the United States, combined doses of these drugs reportedly contribute to as many deaths as occur annually from automobile accidents. A characteristic feature of benzodiazepine drugs is that a user who takes repeated doses develops a tolerance for them. A larger dose is then required to attain the drug’s initial effect. Cross-tolerance results when the tolerance for one drug, like benzodiazepines, is carried over to a different member of the drug group. Cross-tolerance also suggests that benzodiazepines and alcohol act on the nervous system in similar ways. Alcohol (ethyl alcohol, or ethanol) is present in alcoholic beverages and is an extraordinarily popular psychoactive and recreational drug, particularly among college-aged students (see Section 6-3). The fermentation of sugar into alcohol is one of humanity’s earliest biotechnologies, dating back at least 9000 years. Alcohol consumption has short-term psychological and physiological effects that depend on several factors, including the amount and concentration of alcohol, the duration over which it is consumed, the amount of food eaten, and the consumer’s weight and experience with alcohol. Small amounts of alcohol typically cause an overall improvement in mood and possible 654

euphoria, increased self-confidence and sociability, decreased anxiety, impaired judgment and fine muscle coordination, and a flushing of the face. Medium doses result in lethargy, sedation, balance problems, and blurred vision. High doses lead to profound confusion, slurred speech (“wats da proplem, ossifer?”), staggering, dizziness, and vomiting—an adaptive response to poisoning. Very high doses cause stupor, memory loss, unconsciousness, life-threatening respiratory depression, and inhalation of vomit. The long-term and frequent consumption of alcohol can lead to increased risk of alcoholism, a condition ruinous to individuals and families, as well as an enormous economic burden; alcoholism costs $249 billion in the United States alone (Sacks et al., 2015). In the United States, about 8 percent of men and 4 percent of women met criteria for alcoholism in 2015 (Substance Abuse and Mental Health Services Administration, 2015). Alcoholics often are malnourished and typically have elevated levels of chronic pancreatitis, liver disease, and cancer. Alcoholism results in damage to the central and peripheral nervous systems, as well as nearly every other system and organ in the body. Drugs that act on GABA receptors also affect brain development because GABA is one of the substances that regulate brain development. Clinical Focus 6-2, Fetal Alcohol Spectrum Disorder, explores the devastating effects of alcohol on developing fetuses.

CLINICAL FOCUS 6-2

Fetal Alcohol Spectrum Disorder

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The term fetal alcohol syndrome (FAS) was coined in 1973 to describe a pattern of physical malformation and intellectual disability observed in some children born to alcoholic mothers. It is now called fetal alcohol spectrum disorder (FASD) to acknowledge the range of its effects. Children with FASD may have abnormal facial features, such as unusually wide spacing between the eyes. Their brains display a range of abnormalities, from small size with abnormal gyri to abnormal clusters of cells and misaligned cells in the cortex. Related to these brain abnormalities are certain behavioral symptoms that children with FASD tend to have in common. They display varying degrees of learning disabilities and low intelligence test scores, as well as hyperactivity and other social problems. Individuals with FASD are 19 times as likely to be incarcerated as those without it (Popova et al., 2011). Numerous studies have attempted to estimate the prevalence of FASD in the United States, with results ranging from under 1% to 10% and possibly higher, but these estimates are likely not generalizable to all communities. Women who are most at risk for bearing FASD babies are poor and not well educated, their alcohol consumption problems predate pregnancy, and they have little access to prenatal care. It is often difficult to inform these women about the dangers that alcohol poses to a fetus and to encourage them to abstain from drinking alcohol before and during pregnancy. Alcohol-induced abnormalities can vary from hardly noticeable physical and psychological effects to full-blown FASD. The severity of effects is related to when, how much, and how frequently alcohol is consumed over the course of pregnancy. The effects are worse if alcohol is consumed in the first trimester, a time of organogenesis and the highest levels of DNA synthesis. The risks are exacerbated because many women may not yet realize that they are pregnant at this stage. Severe FASD is also more likely to coincide with binge drinking, which produces high blood alcohol levels. Other factors related to severe outcomes

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are poor nutritional health of the mother and the mother’s use of other drugs, including nicotine. In addition, alcohol use by mothers and fathers before conception can change the methylation status of some genes that contribute to disabilities found on the spectrum (Lee et al., 2015). A major question related to FASD is how much alcohol is too much to drink during pregnancy. To be completely safe, it is best not to drink alcohol at all in the months preceding as well as during pregnancy. This conclusion is supported by findings that as little as a single drink of alcohol per day during pregnancy can lead to a decrease in children’s intelligence test scores.

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(Top) Characteristic facial features that indicate FASD. Effects are not merely physical; many children endure severe intellectual disabilities. (Bottom) The convolutions characteristic of the brain of a healthy child at age 6 weeks (left) are grossly underdeveloped in the brain of a child with FASD (right).

Glutamatergic Glutamate is the main excitatory neurotransmitter in the forebrain and cerebellum. Section 14-4 describes how glutamate and NMDA receptors affect long-term learning.

The glutamatergic system has several receptors, such as NMDA, AMPA, and kainate (see Table 5-3). Antagonists for the NMDA receptor, such as phencyclidine (PCP, or angel dust) and ketamine (Special K), can produce hallucinations and out-of-body experiences. Research indicates that PCP inhibits nicotinic acetylcholine receptors as well as inhibiting dopamine reuptake; therefore, PCP is also a dopaminergic agonist, which may account for some of its psychoactive effects. Both PCP and ketamine are also known as dissociative anesthetics, compounds that produce feelings of detachment—dissociation—from the environment and self because they distort perceptions of sight and sound. Ketamine is currently medically prescribed for starting and maintaining anesthesia. It induces a trance-like state while providing pain relief, sedation, and memory loss. Ketamine is being tested as a rapid-acting antidepressant and is in phase III clinical trials for use in 658

treating major depressive disorder (Caddy et al., 2014). Its mechanism of action, as a glutamatergic agonist, is very different from those of most modern drugs prescribed to reduce depression, which operate on serotonin and norepinephrine targets (see the Serotonergic section). Mematine (Namenda) is an NMDA antagonist that is prescribed in the treatment of Alzheimer disease to prevent neuronal loss.

Dopaminergic We first consider dopamine agonists that are used recreationally, such as cocaine, amphetamine, and methamphetamine, and agonists that are medically prescribed, such as dextroamphetamine (Adderall), methylphenidate (Ritalin), and L-dopa. We then consider dopamine antagonists that are medically prescribed for schizophrenia and druginduced psychosis, including chlorpromazine (Thorazine), haloperidol (Haldol), clozapine (Clozaril), and aripiprazole (Abilify, Aripiprex).

Dopamine Agonists Recreationally used dopaminergic agonists include cocaine, amphetamine, and methamphetamine. Cocaine is purified from leaves of the coca plant (Figure 6-8), whereas amphetamine and methamphetamine are synthetically produced.

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FIGURE 6-8 Behavioral Stimulant Cocaine (left) is obtained from the leaves of the coca plant (center). Crack cocaine (right) is chemically altered to form rocks that vaporize when heated at low temperatures.

The indigenous people of Peru have chewed coca leaves through the generations to increase their stamina in the harsh environment and high elevations where they live. Refined cocaine powder can either be sniffed (snorted) or injected. Cocaine users who do not like to inject cocaine intravenously or cannot afford it in powdered form sniff or smoke rocks, or crack, a potent, highly concentrated form (shown at right in Figure 6-8). Crack is chemically altered so that it vaporizes at low temperatures, and the vapors are inhaled. Sigmund Freud (1974) popularized cocaine in the late 1800s as an antidepressant. It was once widely used in soft drinks and wine mixtures promoted as invigorating tonics. It is the origin of the trade name Coca-Cola, which once contained cocaine (Figure 6-9). Its addictive properties soon became apparent, however, and it was replaced in these products with caffeine.

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FIGURE 6-9 Warning Label Cocaine was once an ingredient in such invigorating beverages as Coca-Cola.

Freud also recommended that cocaine be used as a local anesthetic. Cocaine did prove valuable for this purpose, and many derivatives, such as xylocaine (often called Novocain), are used today. These local anesthetic agents reduce a cell’s permeability to sodium ions and so reduce nerve conduction. As Figure 6-10 shows, amphetamine is a dopamine agonist. It prevents dopamine reuptake by reversing the direction of the transporter, allowing dopamine to continue to interact with postsynaptic D2 receptors.

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FIGURE 6-10 Drug Effects at D2 Receptors The antipsychotic agent chlorpromazine (Thorazine) can lessen schizophrenia symptoms, and amphetamine or cocaine abuse can produce them. This suggests that schizophrenia may be related, at least in part, to excessive activity at the D2 receptor.

Section 5-1 describes experiments that Otto Loewi performed to identify epinephrine, or adrenaline. Section 7-7 details symptoms and outcomes of

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ADHD and the search for an animal model of the disease.

Amphetamine is a synthetic compound. It was discovered in attempts to synthesize the CNS neurotransmitter epinephrine, which also acts as a hormone to mobilize the body for fight or flight in times of stress (see Figure 6-20). Both amphetamine and cocaine are dopamine agonists. Amphetamine acts by reversing the dopamine reuptake transporter, whereas cocaine blocks the transporter. Both leave more dopamine available in the synaptic cleft, but amphetamine also reverses the transporter that typically packages dopamine into vesicles, thus removing dopamine that was already packaged and increasing its abundance in the synaptic terminal. The transporter found on the synaptic terminal then pumps the dopamine previously packaged in vesicles into the synaptic cleft. Thus, amphetamine acts in two different ways to increase the amount of dopamine in synapses, which stimulates dopamine receptors. As noted in Clinical Focus 6-1, amphetaminebased drugs are widely prescribed to treat ADHD. Benzedrine, a form of amphetamine, was originally used to treat asthma and sold in inhalers as a nonprescription drug through the 1940s. Soon people discovered that they could open the container and ingest its contents to obtain an energizing effect. Amphetamine was widely used in World War II to help troops and pilots stay alert, increase confidence and aggression, and boost morale—a practice that continues today. It was also used among the civilian population to improve wartime workers’ productivity. Today, amphetamine is used as a popular weight-loss aid. Many over-the-counter compounds marketed as stimulants or weight-loss aids have amphetaminelike pharmacological actions.

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A widely used illegal amphetamine derivative is methamphetamine (also known as meth, speed, crank, smoke, and crystal ice). Lifetime prevalence of methamphetamine use in the U.S. population (the percentage of the population who have used the drug at least once in their lives), once estimated to be as high as 8 percent (Durell et al., 2008), is related to its ease of manufacture in illicit laboratories and to its potency, thus making it a relatively inexpensive yet potentially devastating drug. The process of illicit manufacture makes it difficult to draw conclusions about the effects of methamphetamines compared to the effects of legally synthesized amphetamines. A mphe

Psychosis and schizophrenia are described in detail in Section 16-2.

tamin e (Adderall) and methylphenidate (Ritalin) are medically prescribed to treat ADHD, which is characterized by excessive activity and difficulty controlling behavior or paying attention, though many people with ADHD have very long attention spans for tasks they find interesting. The recreational dosage of both drugs is about 50 times higher than the medically prescribed dosage. Chronic recreational use can lead to psychosis, a term applied to behavioral disorders characterized by hallucinations (false sensory perceptions), delusions (false beliefs), paranoia, and disordered thoughts, among a host of other symptoms. These symptoms are also observed in individuals diagnosed with schizophrenia.

Dopamine Antagonists The dopamine hypothesis of schizophrenia holds that some forms of the disease may be related to excessive dopamine activity—especially

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in the frontal lobes. If excessive dopamine is a consequence of druginduced psychosis and some forms of naturally occurring schizophrenia, then dopamine antagonists should ameliorate the symptomology (see Figure 6-10). In fact, the use of dopamine antagonist drugs that preferentially bind to D2 receptors has improved the functioning of people with schizophrenia. Since 1955, when dopaminergic antagonists (antipsychotic agents, or antipsychotics) were introduced into widespread therapeutic use, resident populations with schizophrenia in state and municipal mental hospitals in the United States have decreased dramatically. The incidence of schizophrenia is about 1 in every 100, making the success of dopamine antagonists an important therapeutic achievement. Although using dopamine antagonists to treat psychosis makes these mental disorders manageable, it does not constitute a cure. In fact, according to the National Institute on Disability, Independent Living, and Rehabilitation Research, although the number of people in mental institutions remains relatively low, as many as 75 percent of those who are homeless and 50 percent of incarcerated people have mental health issues. According to Human Rights Watch, in 2015 in the United States, 10 times as many mentally ill people were incarcerated as resided in mental institutions. Dopamine antagonists have been widely used to treat psychosis since the mid-1950s, beginning with the development of what have been called first-generation antipsychotics (FGAs). They include the drug classes phenothiazines (for example, chlorpromazine [Thorazine]) and butyrophenones (haloperidol [Haldol]). FGAs act mainly by blocking the dopamine D2 receptor, which immediately reduces motor activity

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and alleviates the excessive agitation of some people with schizophrenia. But because schizophrenia involves more than just D2 receptors, changes in dopamine synapses do not completely explain the disorder or the effects of dopaminergic antagonists. Beginning in the 1980s, newer drugs such as clozapine (Clozaril) and several other compounds emerged as second-generation antipsychotics (SGAs). SGAs not only block dopamine D2 receptors but also block serotonin 5HT2 receptors. Tardive dyskinesia is discussed further in Section 16-3.

The therapeutic actions of D2

antagonists are not fully understood, and long-term use of these drugs can produce many unwanted side effects, including tardive dyskinesia (TD). TD is a movement disorder that results in involuntary, repetitive body movements such as grimacing, sticking out the tongue, or smacking the lips, as well as rapid jerking movements or slow writhing movements. Recall that dopamine agonists, such as L-dopa, boost dopamine levels to restore movements in people with Parkinson disease. Thus, dopamine plays a central role in normal movement and mental health and, as discussed in Section 6-3.

Serotonergic We now consider the serotonergic agonists, but keep in mind that most serotonergic agonists also have adrenergic activity. Serotonergic agonists are well known for altering perceptions of one’s surroundings, feelings, sensations, and images (visual hallucinations), producing what are known as “trips.” They were part of

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the counterculture movement of the 1960s and continue to be used recreationally and spiritually. Some, such as mescaline (peyote; 3,4,5trimethoxyphenethylamine), DMT (N, N-Dimethyltryptamine), and psilocybin, are found in plants and mushrooms, while others, such as lysergic acid diethylamide (LSD) and MDMA (Ecstasy, XTC; 3,4Methylenedioxymethamphetamine), are produced synthetically. In the past century, strong advocates for serotonergic agonists in the United States promoted their use for “mind expansion and personal truth.” Mescaline, obtained from the peyote cactus, is legal in the United States for use by Native Americans for spiritual practices. Good trips on serotonergic agonists can be pleasurable and are associated with feelings of joy or euphoria (referred to as a “rush”), disconnection from reality, decreased inhibitions, and the belief that one has extreme mental clarity or superpowers. Bad trips can be associated with irrational fears, panic attacks, paranoia, rapid mood swings, intrusive thoughts of hopelessness, wanting to harm others, and suicidal ideation. Repeated use can lead to problems with sleep, mood, memory, and attention. Currently, these recreationally used drugs are not medically prescribed and are illegal. But there are other serotonergic agonists that are medically prescribed for the treatment of major depression. Major depression is a mood disorder characterized by prolonged feelings of worthlessness and guilt, disruption of normal eating habits, sleep disturbances such as insomnia, a general slowing of behavior, and frequent thoughts of suicide. At any given time, about 6 percent of the adult U.S. population has major depression, and in the course of a lifetime, 30 percent may have at least one episode that lasts for months

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or longer. Major depression is diagnosed in twice as many women as men. Section 12-4 explores the neural control of emotions and emotional disorders such as depression, and Section 16-2 focuses on its neurobiology and treatments for such disorders.

Inadequate nutrition, stress from difficult life conditions, acute changes in neuronal function, and damage to brain neurons are among the factors implicated in depression. These factors may be related: nutritional deficiencies may increase vulnerability to stress; stress may change neuronal function; and if unrelieved, altered neuronal function may lead to neuron damage. Section 6-5 offers more information on stress. Not surprisingly, a number of pharmacological approaches to depression are available. They include normalizing stress hormones, modifying neuronal responses, and stimulating neuronal repair.

Medications Used to Treat Depression Three different types of serotonergic agonist drugs are prescribed for depression: the monoamine oxidase (MAO) inhibitors; the tricyclics, so called because of their three-ring chemical structure; and the selective serotonin reuptake inhibitors (SSRIs). The SSRIs lack a three-ring structure but do share some similarities to the tricyclics in their actions. Drugs prescribed for depression are thought to act by improving chemical neurotransmission at serotonin, noradrenaline

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(norepinephrine), histamine, and acetylcholine synapses and perhaps at dopamine synapses as well. Figure 6-11 shows the actions of MAO inhibitors, tricyclics, and SSRIs at a 5-HT synapse, on which most research is focused. These three drugs act as agonists, but they have different mechanisms for increasing serotonin availability.

FIGURE 6-11 Drug Effects at 5-HT Receptors Different drugs prescribed to treat depression act on the serotonin synapse in different ways to increase its availability.

MAO inhibitors provide for more serotonin release with each action 669

Reuptake is part of transmitter inactivation, the last of the five steps of neurotransmission (see Figure 5-4).

potential by inhibiting monoamine oxidase, an enzyme that breaks down serotonin in the axon terminal. In contrast, the tricyclics and SSRIs block the reuptake transporter that takes serotonin back into the axon terminal. Because the transporter is blocked, serotonin remains in the synaptic cleft, prolonging its action on postsynaptic receptors. Although these drugs begin to affect synapses very quickly, their antidepressant actions take weeks to develop. One explanation is that these drugs, especially SSRIs, stimulate second messengers in neurons to activate the repair of neurons damaged by stress. Of interest in this respect, one particular SSRI, fluoxetine (Prozac), increases the production of new neurons in the hippocampus, a limbic structure in the temporal lobes. As detailed in Section 6-5, the hippocampus is vulnerable to stress-induced damage, and its restoration by fluoxetine is proposed to underlie one of the drug’s antidepressant effects (Hill et al., 2015). Most people recover from depression within a year of its onset. If depression is left untreated, however, the incidence of suicide among depressed individuals is high, as described in Clinical Focus 6-3, Major Depression. Of all psychological disorders, major depression is one of the most treatable. Cognitive-behavioral therapies are most effective when combined with drug therapies (Comer, 2011).

CLINICAL FOCUS 6-3

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Major Depression P. H. was a 53-year-old high school teacher who, although popular with his students, was deriving less and less satisfaction from his work. His marriage was foundering because he was growing apathetic and no longer wanted to socialize or go on vacations. He was having difficulty getting up in the morning and arriving at school on time. P. H. eventually consulted a physician, complaining of severe chest pains, which he feared signaled an impending heart attack. He informed his doctor that a heart attack would be a welcome relief because it would end his problems. The physician concluded that P. H. had depression and referred him to a psychiatrist. Since the 1950s, depression has been treated with serotonergic drugs, a variety of cognitive-behavioral therapies (CBTs), and, when pharmacological approaches fail, electroconvulsive therapy (ECT), in which electrical current is briefly passed through one hemisphere of the brain. The risk of suicide and self-injurious behaviors is high in major depression, especially among depressive adolescents who are resistant to treatment with SSRIs (Asarnow et al., 2011). Even for patients who do respond positively to SSRI treatment, the benefits are usually not observed for the first few weeks of treatment. The glutamate antagonist ketamine, when given in smaller-than-anesthetic doses, can produce rapid beneficial effects that last for weeks, even in patients who are resistant to SSRI medication (Reinstatler & Youssef, 2015). Ketamine is thus proposed to be useful as an acute treatment for patients with major depression who are at risk for suicide as well as for patients with bipolar depression who are at risk for suicide. Prompted by complaints from family members that antidepressant drug treatments have caused suicide, especially in children, the U.S. Food and Drug Administration (FDA) has advised physicians to monitor the side effects of SSRIs, including fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil, Seroxat). Findings from several studies show no difference

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in the suicide rate between children and adolescents who receive SSRIs and a placebo; in addition, the incidence of suicide after prescriptions were curtailed subsequent to the FDA warning actually increased (Isacsson & Rich, 2014).

Despite these successes, about 20 percent of patients with depression fail to respond to antidepressant drugs. Depression can have many causes, including dysfunction in other transmitter systems and even brain damage, such as frontal lobe damage—many of which are not treatable by serotonin agonists. In addition, some people have difficulty tolerating the side effects of antidepressants, which can include increased anxiety, sexual dysfunction, sedation, dry mouth, blurred vision, and memory impairment.

Opioidergic An opioid is any endogenous or exogenous compound that binds to opioid receptors to produce morphine-like effects. These psychoactive compounds have sleep-inducing (narcotic) and pain-relieving (analgesic) properties. There are three sources of opioids: isolated (morphine, codeine), altered (heroin, oxycodone), and synthetic (fentanyl, methadone). Research has identified five classes of opioid peptides: dynorphins, enkephalins, endorphins, endomorphins, and nociceptin. The four receptors on which each opioid peptide binds are the delta, kappa, mu, and nociceptin receptors. All opioid peptides and their receptors occur in many CNS regions, as well as in other areas of the body, including the enteric nervous system (ENS). Morphine most closely mimics the endomorphins and binds most selectively to the mu receptors.

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Opium is a white milky latex extracted from the seed pods of the opium poppy, Papaver somniferum, shown at left in Figure 6-12. Opium, whose primary active ingredient is morphine, has been used for thousands of years to produce euphoria, analgesia, sleep, and relief from diarrhea and coughing. In 1805, chemist Friedrich Sertürner isolated two chemicals from opium: codeine and morphine. Codeine is often an ingredient in prescription cough medicine and pain relievers. The liver has an enzyme that converts it to morphine, although a portion of blond-haired and blue-eyed people lack this enzyme. Morphine, shown at center in Figure 6-12 and named for Morpheus, the Greek god of dreams, alters our perception of pain.

FIGURE 6-12 Potent Poppy Opium is obtained from the seed pods of the opium poppy (left). Morphine (center) is extracted from opium, and heroin (right) is in turn altered from morphine.

In addition to the natural opioids, semi-synthetic opioids, such as heroin and oxycodone, affect mu receptors. Heroin, shown at right in Figure 6-12, is altered from morphine. It is more potent and more fatsoluble than morphine and penetrates the blood–brain barrier more

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quickly, allowing it to produce very rapid but shorter-acting psychoactive affects. Heroin is a legal drug in some countries but continues to be illegal in others, including the United States. Synthetic opioids, like fentanyl, are prescribed for clinical use in pain management. All opioids are potently addictive, and abuse of medically prescribed opioids is at a crisis point worldwide. Opioids also may be illegally modified, manufactured, and distributed. People who use opioids can become addicted; some obtain multiple prescriptions and sell them illicitly. Opioid ingestion produces wide-ranging physiological changes in addition to altering pain perception, including relaxation and sleep, euphoria, and constipation. (And, yes, the use of laxatives to reverse constipation is also on the rise.) Other effects include respiratory depression, which is the primary cause of death of opioid addicts, decreased blood pressure, pupil constriction, hypothermia, drying of secretions (for example, dry mouth), reduced sex drive, and flushed, warm skin. The term “cold turkey” is a reference to the cold skin that accompanies opioid withdrawal, in which the hair stands up and looks like turkey skin. This effect is opposite the warm skin experience after opioid use.

Repeated opioid use produces tolerance such that within a few weeks, the effective dose may increase tenfold. Thereafter, many desired effects no longer occur. An addicted person cannot simply stop using the drug without adverse effects: severe withdrawal symptoms,

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physiologically and behaviorally opposite to those produced by the drug, result if drug use is abruptly stopped. Because opioid use results in both tolerance and sensitization, an opioid user is at constant risk of overdosing. The unreliability of appropriate information on the purity of street forms of opioids contributes to the risk. In the United States and Canada, opioid overdose is currently the number-one cause of death in people under 50 years of age! Drugs such as naloxone (Narcan, Nalone) act as antagonists at opioid receptors. Naloxone is a competitive inhibitor: it competes with opioids for neuronal receptors. Because they can enter the brain quickly, competitive inhibitors rapidly block the actions of opioids and so are essential aids in treating opioid overdoses. Many people addicted to opioids carry a competitive inhibitor as a treatment for overdosing. Because they can also be long-acting, competitive inhibitors can be used to treat opioid addiction after the addicted person has recovered from withdrawal symptoms. Researchers have extensively studied whether opioid peptides produced in the brain can be used as drugs to relieve pain without addictive effects. The answer so far is uncertain, and producing an analgesic that does not produce addiction, which is one of the objectives of pain research, may be difficult to realize. Some countries, like Japan, simply do not treat chronic pain with opioids and are avoiding the opioid crisis. The development of non-opioid pain medications remains an important avenue of research.

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Cannabinergic Marijuana, a Mexican Spanish term with obscure roots, rose in popularity in the early 1900s. The term made the plant sound scary and foreign to White Americans, which fed into a growing racism and xenophobia against Mexicans.

Tetrahydrocannabinol (THC) is one of 84 cannabinoids and the main psychoactive constituent in cannabis (inappropriately referred to as marijuana), obtained from a couple of species of Cannabis plants, shown in Figure 6-13. THC alters mood primarily by interacting with the cannabidiol 1 (CB1) receptor found on neurons, and it also binds with the CB2 receptors found on glial cells and in other body tissues. Cannabis has extremely low toxicity—no one has ever died of an overdose—but may have a detrimental effect on mood and memory as well as a positive effect on mental overload.

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FIGURE 6-13 Cannabis sativa A hemp plant, an annual herb, grows over a wide range of altitudes, climates, and soils. Hemp has myriad uses, including in manufacturing rope, cloth, and paper; tetrahydrocannabinol (THC) is the main psychoactive constituent in cannabis.

Anandamide (from Sanskrit, meaning “joy” or “bliss”) acts on the CB1 receptor that naturally inhibits adenyl cyclase, part of a second messenger system active in sensitization (see Section 5-4).

Our body produces two endogenous molecules that bind to CB1 and CB2 receptors: anandamide and 2-AG. Results from numerous lines of research suggest that anandamide reduces anxiety and enhances

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forgetting. Anandamide may prevent the brain’s memory systems from being overwhelmed by all the information to which we are exposed each day. Evidence points to the usefulness of THC and cannabidiol (CBD), another cannabinoid, as therapeutic agents for a number of disorders. Cannabis relieves nausea and emesis (vomiting) in patients undergoing cancer chemotherapy who are not helped by other treatments and stimulates the appetite in patients with anorexia–cachexia (wasting) syndrome. Cannabis has been found to be helpful for treating chronic pain through mechanisms that appear to be different from those of the opioids. In fact, cannabis reduces the dose of opioids in the treatment of pain. Cannabis has also proved useful for treating glaucoma (increased pressure in the eye), spastic disorders such as multiple sclerosis, disorders associated with spinal cord injury, and some epilepsy syndromes. Cannabis may also have some neuroprotective properties. Many people self-prescribe cannabis for a wide range of ailments, including PTSD (Roitman et al., 2014). Synthetic and derived forms of THC have been developed in part to circumvent legal restrictions on its use. Nevertheless, legal restrictions against cannabis and its derivatives hamper scientific investigations into its useful medicinal effects.

6-2 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 678

, the world’s most widely consumed psychoactive drug, binds to receptors but also has other mechanisms of action.

2. Drugs that reduce anxiety and can induce sedation primarily exert their action on the receptor, which through influx hyperpolarizes neurons. 3. Drugs prescribed for depression primarily exert their effect on the ergic system. 4. Opioids mimic the action of receptors. 5. Amphetamine stimulates , at the

by binding to the same

, and cocaine blocks synapse.

6. On which neurotransmitters do drugs that produce psychotropic effects act?

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6-3 Factors Influencing Individual Responses to Drugs Specific behaviors often trigger predictable results. You strike the same piano key repeatedly and hear the same note each time. You flick a light switch today, and the bulb glows exactly as it did yesterday. This cause-and-effect consistency does not extend to the effects of psychoactive drugs. Individuals respond to drugs in remarkably different ways at different times.

Behavior on Drugs Ellen is a healthy, attractive, intelligent 19-year-old university freshman who knows the risks of unprotected sexual intercourse. She learned about HIV and other sexually transmitted infections (STIs) in her high school health class. A seminar about the dangers of unprotected sexual intercourse was part of her college orientation: seniors provided the freshmen in her residence free condoms and safe sex literature. Ellen and her former boyfriend were always careful to use latex condoms during intercourse. At a homecoming party in her residence hall, Ellen has a great time, drinking and dancing with her friends and meeting new people. She is particularly taken with Brad, a sophomore at her college, and the two of them decide to go back to her room to order a pizza. One

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thing leads to another, and Ellen and Brad have sexual intercourse without using a condom. The next morning, Ellen wakes up, dismayed and surprised at her behavior and concerned that she may be pregnant or may have contracted an STI. She is terrified that she may develop AIDS (MacDonald et al., 2000). What happened to Ellen? What is it about drugs, especially alcohol, that makes people sometimes do things they would not ordinarily do? Alcohol is linked to many harmful behaviors that are costly both to individuals and to society. These harmful behaviors include not only unprotected sexual activity but also driving while intoxicated, date rape, spousal or child abuse and other aggressive behaviors, and crime. Among the explanations for the effects of alcohol are disinhibition, learning, and behavioral myopia.

Disinhibition and Impulse Control An early and still widely held explanation of alcohol’s effects is disinhibition theory. It holds that alcohol has a selective depressant effect on the cortical brain region that controls judgment while sparing subcortical structures that are responsible for more instinctual behaviors, such as desire. Stated differently, alcohol depresses learned inhibitions based on reasoning and judgment while releasing the “beast” within. A variation of disinhibition theory argues that the frontal lobes check impulsive behavior. According to this idea, impulse control is impaired after drinking alcohol because of a higher relative sensitivity of the frontal lobes to alcohol. A person may then engage in risky behavior (Hardee et al., 2014). 681

Proponents of these theories often excuse alcohol-related behavior, saying, for example, “She was too drunk to know better” or “The boys had a few too many and got carried away.” Do disinhibition and impulse control explain Ellen’s behavior? Not entirely. Ellen had used alcohol in the past and managed to practice safe sex despite its effects. Neither theory explains why her behavior was different on this occasion. If alcohol is a disinhibitor, why is it not always so?

Learning Craig MacAndrew and Robert Edgerton (1969) question disinhibition theory along just these lines in their book Drunken Comportment. They cite many instances in which behavior under the influence of alcohol changes from one context to another. People who engage in polite social activity at home when consuming alcohol may become unruly and aggressive when drinking in a bar. Even behavior at the bar may be inconsistent. Take Joe, for example. While drinking one night at a bar, he acts obnoxious and gets into a fight. On another occasion, he is charming and witty, even preventing a fight between two friends; on a third occasion, he becomes depressed and worries about his problems. MacAndrew and Edgerton also cite examples of cultures in which people are disinhibited when sober only to become inhibited after consuming alcohol, as well as cultures in which people are inhibited when sober and become more inhibited when drinking. What explains all these differences in the effects of alcohol? MacAndrew and Edgerton suggest that behavior under the effects of alcohol is learned. Learned behavior is specific to culture, group, 682

and setting and can in part explain Ellen’s decision to have intercourse with Brad. Where alcohol is used to facilitate social interactions, behavior while intoxicated is a time-out from more conservative rules regarding dating.

Behavioral Myopia Ellen’s lapse in judgment regarding safe sex is more difficult to explain by learning theory. Ellen had never practiced unsafe sex before and had never made it a part of her time-out social activities. So why did she engage in it with Brad? A different explanation for alcohol-related lapses in judgment, behavioral myopia (nearsightedness), is the tendency for people under the influence of (in this case) alcohol to respond to a restricted set of immediate and prominent cues while ignoring more remote cues and possible consequences. Immediate and prominent cues are very strong, obvious, and close at hand (Griffin et al., 2010). In an altercation, a person with behavioral myopia will be quicker than usual to throw a punch because the fight cue is so strong and immediate. At a raucous party, the myopic drinker will be more eager than usual to join in because the immediate cue of boisterous fun dominates his or her view. Once Ellen and Brad arrived at Ellen’s room, the sexual cues at the moment were far more immediate than concerns about long-term safety. As a result, Ellen responded to those immediate cues and behaved atypically. Behavioral myopia can explain many lapses in judgment that lead to risky behavior—such as aggression, date rape, or reckless driving

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while intoxicated. Individuals who have been drinking may also have poor insight into their level of intoxication: they may believe that they are less impaired than they actually are (Sevincer & Oettingen, 2014).

Addiction and Dependence B. G., who started smoking when she was 13 years old, has quit many times without success. After successfully abstaining from cigarettes by using a nicotine patch for more than 6 months, B. G. began smoking again. Because the university where she works has a nosmoking policy, she has to leave campus and stand across the street to smoke. Her voice has developed a rasping sound, and she has an almost chronic “cold.” She says that she used to enjoy smoking but does not any more. Concern about quitting dominates her thoughts. B. G. has a drug problem. She is one of the approximately 25 percent of North Americans who smoke. Like B. G., most other smokers realize that it is a health hazard, have experienced unpleasant side effects from it, and have attempted to quit but cannot. Substance abuse is a pattern of drug use in which people rely on a drug chronically and excessively, allowing it to occupy a central place in their life. In a more advanced state of substance dependence, popularly known as addiction, people exhibit three characteristics: escalation, compulsive drug taking, and relapse. Escalation refers to increased drug consumption through increased dose or dosing frequency (Kenny, 2007). Tolerance to the psychoactive effects of the drug cannot explain escalation. Instead, escalation reflects a pathological increase in the motivation to consume a drug (Oleson &

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Roberts, 2009). Escalation of drug use is a critical factor in the transition from sporadic use to the compulsive and relapsing drug use that characterizes addiction. Compulsive drug taking is defined as repetitive and persistent drug administration despite negative consequences. It is related to the inability to completely cease taking drugs. Relapse involves the recurrence of compulsive drug use after a period of abstinence. Addictive drug use is marked by inordinate time spent seeking, preparing, and consuming drugs, at the expense of everyday responsibilities, as well as numerous failed attempts at abstinence (Koob et al., 2014). Drug addicts may also experience unpleasant, sometimes dangerous physical withdrawal symptoms if they suddenly stop taking their drug of choice. Symptoms can include muscle aches and cramps, anxiety attacks, sweating, nausea, and even, for some drugs, convulsions and death. Symptoms of alcohol or morphine withdrawal can begin within hours of the last dose and tend to intensify over several days before they subside. Although B. G. uses nicotine, she is not physically dependent on it. She smokes approximately the same number of cigarettes each day, and she does not suffer severe withdrawal symptoms if she is deprived of cigarettes, although she does display irritability, anxiety, increased appetite, and insomnia. B. G. illustrates that the power of psychological dependence can be as influential as the power of physical dependence.

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Many addictive drugs—particularly the dopaminergics, GABAergics, and opioidergics—have a common property: they produce psychomotor activation in some part of their dose range. That is, at certain levels of consumption, these drugs make the user feel energetic and in control. This common effect has led to the hypothesis that all abused drugs may act on the same target in the brain: the dopaminergic pathway from the ventral tegmental area to the nucleus accumbens. Drugs of abuse increase dopamine activity in the nucleus accumbens, either directly or indirectly, and drugs that blunt abuse and addiction decrease dopamine activity in the nucleus accumbens.

Risk Factors in Addiction A number of environmental factors, called adverse childhood experiences (ACEs), are associated with an increased risk of drug initiation and drug addiction. ACEs include emotional, physical, and sexual abuse; emotional and physical neglect; mental illness of a household member; witnessing violence against one’s mother; substance abuse by a household member; parental separation or divorce; and incarceration of a household member. Each ACE increases the likelihood for early drug initiation by a factor of two to four. Compared to people with 0 ACEs, people with 5 or more ACEs have been found to be 7 to 10 times more likely to report drug use problems and addiction (see Figure 6-14).

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FIGURE 6-14 ACEs and Drug Addiction The percentage of individuals with reported drug addiction increases significantly with the addition of each ACE. Data from Dube et al., 2003.

Data collected over four generations suggests that the effects of these ACEs cannot be accounted for by increased availability of drugs, changing social attitudes toward drugs, or recent massive expenditures and public information campaigns to prevent drug use (Dube et al., 2003). There is some good news here: if you examine Figure 6-14, you will also see that the vast majority (90 percent) of

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individuals who have experienced five or more ACEs have not become addicted to drugs. In the population at large, women are about twice as sensitive to drugs as are men, on average, due in part to their smaller size but also to hormonal differences. The long-held general assumption that men are more likely than women to abuse drugs led investigators to neglect researching drug use in women. But the results of more recent research support quite the opposite view: women surpass males in the incidence of addiction to many drugs. Although the general pattern of drug use is similar in men and women, the sex differences are striking (Becker & Hu, 2008). Women are more likely than men to abuse nicotine, alcohol, cocaine, amphetamine, opioids, cannabinoids, caffeine, and PCP. Women begin to regularly self-administer psychoactive drugs at lower doses than do men, women’s use escalates more rapidly, and women are at greater risk for relapse after abstinence.

6-3 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1.

is the tendency for people under the influence of a drug to respond to a restricted set of immediate and prominent cues while ignoring more remote cues and possible consequences.

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is a condition in which people rely on drugs chronically and to excess, whereas is a condition in which people are physically dependent on a drug as well.

3. The evidence that many abused or addictive drugs produce , which makes the user feel energetic and in control, suggests that activation in the plays a role in drug abuse and addiction. 4. Common wisdom is incorrect in suggesting that are less likely to abuse drugs than are . 5. Why can alcohol-related behavior vary widely in a single individual from time to time?

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6-4 Explaining and Treating Drug Abuse Why do people become addicted to drugs? Early neuropsychological explanations centered on the pleasure associated with natural experiences surrounding sex, chocolate, and catching a fish, as well as the euphoria produced by psychoactive drugs. The pleasurable “rush” would supposedly lead to a variety of impulse control disorders, such as overeating, gambling, and repeated drug taking. But this explanation, known as the hedonia hypothesis, has a central problem: the initial pleasurable experience wears off with repeated drug taking and can become quite aversive, yet the user continues to take the drug. (Most of us have witnessed habitual smokers out in the wind and cold having a cigarette.) In other words, over repeated drug exposure, the pleasurable or hedonic experience becomes dissociated from the drug taking. More recent work has shown that there are separate brain circuits for pleasure (liking) and for repeating behaviors (wanting).

Wanting-and-Liking Theory To account for the three components of addiction—escalation, compulsive drug taking, and relapse—Terry Robinson and Kent Berridge (2008) proposed the incentive sensitization theory, also called the wanting-and-liking theory, because wanting and liking are produced by different brain systems. They define wanting as craving, whereas liking is the pleasure the drug produces. With

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repeated use, tolerance for liking develops, and the expression of liking (pleasure) decreases as a consequence (Figure 6-15). In contrast, the system that mediates wanting sensitizes, and craving increases.

FIGURE 6-15 Wanting-and-Liking Theory With repeated drug use, wanting a drug and liking the drug progress in opposite directions. Wanting (craving) is associated with drug cues.

The first step on the proposed road to drug dependence is the initial experience, when the drug affects a neural system associated with pleasure. At this stage, the user may like the substance— including liking to take it within a given social context. With repeated use, liking the drug may decline from its initial level. At this stage, the user may also begin to show tolerance to the drug’s effects and so may begin to increase the dosage to increase liking. In classical (Pavlovian) conditioning, learning to associate a formerly neutral stimulus (the sound of a bell) with a stimulus (food) elicits an involuntary response (salivation).

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With each use, the drug taker increasingly associates the cues related to drug use—be it a hypodermic needle, the room in which the drug is taken, or the people with whom the drug is taken—with the drug-taking experience. The user makes this association because the drug enhances classically conditioned cues associated with drug taking. Eventually, these cues come to possess incentive salience: they induce wanting, or craving, the drug-taking experience. The neural basis of addiction is proposed to involve multiple brain systems. The decision to take a drug is made in the prefrontal cortex, an area that participates in most daily decisions. When a drug is taken, it activates endogenous opioid systems that are generally related to pleasurable experiences. And wanting drugs may spring from activity in the nucleus accumbens of the dopaminergic activating system. In these mesolimbic pathways, diagrammed in Figure 6-16, the axons of dopamine neurons in the midbrain project to structures in the basal ganglia, including the nucleus accumbens, to the frontal cortex, and to the allocortex. When drug takers encounter cues associated with drug taking, this system becomes active, releasing dopamine. Dopamine release is the neural correlate of wanting and the repetition of behavior.

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FIGURE 6-16 Mesolimbic Dopamine Pathways Axons of neurons in the midbrain ventral tegmentum project to the basal ganglia, including the nucleus accumbens, prefrontal cortex, and hippocampus.

When a rat is placed in an environment where it anticipates a favored food or sex, investigators record dopamine increases in the striatum (see Section 7-5).

Another brain system may be responsible for conditioning drugrelated cues to drug taking. Barry Everitt (2014) proposes that the repeated pairing of drug-related cues to drug taking forms neural associations, or learning, in the dorsal striatum, a region in the basal

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ganglia consisting of the caudate nucleus and putamen. As the user repeatedly takes the drug, voluntary control gives way to unconscious processes—a habit. The result: drug users lose control of decisions related to drug taking, and the wanting—the voluntary control over drug taking—gives way to the craving of addiction. Multiple findings align with the wanting-and-liking explanation of drug addiction. Ample evidence confirms that abused drugs and the context in which they are taken initially has a pleasurable effect and that habitual users continue using their drug of choice even when taking it no longer produces any pleasure. Heroin addicts sometimes report that they are miserable: their lives are in ruins, and the drug is not even pleasurable anymore. But they still want it, and they still take it. What’s more, desire for the drug often is greatest just when the addicted person is maximally high, not during withdrawal. Finally, cues associated with drug taking—the social situation, the sight of the drug, and drug paraphernalia—strongly influence decisions to take, or continue taking, a drug. Notwithstanding support for a dopamine basis for addiction, recent research suggests more than one type of addiction. Some rats become readily conditioned to cues associated with reinforcement—for example, a bar that delivers a reward when pressed. Other animals ignore the bar’s incentive salience but are attracted to the location where they receive reinforcement. Animals that display the former behavior are termed sign trackers; those in the other group are goal trackers. Sign trackers exposed to addictive drugs appear to attribute incentive salience to drug-associated cues. Their drug wanting is dependent on the brain’s dopamine systems. Goal trackers may also 694

become addicted, possibly via different neural systems. Such findings imply at least two types of addiction (Yager et al., 2015). We can extend wanting-and-liking theory to many life situations. Cues related to sexual activity, food, and even sports can induce wanting, sometimes in the absence of liking. We frequently eat when prompted by the cue of other people eating, even though we may not be hungry and may derive little pleasure from eating at that time. The similarities between exaggerating normal behaviors and drug addiction suggest that they depend on the same learning and brain mechanisms. For this reason, any addiction is extremely difficult to treat.

Why Doesn’t Everyone Become Addicted to Drugs? Observing that some people are more prone than others to compulsive drug taking, scientists have investigated and found three lines of evidence suggesting a genetic contribution to differences in drug use. First, if a twin abuses alcohol, his or her identical twin (same genotype) is more likely to abuse it than would be a fraternal twins (only some genes in common). Second, people adopted shortly after birth are more likely to abuse alcohol if their biological parents were alcoholic, even though they have had almost no contact with those parents. Third, although most animals do not care for alcohol, selective breeding of mice, rats, and monkeys can produce strains that consume large quantities of it.

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Each line of evidence presents problems, however. Perhaps identical twins show greater concordance rates (incidence of similar behavioral traits) for alcohol abuse because their environments are more similar than those of fraternal twins. And perhaps the link between alcoholism in adoptees and their biological parents has to do with nervous system changes due to prenatal exposure to the drug. Finally, the fact that animals can be selectively bred for alcohol consumption does not mean that all human alcoholics have a similar genetic makeup. The evidence for a genetic basis of alcoholism will become compelling only when a gene or set of genes related to alcoholism is found.

People who enjoy high-risk adventure may be genetically predisposed to experiment with drugs, but people with no interest in risk taking are just as likely to use drugs.

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Less-than-perfect concordance rates between identical twins for diseases ranging from schizophrenia to asthma point to epigenetic inheritance of behaviors by the next generation (see Section 3-3).

Epigenetics offers another complementary explanation of susceptibility to addiction (Hillemacher et al., 2015). Addictive drugs may reduce the transcriptional ability of genes related to voluntary control and increase the transcriptional ability of other genes related to behaviors susceptible to addiction. Epigenetic changes in an individual’s gene expression may be relatively permanent and can be passed along, perhaps through the next few generations. For these reasons, epigenetics can account both for the enduring behaviors that support addiction and for the tendency of drug addiction to be inherited.

Treating Drug Abuse Figure 6-17 charts the relative incidence of drug use in the United States among people aged 12 and older who reported using at least one psychoactive drug during the preceding year in the National Survey of Drug Use and Health conducted by the National Institute of Drug Use (2016). The two most used drugs, alcohol and tobacco, are legal. The drugs that carry the harshest penalties, cocaine and heroin, are used by far fewer people. But criminalizing drugs clearly is not a solution to drug use or abuse, as illustrated by the widespread use of cannabis, the third most used drug on the chart. In response to its widespread use, several states and Canada have legalized cannabis to some degree, but it remains illegal under U.S. federal law. 697

FIGURE 6-17 Drug Use in the United States in 2016 Results from an annual national survey of Americans aged 12 and older who reported using at least one psychoactive drug during the past year. Percentages for alcohol, tobacco, and marijuana are rounded to the nearest whole numbers. Data from National Institute of Drug Use, 2016.

Treating drug abuse is difficult in part because legal proscriptions are irrational. In the United States, the Harrison Narcotics Act of 698

1914 made heroin and a variety of other drugs illegal and made the treatment of addicted people by physicians in their private offices illegal. The Drug Addiction Treatment Act of 2000 partly reversed this prohibition, allowing the treatment of patients but with a number of restrictions. In addition, legal consequences attending drug use vary greatly depending on the drug and the jurisdiction. From a health standpoint, tobacco has much higher proven health risks than does cannabis. Moderate use of alcohol is likely benign. Moderate use of opioids is likely impossible. Social coercion is useful in reducing tobacco use: witness the marked decline in smoking as a result of prohibitions against smoking in public places. Medical intervention is necessary for the treatment of opioid abusers. The approaches to treating drug abuse vary depending on the drug. Online and in-person communities associated with self-help and professional groups address the treatment of specific drug addictions. Importantly, because addiction is influenced by conditioning to drugrelated cues and by a variety of brain changes, recidivism remains an enduring risk for people who have apparently kicked their habit. Neuroscience research will continue to lead to better understanding of the neural basis of drug use and to better treatment. The best approach to any drug treatment involves recognizing that addiction is a lifelong problem for most people. Thus, drug addiction must be treated in the same way as chronic behavioral addictions and medical problems—analogous to recognizing that controlling weight with appropriate diet and exercise is a lifelong struggle for many people. 699

Can Drugs Cause Brain Damage? Many natural substances can act as neurotoxins; Table 6-2 lists some of them. Ongoing investigations of the neurotoxicity of these substances and other drugs in animal models show that many cause brain damage. Certain drugs of abuse can cause brain damage in humans, but definitive proof is very difficult to obtain. It is difficult to parse other life experiences from drug taking. It is also difficult to obtain the brains of drug users for examination at autopsy. Nevertheless, there is evidence that the developing brain can be particularly sensitive to drug effects, especially in adolescence, a time when drug experimentation is common (Teixeira-Gomes et al., 2015).

TABLE 6-2 Some Neurotoxins, Their Sources, and Their Actions Substance

Origin

Action

Apamin

Bees and wasps

Blocks Ca2+ channels

Botulin

Spoiled food

Blocks ACh release

Caffeine

Coffee seed

Blocks adenosine receptors, blocks Ca2+ channels

Colchicine

Crocus plant

Blocks microtubules

Curare

Berry

Blocks ACh receptors

Ibotenic acid

Mushroom

Similar to domoic acid; mimics glutamate

Magnesium

Natural element

Blocks Ca2+ channels

Rabies virus

Infected animal

Blocks ACh receptors

Reserpine

Tree

Destroys storage granules

Spider venom

Black widow spider

Stimulates ACh release

Strychnine

Plant

Blocks glycine

Tetrodotoxin

Puffer fish

Blocks membrane permeability to Na+

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In the late 1960s, many reports linked monosodium glutamate (MSG), a salty-tasting, flavor-enhancing food additive, to headaches in some people. In investigating this effect, scientists placed large doses of MSG on cultured neurons, which died. Subsequently, they injected MSG into the brains of experimental animals, where it also killed neurons. This line of research led to the discovery that many glutamatelike substances, including domoic acid and kainic acid (both toxins in seaweed) and ibotenic acid (found in some poisonous mushrooms), similarly kill neurons (Figure 6-18). Some drugs, such as PCP and ketamine, also act as glutamate agonists, leaving open the possibility that at high doses they, too, can cause neuronal death.

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FIGURE 6-18 Neurotoxicity (A) Domoic acid damage in this rat’s hippocampus, and to a lesser extent in many other brain regions, is indicated by the darkest coloring. Domoic acid, a Glu analog and therefore a glutamatergic agonist, is the causative agent in amnesic shellfish poisoning, which can result in permanent short-term memory loss, brain damage, and, in severe cases, death. (B) As can be seen here, monosodium glutamate (MSG) and glutamate are nearly identical and have nearly identical properties.

Glutamatelike drugs are toxic because they act on glutamate receptors. Glutamate receptor activation results in an influx of Ca2+ into the cell, which through second messengers activates a suicide gene leading to apoptosis (cell death). This discovery shows that a drug might be toxic not only because of its general effect on cell function but also as an agent that activates normal cell processes related to apoptosis. We must add, though, that there is no evidence that moderate consumption of MSG is harmful. What about the many recreational drugs that affect the nervous system? Are any of them neurotoxic? Sorting out the effects of the drug itself from the effects of other factors related to taking the drug is a major problem. Chronic alcohol use, for instance, can be associated with damage to the thalamus and cortical areas, producing severe memory disorders. Alcohol does not directly cause this damage, though. Alcoholics typically obtain low amounts of thiamine (vitamin B1) in their diet, and alcohol interferes with the ability of the intestines to absorption of thiamine. Thiamine plays a vital role in maintaining cell membrane structure.

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Clinical Focus 5-4 reports the chilling case of heroin addicts who developed Parkinson disease after using synthetic heroin laced with a contaminant (MPTP).

Similarly, among the many reports of people with a severe psychiatric disorder subsequent to abusing certain recreational drugs, in most cases determining whether the drug initiated the condition or aggravated an existing problem is difficult. Exactly determining whether the drug itself or some contaminant in it caused a harmful outcome also is difficult. With the increasing sensitivity of brainimaging studies, however, evidence is increasing that many drugs used recreationally can cause brain damage and cognitive impairments, as discussed in Clinical Focus 6-4, Drug-Induced Psychosis.

CLINICAL FOCUS 6-4

Drug-Induced Psychosis L. V. is 22 years old and has been wandering the halls of a rehabilitation clinic for almost a year. He is either confused or hostile and rarely has lucid moments. L. V. had been using crystal meth during his years as an undergraduate. Just before his final exams in his third year, he had a psychotic attack and since then has been continuously institutionalized. L. V. grew up with an abusive father and alcoholic mother. As a child, he was artistic and sensitive, and he showed a quiet maturity beyond his years. He had a passion for science fiction and mathematics, and his friends thought he was fun to be around. During his high school years, his family noted long-lasting and recurring periods of silence during which he

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often withdrew from socialization. L. V. experimented with alcohol, tobacco, cannabis, mushrooms, and cocaine before he found crystal meth (a drug also known as crank or ice), which he would make by combining cold medication, Ritalin, fertilizer, drain cleaner, antifreeze, and Epsom salts. In low doses, methamphetamine, the active ingredient in crystal meth, elevates mood; increases alertness, concentration, and energy; reduces appetite; and promotes weight loss. At higher doses, it induces psychosis in vulnerable individuals and can cause seizures and brain hemorrhage. Individuals who compulsively take methamphetamine, like L. V., display unpredictable and rapid mood swings, paranoia, hallucinations, delirium, and delusions, often with accompanying violent behavior. Because methamphetamine is a dopaminergic agonist, it interacts directly with the nucleus accumbens, which can lead to compulsive drug use. Withdrawal symptoms during initial abstinence may persist for months beyond the typical withdrawal period observed for other drugs. Chronic methamphetamine use has a toxic effect on human midbrain dopaminergic neurons and serotonin neurons, leading to reductions in gray-matter volume in several brain regions and adverse changes in markers of metabolic integrity (Krasnova & Cadet, 2009). A week before L. V.'s psychotic episode, he said he hadn’t slept for 2 weeks, and his delusions had escalated. His dank apartment was strewn with drug paraphernalia, soiled bed sheets, and foul odors. There was no food in his apartment, and there hadn’t been for some time. Dopaminergic antagonists are used to treat psychosis, but they are not a cure. Despite treatment, L. V. continues to punch himself in the face, masturbate in public, yell obscenities, and make animal sounds. Doctors see little hope of recovery for him, and the medical profession is seeing a surge in young people who are aggressive and violent due to crystal meth.

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The strongest evidence comes from the study of the synthetic amphetaminelike drug MDMA, also called Ecstasy and, in pure powdered form, Molly (Büttner, 2011). Although MDMA is structurally related to amphetamine, it produces hallucinogenic effects and is called a hallucinogenic amphetamine. Findings from animal studies show that doses of MDMA approximating those taken by human users result in the degeneration of very fine serotonergic nerve terminals. In monkeys, significant terminal loss may be permanent. Memory impairments and damage in MDMA users revealed by brain imaging result from similar neuronal damage (Cowan et al., 2008). MDMA may also contain a contaminant called paramethoxymethamphetamine (PMMA). This notoriously toxic amphetamine is often called Dr. Death because the difference between a dose that causes behavioral effects and a dose that causes death is minuscule (Vevelstad et al., 2012). Contamination by unknown compounds can occur in any drug purchased on the street. Clinical Focus 7-3 explores the hypothesis that genetic vulnerability predisposes some adolescents to develop psychosis when exposed to cannabis.

The psychoactive properties of cocaine are similar to those of amphetamine, so cocaine also is suspect with respect to brain damage. Cocaine use is related to the blockage of cerebral blood flow and other changes in blood circulation. Brain-imaging studies show that brain regions are reduced in size in cocaine users, suggesting that cocaine use can be toxic to neurons (Liu et al., 2014).

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THC may trigger psychosis in vulnerable individuals, but there is no evidence that the psychosis is a result of brain damage. Indeed, beyond the therapeutic applications of THC cited in Section 6-2, recent studies suggest that THC may have neuroprotective properties. It can aid brain healing after traumatic brain injury and slow the progression of diseases associated with brain degeneration, including Alzheimer disease and Huntington disease (Nguyen et al., 2014).

6-4 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. The wanting-and-liking theory of addiction suggests that with repeated use, of the drug decreases as a result of , while increases as a result of . 2. At the neural level, the decision to take a drug is made in the brain’s . Once taken, the drug activates opioid systems related to pleasurable experiences in the . Drug cravings may originate in the , and the repeated pairing of drug-related cues and drug taking forms neural associations in the that loosen voluntary control over drug taking. 3. As an alternative to explanations of susceptibility to addiction based on genetic inheritance, can account both for the enduring behaviors that support

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addiction and for the tendency of drug addiction to be inherited. 4. It is difficult to determine whether recreational drug use causes brain damage in humans because it is difficult to distinguish the effects of from the effects of . 5. Briefly describe the basis for a reasonable approach to treating drug addiction.

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6-5 Hormones Many of the principles related to the interactions of drugs and the body also apply to the certain hormones that act on neuronal receptors. Hormones are secreted by glands in the body and by the brain. Interacting brain and body hormones form feedback loops that regulate their activity. Hormonal influences change across the life span, influencing development and body and brain function (Nugent et al., 2012). In many respects, hormone systems are like neurotransmitter-activating systems except that hormones use the bloodstream as a conveyance. Indeed, many hormones act as neurotransmitters, and many neurotransmitters act as hormones.

Hierarchical Control of Hormones Many hormones operate in a feedback system that includes the brain and the body. Figure 6-19 shows how the hypothalamus produces neurohormones that stimulate the pituitary gland to secrete releasing hormones into the circulatory system. The pituitary hormones in turn influence the remaining endocrine glands to release appropriate hormones into the bloodstream to act on various targets in the body and send feedback to the brain about the need for more or less hormone release.

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FIGURE 6-19 Hormonal Hierarchy

Hormones not only affect body organs but also target virtually all aspects of brain function. Almost every neuron in the brain contains receptors on which various hormones can act. In addition to influencing sex organs and physical appearance, hormones affect neurotransmitter function, especially in neurons that influence sexual development and behavior (Barth et al., 2015). Hormones can influence gene expression by binding to special receptors on or in the cell and then being transported to the nucleus to influence gene transcription. Transcription, in turn, influences the synthesis of

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proteins needed for a variety of cellular processes. Thus, hormones influence brain and body structure and behavior. Consult the entry Hormonal Disorders inside the book’s front cover for more information.

Although many questions remain about how hormones produce or contribute to complex behavior, the diversity of their functions clarifies why the body uses hormones as messengers: their targets are so widespread that the best possible way of reaching all of them is to travel in the bloodstream, which goes everywhere in the body.

Classes and Functions of Hormones Hormones can be used as drugs to treat or prevent disease. People take synthetic hormones as replacement therapy if the glands that produce the hormones are removed or malfunction. People also take hormones, especially sex hormones, to counteract the effects of aging, to increase physical strength and endurance, and to gain an advantage in sports. In the human body, as many as 100 hormones are classified chemically as either steroids or peptides. Steroid hormones, such as testosterone and cortisol, are synthesized from cholesterol and are lipid (fat) soluble. Steroids diffuse away from their site of synthesis in glands, including the gonads, adrenal cortex, and thyroid. They bind to steroid receptors on

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the cell membrane or in the cell and frequently act on cellular DNA to influence gene transcription. To refresh your understanding of metabotropic receptors, review Figure 5-15.

Peptide hormones, such as insulin, growth hormone, and the endorphins, are made by cellular DNA in the same way other proteins are made. They influence their target cell’s activity by binding to metabotropic receptors on the cell membrane, generating a second messenger that affects the cell’s physiology or gene transcription. Steroid and peptide hormones fall into one of three main functional groups with respect to behavior, and they may function in more than one group: 1. Homeostatic hormones maintain a state of internal metabolic balance and regulate physiological systems. Mineralocorticoids (e.g., aldosterone) control both the concentration of water in blood and cells and the levels of sodium, potassium, and calcium in the body, and they promote digestive functions. 2. Gonadal (sex) hormones control reproductive functions. They instruct the body to develop as male (testosterone) or female (estrogen); influence sexual behavior and conception; and, in women, control the menstrual cycle (estrogen and progesterone), birthing of babies, and release of breast milk (prolactin, oxytocin). These hormones, especially oxytocin, influence mother–infant bonding and, in some species, including sheep, are essential for bonding to occur. 712

3. Glucocorticoids (e.g., cortisol and corticosterone), a group of steroid hormones secreted in times of stress, are important in protein and carbohydrate metabolism, as well as in controlling blood sugar levels and cellular absorption of sugar. Hormones activated in psychologically challenging events or emergencies prepare the body to cope by fighting or fleeing.

Homeostatic Hormones Homeostasis comes from the Greek words stasis (“standing”) and homeo (“in the same place”). The homeostatic mechanisms that control regulated behavior are discussed in detail in Section 12-3.

Homeostatic hormones are essential to life. The body’s internal environment must remain within relatively constant parameters for us to function. An appropriate balance of sugars, proteins, carbohydrates, salts, and water is necessary in the blood, in the extracellular compartments of muscles, in the brain and other body structures, and in all cells. The internal environment must be maintained regardless of a person’s age, activities, or conscious state. As children or adults, at rest or in strenuous work, when we have overeaten or when we are hungry, to survive we need a relatively constant internal environment. Normal glucose concentration in the bloodstream varies between 80 and 130 mg per 100 milliliters (about 3.3 oz) of blood.

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A typical homeostatic function is controlling blood sugar level. After a meal, digestive processes result in increased glucose in the blood. One group of cells in the pancreas releases insulin, a homeostatic hormone that instructs the enzyme glycogen synthase in liver and muscle cells to start storing glucose in the form of glycogen. The resulting decrease in glucose decreases the stimulation of pancreatic cells so that they stop producing insulin, and glycogen storage stops. When the body needs glucose for energy, another hormone in the liver, glucagon, acts as a countersignal to insulin. Glucagon stimulates another enzyme, glycogen phosphorylase, to initiate glucose release from its glycogen storage site. Diabetes mellitus is caused by a failure of the pancreatic cells to secrete any or enough insulin. As a result, blood sugar levels can fall (hypoglycemia) or rise (hyperglycemia). In hyperglycemia, blood glucose levels rise because insulin does not instruct body cells to take up glucose. Consequently, cell function, including neuronal function, can fail through glucose starvation, even in the presence of high glucose levels in the blood. Chronic high blood glucose levels cause damage to the eyes, kidneys, nerves, heart, and blood vessels. In hypoglycemia, inappropriate diet can lead to low blood sugar severe enough to cause fainting. Eric Steen and his coworkers (2005) propose that insulin resistance in brain cells may be related to Alzheimer disease. Hunger and eating are influenced by a number of homeostatic hormones, including leptin and ghrelin. Leptin (from the Greek for “thin”), secreted by adipose (animal fat) tissue, inhibits hunger and so is called the satiety hormone. Ghrelin (from the IndioEuropean gher, meaning “to grow”), secreted by the gastrointestinal 714

tract, regulates growth hormones and energy use. Ghrelin also induces hunger. It is secreted when the stomach is empty; secretion stops when the stomach is full. Leptin and ghrelin act on receptors on the same neurons of the arcuate nucleus of the hypothalamus and so contribute to energy homeostasis by managing eating.

Anabolic–Androgenic Steroids A cl

The effects of sex hormones on the brain are detailed in Section 12-5.

as s of synthetic hormones related to testosterone, the sex hormone secreted by the testes and responsible for the distinguishing characteristics of the male, has both muscle-building (anabolic) and masculinizing (androgenic) effects. Anabolic–androgenic steroids, commonly known simply as anabolic steroids, were synthesized originally to build body mass and enhance endurance. Russian weight lifters were the first to use them, in 1952, to enhance performance and win international competitions. Synthetic steroid use rapidly spread to other countries and sports, eventually leading to a ban in track and field and then in many other sports, enforced by drug testing. Testing policy has led to a cat-andmouse game in which new anabolic steroids and new ways of taking them and masking them are devised. Today, the use of anabolic steroids is about equal among athletes and nonathletes. More than 1 million people in the United States have used anabolic steroids not only to enhance athletic performance but 715

also to enhance physique and appearance. Anabolic steroid use in high schools may be as high as 7 percent for males and 3 percent for females. The use of anabolic steroids carries health risks. Their administration results in the body reducing its manufacture of testosterone, which in turn reduces male fertility and spermatogenesis. Muscle bulk is increased, and so is aggression. Cardiovascular effects include increased risk of heart attack and stroke. Liver and kidney function may be compromised, and the risk of tumors may increase. Male-pattern baldness may be enhanced. Females may have an enlarged clitoris, acne, increased body hair, and a deepened voice. Anabolic steroids have approved clinical uses. Testosterone replacement is a treatment for hypogonadal males. It is also useful for treating muscle loss subsequent to trauma and for the recovery of muscle mass in malnourished people. In females, anabolic steroids are used to treat endometriosis and fibrocystic disease of the breast.

Glucocorticoids and Stress Stress is a term borrowed from engineering to describe a process in which an agent exerts a force on an object. Applied to humans and other animals, a stressor is a stimulus that challenges the body’s homeostasis and triggers arousal. Stress responses, behavioral as well as physiological, include both arousal and attempts to reduce stress. A stress response can outlast a stress-inducing incident and may even

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occur in the absence of an obvious stressor. Living with constant stress can be debilitating.

Activating a Stress Response Surprisingly, the body’s response is the same whether a stressor is exciting, sad, or frightening. Robert Sapolsky (2004) uses the vivid image of a hungry lion chasing down a zebra to illustrate the stress response. The chase elicits divergent behavior in the two animals, but their physiological responses are identical. The stress response begins when the body is subjected to a stressor and especially when the brain perceives a stressor and responds with arousal, directed from the brain by the hypothalamus. The response consists of two separate sequences, one fast and the other slow.

THE FAST RESPONSE Principle 4: The CNS functions on multiple levels.

Shown at left in Figure 6-20, the sympathetic

division of the ANS is activated to prepare the body and its organs for fight or flight. The parasympathetic division for rest and digest is turned off. The sympathetic division stimulates the medulla on the interior of the adrenal gland to release epinephrine. The epinephrine surge (often called the adrenaline surge, after epinephrine’s original name) prepares the body for a sudden burst of activity. Among its many functions, epinephrine stimulates cell metabolism, readying the body’s cells for action.

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FIGURE 6-20 Activating a Stress Response Two pathways to the adrenal gland control the body’s stress response. The fast-acting pathway primes the body immediately for fight or flight. The slow-acting pathway both mobilizes the body’s resources to confront a stressor and repairs stress-related damage. CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone.

THE SLOW RESPONSE As shown at right in Figure 6-20, the slow response is controlled by the steroid cortisol, a glucocorticoid released from the outer layer (cortex) of the adrenal gland. Activating the cortisol pathway takes anywhere from minutes to hours. Cortisol has wide-ranging functions, including turning off all bodily systems not immediately required to deal with a stressor. For example, cortisol turns off insulin so that the liver starts releasing glucose, thus temporarily increasing the body’s energy supply. It also shuts down reproductive functions and inhibits the production of growth hormone. In this way, it concentrates the body’s energy on dealing with the stress.

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Ending a Stress Response Normally, stress responses are brief. The body mobilizes its resources, deals with the challenge physiologically and behaviorally, and shuts down the stress response. Just as the brain is responsible for turning on the stress reaction, it is also responsible for turning it off. Consider what can happen if the stress response is not shut down: The body continues to mobilize energy at the cost of energy storage. Proteins are used up, resulting in muscle wasting and fatigue. Growth hormone is inhibited, so the body cannot grow. The gastrointestinal system remains shut down, reducing the intake and processing of nutrients to replace used resources. Reproductive functions are inhibited. The immune system is suppressed, contributing to the possibility of infection or disease. Sapolsky (2005) argues that the hippocampus plays an important role in turning off the stress response. The hippocampus contains a high density of cortisol receptors, and it has axons that project to the hypothalamus. Consequently, the hippocampus is well suited to detecting cortisol in the blood and instructing the hypothalamus to reduce blood cortisol levels. There may, however, be a more insidious relationship between the hippocampus and blood cortisol levels. Sapolsky observed wild-born vervet monkeys that had become agricultural pests in Kenya and had

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therefore been trapped and caged. He found that some monkeys sickened and died of a syndrome that appeared to be related to stress. Those that died seemed to have been socially subordinate animals housed with particularly aggressive dominant monkeys. Autopsies showed high rates of gastric ulcers, enlarged adrenal glands, and pronounced hippocampal degeneration. The hippocampal damage may have been due to prolonged high cortisol levels produced by the unremitting stress of being caged with the aggressive monkeys. Cortisol levels are usually regulated by the hippocampus, but if these levels remain elevated because a stress-inducing situation perpetuates, cortisol eventually damages the hippocampus, reducing its size. The damaged hippocampus is then unable to do its work of reducing the level of cortisol. Thus, a vicious circle is set up in which the hippocampus undergoes progressive degeneration and cortisol levels are not controlled (Figure 6-21). Interestingly, other research with rats suggests that following similar stress, the size of the amygdala is increased (Bourgin et al., 2015).

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FIGURE 6-21 Vicious Circle Unrelieved stress promotes excessive release of cortisol, which damages hippocampal neurons. The damaged neurons cannot detect cortisol and therefore cannot signal the adrenal gland to stop producing it. The resulting feedback loop enhances cortisol secretion, further damaging hippocampal neurons.

PTSD, introduced in Section 5-4 in relation to sensitization, is among the anxiety disorders detailed in Section 12-6. Research Focus 16-1 and Section 16-2 consider treatments.

Because stress response circuits in rats and monkeys are similar to those in humans, it is possible that excessive stress in humans can lead to similar brain changes. Because the hippocampus is thought to

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play a role in memory, stress-induced hippocampal damage is postulated to result in impaired memory. Because the amygdala is thought to play a role in emotion, stress-induced changes are postulated to result in increased emotional responses. This pattern of behavioral changes resembles posttraumatic stress disorder (PTSD). People with PTSD feel as if they are reliving the trauma, and the accompanying physiological arousal enhances their belief that danger is imminent. Research has not yet determined whether the cumulative effects of stress can damage the human hippocampus. For example, research on women who were sexually abused in childhood and were diagnosed with PTSD yields some reports of changes in memory or in hippocampal volume, as measured with brain-imaging techniques. Other studies report no differences in abused and nonabused subjects (Landré et al., 2010). The fact that such apparently similar studies can obtain different results can be explained in several ways. First, the amount of damage to the hippocampus that must occur to produce a stress syndrome is not certain. Second, brain-imaging techniques may not be sensitive to subtle changes in hippocampal cell function or to moderate cell loss. Third, wide individual and environmental differences influence how people respond to stress. Fourth, neonatal stress can influence hippocampal neurogenesis (Lajud & Torner, 2015). The long-term consequence is a smaller hippocampus and increased susceptibility to stress. Finally, humans are long lived and gather many life experiences that complicate simple extrapolations from a single stressful event. 722

Nevertheless, Patrick McGowan and his colleagues (2009) report that the density of glucocorticoid receptors in the hippocampus of people who committed suicide and had been sexually abused as children was lower than that of both controls and suicide victims who had not been abused. The decrease in receptors and in glucocorticoid mRNA suggests that childhood abuse induces epigenetic changes in the expression of glucocorticoid genes. The decrease in glucocorticoid receptors presumably renders the hippocampus less able to depress stress responses. The importance of the McGowan study is its suggestion of a mechanism through which stress can influence hippocampal function without necessarily being associated with a decrease in hippocampal volume. This study further underscores the point that stress likely produces many changes in many brain regions. It is unlikely that all these changes have been described or are understood (Clauss et al., 2015).

6-5 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. The hypothalamus produces , which stimulate the to secrete into the circulatory system. Hormone levels circulating in the bloodstream send feedback to the .

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2. Hormones are classified chemically as .

3. Broadly speaking, hormones regulate metabolic balance, hormones regulate reproduction, and regulate stress. 4. One class of synthetic hormones is increase and have

, which effects.

5. The stress response has a fast-acting pathway mediated by the release of and a slow-acting pathway mediated by the release of . 6. Describe the proposed relationship among stress, cortisol, and the hippocampus.

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Summary 6-1 Principles of Psychopharmacology Psychoactive drugs—substances that alter mood, thought, or behavior—produce their effects by acting on neuronal receptors or on chemical processes in the nervous system, especially on neurotransmission at synapses. Drugs act either as agonists to stimulate neuronal activity or as antagonists to depress it. Psychopharmacology is the study of drug effects on the brain and behavior. Drugs can be administered by mouth, by inhalation, by absorption through the skin, rectally by suppository, or by injection. To reach a nervous system target, a psychoactive drug must pass through numerous barriers posed by digestion and dilution, the blood–brain barrier, and cell membranes. Drugs are diluted by body fluids as they pass through successive barriers, are metabolized in the body, and are excreted through sweat glands and in feces, urine, breath, and breast milk. A common misperception about psychoactive drugs is that they act specifically and consistently, but experience and learning also affect individual responses to drugs. The body and brain may rapidly become tolerant of (habituated to) many drugs, so the dose must increase to produce a constant effect. Alternatively, people may become sensitized to a drug, in which case the same dose produces increasingly strong effects. These 725

forms of learning also contribute to a person’s behavior under a drug’s influence.

6-2 Psychoactive Drugs Psychoactive drugs can be organized according to the primary neurotransmitter system they interact with, but all drugs interact with multiple receptor systems. Each group, summarized in Table 6-1, contains recreational and medically prescribed drugs—all of which can be abused.

6-3 Factors Influencing Individual Responses to Drugs A drug does not have a uniform action on every person. Physical differences—in body weight, sex, age, and genetic background— influence a given drug’s effects on a given person, as do behaviors, such as learning, and cultural and environmental contexts. The influence of drugs on behavior varies widely with the situation and as a person learns drug-related behaviors. Behavioral myopia, for example, can influence a person to focus primarily on prominent environmental cues. These cues may encourage the person to act in uncharacteristic ways. Risk factors for addiction include emotional, physical, and sexual abuse; emotional and physical neglect; having a mentally ill household member; having witnessed violence against mother; substance abuse in the home; parental

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separation/divorce; and having an incarcerated household member. Women are more sensitive to drugs than men are and may become addicted more quickly and to lower doses of drugs. The incidence of abuse of many kinds of drugs by women equals or exceeds the abuse of those drugs by men.

6-4 Explaining and Treating Drug Abuse The neural mechanisms implicated in addiction are the same neural systems responsible for wanting and liking more generally. So anyone is likely to be a potential drug abuser. Addiction to drugs involves escalation, compulsive drug taking, and relapse. Initially, drug taking produces pleasure (liking), but with repeated use the behavior becomes conditioned to associated objects, events, and places. Eventually, the conditioned cues motivate the drug user to seek them out (wanting), which leads to more drug taking. These subjective experiences become associated with prominent cues, and drug seeking promotes craving for the drug. As addiction proceeds, the subjective experience of liking decreases, while wanting increases. Treatment for addiction varies with the drug. Whatever the treatment approach, success likely depends on permanent lifestyle changes. Considering how many people use tobacco, drink alcohol, use recreational drugs, or abuse prescription drugs, to find someone who has not used a drug when it was available is probably rare. But because of either genetic or epigenetic 727

influences, some people do seem particularly vulnerable to drug abuse and addiction. Excessive alcohol use can be associated with damage to the thalamus and hypothalamus, but the damage is caused by poor nutrition rather than the direct actions of alcohol. Cocaine can produce brain damage by reducing blood flow or by bleeding into neural tissue. MDMA (Ecstasy) use can result in the loss of fine axon collaterals of serotonergic neurons and associated impairments in cognitive function. Psychedelic drugs, such as methamphetamine and LSD, can be associated with psychotic behavior. Whether this behavior is due to the drugs’ direct effects or to the aggravation of preexisting conditions is not clear.

6-5 Hormones Steroid and peptide hormones produced by endocrine glands circulate in the bloodstream to affect a wide variety of targets. Interacting to regulate hormone levels is a hierarchy of sensory stimuli and cognitive activity in the brain that stimulates the pituitary gland through the hypothalamus. The pituitary stimulates or inhibits the endocrine glands, which send feedback to the brain via other hormones. Homeostatic hormones regulate the balance of sugars, proteins, carbohydrates, salts, and other substances in the body. Glucocorticoids are steroid hormones that regulate the body’s 728

ability to cope with stress—with arousing and challenging situations. The hippocampus plays an important role in ending the stress response. Failure to turn off stress responses after a stressor has passed can contribute to susceptibility to PTSD and other psychological and physical diseases. Stress may activate epigenetic changes that modify the expression of genes regulating hormonal responses to stress and may produce brain changes that persist long after the stress-provoking incident has passed. Synthetic anabolic steroids, used by athletes and nonatheletes alike, mimic the effects of testosterone and so increase muscle bulk, stamina, and aggression but can have deleterious side effects.

Key Terms addiction agonist amphetamine anabolic steroid antagonist attention-deficit/hyperactivity disorder (ADHD) behavioral myopia

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competitive inhibitor disinhibition theory dopamine hypothesis of schizophrenia fetal alcohol spectrum disorder (FASD) glucocorticoid gonadal (sex) hormone homeostatic hormone major depression monoamine oxidase (MAO) inhibitor peptide hormone psychoactive drug psychomotor activation psychopharmacology selective serotonin reuptake inhibitor (SSRI) steroid hormone substance abuse tolerance tricyclic wanting-and-liking theory withdrawal symptom zoopharmacognosy

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CHAPTER 7 How Do We Study the Brain’s Structures and Functions?

7-1 Measuring and Manipulating Brain and Behavior RESEARCH FOCUS 7-1 Tuning In to Language Early Origins of Behavioral Neuroscience RESEARCH FOCUS 7-2 Brainbow: Rainbow Neurons

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EXPERIMENT 7-1 Question: Do Hippocampal Neurons Contribute to Memory Formation? Methods of Behavioral Neuroscience Manipulating Brain–Behavior Interactions 7-2 Measuring the Brain’s Electrical Activity Recording Action Potentials from Single Cells EEG: Recording Graded Potentials from Thousands of Cells Mapping Brain Function with Event-Related Potentials CLINICAL FOCUS 7-3 Mild Head Injury and Depression Magnetoencephalography 7-3 Anatomical Imaging Techniques: CT and MRI 7-4 Functional Brain Imaging Functional Magnetic Resonance Imaging Optical Tomography Positron Emission Tomography 7-5 Chemical and Genetic Measures of Brain and Behavior Measuring Brain Chemistry

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Measuring Genes in Brain and Behavior Epigenetics: Measuring Gene Expression RESEARCH FOCUS 7-4 Attention-Deficit/Hyperactivity Disorder 7-6 Comparing Neuroscience Research Methods 7-7 Using Animals in Brain–Behavior Research Benefits of Animal Models of Disease Animal Welfare and Scientific Experimentation

RESEARCH FOCUS 7-1 Tuning In to Language The continuing search to understand the organization and operation of the human brain is driven largely by emerging technologies. Over the past decades, neuroscience researchers have developed dramatic new, noninvasive ways to image the brain’s activity in people who are awake. One technique, functional near-infrared spectroscopy (fNIRS), gathers light transmitted through cortical tissue to image oxygen consumption in the brain. NIRS, a form of optical tomography, is detailed in Section 7-4. fNIRS allows investigators to measure oxygen consumption as a surrogate marker of neuronal activity in relatively select cortical regions, even in newborn infants. In one study (May et al., 2011), newborns (0–3 days old) wore a mesh cap containing the NIRS apparatus, made up of optical fibers, as they listened to a familiar language as well as unfamiliar languages.

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Newborn with probes placed on the head.

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Probe configurations overlaid on schematics of an infant’s left and right hemispheres. Red dots indicate light-emitting fibers; blue dots indicate light detectors. The light detectors in the outer strips in both hemispheres sit over regions specialized for language in adults.

When newborns listened to a familiar language, their brain showed a general increase in oxygenated hemoglobin; when they heard an unfamiliar language, oxygenated hemoglobin decreased overall. But when the babies heard the same sentences played backward, there was no difference in brain response to either language. The opposing response to familiar and unfamiliar languages demonstrates how prenatal experience shapes the newborn brain’s response. This finding leads to many questions. Among them: How does prenatal exposure to language influence later language learning? Do children who are exposed to multiple languages prenatally show better language acquisition than those exposed to just one? How much and at what point in development is prenatal language exposure necessary? Do premature infants show the same results as full-term babies? Whatever the answers, this study shows that the prenatal brain is tuned in to the language environment into which it will be born.

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The simple, noninvasive nature of fNIRS, described in Research Focus 7-1, likely will yield new insights not only into brain development but also into adult brain function. Over the coming decades, our understanding of the brain–behavior relationship will continue to be driven in large part by new and better technologies, as well as by cleverly exploiting existing ones. Section 4-1 reviews how EEG enabled investigators to explain electrical activity in the nervous system.

If you lived prior to the twentieth century and were interested in studying how the brain works, you had two obvious choices of how to begin. You could study the behaviors of people who had sustained brain injury or had neurological impairment and then examine their brains after their deaths to determine which parts were responsible for the deficits. Alternatively, you could purposely create lesions in animals and examine how their behaviors changed. Indeed, this was how the relationship between brain and behavior was studied well into the twentieth century. Although neuroscience techniques used today are highly sophisticated compared to those of the past, the modern approaches share several commonalities with those historically used. Today, we still observe and quantify behavior and aspects of brain function in people with neurological conditions and in a wide variety of animal models. We also manipulate brain function by either increasing or decreasing activity in a highly specific and controlled fashion and then examining the effect of those changes in activity on behavior. The real difference between the historical approaches and those we use today is that we can

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manipulate and measure the brain with a larger array of tools, many of which are noninvasive and go right down to the molecular level. Advances in understanding molecular genetics and the analysis of behavior in the early 1950s set the stage for phenomenal advances in neuroscience knowledge. Scientists recognize that new technologies allow for novel insights, lead to more questions, and can dramatically advance their discipline. A large number of prizes, including Nobel Prizes, have been awarded for the development and implementation of new technologies. Today, brain–behavior analyses combine the efforts of anatomists and geneticists, psychologists and physiologists, chemists and physicists, endocrinologists and neurologists, pharmacologists and psychiatrists, computer scientists and programmers, engineers, and biologists. For aspiring brain researchers in the twenty-first century, the range of available research methods is breathtaking. We begin this chapter by reviewing how investigators measure behavior in both human and nonhuman subjects and how neuroscientists can manipulate behavior by perturbing the brain. We then consider electrical techniques, including EEG, for recording brain activity; noninvasive procedures, such as fNIRS, that image the brain; and chemical and genetic methods for both manipulating and measuring brain and behavior. After comparing these methods at the chapter’s end, we review some issues surrounding the use of nonhuman animals in research.

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7-1 Measuring and Manipulating Brain and Behavior Section 10-4 explores the anatomy of language and music and describes Broca’s contributions.

During a lecture at a meeting of the Anthropological Society of Paris in 1861, physician Ernest Auburtin argued that language functions are located in the brain’s frontal lobes. Five days later, a fellow physician, Paul Broca, observed a brain-injured patient who had lost his speech and was able to say only “tan” and utter a swear word. The patient soon died. Broca and Auburtin examined the man’s brain and found the focus of his injury in the left frontal lobe. By 1863, Broca had collected eight other similar cases and concluded that speech production is located in the third frontal convolution of the left frontal lobe—a region now called Broca’s area. Broca’s findings attracted others to study brain–behavior relationships in patients. The field that developed is what we now call neuropsychology, the study of the relationships between brain function and behavior with a particular emphasis on humans. Today, measuring brain and behavior increasingly includes noninvasive imaging, complex neuroanatomical measurement, and sophisticated behavioral analyses.

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Early Origins of Behavioral Neuroscience Compare Brodmann’s map of the cortex, based on staining, shown in Figure 2-26.

At the beginning of the twentieth century, the primary tools of neuroanatomy were histological: brains were sectioned postmortem, and the tissue (histo- in Greek) was stained with various dyes. As shown in Figure 7-1, there has been progression in microscopy toward greater resolution and specificity and a movement from visualizing dead tissue to living tissue. Scientists can stain sections of brain tissue to identify cell bodies in the brain viewed with a light microscope (shown in panel A), and they can selectively stain individual neurons to reveal their complete structure (panel B). An electron microscope (panel C) makes it possible to view synapses in detail. Multiphoton imaging (panel D) can generate a three-dimensional image of living tissue.

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FIGURE 7-1 Staining Cerebral Neurons Viewed through a light microscope, (A) a Nissl-stained section of the parietal cortex shows all cell bodies but no cell processes (axons and dendrites). (B) At higher magnification, an individual Golgi-stained pyramidal cell from the parietal cortex is visible. The cell body (dark triangular shape at center) and spiny dendrites (A and B) are visible in detail at right. (C) The view through an electron microscope shows neuronal synapses in detail. (D) Multiple

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images from a multiphoton microscope are merged to generate a three-dimensional image of living tissue.

By the dawn of the twentieth century, light microscopic techniques allowed researchers such as Korbinian Brodmann to divide the cerebral cortex into many distinct zones based on the characteristics of neurons in those zones. Investigators presumed that cortical zones had specific functions. Early in the twenty-first century, dozens of techniques had developed for labeling neurons and their connections, as well as glial cells (for one colorful example, see Research Focus 7-2, “Brainbow”). Today, super-resolution microscopy is also being used to identify the locations of different receptors on the membranes of cells. Contemporary techniques allow researchers to identify molecular, neurochemical, and morphological (structural) differences among neuronal types and ultimately to relate these characteristics to behavior. We have even miniaturized microscopes to the point where they can be mounted on the head of a mouse. These miniscopes can detect dozens to hundreds of neurons simultaneously by imaging a fluorescent signal activated by the neurons’ calcium levels, which indicate firing activity, while the mouse is navigating around an environment (Ghosh et al., 2011).

RESEARCH FOCUS 7-2

Brainbow: Rainbow Neurons Were it not for the discovery of stains that can highlight brain cell features, their complexity and connections would remain unknown. Jean Livet (2007) and his colleagues at Harvard University developed a transgenic technique that involves labeling different neurons by highlighting them with distinct

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colors—a technique called Brainbow, a play on the word rainbow. (Transgenic techniques are a form of genetic engineering discussed in Section 3-3.) To mimic the way an LCD or LED monitor produces the full range of colors that the human eye can see by mixing only red, green, and blue, the Brainbow scientists introduced genes that produce cyan (blue), green, and red fluorescent proteins into mice cells. The red gene is obtained from coral, and the blue and green genes are obtained from jellies. (The 2008 Nobel Prize in chemistry was awarded to Roger Tsien, Osamu Shimomura, and Martin Chalfie for their discovery and development of fluorescent proteins in coral and jellies.) The mice also received a bacterial gene called Cre, which activates the color genes inside each cell; due to chance factors, however, the extent to which each gene is activated varies. As the mice develop, the variable expression of the color-coding genes results in cells that fluoresce in at least 100 hues. When viewed through a fluorescent microscope sensitive to these wavelengths, individual brain cells and their connections can be visualized because they have slightly different hues, as illustrated in the accompanying micrographs.

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Cell Bodies

Axons

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Terminal Buttons

Because individual cells can be visualized, Brainbow offers a way to describe where each neuron sends its processes and how it interconnects with other neurons. You have probably seen an electrical power cord in which the different wires have different colors (black, white, red) that signify what they do and how they should be connected. By visualizing living brain tissue in a dish, Brainbow provides a method for examining changes in neural circuits with the passage of time. In the future, Brainbow will prove useful for examining populations of cells and their connections—such as which cells are implicated in specific brain diseases. In principle, Brainbow could be turned on at specific times, as an individual ages or solves problems, for example (Rojczyk-Gołȩbiewska et al., 2015). Yet despite Brainbow’s promise, challenges remain. Even the simplest brain contains extraordinary numbers of neurons and fibers. Modifications in Brainbow that restrict visualization to only a few cells and fibers at a time are necessary for their connections to be understood.

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These techniques for visualizing neurons play a key role in studying the connections between anatomy and behavior, as can be seen in studies of animals trained on various types of learning tasks, such as spatial mazes. Such learning can be correlated with a variety of neuroanatomical changes, such as modifications in the synaptic organization of cells in specific cortical regions—the visual cortex in animals trained in visually guided mazes is one example—or in the number of newly generated cells that survive in the dentate gyrus, a subregion of the hippocampus. Mammals require this structure for remembering the context in which they encounter information. Corticosterone, a steroid hormone secreted in times of stress, is important in protein and carbohydrate metabolism (see Section 6-5).

Experimental evidence reveals that preventing the growth of new dentate gyrus neurons leads to certain kinds of memory deficits. To test the idea that neurons of the dentate gyrus contribute to object memory formation within a context, researchers tested healthy rats and ADX rats —rats with adrenal glands removed, thus eliminating the hormone corticosterone. Without corticosterone, neurons in the dentate gyrus die. Procedure 1 in Experiment 7-1 contrasts the appearance of a healthy rat dentate gyrus (left) and neuronal degeneration in an ADX rat after surgery (right). The behavior of healthy and ADX rats was studied in the object–context mismatch task diagrammed in Procedure 2. During the training phase, the rats were placed in two distinct contexts, A and B, for 10 minutes on each of 2 days. Each context contained a different type of object. On the test day, the rats were placed in either context A

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or context B but with two different objects—one from that context and a second from the other context. EXPERIMENT 7-1

Question: Do hippocampal neurons contribute to memory formation? Procedure 1

Rat hippocampus before (left) and after (right) surgical removal of the adrenal glands. Note fewer neurons resulting from a lack of corticosterone.

Procedure 2

The behavior of healthy rats, ADX rats receiving no treatment, and ADX rats given treatments known to increase neuron generation in the dentate gyrus (enriched housing and exercise in running wheels) was studied in an object– context mismatch task in which two distinct contexts each contained a different type of object.

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Information from Spanswick & Sutherland, 2010, and Spanswick et al., 2011. Results

Healthy rats investigate the mismatch object more than the object that is in context, but the non-treated ADX rats performed at chance. The ADX rats given enriched housing and exercise in running wheels showed regeneration of dentate granule cells and performed like healthy rats. The photo at right shows a rat hippocampus. A specific stain was used to identify new neurons

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in the dentate gyrus, which appear yellow. Conclusion: Dentate gyrus neurons are necessary for contextual learning.

As noted in the Results section of Experiment 7-1, when healthy rats encounter objects in the correct context, they spend little time investigating because the objects are familiar. If, however, they encounter an object in the wrong context, they are curious and spend about three-quarters of their time investigating, essentially treating the mismatched object as new. But the ADX rats with fewer cells in the dentate gyrus treated the mismatched and in-context objects the same, spending about half of their investigation time with each object. Another group of ADX rats given treatment known to increase neuron generation in the dentate gyrus—enriched housing and exercise in running wheels—was unimpaired at the object–context mismatch task. Experiment 7-1 concludes that cellular changes in the dentate gyrus and behavioral changes are closely linked: neurons of the dentate gyrus are necessary for contextual learning.

Methods of Behavioral Neuroscience Behavioral neuroscience—the study of the biological bases of behavior—seeks to understand the brain–behavior relationships in humans and other animals. The object–context mismatch task described in Experiment 7-1 is one of hundreds of different behavioral tests used by neuroscientists in this area. In this section, we describe several neuropsychological tests for humans, as well as some spatial navigation

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and skilled reaching tasks, including one used with rodents that involves an automated touchscreen apparatus. A major challenge for behavioral neuroscientists is developing methods for studying both typical and atypical behavior. Measuring behavior in humans and laboratory animals differs in large part because humans speak: investigators can ask them about their symptoms or give them paper-and-pencil and computer-based tests to identify specific symptoms. Table 7-3 in Section 7-6 summarizes selected brain measurement techniques, their goals, and examples.

Measuring behavior in laboratory animals is more complex. Researchers must learn to speak “ratese” with rat subjects or “monkeyese” with monkeys. In short, researchers must develop ways to enable the animals to reveal their symptoms. The development of the fields of animal learning and ethology, the objective study of animal behavior, especially under natural conditions, provided the basis for modern behavioral neuroscience (see Whishaw & Kolb, 2005).

Neuropsychological Testing of Humans The brain has exquisite control of an amazing array of functions ranging from movement control and sensory perception to memory, emotion, and language. As a consequence, any analysis of behavior must be tailored to the particular function(s) under investigation. Consider the analysis of memory.

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People with damage to the temporal lobes often complain of memory disturbance. But memory is not a single function; rather, multiple, independent memory systems exist. We have memory for events, colors, names, places, and motor skills, among other categories, and each must be measured separately. It would be rare indeed for someone to be impaired in all forms of memory. Neuropsychological tests of three distinct forms of memory are illustrated in Figure 7-2. The Corsi block-tapping test shown in Figure 7-2A requires participants to observe an experimenter tap a sequence of blocks—blocks 4, 6, 1, 8, 3, for instance. The task is to repeat the sequence correctly. The participant does not see numbers on the blocks but rather must remember the locations of the tapped blocks.

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FIGURE 7-2 Neuropsychological Tests of Memory

The Corsi test provides a measure of short-term recall of spatial position, an ability we can call block span. The test can be made more difficult by determining the maximum block span of an individual participant (say, 6 blocks) and then adding one (span + 1). By definition, the participant will fail on the first presentation but, given the span + 1 repeatedly, will eventually learn it. In this book, we refer to healthy human volunteers in research studies as participants and to people that have a brain or behavioral impairment as patients or subjects.

Span + 1 identifies a different form of memory from block span. Different types of neurological dysfunction interfere differentially with tasks that superficially appear quite similar. Block span measures the short-term recall of information, whereas the span + 1 task reflects the learning and longer-term memory storage of information. The mirror-drawing task (Figure 7-2B) requires a person to trace a pathway, such as a star, by looking in a mirror. This motor task initially proves difficult because our movements appear backward in the mirror. With practice, participants learn how to accomplish the task accurately, and they show considerable recall of the skill when retested days later. Curiously, patients with certain types of memory problems have no recollection of learning the task on the previous day but nevertheless perform it flawlessly.

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Memory is covered in more detail in Sections 14-1 through 14-3, including a discussion of dissociated memory circuits in Section 14-2.

Clinical Focus 15-3 compares effects of injuries to particular brain regions on performance of particular neuropsychological tasks.

In the recency memory task (Figure 7-2C), participants are shown a long series of cards, each bearing two stimulus items that are words or pictures. On some trials, a question mark appears between the items. Their task is to indicate whether they have seen the items before and, if so, which item they saw most recently. They might be able to recall that they have seen items before but may be unable to recall which was most recent. Conversely, they might not be able to identify the items as being familiar, but when forced to choose the most recent one, they may be able to identify it correctly. The latter, counterintuitive result reflects the need for behavioral researchers to develop ingenious ways of identifying memory abilities. It is not enough simply to ask people to recall information verbally, although this too measures a form of memory.

Behavioral Analysis of Rodents Over the past century, researchers interested in the neural bases of sensation, cognition, memory, emotion, and movement have devised a vast array of mazes and other tests and tasks to determine the neural circuitry underlying specific behaviors in laboratory animals. Rats have very large behavioral repertoires, meaning that they display a long list of capabilities, some of which are categorized in Table 7-1, that can be

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independently examined to understand the functional underpinnings of those behaviors.

TABLE 7-1 Partial List of Rat Behaviors by Category Learning and memory Avoiding Burying Discrimination between sensory stimuli Preferring places Recognizing objects Spatial navigating Species-typical behaviors Aggression Caring of young Circadian activity Exploring and nose poking Food hoarding Food selection and foraging Grooming and nail trimming Nest building Orienting Playing Sexual behavior Social behavior Vocalizing Locomotion Climbing Jumping Rearing Swimming Turning Walking, trotting, and running Skilled movement

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Handling food Pulling string Walking on beams, posts, rotating rods, ladders Reflexes Placing and bracing Posture and support Righting Emotions Anxiety and fear Depression Responses to stress

Figure 7-3 illustrates three tests based on a navigation task devised by Richard Morris (1981). Rats are placed in a large swimming pool with high slippery walls that do not allow the rats to escape. A hidden platform lies just below the water surface. Rats are terrific swimmers, and they quickly navigate around the pool until they bump into the platform. They learn that when they climb onto the platform, they are removed from the pool and returned to their home cage—their preferred place.

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FIGURE 7-3 Swimming Pool Tasks General arrangement of the swimming pool used in three visuospatial learning tasks for rats. Red lines in parts A, B, and C mark the rat’s swimming path on each trial (T). (A) Information from Morris, 1981. (B) Information from Whishaw, 1989. (C) Information from Kolb & Walkey, 1987.

In one version of the task, place learning, the rat must find the platform from a number of different starting locations in the pool (Figure 7-3A). The only cues available are outside the pool, so the rat

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must learn the relationship between several cues in the room and the platform’s location. In a second version of the task, matching-to-place learning, the rat has already learned that a platform always lies somewhere in the pool, but the rat enters the pool from a different starting location every day. The rat is released and searches for the platform (Figure 7-3B). Once the rat finds the platform, the rat is removed from the pool and, after a brief delay (such as 10 seconds), is released again. The rat’s task is to swim directly to the platform. The challenge for the rat in the matchingto-place test is to develop a strategy for finding the platform consistently: it is always in the same location on each trial each day, but each new day brings a new location. In the landmark version of the task, the platform’s location is identified by a cue on the pool wall (Figure 7-3C). The platform moves on every trial, but the relationship to the cue is constant. In this task, the brain is learning that the distant cues outside the pool are irrelevant; only the local cue is relevant. Rats with different neurological perturbations are selectively impaired in the three versions of the swimming pool task. Another type of behavioral analysis in rats is related to movement. A major problem facing people with stroke is a deficit in controlling hand and limb movements. The prevalence of stroke has prompted considerable interest in devising ways to analyze such motor behaviors for the purpose of testing new therapies for facilitating recovery. In one test, rats are trained to reach through a slot to obtain a pellet of sweet food. The movements, which are remarkably similar to the movements people make in a similar task, can be broken down into segments. 758

Investigators can score the segments separately, as they are differentially affected by different types of neurological perturbation. The photo series in Figure 7-4 details how a rat orients its body to the slot (shown in panel A), puts its hand through the slot (panel B), rotates the hand horizontally to grasp the food (panel C), and rotates the hand vertically and withdraws it to obtain the food (panel D). Primates are not the only animals to make fine digit movements, but because the rat’s hand is small and moves so quickly, digit dexterity can be properly observed only during slow-motion video playback.

FIGURE 7-4 Skilled Reaching in Rats Movement series displayed by rats trained to reach through a narrow vertical slot to obtain a food pellet: (A) aim the hand, (B) reach over the food, (C) grasp the food, (D) withdraw and move food to the mouth.

Tim Bussey, Lisa Saksida, and their colleagues have developed an automated touchscreen platform for cognitive and motivational testing of rodents (Figure 7-5). This innovation removes the variation and stress that humans introduce when testing animals. Moreover, it is possible to program the platform to deliver tests that are highly similar to touchscreen tasks used in human cognitive testing (Oomen et al., 2013; Phillips et al., 2018).

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FIGURE 7-5 Automated Touchscreen Platform for Testing Rodents Mice or rats are placed in the apparatus and receive a strawberry milkshake reward when they choose the correct visual image by touching the screen.

Manipulating Brain–Behavior Interactions A predominant strategy for studying brain–behavior relationships is to manipulate some aspect of brain function and see how behavior changes. Investigators do so to develop hypotheses about how the brain affects behavior and to test those hypotheses. Table 7-2 in Section 7-6 summarizes selected brain manipulation techniques, their goals, and examples.

A second reason to manipulate the brain is to develop animal models of neurological and psychiatric disorders. The general presumption in neurology and psychiatry is that it ought to be possible to restore at least some healthy functioning by pharmacological, behavioral, or other

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interventions. A major hurdle for developing such treatments is that, like most other new medical treatments, they must be tested in nonhuman subjects first. (In Section 7-7, we take up scientific and ethical issues surrounding the use of animals in research.) Brains can be manipulated in various ways, the precise manner depending on the specific research question being asked. Researchers can manipulate the whole animal by exposing it to differing diets, social interactions, exercise, sensory stimulation, and a host of other experiences. For brain manipulation, the principal direct techniques are to inactivate the brain via lesions or with drugs or to activate it with electrical stimulation, drugs, or light. Behavioral neuroscientists make a manipulation and then measure brain function and behavioral performance. Because a large variety of manipulation techniques and measurement techniques are available to researchers, techniques from these two categories are mixed and matched.

Brain Lesions The first—and the simplest—technique used for brain manipulation is to ablate (remove or destroy) tissue. Beginning in the 1920s, Karl Lashley, a pioneer of neuroscience research, used ablation, and for the next 30 years, he tried to find the site of memory in the brain. He trained monkeys and rats on various mazes and motor tasks and then removed bits of cerebral cortex, with the goal of producing amnesia for specific memories. To his chagrin, Lashley failed in his quest. He observed instead that memory loss was related to the amount of tissue he removed. The 761

Both Lashley’s work and Scoville and Milner’s iconic patient, H. M., are discussed further in Section 14-2.

conclusion that Lashley reached was that memory is distributed throughout the brain and not located in any single place. Subsequent research strongly indicates that specific brain functions and associated memories are indeed localized to specific brain regions. Ironically, just as Lashley was retiring, William Scoville and Brenda Milner (1957) described a patient from whose brain Scoville had removed both hippocampi as a treatment for epilepsy. The surgery rendered this patient amnesic. During his ablation research, Lashley had never removed the hippocampi because he had no reason to believe the structures had any role in memory. And because the hippocampus is not accessible on the brain’s surface, other techniques had to be developed before subcortical lesions could be used. The solution to accessing subcortical regions is to use a stereotaxic apparatus, a device that permits a researcher or a neurosurgeon to target a specific part of the brain for destruction, as shown in Figure 76. The head is held in a fixed position, and because the location of brain structures is fixed in relationship to the junction of the skull bones, it is possible to visualize a three-dimensional brain map.

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FIGURE 7-6 Stereotaxic Apparatus This instrument allows the precise positioning of all brain regions relative to each other and to landmarks on the skull.

Rostral–caudal (front-to-back) measurements correspond to the y763

Review the brain’s anatomical locations and orientations in The Basics in Section 2-1.

axis in Figure 7-6. Dorsal–ventral (top-to-bottom) measurements, the zaxis, are made relative to the surface of the brain. Medial–lateral measurements, the x-axis, are made relative to the midline junction of the cranial bones. Atlases of the brains of humans and laboratory animals have been constructed from postmortem tissue so that the precise location of any structure can be specified in three-dimensional space. Consider Parkinsonian tremor, in which the hands can shake so severely that the afflicted person cannot hold a glass of water. The most widely used surgical treatment today is to drill a hole in the skull and, using stereotaxic coordinates obtained for that patient with an MRI (described in detail in Section 7-3), target the globus pallidus. An electrode is then lowered into the globus pallidus, and current is passed through it to destroy the structure and relieve the patient of the tremor. However, a new technique called high-intensity focused ultrasound (HIFU) can now achieve the same result without the invasive surgery (Quadri et al., 2018). Focused ultrasound uses many individual ultrasonic beams that are all pointed at the same spot in the brain. Each beam passes through tissue with little effect; at the convergent point where all the beams intersect, the energy heats the tissue. Lightly heating the tissue temporarily prevents that part of the brain from working properly, thereby informing the surgeons that their targeting is correct. The tissue heating can then continue until the target is permanently destroyed and the tremor is noninvasively eliminated.

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Principle 10: The nervous system works by juxtaposing excitation and inhibition.

The techniques described so far result in permanent brain damage. With time, the research subject will show compensation, the neuroplastic ability to modify behavior from that used prior to the damage. To avoid compensation following permanent lesions, researchers have also developed temporary and reversible lesion techniques such as regional cooling, which prevents synaptic transmission. A hollow metal coil is placed next to a neural structure; then chilled fluid is passed through the coil, cooling the brain structure to about 18ºC (Lomber & Payne, 1996). When the chilled fluid is removed from the coil, the brain structure quickly warms, and synaptic transmission is restored. Another technique involves local administration of a GABA agonist, which increases local inhibition and in turn prevents the brain structure from communicating with other structures. Degradation of the GABA agonist reverses the local inhibition and restores function.

Brain Stimulation Read more about Penfield’s dramatic discoveries in Sections 10-4 and 112.

The brain operates on both electrical and chemical energy, so it is possible to selectively turn brain regions on or off by using electrical or chemical stimulation. Wilder Penfield, in the mid-twentieth century,

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was the first to use electrical stimulation directly on the human cerebral cortex during neurosurgery. Later researchers used stereotaxic instruments to place an electrode or a cannula in specific brain locations. The objective: enhancing or blocking neuronal activity and observing the behavioral effects. Figure 12-12 diagrams hypothalamus anatomy. Chapter 12 details its role in motivated, regulatory, sexual, and emotional behavior.

Perhaps the most dramatic research example comes from stimulating specific regions of the hypothalamus. Rats with electrodes placed in the lateral hypothalamus will eat whenever the stimulation is turned on. If the animals have the opportunity to press a bar that briefly turns on the current, they quickly learn to press the bar to obtain the current, a behavior known as electrical self-stimulation. It appears that the stimulation is affecting a neural circuit that involves both eating and pleasure. Brain stimulation can also be used as a therapy. When the intact cortex adjacent to cortex injured by a stroke is stimulated electrically, for example, it leads to improvement in motor behaviors such as those illustrated in Figure 7-4. Cam Teskey and his colleagues (Brown et al., 2011) successfully restored motor deficits in a rat model of Parkinson disease by electrically stimulating a specific brain nucleus. View DBS in place in Figure 1-3.

Deep-brain stimulation (DBS) is a neurosurgical technique. Electrodes implanted in the brain

stimulate a targeted area with continuous pulses of low-voltage

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electrical current to facilitate behavior. DBS is used with subcortical structures; for example, DBS to the globus pallidus in the basal ganglia of Parkinson patients makes movements smoother, often allowing patients to dramatically reduce their intake of medications. DBS using several neural targets is an approved treatment for obsessivecompulsive disorder. Experimental trials are under way to identify the brain regions optimal for DBS to be used as a treatment for intractable psychiatric disorders such as major depression (Schlaepfer et al., 2013), schizophrenia, and possibly for epilepsy; DBS may also be used as a treatment for stimulating recovery from traumatic brain injury (TBI). Electrical stimulation of the brain is invasive: holes must be drilled in the skull and an electrode lowered into the brain. Researchers have taken advantage of the relationship between magnetism and electricity to develop a noninvasive technique called transcranial magnetic stimulation (TMS). During a treatment session, a small wire coil is placed adjacent to the skull, as illustrated in Figure 7-7A. A highvoltage current pulsed through the coil produces a rapid increase and subsequent decrease in the magnetic field around the coil. The magnetic field easily passes through the skull and causes a population of neurons in the cerebral cortex to depolarize and fire (Figure 7-7B).

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FIGURE 7-7 Transcranial Magnetic Stimulation (A) In clinical therapy for depression, TMS influences neural activity in a localized region. (B) Composite photo shows how TMS works.

Research Focus 16-5 describes use of rTMS to treat depression and other behavioral disorders.

If the motor cortex is stimulated, movement is evoked; or if a movement is in progress, it is disrupted. Similarly, if the visual cortex is stimulated, the participant sees dots of light (phosphenes). The effects of brief pulses of TMS do not outlive the stimulation, but repetitive TMS (rTMS), or continuous stimulation for up to several minutes, produces more long-lasting effects, including changing function or temporarily inactivating tissue. TMS and rTMS can be used to study brain–behavior relationships in healthy participants, and rTMS has been tested as a potential treatment for a variety of behavioral disorders. A growing body of research also supports its antidepressant actions.

Drug Manipulations Brain activity can also be stimulated by administration of drugs that pass either into the bloodstream and eventually enter the brain or through an indwelling cannula (illustrated in Figure 7-21) that allows direct application of the drugs to specific brain structures. Drugs can influence the activity of specific neurons in specific brain regions. For example, the drug haloperidol, used to treat schizophrenia, reduces dopaminergic neuron function and makes healthy rats dopey and inactive (hypokinetic).

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In contrast, drugs that increase dopaminergic activity, such as amphetamine, produce hyperkinetic rats—rats that are hyperactive. The advantage of administering drugs is that their effects wear off in time as the drugs are metabolized. It thus is possible to study drug effects on learned behaviors, such as skilled reaching (see Figure 7-4) and then to re-examine the behavior after the drug effect wears off. Chapter 6 discusses the influence of drugs on behavior, and Section 6-2 specifically details the effects of the drugs described here, among others.

Claudia Gonzalez and her colleagues (2006) administered nicotine to rats as they learned a skilled reaching task, then studied their later acquisition of a new skilled reaching task. The researchers found that the earlier nicotine-enhanced motor learning impaired the later motor learning. This finding surprised the investigators, but it now appears that repeated exposure to psychomotor stimulants such as amphetamine, cocaine, and nicotine can produce long-term effects on the brain’s later plasticity (its ability to change in response to experience), including learning specific tasks.

Genetic Manipulations and Combinations with Light and Drugs In the past two decades, synthetic biology—the design and construction of biological devices, systems, and machines not found in nature—has transformed how neuroscientists manipulate brain cells. Techniques include inserting or deleting a genetic sequence into the genome of a living organism.

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A new technique called CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats), one of many CRISPR techniques, was discovered in bacteria for fighting viruses; it serves as an all-purpose tool for cutting the DNA of any cell. Scientists simply provide the bacteria’s Cas9 protein with the RNA sequence corresponding to the length of DNA they would like to remove from the subject. In this way, the CRISPR system can be used to silence one or many genes by cutting out those regions in the DNA. Then the DNA’s repair machinery can be harnessed to insert a new sequence that replaces the one that was removed. It is difficult to overestimate the potential impact of CRISPR. As an experimental tool, it can help answer the question: What is the role of this gene or these genes in this behavior? As a therapeutic intervention, it could eventually lead to the elimination of many forms of inherited disease. It could also counter antibiotic-resistant microbes, disable parasites, and improve food security. Section 3-3 explores some techniques in genetic and transgenic engineering.

Another transgenic technique, optogenetics, combines genetics and light to control targeted cells in living tissue. A sequence that codes for a light-sensitive protein associated with an ion channel enables investigators to use light to change the shape (conformation) of the channel. Optogenetics is based on the discovery that light can activate certain proteins that occur naturally and have been inserted into cells of model

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organisms. For example, opsins, proteins derived from microorganisms, combine a light-sensitive domain with an ion channel, as shown in Figure 7-8. The first opsin used for the optogenetic technique was channelrhodopsin-2 (ChR2). When ChR2 is expressed in neurons and exposed to blue light, the ion channel opens and immediately depolarizes the neuron, causing excitation. In contrast, stimulation of halorhodopsin (NpHR) with a green-yellow light activates a chloride pump, hyperpolarizing the neuron and causing inhibition. A fiber-optic light can be delivered to selective brain regions such that all genetically modified neurons exposed to the light respond immediately (Haubensak et al., 2010).

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FIGURE 7-8 Lighting Up Neurons Optogenetics allows precise temporal control of cell firing and is rapidly reversible. Specific wavelengths activate light-sensitive proteins expressed in neurons. At bottom left, when blue light illuminates a cell in which ChR2 has been incorporated, its firing rate increases dramatically. At right, when green-yellow light illuminates a cell in which NpHR is incorporated, its firing rate decreases dramatically.

Figure 2-21 diagrams the relative location of the amygdala.

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Optogenet ics has

tremendous potential as a research tool. Investigators can insert lightsensitive proteins into specific neuron types, such as pyramidal cells of the CA1 region of the hippocampus, and use light to selectively activate just that cell type. Researchers hail optogenetics for its high spatial and temporal (time) resolution. Ion channels can be placed into specific cell lines and turned on and off on millisecond time scales. Optogenetics also finds application in behavioral studies. For example, the amygdala is a key structure in generating fear in animals; if it is targeted with opsins and then exposed to an inhibitory light, rats immediately show no fear and wander about in a novel open space. As soon as the light is turned off, they scamper back to a safe hiding place. In the transgenic technique called chemogenetics, the inserted synthetic genetic sequence codes for a G protein–coupled receptor engineered to respond exclusively to a synthetic small-molecule “designer drug.” Chemogenetics is best known by the acronym DREADD (designer receptor exclusively activated by designer drugs). Its principal advantage is that the drug activates only the genetically modified receptors, and the receptors are activated only by the designer drug, not by endogenous molecules (Wess et al., 2013). Thus, specificity is high, but temporal resolution is much lower than with optogenetics because receptors are activated by drugs rather than by light.

7-1 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests.

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1. Behavioral neuroscience is the study of relationships between and . 2. Anatomical studies rely on techniques such as tissue postmortem or visualizing living tissue using . 3. A new innovation in behavioral testing in rodents uses automated , which removes the variation and stress that humans introduce when testing animals. 4. Outline the various brain-stimulation methods that either activate or inhibit neural activity.

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7-2 Measuring the Brain’s Electrical Activity The brain is always electrically active, even when we sleep. Electrical measures of brain activity are important for studying brain function, for medical diagnosis, and for monitoring the effectiveness of therapies used to treat brain disorders. The four major techniques for tracking the brain’s electrical activity are single-cell recording, electroencephalography (EEG), event-related potentials (ERPs), and magnetoencephalography (MEG). Figure 4-10 diagrams a cell membrane at rest, Figure 4-13 during graded potentials, and Figure 4-15 generating the action potential.

In part, these techniques are used to record electrical activity from different parts of neurons. The electrical behavior of cell bodies and dendrites, which give rise to graded potentials, tends to be much more varied and slower than the behavior of axons, which conduct action potentials.

Recording Action Potentials from Single Cells By the early

Figure 4-6 illustrates the structure and use of microelectrodes.

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1950s, it was becoming possible to record the activity of individual cells by measuring a single neuron’s action potentials with fine electrodes inserted into the brain. These microelectrodes can be placed next to cells (extracellular recording) or inside cells (intracellular recording). Modern extracellular recording techniques make it possible to distinguish the activity of as many as 40 neurons at once. Intracellular recording allows direct study and recording of a single neuron’s electrical activity. The two disadvantages of inserting an electrode into a cell are that (1) it can kill the cell, and (2) it cannot be done in awake, freely moving animals. Single-cell recording is therefore confined to neurons grown in a dish or, for short periods (hours), to neurons in living brain slices. See, for example, “Seeing Shape” and “Seeing Color” in Section 9-4 and “Processing Language” in Section 10-4.

We now know from extracellular recordings that cells in the brain’s various sensory regions are highly sensitive to specific stimuli. Some cells in the visual system fire vigorously to specific wavelengths of light (a color) or to specific orientations of bars of light (vertical, for example). Other cells in this region respond to more complex patterns, such as faces or hands. Similarly, cells in the auditory system respond to specific sound frequencies (a low or high pitch) or to more complex sound combinations, such as speech (the syllable ba, for example). But certain

Section 13-4 discusses how place cells help store memories.

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cells respond to inputs that are rich in information—a fact that reveals much about brain–behavior relationships. John O’Keefe and his colleagues (O’Keefe & Dostrovsky, 1971) showed that neurons in the rat and mouse hippocampus vigorously fire when an animal is in a specific place in the environment. These place cells, illustrated in Figure 7-9, code the spatial location of the animal and contribute to a spatial map of the world in the brain. The 2014 Nobel Prize in Physiology or Medicine was awarded to John O’Keefe, May-Britt Moser, and Edvard I. Moser “for their discoveries of cells that constitute a positioning system in the brain.”

FIGURE 7-9 Classes of Spatially Related Cells in the Hippocampal Formation (A and B) Place cells discharge when a rat is at a spatial location, regardless of its orientation. (C) Head-direction cells discharge to indicate where the rat’s head points, regardless of its location. (D) Grid cells discharge at many locations, forming a virtual grid that is invariant in the face of changes in the rat’s direction, movement, or speed. At right in each part, xy coordinates indicate the directional selectivity of the cell recorded at left.

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O’Keefe’s group (Cacucci et al., 2008) also demonstrated that, in mice with a genetically engineered mutation that produces deficits in spatial memory, place cells lack specificity: the cells fire to a very broad region of their world. As a result, these mice have difficulty finding their way around, much as human patients with dementia tend to get lost. One reason may be that a change similar to the engineered mutation in mice takes place in human brain cells.

EEG: Recording Graded Potentials from Thousands of Cells In the early 1930s, Hans Berger discovered that the brain’s electrical activity could be recorded simply by placing electrodes on the scalp. In Berger’s words, recording these “brain waves” produces an “electrical record from the head”—an electroencephalogram. The EEG measures the summed graded potentials from many thousands of neurons. EEG waves, shown in Figure 7-10, are recorded by a computer. In electrocorticography (ECoG), a method used during neurosurgery, electrodes are placed directly on the cerebral cortex.

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FIGURE 7-10 Recording EEG Waves EEG is a simple, noninvasive method for recording the brain’s electrical activity. EEG waves recorded via computer (see Figure 4-5) can match wave activity to specific brain regions.

EEGs reveal some remarkable features of the brain’s electrical activity. The EEG recordings in Figure 7-11 illustrate three of them: 1. EEG changes as behavior changes. 2. An EEG recorded from the cortex displays an array of patterns, some rhythmical. 3. The living brain’s electrical activity is never silent, even when a person is asleep or comatose.

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FIGURE 7-11 Characteristic EEG Recordings Brain-wave patterns reflect different states of consciousness in humans. Data from Penfield & Jasper, 1954.

Amplitude is a recorded brain wave’s height. Frequency is the number of brain waves recorded per second.

When a person is aroused, excited, or even just alert, the EEG pattern has a low amplitude and a fast frequency, as shown in Figure 7-11A. This pattern is typical of an EEG taken from anywhere on the skull of an alert subject—not only humans but other animals, too. In contrast, when a participant is calm and quietly relaxed, especially with eyes closed, the rhythmical brain waves shown in Figure 7-11B often emerge. These alpha rhythms are extremely regular, with a frequency of approximately 11 cycles per second and amplitudes that wax and wane as the pattern is recorded. In humans, alpha rhythms are generated in the region of the visual cortex at the back of the brain. If a relaxed person is disturbed, performs mental arithmetic, or opens his or her eyes, the alpha rhythms abruptly stop.

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Section 13-3 describes how EEG measures sleep and dreaming. Clinical Focus 4-1 details epilepsy diagnoses, and Section 16-3 explores treatments.

EEG is a sensitive indicator of behaviors beyond simple arousal and relaxation. Parts C, D, and E of Figure 7-11 illustrate EEG changes as a person moves from drowsiness to sleep and finally into deep sleep. EEG rhythms become progressively slower and larger in amplitude. Still slower waves appear during anesthesia, after brain trauma, or when a person is in a coma (shown in Figure 7-11F). Only in brain death does the EEG permanently become a flat line. These distinctive brain-wave patterns make EEG a reliable tool for monitoring sleep stages, estimating the depth of anesthesia, evaluating the severity of head injury, and searching for brain abnormalities. In epilepsy, for example, brief periods of impaired awareness or unresponsiveness and involuntary movements associated with spiking patterns in the EEG characterize electrographic seizures. EEG is an essential tool in the diagnosis of epilepsy and in determining the kind of epilepsy and seizures a person has. The important point here is that EEG recording provides a useful tool both for research and for diagnosing brain dysfunction. EEG can also be used in combination with the brain-imaging techniques described in Sections 7-3 and 7-4 to provide more accurate identification of the source of the large and highly synchronized EEG waves in epilepsy.

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Mapping Brain Function with Event-Related Potentials Brief changes in an EEG signal in response to a discrete sensory stimulus produce complex electroencephalographic waveforms called event-related potentials (ERPs). ERPs are largely the graded potentials on dendrites that a sensory stimulus triggers. You might think that they should be easy to detect, but they are not. ERPs are mixed in with so many other electrical signals in the brain that they are difficult to spot just by visually inspecting an EEG record. One way to detect ERPs is to produce the stimulus repeatedly and average the recorded responses. Averaging tends to cancel out any irregular and unrelated electrical activity, leaving in the EEG record only the potentials the stimulus generated. To clarify this procedure, imagine throwing a small stone into a lake of choppy water. Although the stone produces a splash, the splash is hard to see among all the ripples and waves. Like a splash surrounded by choppy water, an ERP caused by a sensory stimulus is hard to discern from all the other electrical activity around it. A solution is to throw a number of stones exactly the same size, always hitting the same spot in the water and producing the same splash over and over. If a computer then calculates an average of the water’s activity, random wave movements will tend to average one another out, and an observer will see the splashes produced by the stones as clearly as a single stone thrown into a pool of calm water.

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Figure 7-12 shows an ERP record (top) that results when a person hears a tone. The EEG record is highly irregular when the tone is first presented. But by averaging more than 100 stimulus presentations, a distinctive wave pattern appears, as shown in the bottom panel of Figure 7-12. This ERP pattern consists of a number of negative (N) and positive (P) waves that occur within a few hundred milliseconds after the stimulus.

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FIGURE 7-12 Detecting ERPs In the averaging process for an auditory ERP, a tone is presented at time 0, and EEG activity in response is recorded. After many successive presentations of the tone, the EEG wave sequence develops a distinctive shape that becomes extremely clear after 100 responses are averaged (bottom panel). Positive and negative waves that appear at different times after the stimulus presentation are used for analysis.

The waves are numbered in time sequence. For instance, in Figure 7-12, N1 is a negative wave occurring about 100 milliseconds after the stimulus, whereas P2 is a positive wave occurring about 200 milliseconds after the stimulus. (The waves may also be labeled N100 and P200.) Not all these waves are unique to this particular stimulus. Some are common to any auditory stimulus. Other waves, however, correspond to important differences in specific tone. ERPs to spoken words even contain distinctive peaks and patterns that differentiate such similar-sounding words as cat and rat. Among the many practical reasons for using ERPs to study the brain is the advantage that this EEG technique is noninvasive. Electrodes are placed on the scalp, not in the brain. Therefore, ERPs can be used to study humans, including those most frequently used participants: college students. Another advantage is cost. Compared to other techniques, such as brain imaging, EEG and ERP are inexpensive and can be recorded from many brain areas simultaneously by pasting an array of electrodes (sometimes more than 200) onto different parts of the scalp. Because certain brain areas respond only to certain sensory stimuli (for example, auditory areas respond to sounds and visual

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areas to sights), relative responses at different locations can be used to map brain function. Figure 7-13 shows a multiple-recording method that uses 128 electrodes simultaneously to detect ERPs at many cortical sites. Computed averaging techniques reduce the masses of information obtained to simpler comparisons between electrode sites. For example, if the focus of interest is P3, a positive wave occurring about 300 milliseconds after the stimulus, the computer can display a graph of the skull showing only the amplitude of P3. A computer can also convert the averages at different sites into a color code, graphically representing the brain regions most responsive to the signal. ERPs can not only detect which brain areas are processing particular stimuli but can also be used to study the order in which different regions participate. This second use of ERPs is important because we want to know the route that information takes as it travels through the brain. In Figure 7-13, the participant is viewing a picture of a rat that appears repeatedly in the same place on a computer screen. The P3 recorded from the posterior right side of the head is larger than any other P3 occurring elsewhere, meaning that this region is a hot spot for processing the visual stimulus. Presumably, this particular participant’s right posterior brain is central in decoding the picture of the rat 300 milliseconds after it is presented. Many other interesting research areas benefit from using ERPs, as described in Clinical Focus 7-3, “Mild Head Injury and Depression.” ERPs can also be used to study how children learn and process information differently as they mature, as well as how a person with a 786

brain injury compensates for the impairment by using undamaged brain regions. ERPs can even help reveal which brain areas are most sensitive to aging and are therefore most closely related to declining behavioral functions among the elderly. This simple, inexpensive research tool can address all these areas.

CLINICAL FOCUS 7-3

Mild Head Injury and Depression When a pallet of boxed tools tipped and part of the load struck his head, B. D., an industrial tool salesman, did not lose consciousness, but he did sustain a serious cut to his scalp and damage to two spinal vertebrae. The attending physician at the hospital emergency room suspected mild concussion but ordered no further neurological workup at the time. B. D.’s spinal symptoms gradually cleared, but irritability, anxiety, and depression persisted even 2 years later. B. D. was unable to work, and his behavioral changes placed a major strain on his family. His emotional problems led him to withdraw from the world, only worsening his predicament. While a neuropsychological exam administered to B. D. about 2 years after the injury found his general cognitive ability to be well above average (with an IQ score of 115), he did display significant attentional and shortterm memory deficits. A subsequent magnetic resonance image of his brain failed to find any injury that could explain his symptoms. In fact, B. D.’s serious emotional symptoms are common following mild head injury, even when no other neurological or radiological signs of brain injury present themselves. One tool for investigating brain functioning in such cases is ERP. Reza and colleagues (2007) compared healthy controls to groups of subjects

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with mild head injuries, with and without depression. The investigators found that all subjects with head injury displayed a delayed P3 wave, but only those who were depressed as well also had a delayed N2 wave. These findings demonstrate that ERP can identify cerebral processing abnormalities in people with depression after mild head injury, even when MRI scans are negative. Such evidence can be critical for people like B. D., who are seeking long-term disability support following what appears to be a mild head injury.

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FIGURE 7-13 Using ERPs to Image Brain Activity

Magnetoencephalography Passing a magnetic field across a wire induces an electrical current in the wire. Conversely, current flowing along a wire induces a magnetic field around the wire. The same is true in the brain. Neural activity, by generating an electrical field, also produces a magnetic field. Although the magnetic field produced by a single neuron is vanishingly small, the field produced by many neurons is sufficiently strong to be recorded on the scalp. The record of this phenomenon, a magnetoencephalogram (MEG), is the magnetic counterpart of the EEG or ERP. Calculations based on MEG measurements not only describe the electrical activity of neuronal groups but also localize the cell groups generating the measured field in three dimensions. Magnetic waves conducted through living tissue undergo less distortion than electrical signals do, so an MEG can yield a higher resolution than an ERP. A major advantage of MEG over EEG and ERP, then, is the ability of MEG to more precisely identify the source of the activity being recorded. For example, MEG has proved useful in locating the source of epileptic discharges. The disadvantage of MEG is its high cost in comparison with the apparatus used to produce EEGs and ERPs.

7-2 Review

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Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. The four major techniques for tracking the brain’s electrical activity are , , , and . 2. Single-cell recording measures single neuron. 3. EEG measures

potentials from a

potentials on the cell membrane.

4. Magnetoencephalography measures the provides a(n) .

and also

5. What is the advantage of EEG techniques over MEG?

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7-3 Anatomical Imaging Techniques: CT and MRI Until the early 1970s, the only way to actually image the living brain was by using X-rays that produce static images of brain anatomy from one angle. The modern era of brain imaging began in the early 1970s, when Allan Cormack and Godfrey Hounsfield independently developed an X-ray approach now called computed tomography (CT): the CT scan. Cormack and Hounsfield both recognized that a narrow X-ray beam could be passed through the same object at many angles, creating many images; the images could then be combined with the use of computing and mathematical techniques to produce a three-dimensional image of the brain. Tomo- comes from the Greek word for “section,” indicating that tomography yields a picture through a single brain slice. The CT method resembles the way in which our two eyes (and our brain) work in concert to perceive depth and distance to locate an object in space. The CT scan, however, coordinates many more than two images—roughly analogous to our walking to several vantage points to obtain multiple views. X-ray absorption varies with tissue density. High-density tissue, such as bone, absorbs a lot of radiation. Low-density material, such as ventricular fluid or blood, absorbs little. Neural tissue absorption lies between these extremes. CT scanning software translates these differences in absorption into a

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brain image in which dark colors indicate low-density regions and light colors indicate high-density regions. Figure 7-14A shows a typical CT scan. The dense skull forms a white border. The brain’s gray-matter density does not differ sufficiently from that of white matter for a CT scan to distinguish between the two clearly, so the cortex and its underlying white matter show up as a more or less homogeneous gray. Ventricles can be visualized, however, because the fluid in them is far less dense: they, as well as some major fissures in the cortex, are rendered darker in the CT scan. Each point on the image in Figure 7-14A represents about a 1-millimeter-diameter circle of tissue, a resolution sufficient to distinguish two objects about 5 millimeters apart and appropriate for localizing brain tumors and lesions.

FIGURE 7-14 CT Scan and Brain Reconstruction (A) Dorsal view of a horizontal CT scan of a subject with Broca’s aphasia. The dark region at the left anterior is the area of the lesion. (B) A schematic representation of the horizontal section, with the area of the lesion shown in blue. (C) A reconstruction of the brain, showing a lateral view of the left hemisphere with the lesion shown in blue. Research from Damasio & Damasio, 1989.

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Section 10-4 delves into aphasias that result from damaged speech areas.

The lesion revealed in Figure 7-14A is a damaged region where the presence of fewer neurons and more fluid produces a contrast that appears as a dark area in the CT scan. This subject presented with symptoms of Broca aphasia, the inability to speak fluently despite having average comprehension and intact vocal mechanisms. The location of the lesion, in the left frontal cortex (adjacent to the butterfly-shaped lateral ventricles), confirms this diagnosis. Figure 714B, a drawing of the same horizontal section, uses color to portray the lesion. Figure 7-14C is a lateral view of the left hemisphere reconstructed from a series of horizontal CT scans and showing the extent of the lesion. An anatomical alternative to the CT scan, magnetic resonance imaging (MRI), is based on the principle that hydrogen atoms behave like spinning bar magnets in the presence of a magnetic field. The MRI procedure is illustrated in Figure 7-15. The dorsal view of the brain portrays density differences among the hydrogen atoms in different neural regions as lighter or darker, depending on density, on the horizontal slice through the head.

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FIGURE 7-15 Magnetic Resonance Imaging (A and B) The subject is placed in a long metal cylinder that has two sets of magnetic coils arranged at right angles. An additional radiofrequency coil (not shown) surrounds the head, perturbing the static magnetic fields to produce an MRI image of a horizontal section through the head, shown in dorsal view. Electrical currents emitted by wobbling atoms are recorded by MRI to represent different types of tissue—cerebrospinal fluid, brain matter, and bone, for example—as lighter or darker, depending on the density of hydrogen atoms in the tissue, as seen in (C) on the left.

Normally, hydrogen atoms point randomly in different directions, but when placed in a large, static magnetic field, they line up in parallel as they orient themselves with respect to the static field’s

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lines of force. In an MRI scanner, radio pulses are applied to a brain whose atoms have been aligned in this manner, and each radio pulse forms a second magnetic field. The second field causes the spinning atoms to deviate from the parallel orientation caused by the static magnetic field to a new orientation. As each radio pulse ends and the hydrogen atoms realign with the static field, they emit a tiny amount of energy, and a coil detects this realignment. Based on the signals from the coil, a computer re-creates the position of the hydrogen nuclei, producing a magnetic resonance image. Magnetic resonance images may be based on the density of the hydrogen atoms in different brain regions. Areas with high water (H2O) content (cell body–rich areas), for example, stand out from areas with lower water content (axon-rich areas). Figure 7-15c shows such a magnetic resonance image. Clinical Focus 4-2 describes how myelin loss in MS disrupts neuronal function.

Diffusion tensor imaging (DTI) is an MRI method that detects the directional movements of water molecules to image nerve fiber pathways in the brain. Water can move relatively freely along the axon but less freely across cell membranes. The direction of this water movement is detected by a coil and interpreted by a computer. DTIs can delineate abnormalities in neural pathways. They are also used to identify changes in fiber myelination, such as the damage that leads to myelin loss in multiple sclerosis.

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Clinical Focus 16-3 explores the relationship between concussion and degenerative brain disease.

Each scan in the series of DTIs shown in Figure 7-16 represents a dorsal view at increasing depths through the brain. Although the images appear to show real fibers, DTIs are virtual and based on computer reconstructions of water movement along axons, which should correspond to actual fibers. Nonetheless, DTI easily detects abnormalities such as those that occur in multiple sclerosis, stroke, or concussion, in the imaged fiber pathways and in their myelin sheaths.

FIGURE 7-16 Diffusion Tensor Imaging MRI can measure the diffusion of water molecules in white matter, allowing the visualization of nerve fiber tracts. The front of the brain is at the top in these scans of sections through a healthy brain. The axons are colored according to orientation: fibers running left–right are

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red, front–back are blue, and up–down are green. Section 15-3 outlines how DTI is helping researchers develop a brain connectome to map functional connections in the living brain.

Magnetic resonance spectroscopy (MRS) is an MRI method that uses the hydrogen proton signal to determine the concentration of brain metabolites such as N-acetylaspartate (NAA) in brain tissue. This measurement is especially useful for detecting persisting abnormalities in brain metabolism in disorders such as concussion.

7-3 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. The principal anatomical brain-imaging methods are and . 2. Diffusion tensor imaging identifies , whereas magnetic resonance spectroscopy determines . 3. In addition to imaging the density of different brain regions, CT and MRI can be used to assess . 4. Explain briefly the computed tomography (CT) method of brain imaging.

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7-4 Functional Brain Imaging Advances in MRI and computing technologies led to a shift from purely anatomical imaging—which presented a static image of the tissue, as if it were not alive—to functional brain-imaging techniques, which allow investigators to measure the amount of blood flow, oxygen, and glucose usage in the brain as patients or participants solve cognitive problems. When a brain region is active, the amount of blood, oxygen, and glucose flowing to the region increases. It is therefore possible to infer changes in brain activity by measuring either blood flow or levels of the blood’s constituents, such as oxygen, glucose, and iron. Three techniques developed from this logic are functional MRI, optical tomography, and positron emission tomography.

Functional Magnetic Resonance Imaging As neurons become active, they use more oxygen, resulting in a temporary dip in the blood oxygen level. At the same time, active neurons increase blood carbon dioxide levels, which signal blood vessels to dilate, increasing blood flow and bringing more oxygen to the area. Peter Fox and colleagues (Fox & Raichle, 1986) discovered that when human brain activity increases, the extra oxygen produced

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by increased blood flow actually exceeds the tissue’s needs. As a result, the amount of oxygen in an activated brain area increases. Oxygen is carried on the hemoglobin molecule in red blood cells. Changes in the ratio of oxygen-rich hemoglobin to oxygen-poor hemoglobin alters the blood’s magnetic properties because oxygenrich hemoglobin is less magnetic than oxygen-poor hemoglobin. In 1990, Segi Ogawa and his colleagues showed that MRI could accurately match these changes in magnetic properties to specific brain locations (Ogawa et al., 1990). This process, called functional magnetic resonance imaging (fMRI), signals which areas are displaying changes in activity. Figure 7-17 shows changes in the fMRI signal in the visual cortex of a person who is being stimulated with light. When the light is turned on, the visual cortex (bottom of the brain images) becomes more active than during baseline (no light). In other words, functional changes in the brain are inferred from increases and decreases in the MRI signal produced by changes in oxygen levels.

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FIGURE 7-17 Imaging Changes in Brain Activity A functional MRI sequence of a horizontal section at the mid-occipital lobe (bottom of each image) in a normal human brain during visual stimulation. A baseline acquired in darkness (far left) was subtracted from the subsequent images. The participant wore tightly fitting goggles containing light-emitting diodes that were turned on and off as a rapid sequence of scans was obtained over 270 seconds. Note the prominent activity in the visual cortex when the light is on and the rapid cessation of activity when the light is off, all measured in the graph of signal intensity below the images.

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Figure 2-7 diagrams the extent of the major cerebral arteries.

osed on MRI-produced anatomical brain images, fMRI changes in activity can be attributed to particular structures. The dense blood vessel supply to the cerebral cortex allows for a spatial resolution of fMRI on the order of 1 millimeter, affording good spatial resolution of the brain activity’s source. On the other hand, because changes in blood flow

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take as long as one-third of a second, the temporal resolution of fMRI is not as precise as that obtained with EEG recordings and ERPs. Another disadvantage of fMRI is that subjects must lie motionless in a long, noisy tube, an experience that can prove claustrophobic. The confined space and lack of mobility also restrict the types of behavioral experiments that can be performed. Nonetheless, fMRI is a major tool in cognitive neuroscience. The living brain is always active, and researchers have succeeded in inferring brain function and connectivity by studying fMRI signals when participants are resting—that is, not engaged in any specific task. This signal, resting-state fMRI (rs-fMRI), is collected when participants have their eyes closed or are asked to look at a fixation cross and to keep their eyes open. The scanner collects brain activity, typically for at least 4-minute blocks. Researchers are attempting to shorten this period by increasing the strength of the static magnetic field and developing more sensitive coils. Statistical analysis of the data entails correlating activity in different brain regions over time. Although rs-fMRI is still in its growth phase, investigators already have identified many consistent networks of brain activity and abnormalities in disease states such as dementia and schizophrenia where patients have trouble with performing cognitive tasks (Takamura & Hanakawa, 2017).

Optical Tomography Research Focus 7-1, “Tuning In to Language”, describes a brainimaging study that used functional near-infrared spectroscopy 802

(fNIRS) to investigate newborn infants’ responses to language. fNIRS is a form of optical tomography, a functional imaging technique that operates on the principle that an object can be reconstructed by gathering light transmitted through it. One requirement is that the object at least partially transmit light. Thus, optical tomography can image soft body tissue, such as that in the breast or the brain. In fNIRS, reflected infrared light is used to determine blood flow because oxygen-rich hemoglobin and oxygen-poor hemoglobin differ in their absorption spectra. By measuring the blood’s light absorption, it is possible to measure the brain’s average oxygen consumption. So fNIRS and fMRI measure essentially the same thing but with different tools. In fNIRS, an array of optical transmitter and receiver pairs are fitted across the scalp, as illustrated in Figure 7-18A.

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FIGURE 7-18 How NIRS Works (A) Light injectors (red) and detectors (blue) are distributed in an array across the head. (B) Light injected through the scalp and skull penetrates the brain to a depth of about 2 centimeters. A small fraction of the light is reflected and captured by a detector on the scalp surface. Light is reflected from as deep as 2 centimeters but also from the tissue above it, as illustrated by the banana shape of the curves. Information from Spinney, 2005.

The obvious advantage of fNIRS is that it is relatively easy to hook up subjects repeatedly and record from them for short periods, from infancy to senescence. The disadvantage is that the light does not penetrate far into the brain, so researchers are restricted to measuring cortical activity (Figure 7-18B). The spatial resolution is also not as good as with other noninvasive methods, although NIRS equipment can now use more than 100 light detectors on the scalp, which allows acceptable spatial resolution in the image. NIRS has been used to differentiate cancerous from noncancerous brain tissue. This advance could potentially lead to safe, extensive surgical removal of brain cancers and improved outcomes (Kut et al., 2015).

Positron Emission Tomography Tagged to a glucose molecule, fluorine-18 (18F) acts as a marker for metabolism. The 18F and 15O methods are essentially the same.

Researchers use positron emission tomography (PET) to study the metabolic activity of brain cells engaged in processing brain functions such as language. PET imaging detects changes in the brain’s blood 805

flow by measuring changes in the uptake of compounds such as oxygen and glucose (Posner & Raichle, 1997). A PET camera, like the one shown in Figure 7-19, is a doughnut-shaped array of radiation detectors that encircles a person’s head. A small amount of water labeled with radioactive molecules is injected into the bloodstream. The person injected with these molecules is in no danger because the molecules used, including the radioactive isotope oxygen-15 (15O), are very unstable. They break down in just a few minutes and are quickly eliminated from the body. (Most of the oxygen in air we breathe is the stable 16O molecule.)

FIGURE 7-19 PET Scanner and Image The photo on the left shows a subject lying in a PET scanner, whose design is illustrated in the drawing. In the scan to the right, the bright red and yellow areas are regions of high blood flow.

Radioactive 15O molecules release tiny positively charged subatomic particles known as positrons (electrons with a positive charge). Positrons are emitted from an unstable atom because the atom is deficient in neutrons. The positrons are attracted to the

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negatively charged electrons in the brain, and the collision of the two particles leads to annihilation of both, which produces energy. This energy, in the form of two photons (a unit of light energy), leaves the head at the speed of light and is detected by the PET camera. The photons leave the head in exactly opposite directions from the site of positron–electron annihilation, so annihilation photon detectors can detect their source, as illustrated in Figure 7-19. A computer identifies the coincident photons and locates the annihilation source to generate the PET image. The PET system enables blood-flow measurement in the brain because the unstable radioactive molecules accumulate there in direct proportion to the rate of local blood flow. Local blood flow in turn is related to neural activity because potassium ions released from stimulated neurons dilate adjacent blood vessels. The more the blood flow, the higher the radiation counts recorded by the PET camera. But PET researchers who are studying the link between blood flow and mental activity use a subtraction procedure. They subtract the blood-flow pattern when the brain is in a carefully selected control state from the pattern of blood flow imaged when the subject is engaged in the task under study, as illustrated in the top row of Figure 7-20. This subtraction process images the change in blood flow between the two states. The change can be averaged across subjects (middle row) to yield a representative average image difference that reveals which brain areas are selectively active during the task (bottom). PET does not measure local neural activity directly;

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rather, it infers activity on the assumption that blood flow increases where neuron activity increases.

FIGURE 7-20 The Procedure of Subtraction In the upper row of scans, the control condition, resting while looking at a static fixation point (control), is subtracted from the experimental condition, looking at a flickering checkerboard (stimulation). The subtraction produces a different scan for each of five experimental subjects, shown in the middle row, but all show increased blood flow in the occipital region. The difference scans are averaged to produce the representative image at the bottom.

A significant limitation of PET is that radiochemicals, including the so-called radiopharmaceuticals used in diagnosing human

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patients, must be prepared in a cyclotron quite close to the scanner because their half-lives are so short that transportation time is a severely limiting factor. Generating these materials is very expensive. Despite the expense, PET has important advantages over other imaging methods: PET can detect the decay of literally hundreds of radiochemicals, which allows the mapping of a wide range of brain changes and conditions, including changes in pH, glucose, oxygen, amino acids, neurotransmitters, and proteins. PET can detect relative amounts of a given neurotransmitter, the density of neurotransmitter receptors, and metabolic activities associated with learning, brain poisoning, and degenerative processes that might be related to aging. PET is widely used to study cognitive function with great success. For example, PET confirms that various brain regions perform different functions. There are now hybrid scanners for diagnostic imaging, and they come in different combinations, such as PET with CT, PET with MRI, and PET with MRI and EEG. The advantage of these hybrid scanners is that they can acquire high-quality anatomical images and then overlay the functional/metabolic image information, allowing for precise localization that was not available before—all within a single examination.

7-4 Review

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Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. The principal methods of functional brain imaging are , , and . 2. PET uses identify

to measure brain processes and to changes in the brain.

3. fMRI and optical imaging measure changes in

4. Why are resting-state measurements useful to researchers?

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7-5 Chemical and Genetic Measures of Brain and Behavior Section 3-2 investigates how neurons function. Section 3-3 relates genes to cell function, genetic engineering, and epigenetic mechanisms.

Our focus so far has been on how neuroscientists study the individual and collective activity of neurons and how neuronal activity relates to behavior. Neurons are regulated by genes, DNA segments that encode the synthesis of particular proteins within cells. Genes control the production of chemicals in a cell, so it is possible to relate behavior to genes and to chemicals inside and outside the cell. Chemical and genetic approaches require sophisticated technologies that have seen major advances in the past two decades.

Measuring Brain Chemistry The brain contains a wide mixture of chemicals, ranging from neurotransmitters and hormones to glucose and gases, among many others. Abnormalities in the amounts of these chemicals can cause serious disruptions in behavior. Prime examples are Parkinson disease, characterized by low dopamine levels in the substantia nigra, and depression, correlated with low serotonin and/or noradrenaline production. The simplest way to measure brain chemistry in such diseases is to extract tissue postmortem from affected humans or 811

laboratory animals and undertake traditional biochemical techniques, such as high-performance liquid chromatography (HPLC), to measure specific chemical levels. Section 12-7 explores neural effects of rewarding events.

Fluctuations in brain chemistry are

associated not only with behavioral dysfunction but also with ongoing healthy behavior. For example, research over at least the past 35 years shows that dopamine levels fluctuate in the nucleus accumbens (a structure in the subcortical basal ganglia) in association with stimuli related to rewarding behaviors such as food and sex. Changes in brain chemistry can be measured in freely moving animals using two methods: cerebral microdialysis and cerebral voltammetry. Section 4-1 explains diffusion and concentration gradients in detail.

Mi crodi alysis

, which can determine the chemical constituents of extracellular fluid, is widely used in the laboratory. The technique has found clinical application over the past 15 years. A catheter with a semipermeable membrane at its tip is placed in the brain, as illustrated in Figure 7-21. A fluid flows through the cannula and passes along the cell membrane. Simple diffusion drives extracellular molecules across the membrane along their concentration gradient.

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FIGURE 7-21 Microdialysis Information from Tisdall & Smith, 2006.

Fluid containing the molecules from the brain exits through tubing to be collected for analysis. The fluid is removed at a constant rate so that changes in brain chemistry can be correlated with behavior. For example, if a rat is placed in an environment in which it anticipates sex or a favored food, microdialysis will record an increase in dopamine within the basal ganglia regions of the caudate nucleus and putamen, known as the striatum. Microdialysis is used in some medical centers to monitor chemistry in the injured brain. The effects of TBI or stroke can be worsened by 813

Section 6-4 investigates why glutamate and similar chemicals can act as neurotoxins.

secondary events such as a drastic increase in the neurotransmitter glutamate. Such biochemical changes can lead to irreversible cell damage or death. Physicians use microdialysis to monitor such changes, which can then be treated. Cerebral voltammetry works on a different principle. A small carbon fiber electrode and a metal electrode are implanted in the brain, and a weak current is passed through the metal electrode. The current causes electrons to be added to or removed from the surrounding chemicals. Changes in extracellular levels of specific neurotransmitters can be measured as they occur. Because different currents lead to changes in different compounds, it is possible to identify levels of different transmitters, such as serotonin or dopamine, and related chemicals. Voltammetry has the advantage of not requiring the chemical analysis of fluid removed from the brain, as microdialysis does, but it has the disadvantage of being destructive. That is, the chemical measurements require the degradation of one chemical into another, making the technology suitable only for scientific studies in animals. As an example, Wheeler and colleagues used voltammetry to demonstrate that the stress hormone corticosterone induced an increase in the amount of dopamine as well as how long it was detected in the nucleus accumbens (Wheeler et al., 2017). This finding is important because it provides evidence that stress can potentiate the effect of reinforcers.

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Measuring Genes in Brain and Behavior Most human behaviors cannot be explained by genetic inheritance alone, but variations in gene sequences do contribute significantly to brain organization. About 1 in 250 live births are identical twins, people who share an identical genome. Identical twins often have remarkably similar behavioral traits. Twin studies show strong concordance rates that support genetic contributions to drug addiction and other psychiatric disorders. But twin studies also show that environmental factors and life experience must be involved: concordance for most behavioral disorders, such as schizophrenia and depression, is far less than 100 percent. Life experiences act epigenetically to alter gene expression. Genetic factors can also be studied by comparing people who were adopted early in life and usually would not have a close genetic relationship to their adoptive parents. Here, a high concordance rate for behavioral traits would imply a strong environmental influence on behavior. Ideally, an investigator would be able to study both the adoptive and biological parents to tease out the relative heritability of behavioral traits. Section 8-2 explains how neurotrophic factors (nourishing chemical compounds) support growth and differentiation in developing neurons.

With the development of relatively inexpensive methods of identifying specific genes in people, it is now possible to relate the alleles (different forms) of specific genes to behaviors. A gene related

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to the production of a compound called brain-derived neurotrophic factor (BDNF) is representative. BDNF plays an important role in stimulating neural plasticity, and low levels of BDNF have been found with mood disorders such as depression. The two alleles of this gene are BDNF Val 66Met and BDNF Val 66Val. Principle 2: Neuroplasticity is the hallmark of nervous system functioning.

Sections 2-6 and 5-3 introduce factors that contribute to dementias. Clinical Focus 14-3 describes research, and Section 16-3 examines treatments.

Joshua Bueller and his colleagues (2006) showed that the Met allele is associated with an 11 percent reduction in hippocampal volume in healthy participants. Other studies have associated the Met allele with poor memory for specific events (episodic memory) and a high incidence of dementia later in life. However, the Val allele is by no means the better variant: although Val carriers have better episodic memory, they also have a higher incidence of neuroticism and anxiety disorders. The two alleles produce different phenotypes because they influence brain structure and functions differently. Other genes that were not measured also differed among Bueller’s participants and may have contributed to the observed difference. Research Focus 7-4, “Attention-Deficit/Hyperactivity Disorder,” gives another example of a common disorder of brain and behavior with a genetic contribution.

RESEARCH FOCUS 7-4

Attention-Deficit/Hyperactivity Disorder 816

Together, attention-deficit/hyperactivity disorder (ADHD) and attentiondeficit disorder (ADD) are probably the most common disorders of brain and behavior in children, with an incidence of 4 percent to 10 percent of schoolaged children. Although it often goes unrecognized, an estimated 50 percent of children with ADHD still show symptoms in adulthood, where its behaviors are associated with family breakups, substance abuse, and driving accidents. The neurobiological basis of ADHD and ADD is generally believed to be a dysfunction in the noradrenergic or dopaminergic activating system, especially in the frontal basal ganglia circuitry. Psychomotor stimulants such as Ritalin (methylphenidate) and Adderall (mainly dextroamphetamine) act to increase brain levels of noradrenaline and dopamine and are widely used for treating ADHD. About 70 percent of children show improvement of attention and hyperactivity symptoms with treatment, but there is little evidence that drugs directly improve academic achievement. This is important because about 40 percent of children with ADHD fail to get a highschool diploma, even though many receive special education for their condition.

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In this mainstreamed first-grade classroom, a special education student with ADHD uses the turtle technique to cope with frustration and stress.

Stephen Faraone and coworkers (Lecendreux et al., 2015) have challenged a common view that ADHD is a cultural phenomenon reflecting parents’ and teachers’ tolerance of children’s behavior. These investigators conclude that the prevalence of ADHD worldwide is remarkably similar when the same rating criteria are used. Little is known about incidence in developing countries, however. It is entirely possible that the incidence may actually be higher in developing countries, given that the learning environment for children is likely to be less structured than it is in developed nations. The cause of ADHD is unknown but probably involves dopamine receptors in the forebrain. The most likely areas are the frontal lobe and subcortical basal ganglia. Evidence of reduced brain volumes in these regions in ADHD patients is growing, as is evidence of an increase in the dopamine transporter protein. The dopamine transporter increase would mean that

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dopamine reuptake into the presynaptic neuron occurs faster than it does in the brains of people without ADHD. The result is a relative decrease in dopamine. Ritalin works by blocking dopamine reuptake. ADHD is believed to be highly heritable, a conclusion supported by twin studies showing a concordance of about 75 percent in identical twins. Molecular genetic studies have identified at least seven candidate genes, and several of them are related to the dopamine synapse, in particular to the D4 receptor gene.

Epigenetics: Measuring Gene Expression An individual’s genotype exists in

See “A Case of Inheriting Experience” in Section 3-3.

an environmental context fundamental to gene expression, the way genes become active or not. While epigenetic factors do not change the DNA sequence, the genes that are expressed can change dramatically in response to environment and experience. Epigenetic changes can persist throughout a lifetime and even across multiple generations. Changes in gene expression can result from widely ranging experiences, including chronic stress, traumatic events, drugs, culture, and disease. A study by Mario Fraga and his colleagues (2005) stands as a powerful example of gene–experience interactions. The investigators examined epigenetic patterns in 40 pairs of identical twins by measuring two molecular markers related to gene expression.

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Although twins’ patterns of gene expression were virtually identical when measured in childhood, 50-year-old twins exhibited differences so remarkable as to make them as different epigenetically as young nontwin siblings! The specific cause or causes of such differences are unknown but are thought to be related to lifestyle factors, such as smoking and exercise habits, diet, stressors, drug use, and education, as well as to social experiences, such as marriage and child rearing, among others. The epigenetic drift in the twins supports the findings of less than 100 percent concordance for diseases in identical twins. The role of epigenetic differences can also be seen across populations. Moshe Szyf, Michael Meaney, and their colleagues (see Szyf et al., 2008) have shown, for instance, that the amount of maternal attention mother rats give to their newborn pups alters the expression of certain genes in the adult hippocampus. These genes are related to the infants’ stress response when they are adults. (Maternal attention is measured as the amount and type of mother–infant contact; a difference of up to 6 hours per day can exist between attentive and inattentive mothers.) A subsequent study by the same group (McGowan et al., 2009) examined epigenetic differences in hippocampal tissue obtained from two groups of humans: (1) suicides with histories of childhood abuse and (2) either suicides with no childhood abuse or controls who died of other causes. The epigenetic changes found in the abused suicide victims parallel those found in the rats with inattentive mothers, again suggesting that early experiences can alter hippocampal organization and function via changes in gene expression.

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Experience-dependent changes in gene expression are probably found not only in the hippocampus but throughout the brain as well. For example, Richelle Mychasiuk and colleagues (2011) found that stressing pregnant rats led to wide changes in gene expression in their offspring, in both the frontal cortex and the hippocampus. However, the investigators found virtually no overlap in the altered genes in the two brain regions: the same experience changed different brain regions differently. Epigenetic studies promise to revolutionize our understanding of gene–brain interactions in healthy brain development and brain function. They will also help researchers develop new treatments for neurological disorders. For example, specific epigenetic changes appear to be related to the ability to make a functional recovery after stroke.

7-5 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. Concentrations of different chemicals in the brain can be measured in postmortem tissue using a(n) or in vivo using or . 2. Gene–environment interactions can be investigated in human populations by comparing of behavioral traits in identical twins and adopted children. 3. The study of genes and behavior focuses on individual differences in , whereas the study of epigenetics and behavior examines differences in .

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4. Describe briefly how epigenetic studies have led to the recognition that life experience and the environment can alter brain function.

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7-6 Comparing Neuroscience Research Methods We have considered a wide range of research methods for manipulating and measuring brain–behavior interactions. Tables 7-2 and 7-3 summarize these methods, including goals and examples of each method. How do researchers choose among them all? Their main consideration is their research question. Ultimately, that question is behavioral, but many steps lie along the route to understanding behavior.

TABLE 7-2 Manipulating Brain and Behavior Method

Experimental goal

Examples

Whole-animal manipulations (Section 7-1)

Determine how an environmental condition affects brain and behavior

Diet, exercise, social interactions, sensory stimulation, drug usage

Brain lesions, permanent (Section 7-1)

Remove or destroy neural tissue to observe behavioral changes

Knife cuts or aspirations, electrolytic lesions, neurotoxic lesions, high-intensity focused ultrasound

Brain lesions, temporary and reversible (Section 7-1)

Short-term silencing of neural tissue to observe behavioral changes

Regional cooling to arrest synaptic transmission, delivery of an agonist for GABA through a cannula to increase local inhibition

Genetic lesions (Sections 3-3; 7-1)

Remove genetic material

Knockout technology, CRISPR

Genetic stimulation (Section 3-3)

Add genetic material

Knock-in technology

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Drug manipulations (Section 7-1)

Determine receptor system’s role in the CNS

Use drugs to activate (agonists) or inactivate (antagonists) a receptor system

Electrical and magnetic stimulation (Section 7-1)

Excite tissue activity

DBS, TMS

Optogenetics (Section 7-1)

Use light to activate specific ion channels and relate to behavior

Insertion of specific light-sensitive proteins

Chemogenetics (Section 7-1)

Use specific synthetic drugs to activate designer receptors

Insertion of specific G protein–coupled receptors

TABLE 7-3 Measuring Brain and Behavior Method

Experimental goal

Examples

Behavioral analysis (Section 7-1)

Observe behavior; generate tests to allow people and lab animals to demonstrate behavioral capacities

Naturalistic observation; tests, mazes; automated touchscreen platform

Tissue analysis (Section 7-1)

Identify cell types and connections; identify disease states

Stains

Record electrical and magnetic activity (Section 7-2)

Measure action potentials from individual neurons; measure graded potentials to assess coordinated activity of thousands of neurons; measure magnetic fields

Single-cell recording; EEG, ERP; MEG

Anatomical brain imaging (Section 7-3)

Noninvasive examination of brain structures

Miniature microscopes; X-ray; CT; MRI; DTI

Functional brain imaging (Section 7-4)

Measure brain activity as specific behaviors are performed

fMRI; fNIRS; MRS; PET

In vivo chemistry (Section 7-5)

Relate fluctuations in transmitter release to behavior

HPLC; microdialysis, voltammetry

Genetics (Section 7-5)

Determine presence of a gene and its products

DNA, RNA, protein analysis

Epigenetics (Section 7-5)

Discover effect of experience on gene expression, brain, and behavior

Gene expression analysis

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Some researchers focus on morphology (structure) in postmortem tissue. This approach allows detailed analysis of both macro and micro structure, depending on the method chosen. Identifying brain pathology, as in Parkinson disease, can lead to insights about the causes and nature of a disorder. Other investigators focus more on the ways neurons generate electrical activity in relationship to behavior or on functional changes in brain activity during specific types of cognitive processing. Both approaches are legitimate: the goal is gaining an understanding of brain–behavior relationships. But investigators must consider practical issues, too. Temporal resolution (how quickly the measurement or image is obtained); spatial resolution (the accuracy of localization in the brain); and the degree of invasiveness are all pertinent. In addition, it is not feasible to consider MRI-based methods for studies of very young children because they have difficulty remaining absolutely still for long periods. Similarly, studies of brain-injured patients must take into account factors such as the subject’s ability to maintain attention for long periods—during neuropsychological testing or imaging studies, for example. In addition, practical problems such as motor or language impairment may limit the types of methods that researchers can use. Of course, cost is an ever-present practical consideration. Studying brain and behavior linkages by perturbing the brain is generally less costly than some imaging methods, many of which 825

require expensive machinery. EEG, ERP, and fNIRS are noninvasive and relatively inexpensive to set up (less than $100,000 each). MRIbased methods, MEG, and PET are very expensive (more than $2 million each) and are therefore typically found only in large research centers or hospitals. Similarly, epigenetic studies can be very expensive if investigators consider the entire genome in a large number of biological samples.

7-6 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. Neuroscience measurements and imaging vary along the dimensions , , and . 2. Relative to the expense of fMRI and PET imaging, noninvasively perturbing the brain using methods such as or administering neuropsychological testing is . 3. Catherine is interested in the relationship between dopamine levels in the nucleus accumbens and drug taking. What method(s) could she use to determine this relationship?

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7-7 Using Animals in Brain–Behavior Research A complete understanding of brain–behavior relationships is limited in part by the ethical constraints placed on experimentation with both humans and nonhuman species. Most countries decide independently which experimental practices are acceptable for humans, for other vertebrates, and for invertebrate species. In general, fewer experimental methods are acceptable for use on humans than are employed on our most closely related primate relatives. Thus, as in most new treatments in medicine, a wide variety of nonhuman species are used to develop and test treatments for human neurological or psychiatric disorders before they are tested on humans. Although the human and the nonhuman brain have obvious differences with respect to language, the general brain organization across mammalian species is remarkably similar, and the functioning of basic neural circuits in nonhuman mammals appears to generalize to humans. Thus, neuroscientists use widely varying animal species to model human brain diseases as well as to infer typical human brain functioning. Two important issues surface in use of animal models to develop treatments for brain and behavioral disorders. The first is whether animals actually display neurological diseases in ways similar to

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humans. The second involves the ethics of using animals in research. We consider each separately.

Benefits of Animal Models of Disease Some disorders—stroke, for example—seem relatively easy to model in laboratory animals because it is possible to interrupt blood supply to a brain area and induce injury and consequent behavioral change. However, it is far more difficult to determine whether human behavioral disorders can actually be induced in laboratory animals. Consider attention-deficit/hyperactivity disorder (ADHD), a developmental disorder characterized by the core behavioral symptoms impulsivity, hyperactivity, and/or inattention. The most common issue for children with ADHD is problems at school. Lab animals such as rats and mice do not go to school, so how does one model ADHD in rodents? Clinical Focus 6-1 reports on illicit use of prescription ADHD medications to boost performance at school and at work. Section 15-2 explores the nature of attention and disorders that result in deficits of attention.

ADHD has proved difficult to treat in children, and interest in developing an animal model is high. One way to proceed is to take advantage of the normal variance in the performance of rats on a variety of tests of working memory and cognitive functioning—tests that require attentional processes. The idea is that we can think of

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ADHD in people or in rats as one extreme on a spectrum of behaviors that are part of a normal distribution in the general population. Many studies show that treating rats with the dopaminergic agonist methylphenidate (Ritalin), a common treatment for children diagnosed with ADHD, actually improves the performance of rats that do poorly on tests requiring attentional processes. One rat strain, the Kyoto SHR rat, has proved an especially good model for ADHD and is widely used in the lab. The strain presents known abnormalities in prefrontal dopaminergic innervation that correlate with behavioral abnormalities such as hyperactivity. Dopaminergic abnormalities are believed to be one underlying symptom of ADHD in children (as explained in Research Focus 74). Methylphenidate can reverse behavioral abnormalities, both in children with ADHD and in the SHR rats.

Animal Welfare and Scientific Experimentation We present experiments that predate current ethical standards. Bartholow’s brain stimulation (Section 4-1) and the inmate volunteers in Experiment 6-1 are examples.

Using nonhuman animals in scientific research has a long history, but only in the past century have ethical issues surrounding animal research gained considerable attention and laws been instituted. Just

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as the scientific community has established ethical standards for research on humans, it has also developed regulations governing experimentation on animals. The governments of most developed nations regulate the use of animals in research; most states, territories, and provinces within a country have additional legislation. Universities engaged in research have their own rules governing animal use, as do professional societies of scientists and the journals in which they publish. Here are four principles used as guidelines in Canada for reviewing experimental and teaching protocols that will use animals: 1. The use of animals in research, teaching, and testing is acceptable only if it promises to contribute to the understanding of environmental principles or issues, fundamental biological principles, or development of knowledge that can reasonably be expected to benefit humans, animals, or the environment. 2. Optimal standards for animal health and care result in enhanced credibility and reproducibility of experimental results. 3. Acceptance of animal use in science critically depends on maintaining public confidence in the mechanisms and processes used to ensure necessary, humane, and justified animal use. 4. Animals are used only if the researcher’s best efforts to find an alternative have failed. Researchers who use animals employ the most humane methods on the smallest number of appropriate animals required to obtain valid information.

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Legislation concerning the care and use of laboratory animals in the United States is set forth in the Animal Welfare Act, which includes laws passed by Congress in 1966, 1970, 1976, and 1985. Legislation in other countries is similar to that of the United States, and in some European countries, it is much stricter. The U.S. act covers mammals, including rats, mice, cats, dogs, and primates, and birds, but it excludes farm animals that are not used in research. The U.S. Department of Agriculture (USDA) administers the act through inspectors in the Animal Care section of the Animal and Plant Health Inspection Service. In addition, the Office of Human Research Protections of the National Institutes of Health (NIH) administers the Health Research Extension Act (passed in 1986). The act covers all animal uses conducted or supported by the U.S. Public Health Service and applies to any live vertebrate animal used in research, training, or testing. The act requires that each institution provide acceptable assurance that it meets all minimum regulations and conforms with The Guide for the Care and Use of Laboratory Animals (National Research Council, 2011) before conducting any activity that includes animals. The typical method for demonstrating conformance with the guide is to seek voluntary accreditation from the Association for Assessment and Accreditation of Laboratory Animal Care International, a private, nonprofit organization that promotes the humane treatment of animals. All accredited U.S. and Canadian universities that receive government grant support are required to provide adequate treatment

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for all vertebrate animals. Reviews and specific protocols for vertebrates, including fish, amphibians, reptiles, birds, and mammals, to be used in research, teaching, or testing are administered through the same process. Anyone using animals in a U.S. or Canadian university submits a protocol to the university’s institutional animal care and use committee, composed of researchers, veterinarians, people who have some knowledge of science, and laypeople from the university and the community. Companies that use animals for research are not required to follow this process. In effect, however, if they do not, they will be unable to publish the results of their research because journals require that research conform to national guidelines on animal care. In addition, discoveries made using animals are not recognized by government agencies that approve drugs for clinical trials with humans if they do not follow the prescribed process. Companies therefore use Good Laboratory Practice (GLP) standards, which are as rigorous as those used by government agencies. Researchers are to consider alternatives to procedures that may cause more than momentary or slight pain or distress to animals. Most of the attention on alternatives has focused on the use of animals in testing and stems from high public awareness of some tests for pharmacological compounds, especially toxic compounds. In the United States, the National Institute of Environmental Health Sciences now regulates testing of such compounds.

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Despite the legislation related to animal use, some controversy remains over using animals in scientific research. Those at one extreme approve any usage, and those at the other extreme disapprove of using animals for any form of research. Most fall somewhere in between. The debate touches on issues of philosophy, law, morals, custom, and biology. The issues in this debate are important to researchers in many branches of science who experiment with animals to understand the functions of the human and nonhuman body, brain, and behavior. They are also important to human and veterinary medicine that can benefit from this research, as well as to people and other animals with diseases or damage to the nervous system. And they are important to those who are philosophically opposed to using animals for work or food. Finally, because you, as a student, encounter many experiments on animals in this book, these issues are important to you as well.

7-7 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. Laboratory animals can model some disorders, such as stroke, but are less useful for modeling most disorders, such as ADHD, because it is difficult to re-create the human-specific conditions for these disorders.

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2. Legislation governing the care and use of laboratory animals used in the United States was set forth in the . 3. List some of the reasons for conducting scientific research in animals.

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Summary 7-1 Measuring and Manipulating Brain and Behavior The brain’s primary function is to produce behavior, so the fundamental research technique in behavioral neuroscience is to study the direct relationship between brain and behavior. Investigators study healthy humans and other animals as well as human patients and laboratory animals with neurological problems. Initially, scientists simply observed behavior, but they later developed neuropsychological testing measures designed to study specific functions such as fine movements, memory, and emotion. Today, researchers correlate these behavioral outcomes with anatomical, physiological, chemical, genetic, and other molecular measures of brain organization. Brain and behavioral relationships can be manipulated by altering brain function, either permanently or temporarily. Permanent changes involve damaging the brain directly by ablation or with neurotoxins that remove or destroy brain tissue. Transient changes in brain activity can be induced either by use of a mild electrical or magnetic current, as in DBS or TMS, or by administration of drugs. The synthetic biology technique CRISPR-Cas9 uses the Cas9 protein in bacteria to cut and replace a sequence of DNA of any cell. Optogenetics, a transgenic technique, employs light-activated ion channels to 835

excite or inhibit targeted cells in living tissue. Chemogenetic stimulation combines designer receptors and synthetic drugs to excite targeted cells in living tissue.

7-2 Measuring the Brain’s Electrical Activity Recordings from single or multiple cells show that neurons fire in specific patterns and that cortical neurons are organized into functional groups that work as coordinated networks. Neurons in sensory areas respond to specific characteristics of stimuli, such as color or pitch. Other neurons, such as place cells in the hippocampal formation, can code for more complex information, such as an object’s location in space. Electroencephalographic or magnetoencephalographic recordings measure electrical or magnetic activity from thousands of neurons at once. EEG can reveal a gross relationship between brain and behavior, as when a person is alert and displays the beta-wave pattern versus when the person is resting or sleeping, indicated by the slower alpha-wave patterns. Event-related potentials, on the other hand, tell us that even though the entire brain is active during waking, certain parts are momentarily much more active than others. ERP records how the location of increased activity changes as information moves from one brain area to another. EEG and ERP are noninvasive methods that record information from electrodes on the scalp; in the case of MEG, magnetic detectors above the head are used. 836

Electrocorticography, by contrast, records information via electrodes attached directly to the cortex. ECoG and single-cell recording techniques are invasive.

7-3 Anatomical Imaging Techniques: CT and MRI Computed tomography (CT) and magnetic resonance imaging (MRI) are sensitive to the density of brain structures, ventricles, nuclei, and pathways. CT is a form of three-dimensional X-ray, whereas MRI works on the principle that hydrogen atoms behave like spinning bar magnets in the presence of a magnetic field. Although CT scans are quicker and less expensive, MRI provides exceptionally clear images, both of nuclei and of fiber pathways in the brain. MRI also indicates that people’s brain structure varies widely. Both CT and MRI can be used to assess brain damage from neurological disease or injury, but MRI is more useful as a research tool. Diffusion tensor imaging is a form of MRI that makes it possible to identify normal or abnormal fiber tracts and myelin in the brain. Magnetic resonance spectroscopy (MRS), another form of MRI, permits practitioners to detect brain metabolites, such as those produced following concussion.

7-4 Functional Brain Imaging Metabolic imaging shows that any behavior requires the collaboration of widespread neural circuits. Positron emission

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tomography records blood-flow and other metabolic changes in periods measured in minutes; it requires complex subtraction procedures and the averaging of responses across multiple subjects. Records of blood flow obtained using functional magnetic resonance imaging can be combined with anatomical MRI images to locate changes in an individual brain and to complement ERP results. Resting-state fMRI allows investigators to measure connectivity across brain regions. Functional near-infrared spectroscopy is the form of optical tomography usually used for functional brain-imaging studies. It works on the principle that an object, including brain tissue, can be reconstructed by gathering light transmitted through the object. fNIRS is much simpler to use than PET or fMRI, but because light does not penetrate very far into the brain, it can be used only to study cortical function.

7-5 Chemical and Genetic Measures of Brain and Behavior Analysis of changes in both genes and neurochemicals provides insight into the molecular correlates of behavior. Although genes code all the information needed to construct and regulate cells, epigenetic research reveals that the environment and life experience can modify gene expression. Even identical twins, who have an identical genome at birth, in adulthood have widely differing patterns of gene expression and very different brains.

7-6 Comparing Neuroscience Research Methods 838

The main consideration in neuroscience research is matching the question being posed with the appropriate methodologies to best answer that question. Whatever the approach, the goal is to understand brain–behavior relationships. Tables 7-1 and 7-2 summarize the manipulations and measurements used in behavioral neuroscience. Among all the practical issues of measurement resolution and invasiveness, cost is often the ultimate consideration.

7-7 Using Animals in Brain–Behavior Research Understanding brain function in both the healthy brain and the disordered brain often benefits from animal models. Investigators develop animal models to manipulate the brain, to determine how experiential factors and neurological treatments affect brain function. Because animal subjects cannot protect themselves from abuse, governments and researchers have cooperated to develop ethical guidelines for the use of laboratory animals. These guidelines are designed to ensure that discomfort is minimized, as is the number of animals used for invasive procedures.

Key Terms alpha rhythm behavioral neuroscience

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cerebral voltammetry chemogenetics compensation computed tomography (CT) deep-brain stimulation (DBS) diffusion tensor imaging (DTI) electrocorticography (ECoG) event-related potential (ERP) functional magnetic resonance imaging (fMRI) functional near-infrared spectroscopy (fNIRS) magnetic resonance imaging (MRI) magnetic resonance spectroscopy (MRS) magnetoencephalogram (MEG) microdialysis neuropsychology optogenetics place cells positron emission tomography (PET) resting-state fMRI (rs-fMRI) stereotaxic apparatus striatum

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synthetic biology transcranial magnetic stimulation (TMS)

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CHAPTER 8 How Does the Nervous System Develop and Adapt?

8-1 Three Perspectives on Brain Development RESEARCH FOCUS 8-1 Linking Socioeconomic Status to Cortical Development Correlating Emerging Brain Structures with Emerging Behaviors Correlating Emerging Behaviors with Neural Maturation

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Identifying Influences on Brain and Behavior 8-2 Neurobiology of Development Gross Development of the Human Nervous System Origins of Neurons and Glia Neuronal Growth and Development CLINICAL FOCUS 8-2 Autism Spectrum Disorder Glial Development Unique Aspects of Frontal Lobe Development 8-3 Using Emerging Behaviors to Infer Neural Maturation Motor Behaviors Language Development Development of Problem-Solving Ability EXPERIMENT 8-1 Question: In What Sequence Do the Forebrain Structures Required for Learning and Memory Mature? A Caution about Linking Correlation to Causation 8-4 Brain Development and the Environment Experience and Cortical Organization 843

RESEARCH FOCUS 8-3 Keeping Brains Young by Making Music Experience and Neural Connectivity Critical Periods for Experience and Brain Development Hormones and Brain Development Gut Bacteria and Brain Development 8-5 Abnormal Experience and Brain Development Early Life Experience and Brain Development CLINICAL FOCUS 8-4 Romanian Orphans Injury and Brain Development Drugs and Brain Development Other Sources of Abnormal Brain Development CLINICAL FOCUS 8-5 Schizophrenia Developmental Disability How Do Any of Us Develop a Normal Brain?

RESEARCH FOCUS 8-1 Linking Socioeconomic Status to Cortical Development 844

Nobel Prize–winning American economist James Heckman has argued passionately about one effective strategy for economic growth: investing as early as possible in disadvantaged families promotes optimal development of young children at risk. Heckman notes that children from lower-SES families typically develop gaps in knowledge and ability relative to their more advantaged peers. These gaps influence health and prosperity, and they persist throughout life. Childhood SES correlates with cognitive development, language, memory, social and emotional processing, and ultimately income and health in adulthood. One reason: early experiences related to SES influence children’s cerebral development. To examine cerebral development, neuroimaging studies visualize differences in brain development that relate to growing up in under-resourced environments. As the brain grows throughout childhood and adolescence, the cortical surface area expands before declining in adulthood (Schnack et al., 2014; also see Figure 8-14). Cortical surface area reflects the amount of neural tissue available for different behaviors and correlates positively with cognitive ability. It should be possible to estimate the effect of early experiences on brain and behavioral development by comparing the cortical surface area and cognitive abilities of people raised in lower- or higher-SES families. Kimberly Noble and her colleagues (2015) used neuroimaging to investigate the relationship between SES and cortical surface area in more than 1000 participants aged 3 to 20. As shown in the illustration, lower family income, independent of race or sex, was associated with decreased cortical surface area in widespread regions of frontal, temporal, and parietal lobes, the regions shown in red. A follow-up study by the same group found SES moderates patterns of age-related cortical thinning, especially in language-related cortical regions (Piccolo et al., 2016).

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After adjusting for age, sex, race, and parental education, Noble and colleagues associated family income with cortical surface area. Areal brain regions shown in red were significantly smaller in children from low-SES families.

The investigators also measured participants’ cognitive performance on tests of attention, memory, vocabulary, and reading. The larger the cortical surface area, the better the test outcomes. The negative effects of low SES were especially dramatic at the lower end of the family income spectrum, especially in families with annual incomes less than $30,000. Follow-up studies by Noble’s group have also shown that lower SES is associated with reduced white matter volume and reduced cognitive flexibility, as well as age-related differences in cortical thickness (Ursache & Noble, 2016). Low SES is associated with poor nutrition, high stress, and insufficient prenatal and infant care. Following on Heckman’s thesis, investing in children from low-income families will increase societal health and prosperity because these children can optimize their brain development and realize their developmental potential. Policies aimed toward decreasing poverty can lead to clear improvements in children’s cognitive and brain development.

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To see how scientists go about studying the interconnected processes of brain and behavioral development, think about all the architectural parallels between how the brain is constructed and how a house is built. House plans are drawn as blueprints; the plans for a brain are encoded in genes. Architects do not specify every detail in a blueprint, nor do genes include every instruction for brain assembly and wiring. The brain is too complex to be encoded entirely and precisely in genes. This leaves the fate of billions of brain cells partly undecided, especially in regard to the massive undertaking of forming appropriate connections between cells. If the structure and fate of each brain cell are not specified in advance, what controls brain development? Many factors are at work, and, as with house building, brain development is influenced by the environment in the course of the construction phase and by the quality of the materials. For example, as we saw in Research Focus 8-1, Linking Socioeconomic Status to Cortical Development, living in poverty can compromise children’s brain development. We can shed light on nervous system development by viewing its architecture from different vantage points—structural, functional, and environmental. In this chapter, we consider the neurobiology of development first, explore behavioral correlates of developing brain functions next, and then explore how experiences and environments influence neuroplasticity over the life span.

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8-1 Three Perspectives on Brain Development Brain and behavior develop apace, and scientists thus reason that the two are closely linked. Events that alter behavioral development should similarly alter the brain’s structural development and vice versa. As the brain develops, neurons become more and more intricately connected, and these increasingly complex interconnections underlie increasingly complex behaviors. These observations enable neuroscientists to study the relationship between brain and behavioral development from three perspectives: 1. Structural development can be correlated with emerging behaviors. 2. Behavioral development can be predicted by the underlying circuitry that must be emerging. 3. Research can focus on factors such as hormones, injury, or socioeconomic status (SES) that influence both brain structure and behavioral development.

Correlating Emerging Brain Structures with Emerging Behaviors We can look at the nervous system’s structural development and correlate it with the emergence of specific behaviors. For example, 848

the development of certain brain structures links to the motor development of, say, grasping or crawling in infants. As brain structures mature, their functions emerge and develop, as manifested in behaviors we can observe. Neural structures that develop quickly—the visual system, for instance—exhibit their functions sooner than do structures that develop more slowly, such as those used for speech. Because the human brain continues to develop well into adulthood, some abilities emerge or mature rather late. Some cognitive behaviors controlled by the frontal lobes are among the last to develop. One such behavior, the ability to plan efficiently, is a skill vital to many complexities of life, including organizing daily activities or making travel plans. The Tower of Hanoi test, illustrated in Figure 8-1, shows how planning skills can be measured in the laboratory. The task is to plan how to move colored discs one by one, in the minimum number of moves, from one configuration to another. Most 10-year-olds can solve simple configurations, but more difficult versions of the task, such as that shown in Figure 8-1, cannot be performed efficiently until about age 15 to 17. No surprise, then, that adolescents often appear disorganized: their ability to plan has yet to mature.

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FIGURE 8-1 Testing Cognitive Development The Tower of Hanoi is a mathematical puzzle consisting of three rods and several different-sized discs. The task is to match the goal in as few moves as possible, obeying two rules: (1) only one disc may be moved at a time and (2) no disc may be placed on top of a smaller disc.

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Mature adults with acquired frontal lobe injuries also fail to perform well on the Tower of Hanoi test. Such evidence reinforces the idea that children are not miniature adults who simply need to learn the “rules” of adult behavior. A child’s brain is vastly different from an adult’s, and the brains of children at different ages are not really comparable, either.

Correlating Emerging Behaviors with Neural Maturation We can turn our focus around and scrutinize behavior for the emergence of new abilities, and then we can infer underlying neural maturation. For example, as language emerges in a young child, we expect to find corresponding changes in neural structures that control language. In fact, neuroscientists do find such changes. At birth, children do not speak, and even extensive training would not enable them to do so because the neural structures that control language production are not yet ready. Thus, as language emerges, the speech-related structures in the brain are undergoing the necessary maturation. The same reasoning can be applied to frontal lobe development. As frontal lobe structures mature through adolescence and into early adulthood, we look for related changes in behavior. We can also do the reverse: because we observe new abilities emerging in the teenage years and even later, we infer that they must be controlled by latematuring neural structures and connections.

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Identifying Influences on Brain and Behavior The third approach to developmental interrelations between brain and behavior is to identify and study factors that influence both. From this perspective, the mere emergence of a fully developed brain structure is not enough. We must also know the events that shape how that structure functions and produces behaviors. Some events that influence brain function are sensory experience, injuries, the actions of hormones and genes, and SES. Section 12-5 offers a detailed discussion of the mechanisms that control nonregulatory behavior, including sexual behavior.

Logically, if one factor influences behavior, then the brain structures changed by that factor are those responsible for the behavioral outcomes. For example, we might study how the atypical secretion of a hormone affects both a certain brain structure and a certain behavior. We can then infer that because the observed behavior results from the change in brain structure functioning, the structure must typically play some role in controlling the behavior. For example, the presence of testosterone in early development typically occurs only in males and results in changes in the organization and function of specific hypothalamic nuclei. But if the amount of testosterone release is low or if the release occurs at a different developmental time in males, or, alternatively, occurs in females, the structure of the hypothalamus may be altered and, consequently, so may sexual preference and perhaps gender identity. 852

8-1 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. Structural brain development is correlated with the emergence of . 2. Behavioral development predicts the maturation of . 3. Three factors that influence brain function are , and .

4. What important constraint determines when behaviors emerge?

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8-2 Neurobiology of Development Some 2000 years ago, the Roman philosopher Seneca the Younger proposed that a human embryo is an adult in miniature, and thus the task of development is simply to grow bigger. This idea of preformation was so appealing that it was widely believed for centuries. Even with the development of the microscope, the appeal of preformation proved so strong that biologists claimed to see microscopic horses in horse semen. By the mid-1800s, preformation began to lose ground as people realized that embryos look nothing like the adults they become. In fact, it was obvious that embryos of different species more closely resemble one another than their respective parents. The top row of Figure 8-2 shows the striking similarity among embryos of species as diverse as salamanders, chickens, and humans, each shown in fetal form in the bottom row.

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FIGURE 8-2 Embryos and Evolution The physical similarity of embryos of different species is striking in the earliest stages of development, as the salamander, chick, and human embryos in the top row show. This similarity led to the conclusion that embryos are not simply miniature versions of adults.

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As embryos, all vertebrate species have a similar-looking primitive head, a region with bumps or folds, and a tail. Only as an embryo develops does it acquire the distinctive characteristics of its species. The similarity of young embryos is so great that many nineteenthcentury biologists saw it as evidence for Darwin’s view that all vertebrates arose from a common ancestor millions of years ago. The embryonic nervous systems of vertebrates are as similar structurally as their bodies are. Figure 8-3 details the three-chambered brain of a young vertebrate embryo: forebrain, midbrain, and hindbrain. The remaining neural tube forms the spinal cord. How do these three regions develop? We can trace the events as the embryo matures.

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FIGURE 8-3 Embryonic Vertebrate Nervous System Forebrain, midbrain, and hindbrain are visible in the human embryo at about 28 days, as is the remaining neural tube, which will form the spinal cord.

Gross Development of the Human Nervous System When a sperm fertilizes an egg, the resulting human zygote consists of just a single cell. But this cell soon begins to divide. By the fifteenth day after fertilization, the emerging embryo resembles a fried egg 857

(Figure 8-4), a structure formed by several sheets of cells with a raised area in the middle called the embryonic disc—essentially the primitive body.

FIGURE 8-4 From Fertilization to Embryo Development begins at fertilization (day 1), with the formation of the zygote. On day 2, the zygote begins to divide. On day 15, the raised embryonic disc begins to form. Information from Moore, 1988.

Prenatal Stages Zygote

Fertilization to 2 weeks

Embryo

2 to 8 weeks

Fetus

9 weeks to birth

By 3 weeks after conception, primitive neural tissue, the neural plate, occupies part of the outermost layer of embryonic cells. First, the neural plate folds to form the neural groove, detailed in Figure 8-5. The neural groove then curls to form the neural tube, much as you can curl a flat sheet of paper to make a cylinder.

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FIGURE 8-5 Formation of the Neural Tube A long depression, the neural groove, first forms in the neural plate. By day 21, the primitive brain and neural groove are visible. On day 23, the neural tube is forming as the neural plate collapses inward along the length of the embryo’s dorsal surface. The embryo is shown in a photograph at 24 days.

The cells that form the neural tube can be regarded as the nursery for the rest of the central nervous system. The open region in the tube’s center remains open and matures into the brain’s ventricles and the spinal canal. The micrographs in Figure 8-6 show the neural tube closing in a mouse embryo.

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FIGURE 8-6 Neural Tube Development Scanning electron micrographs show the neural tube closing in a mouse embryo. Reproduced with the permission of Prof. Dr. R. E. Poelmann, Dept. Cardiology, Leiden University Medical Center, Leiden University Medical Center, Institute of Biology IBL, University of Leiden, Leiden, The Netherlands.

Gyri and sulci are introduced in Section 2-1. Adult stem cells that line the subventricular zone also are located in the hippocampus, spinal cord, and retina.

The human body and nervous system change rapidly in the ensuing 3 weeks (Figure 8-7). By 7 weeks (49 days), the embryo begins to resemble a person. The brain looks distinctly human by about 100 days after conception, but it does not begin to form gyri and sulci until about 7 months. By the end of the ninth month, the fetal brain has the gross appearance of the adult human brain, but its cellular structure is different.

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FIGURE 8-7 Prenatal Brain Development The developing human brain undergoes a series of embryonic and fetal stages. You can identify the forebrain, midbrain, and hindbrain by color (review Figure 8-3) as they develop in the course of gestation. At 6 months, the developing forebrain has enveloped the midbrain structures. Research from Cowan, 1979.

Origins of Neurons and Glia As we have noted, the neural tube is the brain’s nursery. Neural stem cells lining it have an extensive capacity for self-renewal. When a stem cell divides, it produces two stem cells; one dies and the other lives to divide again. This process repeats again and again throughout life. In an adult human, neural stem cells line the ventricles, forming the subventricular zone.

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If lining the ventricles were all that stem cells did throughout the decades of a human life, they would seem very odd cells to possess. But neural stem cells have a function beyond self-renewal: they give rise to progenitor cells (precursor cells), which also can divide. As shown in Figure 8-8, progenitor cells eventually produce nondividing cells known as neuroblasts and glioblasts. In turn, neuroblasts and glioblasts mature into neurons and glia. Neural stem cells, then, are multipotent: they give rise to all the many specialized cell types in the CNS.

FIGURE 8-8 Origin of Brain Cells Cells in the brain begin as multipotential stem cells, develop into precursor cells, then produce blasts that finally develop into specialized neurons or glia.

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Sam Weiss and his colleagues (1996) discovered that stem cells remain capable of producing neurons and glia not just into early adulthood but even in an aging brain. This important discovery implies that neurons that die in an adult brain should be replaceable. But neuroscientists do not yet know how to instruct stem cells to replace them. One possibility is to make use of signals that the brain typically uses to control stem cell production in adults. For example, the level of the neuropeptide prolactin increases when female mice are pregnant and stimulates the fetal brain to produce more neurons. These naturally occurring hormonal signals have been shown to replace lost neurons in brain-injured laboratory animals (see reviews by Bond et al., 2015, and Faiz & Morshead, 2018). How does a stem cell know to become a neuron rather than a skin cell? In each cell, certain genes are expressed (turned on) by a signal, and those genes then produce a particular cell type. Gene expression is a process whereby information from a gene is used in the synthesis of a gene product, such as a protein. You can easily imagine that certain proteins produce skin cells, whereas other proteins produce neurons. Similarly, certain proteins produce one type of neuron, such as pyramidal cells, whereas others might produce granule cells. Protein synthesis is described in more detail in Section 3-2, and the epigenetic factors influencing gene expression are discussed in Section 33.

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The specific signals for gene expression are largely unknown but are probably chemical, and they form the basis of epigenetics. A common epigenetic mechanism that suppresses gene expression during development is gene methylation, or DNA methylation. In this process, a methyl group (CH3) attaches to the nucleotide base cytosine lying next to guanine on the DNA sequence. It is relatively simple to quantify gene methylation in different phenotypes, reflecting either an increase or a decrease in overall gene expression.

Figure 3-25 (excerpted above), showing gene methylation, contrasts the mechanisms of histone and mRNA modification to DNA methylation.

Methylation alters gene expression dramatically during development. Prenatal stress can reduce gene methylation by 10 percent. This means that prenatally stressed infants express 2000 more genes (of the more than 20,000 in the human genome) than unstressed infants (Mychasiuk et al., 2011). Other epigenetic mechanisms, such as histone

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modification and mRNA modification, can regulate gene expression, but these mechanisms are more difficult to quantify. Thus, the chemical environment of a brain cell is different from that of cells elsewhere in the body: different genes in brain cells are activated, producing different proteins and different cell types. The chemical environments needed to trigger cellular differentiation could be produced by the activity of neighboring cells or by chemicals, such as hormones, that are transported in the bloodstream. The differentiation of stem cells into neurons requires a series of gene-activating signals. A chemical signal must induce stem cells to produce progenitor cells; another chemical signal must induce the progenitor cells to produce either neuroblasts or glioblasts. Finally, a chemical signal—perhaps a set of signals—must induce the genes to make a particular type of neuron. Compounds that signal cells to develop in particular ways are neurotrophic factors (trophic means “nourishing”). By removing stem cells from an animal’s brain and placing those cells in solutions that keep them alive, researchers can study how neurotrophic factors function. One compound, epidermal growth factor (EGF), when added to the stem cell culture stimulates production of progenitor cells. Another compound, basic fibroblast growth factor (bFGF, or FGF-2), stimulates progenitor cells to produce neuroblasts. At this point, the destiny of a given neuroblast is undetermined. The blast can become any type of neuron if it receives the right chemical signals. The body relies on a general-purpose neuron that matures into a

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specific cell type in a particular location when exposed to certain neurotrophic factors. This flexibility makes brain development simpler than it would be if each different cell type, as well as the number of cells of each type, had to be specified precisely in an organism’s genes. In the same way, building a house from all-purpose two-by-fours that can be cut to any length as needed is easier than specifying in a blueprint a precise number of precut pieces of lumber that can be used only in a certain location.

Neuronal Growth and Development The human brain requires approximately 10 billion (1010) cells to form just the cortex that blankets a single hemisphere. This means it must produce about 250,000 neurons per minute at the peak of prenatal brain development. But as Table 8-1 shows, this rapid formation of neurons (neurogenesis) and glia (gliogenesis) is just the first step in brain growth. These new cells must travel to the correct destination (migration), they must differentiate into the right type of neuron or glial cell, and the neurons must then grow dendrites and axons and form synapses.

TABLE 8-1 Stages of Brain Development 1. Cell birth (neurogenesis; gliogenesis) 2. Neural migration 3. Cell differentiation 4. Neural maturation (dendrite and axon growth) 5. Synaptogenesis (formation of synapses) 6. Cell death and synaptic pruning

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7. Myelogenesis (formation of myelin)

In Research Focus 8-1, investigators used cortical development as a measure of the effects of SES.

The brain also prunes unnecessary cells and connections, sculpting itself according to the particular person’s experiences and needs. We consider these stages in brain development next, focusing on cortical development, because neuroscientists know more about development of the cortex than of any other area of the human brain. The principles derived from our examination of the cortex, however, apply to neural growth and development in other brain regions as well.

Neuronal Generation, Migration, and Differentiation Figure 8-9 shows that neurogenesis is largely complete after about 25 weeks of gestation. (Some growth continues until about 5 years of age.) An important exception is the hippocampus, where new neurons continue to develop throughout life.

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FIGURE 8-9 Prenatal Development of the Human Cerebral Cortex Brain weight and body weight increase rapidly and in proportion. The cortex begins to form about 6 weeks after conception, with neurogenesis largely complete by 25 weeks. Neural migration and cell differentiation begin at about 8 weeks and are largely complete by about 29 weeks. Neuron maturation, including axon and dendrite growth, begins at about 20 weeks and continues until well after birth. Information from Marin-Padilla, 1993.

Until after full-term birth, however, the fetal brain is especially delicate and extremely vulnerable to injury, teratogens (chemicals that cause malformations), and trauma. Apparently, the developing brain can more easily cope with injury earlier, during neurogenesis, than it can during the later stages of cell migration or cell differentiation, when cell maturation begins (see Table 8-1). One reason may be that once neurogenesis has slowed, it is very hard to start it up again. If neurogenesis is still progressing at a high rate, more neurons can be made to replace injured ones, or perhaps existing neurons can be allocated differently.

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The absence of neurogenesis in adulthood, other than in the hippocampus, also explains why adult brain tumors arise from glial cells, which are generated throughout adulthood, rather than from neurons. In contrast, brain tumors in young children are sometimes neuronal, reflecting some lingering neurogenesis. Clinical Focus 11-2 describes outcomes resulting from cerebral palsy, caused by brain trauma acquired perinatally.

The hippocampus (see Figure 2-25) is critical to memory (Section 14-3) and vulnerable to stress (Section 6-5).

Cell migration begins shortly after the first neurons are generated and continues for about 6 weeks in the cerebral cortex (and throughout life in the hippocampus). Cell differentiation, in which neuroblasts become specific types of neurons, follows migration. Cell differentiation is essentially complete at birth, although neuron maturation, which includes the growth of dendrites, axons, and synapses, goes on for years and in some parts of the brain may continue throughout adulthood. The cortex is organized into layers distinctly different from one another in their cellular makeup. How does this arrangement of differentiated areas develop? Neuroscientist Pasko Rakic and his colleagues (e.g., Geschwind & Rakic, 2013) have been finding answers to this question for more than four decades. Apparently, the subventricular zone contains a primitive cortical map that predisposes cells formed in a certain ventricular region to migrate to a certain

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cortical location. One subventricular region may produce cells destined to migrate to the visual cortex; another might produce cells destined to migrate to the frontal lobes, for example. How do the migrating cells know where to find these different parts of the cortex? They follow a path made by radial glial cells. A glial fiber from each of these path-making cells extends from the subventricular zone to the cortical surface, as illustrated in Figure 810A. The close-up views in Figures 8-10B and C show that neural cells from a given subventricular region need only follow the glial road to end up in the correct location.

FIGURE 8-10 Neuronal Migration (A) Neuroscientists hypothesize that the cortical map is represented in the subventricular zone. (B) Radial glial fibers extend from the subventricular zone to the cortical surface. (C) Neurons migrate along the radial glial fibers that take them from the protomap in the subventricular zone to the corresponding region in the cortex. Information from Rakic, 1974.

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As the brain grows, the glial fibers stretch but still go to the same place. Figure 8-10B also shows a cell moving across the radial glial fibers. Although most cortical neurons follow the radial glial fibers, a small number appear to migrate by seeking some type of chemical signal. Cortical layers develop from the inside out, much like adding floors to a house. The neurons of innermost layer VI migrate to their locations first, followed by those destined for layer V and so on, as successive waves of neurons pass earlier-arriving neurons to assume progressively more exterior positions in the cortex. And, as with building a house from the ground up, where materials needed to build higher floors must pass through lower floors to get to their destinations, so do the new cells migrate through the lower layers. Figure 2-22 contrasts the sensory and motor cortices’ six distinct layers and their functions.

To facilitate house construction, each new story has a blueprintspecified dimension, such as 10 feet high. How do neurons determine how thick a cortical layer should be? This is a tough question, especially when you consider that the cortical layers are not all the same thickness. Local environmental signals—chemicals produced by other cells— likely influence the way cells form layers in the cortex. These intercellular signals progressively restrict the choice of traits a cell can express, as illustrated in Figure 8-11. Thus, the emergence of distinct cell types in the brain results not from the unfolding of a specific

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genetic program but rather from the interaction of genetic instructions, timing, and signals from other cells in the local environment.

FIGURE 8-11 Cellular Commitment As also shown in Figure 8-8, precursor cells have unlimited possibilities, but as they develop, interacting genetic, maturational, and environmental influences increasingly steer them toward developing into a particular cell type.

Neuronal Maturation After neurons migrate to their destination and differentiate, they begin to mature by first growing dendrites to provide surface area for synapses with other cells and then extending their axons to appropriate targets to initiate synapse formation. Two events take place in dendrite development: dendritic arborization (branching) and the growth of dendritic spines. As illustrated in Figure 8-12, dendrites in newborn babies begin as individual processes protruding from the cell body. In the first 2 years of life, dendrites undergo arborization: They develop increasingly complex extensions that look much like leafless tree branches. The 872

dendritic branches then begin to form spines, where most synapses on dendrites are located.

FIGURE 8-12 Neuronal Maturation in Cortical Language Areas In postnatal cortical differentiation—shown here around Broca’s area, which controls speaking— neurons begin with simple dendritic fields that become progressively more complex until a child reaches about 2 years old. Brain maturation thus parallels a behavioral development: the emergence of language. Book: E. Lenneberg. Biological Foundations of Language, New York: Wiley, 1967, pp. 160–161.

Although dendritic development begins prenatally in humans, it continues for a long time after birth, as Figure 8-12 shows. Dendritic growth proceeds at a slow rate, on the order of microns (μm, millionths of a meter) per day. Contrast this with the development of axons, which grow on the order of a millimeter per day—about a thousand times faster. The disparate developmental rates of axons and dendrites are 873

Recall from Section 3-1 that dendrites collect information and that axons transmit information to other neurons.

important because the faster-growing axon can reach its target cell before the cell’s dendrites are completely formed. Thus, the axon may play a role in dendritic differentiation and ultimately in neuron function —for example, as part of the brain’s visual, motor, or language circuitry. Abnormalities in neuronal maturation rate can produce abnormalities in patterns of neural connectivity, as explained in Clinical Focus 8-2, Autism Spectrum Disorder.

CLINICAL FOCUS 8-2

Autism Spectrum Disorder In the 1940s, Leo Kanner and Hans Asperger first used the term autism (from the Greek autos, meaning “self”) to describe children who seem to live in their own world. Some were classified as intellectually disabled; others seemed to function intellectually. The contemporary term autism spectrum disorder (ASD) accommodates this behavioral range to include children with mild and severe symptoms. Severe symptoms include greatly impaired social interaction, a bizarre and narrow range of interests, marked abnormalities in language and communication, and fixed, repetitive movements. The autism spectrum includes classic autism and related disorders. Asperger syndrome, for example, is distinguished by an obsessive interest in a single topic or object to the exclusion of nearly any other. Children with Asperger are socially awkward and also usually have delayed motor skill

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development. Rett syndrome, characterized by poor expressive language and clumsy hand use, almost exclusively affects girls. The rate of ASD has been rising over the past four decades, from fewer than 1 person in 2000 in 1980 to the 2016 estimate by the Centers for Disease Control and Prevention that as many as 1 in 68 children has some form of autism. The cause of this increased incidence is uncertain. Suggestions include changes in diagnostic criteria, diagnosis of children at a younger age, and epigenetic influences. Although it knows neither racial nor ethnic nor social boundaries, ASD is four times as prevalent in boys as in girls.

Children with ASD often look typical, but some physical anomalies do characterize the condition. The corners of the mouth may be low compared with the upper lip (left), and the tops of the ears may flop over (right). The ears may be a bit lower than average and have an almost square shape.

The behavior of many children with ASD is noticeable from birth. To avoid physical contact, these babies arch their backs and pull away from caregivers or grow limp when held. But approximately one-third of children

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develop typically until somewhere between 1 and 3 years of age, when symptoms of autism emerge. Perhaps the most recognized characteristics of ASD are failure to interact socially, repetitive rocking or hand flapping, impairments in language development, and resistance to any change in routine. Some children on the autism spectrum are severely impaired; others learn to function quite well. Still others display savant syndrome, a narrow range of exceptional abilities such as in music, art, or mathematics, often accompanied by severe cognitive deficits. The brains of children diagnosed with ASD look remarkably typical. One emerging view is that these brains are characterized by unusual neuronal maturation rates. MRI studies show that at about 6 months of age, the autistic brain’s growth rate accelerates to the point that its total volume is 6 percent to 10 percent greater than that of typical children. Excessive brain volume is especially clear in the amygdala (Nordahl et al., 2012) and in the temporal and frontal lobes, the latter showing greater gray matter volume (see the review by Chen et al., 2011). The subcortical amygdala plays an important role in generating fear, and the social withdrawal component of ASD may be related to the enlarged amygdala. Accelerated brain growth associated with enlarged regions suggests that connections between cerebral regions are atypical, which would in turn produce atypical functioning. What leads to such brain development? More than 100 genetic differences have been described in children with ASD, so it is clear that no “autism gene” is at work. The mechanism that translates genetic irregularities into the autistic brain is unknown but likely includes epigenetic factors that could be prenatal, postnatal, or both. Women who have been exposed to rubella (German measles) in the first trimester of pregnancy have an increased risk of giving birth to a child who develops ASD. Researchers also suspect that industrial toxins can trigger autism, but the cause or causes remain uncertain.

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No medical interventions exist for ASD. Behavioral therapies are the most successful, provided they are intense (20 to 40 hours per week) and the therapists are trained practitioners. The earlier interventions begin, the better the prognosis. Neuroscience has so far offered little insight into why behavioral therapies are effective, although in an animal model of autism, Raza and colleagues (2015) showed that tactile stimulation from birth until weaning reverses many morphological abnormalities in cortical neurons, suggesting a possible mechanism. Autism may appear puzzling because no evolutionary advantage for its symptoms is apparent, but perhaps one exists. Characteristically, children with ASD are overly focused on specific tasks or information. The ability to concentrate on a complex problem for extended periods, it is suggested, is the basis for humankind’s development and for cultural advances. But too much of such a good thing may lead to conditions such as ASD.

Axon connections present a significant engineering problem for the developing brain. An axon might connect to a cell that is millimeters or even a meter away in the developing brain, and the axon must find its way through complex cellular terrain to get there. Genetic– environmental interaction is at work again, as various molecules that attract or repel the approaching axon tip guide the formation of axonic connections. Santiago Ramón y Cajal was the first scientist to describe this developmental process a century ago. He called the growing tips of axons growth cones. Figure 8-13A shows that as growth cones extend, they send out shoots, analogous to fingers reaching out to find a pen on a cluttered desk. When one shoot, known as a filopod (pl. filopodia), reaches an appropriate target, the others follow.

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FIGURE 8-13 Seeking a Path (A) At the tip of this axon, nurtured in a culture, a growth cone sends out filopodia seeking specific molecules to guide the axon’s direction of growth. (B) Filopodia guide the growth cone toward a target cell that is releasing cell adhesion or tropic molecules, represented in the drawing by red dots.

Growth cones are responsive to cues from two types of molecules (Figure 8-13B): 1. Cell adhesion molecules (CAMs) are cell-manufactured molecules that either lie on the target cell’s surface or are secreted into the intercellular space. Some provide a surface to which growth cones can adhere, hence the name cellular adhesion molecule; others serve to attract or repel growth cones. 2. Tropic molecules, produced by the targets that the axons’ growth cones are seeking (tropic means “moving toward”; pronounced as in trope, not tropical), essentially tell growth cones to come over here (chemoattractive). They likely also tell other growth cones seeking different targets to keep away (chemorepulsive). Do not confuse tropic (guiding) molecules with the trophic (nourishing) molecules, discussed earlier, which support neuronal growth.

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Although Ramón y Cajal predicted their existence more than 100 years ago, tropic molecules have proved difficult to find. The best understood chemoattractive molecules are the netrins (from Sanskrit, meaning “to guide”). But the guidance of axon growth also entails telling axons where not to go. One class of these chemorepulsive molecules is called the semaphorins (Greek for “signal”), which act to prevent axon extension in their vicinity.

Synaptic Development The number of synapses in the human cerebral cortex is staggering, on the order of 1014, or 100,000 trillion. A genetic program that assigns each synapse a specific location could not possibly determine each spot for this huge number. As with all other stages of brain development, only the general outlines of neuronal connections in the brain are likely to be genetically predetermined. The vast array of specific synaptic contacts is then guided into place by a variety of local environmental cues and signals. A human fetus displays simple synaptic contacts in the fifth gestational month. By the seventh gestational month, synaptic development on the deepest cortical neurons is extensive. After birth, synapse numbers increase rapidly. In the visual cortex, synaptic density almost doubles between ages 2 months and 4 months and then continues to increase until age 1 year. Not all synapses in the developing visual cortex are visually related, however, leading to a phenomenon called synesthesia, which is the ability to perceive a sensation of one sense as a sensation of another sense, as when sound leads to a sense of color (see Section 15-5 for a more detailed discussion of this phenomenon).

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Cell Death and Synaptic Pruning To carve statues, sculptors begin with blocks of stone and chisel away the unwanted pieces. The brain does something similar during cell death and synaptic pruning. The chisel in the brain could be a genetic signal, an experience, reproductive hormones, stress, or even SES. The effects of these chisels can be seen in changes in cortical thickness over time, as illustrated in Figure 8-14, an atlas of brain images. The cortex actually becomes measurably thinner in a caudal–rostral (back-to-front) gradient, a process that is probably due both to synaptic pruning and to white matter expansion. This expansion stretches the cortex, leading to increased surface area, as illustrated in Research Focus 8-1.

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FIGURE 8-14 Progressive Changes in Cortical Thickness MRI scans track the maturation of gray matter in typical development, revealing the length and pattern of maturation from the back of the cortex to the front. Cortical thinning and increased surface area progress together. Courtesy Paul M Thompson/Laboratory of Neuro Imaging, Keck School of Medicine of USC.

The graph in Figure 8-15 plots this rise and fall in synaptic density. Pasko Rakic (1974) estimated that at the peak of synapse loss, a person may lose as many as 100,000 per second. Synapse elimination is extensive and prolonged. Peter Huttenlocher (1994) estimated that the process affects 42 percent in the human cortex and, in the prefrontal cortex, it continues into an individual’s thirties. We can only wonder what the behavioral consequence of this rapid synaptic loss might be. It is probably no coincidence that children, especially toddlers and adolescents, seem to change moods and behaviors quickly.

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FIGURE 8-15 Synapse Formation and Pruning Changes in the relative density of synapses in the human visual cortex and prefrontal cortex (its frontmost part) as a function of age. Data from Bourgeois, 2001.

How does the brain eliminate excess neurons? The simplest explanation is competition, sometimes referred to as neural Darwinism. Charles Darwin believed that one key to evolution is the variation it produces in the traits possessed by a species. Those whose traits are best suited to the local environment are most likely to survive. From a Darwinian perspective, then, more animals are born than can survive to adulthood, and environmental pressures weed out the less fit ones. Similar pressures cause neural Darwinism. What exactly causes this cellular weeding out in the brain? It turns out that when neurons form synapses, they become somewhat

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dependent on their targets for survival. In fact, deprived of synaptic targets, neurons eventually die. They die because target cells produce neurotrophic (nourishing) factors absorbed by the axon terminals that function to regulate neuronal survival. Nerve growth factor (NGF), for example, is made by cortical cells and absorbed by cholinergic neurons in the basal forebrain. If many neurons compete for a limited amount of a neurotrophic factor, only some can survive. The death of neurons deprived of a neurotrophic factor is different from the cell death caused by injury or disease. When neurons are deprived of a neurotrophic factor, certain genes seem to be expressed, resulting in a message for the cell to die. This programmed process is called apoptosis. Apoptosis accounts for the death of overabundant neurons, but it does not account for the synaptic pruning from cells that survive. In 1976, French neurobiologist Jean-Pierre Changeux proposed a theory for synapse loss that also is based on competition (Changeux & Danchin, 1976). According to Changeux, synapses persist into adulthood only if they have become members of functional neural networks. If not, they are eventually eliminated from the brain. We can speculate that environmental factors such as hormones, drugs, and experience would influence active neural circuit formation and thus influence synapse stabilization and pruning. In addition to outright errors in synapse formation that give rise to synaptic pruning, subtler changes in neural circuits may trigger the same process. One such change accounts for the findings of Janet Werker and Richard Tees (1992), who studied the ability of infants to discriminate speech sounds taken from widely disparate languages, 883

such as English, Hindi (from India), and Salish (a Native American language). Their results show that young infants can discriminate speech sounds of different languages without previous experience, but their ability to do so declines in the first year of life. An explanation for this declining ability is that synapses encoding speech sounds not typically encountered in an infant’s daily environment are not active simultaneously with other speech-related synapses. As a result, they are eliminated. Synaptic pruning may also allow the brain to adapt more flexibly to environmental demands. Human culture is probably the most diverse and complex environment with which any animal must cope. Perhaps the flexibility in cortical organization achieved by the mechanism of selective synaptic pruning is a necessary precondition for successful development in a cultural environment. Synaptic pruning may also be a precursor related to different perceptions that people develop about the world. Consider, for example, the obvious differences in Eastern and Western philosophies about life, religion, and culture. Given the cultural differences to which people in the East and West are exposed as their brain develops, imagine how different their individual perceptions and cognitions may be. Considered together as a species, however, we humans are far more alike than we are different. An important and unique characteristic common to all humans is language. As illustrated in Figure 8-14, the cortex generally thins from age 5 to age 20. The sole exception is that major language regions of the cortex actually show an increase in gray matter. Figure 8-16 contrasts the thinning of other cortical regions with the thickening of 884

language-related regions (O’Hare& Sowell, 2008). A different pattern of development for brain regions critical in language processing makes sense, given language’s unique role in cognition and the long learning time.

FIGURE 8-16 Gray Matter Thickness Brain maps showing the statistical significance of yearly change in cortical thickness measures taken from MRIs. Shading represents increasing (white) or decreasing (red) cortical thickness. Research from Sowell, Thompson, & Toga, 2004.

Glial Development Astrocytes and oligodendrocytes begin to develop after most neurogenesis is complete and continue to develop throughout life. Radial glial cells form during embryonic development, and most of them differentiate into astrocytes once neural migration along them is complete. Others remain in the subventricular zone and later can give rise to neurons, oligodendrocytes, and more astrocytes (for a review, see Arai & Lo, 2017). Astrocytes play a key role in synaptic pruning during development and contribute to plasticity throughout life (for a review, see Zuchero & Barres, 2015). Oligodendroctyes myelinate axons, which increases the efficiency of axonal function. Consequently, myelination is a useful rough index of cerebral maturation. 885

Astrocytes nourish and support neurons; oligodendroglia form myelin in the CNS (see Table 3-1).

In the early 1920s, Paul Flechsig noticed that cortical myelination begins just after birth and continues until at least 18 years of age. He also noticed that some cortical regions were myelinated by age 3 to 4 years, whereas others showed virtually no myelination at that time. Figure 8-17 shows one of Flechsig’s cortical maps with areas shaded according to earlier or later myelination.

FIGURE 8-17 Progress of Myelination The fact that the light-colored zones are very late to myelinate led Flechsig to propose that they are qualitatively different in

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function from those that mature earlier.

Flechsig hypothesized that the earliest-myelinating areas control simple movements or sensory analyses, whereas the latest-myelinating areas control the highest mental functions. MRI analyses of myelin development in the cortex show that white matter thickness largely does correspond to the progress of myelination, confirming Flechsig’s ideas. Myelination continues until at least 20 years of age, as illustrated in Figure 8-18, which contrasts total brain volume, gray matter volume, and white matter volume during brain development in females and males.

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FIGURE 8-18 Sex Differences in Brain Development Mean brain volume by age in years for males (green) and females (orange). Arrows above the curves indicate that females show more rapid growth than males, reaching maximum overall volume (A) and gray matter volume (B) sooner. Decreasing gray matter corresponds to cell and synaptic loss. Increasing white matter volume (C) largely corresponds to myelin development. Information from Lenroot et al., 2007.

Unique Aspects of Frontal Lobe Development The imaging atlas in Figure 8-14 confirms that the frontal lobe is the last brain region to mature. Since the atlas was compiled, neuroscientists have confirmed that frontal lobe maturation extends far beyond its age 20 boundary, including in the dorsolateral prefrontal cortex (DLPFC). The DLPFC, which comprises Brodmann areas 9 and 46, makes reciprocal connections with the posterior parietal cortex and the superior temporal sulcus: it selects behavior and movement with respect to temporal memory. Zdravko Petanjek and colleagues (2011) analyzed synaptic spine density in the DLPFC in a large sample of human brains ranging in age at death from newborn to 91 years. Three-dimensional atlases guide researchers to the precise locations of various brain regions (Section 7-1). See Sections 12-4 and 15-3 for more on how the DLPFC functions.

The analysis confirms that dendritic spine density, a good measure of the number of excitatory synapses, is two to three times greater in children than in adults and that spine density begins to decrease during

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puberty. The analysis also shows that dendritic spines continue to be eliminated well beyond age 20, stabilizing at the adult level around age 30. Two important correlates attend slow frontal lobe development: 1. The frontal lobe is especially sensitive to epigenetic influences (Kolb et al., 2012). In a study of more than 170,000 people, Robert Anda and colleagues (Anda et al., 2006) show that aversive childhood experiences (ACEs) such as verbal or physical abuse, a family member’s addiction, or loss of a parent are predictive of physical and mental health in middle age. People with two or more ACEs, for example, are 50 times more likely to acquire addictions or attempt suicide. Women with two or more ACEs are 5 times more likely to have been sexually assaulted by age 50. We hypothesize that early aversive experiences promote ACE-related susceptibilities by compromising frontal lobe development. The Adverse Childhood Experience (ACE) Questionnaire is available online, where you can view and answer the questions.

2. The trajectory of frontal lobe development correlates with adult intelligence. Two important features of frontal lobe development are (a) the reduction in cortical thickness and (b) the increase in connectivity between the medial regions of the frontal lobe, the posterior regions of the cingulate cortex, and the lateral regions of the parietal lobe, which together are referred to as the default network (see Figure 8-19). The trajectory of change in cortical thickness, which continues until late adolescence, and the increased connectivity in the default network, which appears adult-like by about age 13, is related to intelligence. Thus, children who score

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highest in intelligence show the greatest plastic changes in the frontal lobe over time.

FIGURE 8-19 The Default Network These regions of the cerebral cortex that show increased connectivity related to intelligence form the default network. Data after Sherman et al., 2014.

8-2 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. The central nervous system begins as a sheet of cells, which folds inward to form the . 2. The growth of neurons is referred to as formation of glial cells is known as

, whereas .

3. Growth cones are responsive to two types of cues: and .

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4. The adolescent period is characterized by two ongoing processes of brain maturation: and 5. What is the functional significance of the prolonged development of the frontal lobe?

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8-3 Using Emerging Behaviors to Infer Neural Maturation As brain areas mature, a person’s behaviors correspond to the functions of the maturing areas. Stated differently, behaviors cannot emerge until the requisite neural machinery has developed. When that machinery is in place, however, related behaviors develop quickly through stages and are shaped significantly by epigenetic factors. Researchers have studied these interacting changes in the brain and behavior, especially in regard to the emergence of motor skills, language, and problem solving in children. We now explore development in these three areas.

Motor Behaviors Developing locomotion skills are easy to observe in human infants. At first, babies cannot move about independently, but eventually, they roll over, then crawl, then walk. Other motor skills develop in less obvious but no less systematic ways. Shortly after birth, infants are capable of flexing their arms in such a way that they can scoop something toward their body, and they can direct a hand, as toward a breast when suckling. Between 1 and 3 months of age, babies also begin to make spontaneous hand and digit

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movements consisting of almost all the skilled finger movements they will make as an adult—a kind of motor babbling. These movements at first are directed toward handling parts of their body and their clothes (Wallace & Whishaw, 2003). Only then are reaching movements directed toward objects in space. Tom Twitchell (1965) studied and described how the ability to reach for objects and grasp them progresses in stages, illustrated in Figure 820.

FIGURE 8-20 Development of the Grasping Response of Infants. Information from Twitchell, 1965.

Between 8 and 11 months, infants’ grasping becomes more sophisticated as the pincer grasp, employing the index finger and the thumb, develops. The pincer grasp is significant developmentally: it allows babies to make the very precise finger movements needed to manipulate small objects. What we see, then, is a sequence in the development of grasping: first scooping, then grasping with all the fingers, then grasping with independent finger movements.

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If increasingly well-coordinated grasping depends on the emergence of certain neural machinery, anatomical changes in the brain should accompany the emergence of these motor behaviors. Such changes do take place, especially in the development of dendritic arborizations and in fiber connections between neocortex and spinal cord. And a correlation has been found between myelin formation and the ability to grasp (Yakovlev & Lecours, 1967). A classic symptom of motor cortex damage, detailed in Section 11-1, is permanent loss of the pincer grasp.

In particular, a group of axons from motor cortex neurons myelinate at about the same time that whole-hand reaching and grasping develop. Another group of motor cortex neurons known to control finger movements myelinates at about the time that the pincer grasp develops. MRI studies of changes in cortical thickness show that increased motor dexterity is associated with decreased cortical thickness in the hand region of the left motor cortex of right-handers (Figure 8-21A). It might seem odd that both cortical thinning and thickening can be associated with improved performance, but the reason is straightforward. Thinning partly reflects the pruning of neurons and synapses throughout development, whereas thickening reflects the addition of synapses, along with associated astrocytes and blood vessels related to learning.

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FIGURE 8-21 Correlations Between Gray Matter Thickness and Behavior (A) Red shading corresponds to regions showing significant cortical thinning correlated with improved motor skills. (B) White shading corresponds to regions showing significant cortical thickening correlated with improved language skills. (C) Red shading shows regions of decreased cortical thickness correlated with improved vocabulary scores. (A) and (B): Research from Lu et al., 2007; (C): Research from Sowell, Thompson, Leonard et al., 2004.

Principle 6: Brain systems are organized hierarchically and in parallel.

We can now make a simple prediction. If specific motor cortex neurons are essential for adult-like grasping movements to emerge, removing those neurons should make an adult’s grasping ability similar to a young infant’s, which is in fact what happens.

Language Development According to Eric Lenneberg (1967), children reach certain important speech milestones in a fixed sequence and at constant chronological ages. Children start to form a vocabulary by 12 months. Their 5- to 10-word repertoire typically doubles over the next 6 months. By 2 years, vocabulary will range from 200 to 300 words that include mostly everyday objects. In another year, vocabulary approaches 1000 words and begins to include simple sentences. At 6 years, children 896

boast a vocabulary of about 2500 words and can understand more than 20,000 words en route to an adult vocabulary of more than 50,000 words. Although language skills and motor skills generally develop in parallel, the capacity for language depends on more than the ability to make controlled movements of the mouth, lips, and tongue. Precise movements of the muscles controlling these body parts develop well before children can speak. Furthermore, even when children have sufficient motor skill to articulate most words, their vocabulary does not rocket ahead but rather progresses gradually. A small proportion of children (about 1 percent) have typical intelligence and motor skill development, yet their speech acquisition is markedly delayed. Such children might not begin to speak in phrases until after age 4, despite an apparently healthy environment and the absence of any obvious neurological signs of brain damage. Because the timing of speech onset appears universal in the remaining 99 percent of children across all cultures, something different has likely taken place in the brain maturation of a child with late language acquisition. The difficulty comes in specifying that difference. Because the age of language onset is usually between 1 and 2 years and language acquisition is largely complete by age 12, the best strategy for determining the reasons for these differences is to consider how the cortex is different before and after these two milestones. By age 2, cell division and migration are complete in the language zones of the cerebral cortex. The major changes that take

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place from ages 2 to 12 are in neuronal connectivity and myelination of the speech zones. Changes in dendritic complexity in speech zones are among the most impressive in the brain. Recall from Figure 8-12 that the axons and dendrites of the speech zone called Broca’s area are simple at birth but grow dramatically denser at age 15 to 24 months. This neuronal development correlates with an equally dramatic change in language ability, given that a baby’s vocabulary starts to expand rapidly at about age 2. We can therefore infer that language development may be constrained, at least in part, by the maturing language areas in the cortex. Individual differences in the speed of language acquisition may be accounted for by differences in this neural development. Children with early language ability may have an early-maturing speech zone, whereas this zone may develop later in children with delayed language onset. Research Focus 7-1 describes research on newborns’ reactions to language.

Results of MRI studies of the language cortex show that, in contrast with the thinning of motor cortex associated with enhanced dexterity shown in Figure 8-21A, there is a thickening of the left inferior frontal cortex areas associated with enhanced phonological processing (understanding speech sounds), as shown in Figure 8-21B. The unique association between cortical thickening and phonological

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processing is not due to a general relationship between all language functions and cortical thickening, however. Figure 8-21C shows significant thinning of diffuse cortical regions associated with better vocabulary—regions outside the language areas—and vocabulary is one of the best predictors of general intelligence.

Development of Problem-Solving Ability The first researcher to try to identify discrete stages of cognitive development was psychologist Jean Piaget (1952). He realized that he could infer children’s understanding of the world by observing their behavior. For example, a baby who lifts a cloth to retrieve a hidden toy shows an understanding that objects continue to exist even when out of sight. This understanding of object permanence is revealed by the behavior of the infant in the top row of photographs in Figure 822.

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FIGURE 8-22 Two Stages of Cognitive Development The infant shows that she understands object permanence—that things continue to exist when they are out of sight (top). The young girl does not yet understand the principle of conservation of liquid volume. Beakers with identical volumes but different shapes seem to her to hold different amounts of liquid (bottom).

An absence of understanding also can be seen in children’s behavior, as shown by the actions of the 5-year-old girl in the bottom row of photographs in Figure 8-22. She was shown two identical beakers with identical volumes of liquid, then watched as one beaker’s liquid was poured into a shorter, wider beaker. When asked which beaker contained more liquid, she pointed to the taller beaker, not understanding that the amount of liquid remains constant despite the difference in appearance. Children display an understanding of this principle, the conservation of liquid volume, at about age 7. By studying children engaged in such tasks, Piaget concluded that cognitive development is a continuous process. Children’s strategies for exploring the world and their understanding of it are constantly changing. These changes are not simply the result of acquiring specific pieces of new knowledge. Rather, at certain points in development, fundamental changes take place in the organization of a child’s strategies for learning about the world and for solving problems. With these developing strategies comes new understanding. Piaget identified four major stages of cognitive development, summarized in Table 8-2:

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Stage I is the sensorimotor period, from birth to about 18 to 24 months of age. During this time, babies learn to differentiate themselves from the external world, come to realize that objects exist even when out of sight, and gain some understanding of cause and effect. Stage II, the preoperational period, takes place at age 2 to 6 years. Children gain the ability to form mental representations of things in their world and to represent those things in words and drawings. Stage III is the period of concrete operations, which typically occurs around 7 to 11 years. Children learn to mentally manipulate ideas about material (concrete) things such as volumes of liquid, dimensions of objects, and arithmetic problems. Stage IV, the period of formal perations, is attained sometime after age 11. Children are now able to reason in the abstract, not just in concrete terms.

TABLE 8-2 Piaget’s Stages of Cognitive Development Approximate typical age range (yr)

Description of stage

0–2

I: Sensorimotor Experiences the world through senses and actions (looking, touching, mouthing)

Object permanence Stranger anxiety

2–6

II: Preoperational Represents things with words and images but lacks logical reasoning

Pretend play Egocentrism Language development

7–11

III: Concrete operational Thinks logically about concrete events; grasps concrete analogies and performs arithmetical operations

Conservation Mathematical transformations

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Developmental phenomena

12+

IV: Formal operational Reasons abstractly

Abstract logic Potential for mature moral reasoning

Adapted from Myers, 2015.

Although there have been many revisions to Piaget’s stage theory in the nearly 70 years since it was first proposed, we can still take Piaget’s stages as rough approximations of qualitative changes that take place in children’s thinking as they grow older, and we can ask what neural changes might underlie them. One place to look for brain changes is in the relative rate of brain growth. After birth, brain and body do not grow uniformly but rather during irregularly occurring periods commonly called growth spurts. In his analysis of ratios of brain weight to body weight, Herman Epstein (1979) found consistent spurts in brain growth between 3 and 10 months (accounting for an increase of 30 percent in brain weight by age 18 months), as well as ages 2 to 4, 6 to 8, 10 to 12, and 14 to 16+ years. The increments in brain weight were about 5 percent to 10 percent in each of these 2-year periods. Brain growth takes place without a concurrent increase in the number of neurons, so it is most likely due to the growth of glial cells, blood vessels, myelin, and synapses. Although synapses themselves would be unlikely to add much weight to the brain, their growth is accompanied by increased metabolic demands that cause neurons to become larger, new blood vessels to form, and new astrocytes to be produced for neuronal support and nourishment.

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We would expect such an increase in cortical complexity to generate more complex behaviors, so we might predict significant, perhaps qualitative, changes in cognitive function during each growth spurt. The first four brain growth spurts Epstein identified coincide nicely with the four main stages of cognitive development Piaget described. Such correspondence suggests significant alterations in neural functioning with the onset of each cognitive stage. At the same time, differences in the rate of brain development, or perhaps in the rate at which specific groups of neurons mature, may account for individual differences in the age at which the various cognitive advances identified by Piaget emerge. Although Piaget did not identify a fifth stage of cognitive development in later adolescence, a growth spurt that occurs then implies one. Growth spurts are superficial measures of changes taking place in the brain. To link them to cognitive development, we need to know at a deeper level what neural events are contributing to brain growth and just where they are taking place. A way to find out is to observe healthy children’s attempts to solve specific problems that are diagnostic of damage to discrete brain regions in adults. If children perform a particular task poorly, then whatever brain region regulates that task must not yet be mature. Similarly, if children can perform one task but not another, the tasks apparently require different brain structures, and these structures must mature at different rates. William Overman and Jocelyne Bachevalier (Overman et al., 1992) used this logic to study the development of forebrain structures required for learning and memory in young children and in monkeys.

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The Procedure section of Experiment 8-1 shows the three intelligence test items presented to their participants. The first task was simply to learn to displace an object to obtain a food reward. When participants had learned the displacement task, they were trained in two more tasks believed to measure temporal lobe and basal ganglia functioning, respectively. EXPERIMENT 8-1

Question: In what sequence do the forebrain structures required for learning and memory mature? Procedure

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Results Both human and monkey infants learn the concurrent-discrimination task at a younger age than the nonmatching-to-sample task. Conclusion: Neural structures underlying the concurrent-discrimination task mature sooner than those underlying the nonmatching-to-sample task. Research from Overman et al., 1992.

In the nonmatching-to-sample task, participants were shown an object they could displace to receive a food reward. After a brief (15second) delay, two objects were presented: the first object and a novel object. The participants then had to displace the novel object to obtain the food reward. Nonmatching to sample is thought to measure object recognition, which is a temporal lobe function. The participant can find the food only by recognizing the original object and not choosing it. In the third task, concurrent discrimination, participants were presented with a pair of objects and had to learn that one object in that pair was always associated with a food reward, whereas the other object was never rewarded. The task was made more difficult by sequentially giving participants 20 different object pairs. Each day, they were presented with one trial per pair. Concurrent discrimination is thought to measure trial-and-error learning of specific object information, a function of the basal ganglia. Healthy adults easily solve both the nonmatching and the concurrent tasks but report that the concurrent task is more difficult because it requires remembering far more information. The key

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question developmentally is whether there is a difference in the ages at which children (or monkeys) can solve these two tasks. It turns out that children can solve the concurrent task by about 12 months of age, but not until about 18 months can they solve what most adults believe to be the easier nonmatching task. These results imply that the basal ganglia, the critical area for the concurrent discrimination task, mature more quickly than the temporal lobe, the critical region for the nonmatching-to-sample task.

A Caution about Linking Correlation to Causation Throughout this section, we have described research results implying that changes in the brain cause changes in behavior. Neuroscientists assert that by looking at behavioral development and brain development in parallel, they can make some inferences regarding the causes of behavior. Bear in mind, however, that the fact that two things correlate (take place together) does not prove that one of them causes the other. The correlation–causation problem raises red flags in brain and behavior studies because research in behavioral neuroscience, by its very nature, is often based on correlations. For example, knowing that children with a specific neurodevelopmental disorder were exposed to nicotine in utero does not prove that nicotine caused the disorder, but it does provide a powerful source of insight into the potential cause of the disorder.

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8-3 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. The last stage in motor development in infants is the ability to make . 2. Language development is correlated with cortical thinning related to and cortical thickening related to . 3. Brain growth spurts correlate with

4. The nonmatching-to-sample task is believed to measure the function of the ; the concurrent-discrimination learning task is believed to measure the function of the . 5. Describe a major challenge in inferring changes in brain development from the emergence of behaviors.

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8-4 Brain Development and the Environment Principle 2: Neuroplasticity is the hallmark of nervous system functioning.

Developing behaviors are shaped not only by the maturation of brain structures but also by each person’s environment and experience. Neuroplasticity suggests that the brain can be molded, at least at the microscopic level. Brains exposed to different environmental experiences are molded in different ways. For example, culture is an important aspect of the human environment, so culture must help mold the human brain. We would therefore expect people raised in widely differing cultures to acquire brain structure differences that have lifelong effects on their behavior. Section 1-5 summarizes humanity’s acquisition of culture. Section 15-3 discusses the emerging field of social neuroscience.

The brain is plastic not only in response to external events but also in response to events within a person’s body, including the effects of hormones, injury, and genetic mutations. The developing brain early in life is especially responsive to these internal factors, which in turn alter how the brain responds to external experiences. In this section, we explore a whole range of external and internal environmental influences

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on brain development. We start with a question: Exactly how does experience alter brain structure?

Experience and Cortical Organization Researchers can study the effects of experience on the brain and behavior by placing laboratory animals in different environments and observing the results. In one of the earliest such studies, Donald Hebb (1947) took a group of young laboratory rats home and let them grow up in his kitchen. A control group grew up in standard laboratory cages at McGill University. The Hebb synapse, diagrammed in Section 15-1, illustrates Hebb’s predictions about synaptic plasticity. Section 14-4 elaborates his contributions to learning theory.

The home-reared rats had many experiences that the caged rats did not, including being chased with a broom by Hebb’s less-thanenthusiastic wife. Subsequently, Hebb gave both groups a rat-specific intelligence test that consisted of learning to solve a series of mazes, collectively known as Hebb–Williams mazes. Figure 8-23 shows a sample maze. Home-reared rats performed far better on these tasks than caged rats did. Hebb therefore concluded that experience must influence intelligence.

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FIGURE 8-23 Hebb–Williams Maze In this version of the maze, a rat is placed in the start box (S) and must learn to find the food in the goal box (G). Investigators can reconfigure the walls of the maze to set new problems. Rats raised in complex environments solve such mazes much faster than do rats raised in standard laboratory cages.

On the basis of his research, Hebb reasoned that people reared in a stimulating environment will maximize their intellectual development, whereas people raised in impoverished or under-resourced

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environments, such as those described in the SES study in Research Focus 8-1, will not reach their intellectual potential. Although a generalization, Hebb’s reasoning seems logical. But how do we define an environment as stimulating or impoverished? People living in slums typically have few formal educational resources—decidedly not an enriched setting—but that does not mean that the environment offers no cognitive stimulation or challenge. On the contrary, people raised in slums are better adapted for survival in a slum than are people raised in upper-class homes. Does this adaptability make them more intelligent in a certain way? Could it make them more resilient? On the other hand, slum dwellers may not be well adapted for college life. This is probably closer to what Hebb had in mind when he referred to an impoverished environment as limiting intellectual potential. Indeed, Hebb’s logic influenced the development of preschool television programs, such as Sesame Street, that offer enrichment for children who would otherwise have little preschool exposure to reading. At 36 months of age, on average, the vocabulary of children from a low-SES environment is less than one-third that of high-SES children (400 versus 1200 words). This difference grows wider as children develop. It is hypothesized to result from less direct conversation with caregivers and less reading to the children by caregivers. Estimates suggest that by age 4, low-SES children have been exposed to about 30 million fewer words than high-SES children (see review by Kolb & Gibb, 2015)!

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The weaker language skills demonstrated by children of low SES is related to the size of cortical language areas as early as age 5 years (Raizada et al., 2008). Patricia Kuhl (2011) makes the important point that SES itself is not the variable that drives the effects on language and brain development. Rather, SES is likely a proxy for the opportunity to learn language, a point that takes us back to James Heckman’s thesis in Research Focus 8-1. Recall from the previous section that correlation does not prove causation.

Seven decades ago, Hebb’s studies used complex stimulating environments, but much simpler experiences can also influence brain development. Tactile stimulation of human infants—such as being held closely, massaged, or stroked—is important not only for bonding with caregivers but also for stimulating brain development. For example, tactile stimulation of premature infants in incubators speeds their growth and allows for quicker release from the hospital. Laboratory studies show that brushing infant rats for 15 minutes 3 times per day for the first 3 weeks of life also speeds up growth and development. The rats show enhanced motor and cognitive skills in adulthood as well. Tactile stimulation also dramatically improves recovery from brain injury incurred early in development. The idea that early experience can affect later behavior seems sensible enough, but we are left to question why experience should make such a difference. One reason is that experience changes neuronal structure, which is especially evident in the cortex. Neurons in the brains of animals raised in complex environments, such as that shown in Figure 8-24A, are larger and richer in synapses than are those of 913

animals reared in barren cages. Compare the neurons in Figure 8-24B. Similarly, 3 weeks of tactile stimulation in infancy increases synapse numbers all over the cortex in adulthood.

FIGURE 8-24 Enriched Environment, Enhanced Development (A) A complex environment for a group of about six rats allows the animals to move about and to interact with one another and with toys that are changed weekly. (B) Representative neurons from the parietal cortex of a laboratory-caged rat and a complexenvironment-housed rat; the latter has about 25 percent more dendritic space for synapses.

Research Focus 5-5 describes some structural changes that neurons undergo as a result of learning.

Presumably, increased synapse numbers result from increased sensory processing in a complex and stimulating environment. The

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brains of animals raised in complex settings also display more (and larger) astrocytes. Although complex-rearing studies do not address the effects of human culture directly, making predictions about human development on the basis of their findings is easy. We know that experience can modify the brain, so we can predict that different experiences might modify the brain differently. Take musical training, for example, as Research Focus 8-3, Keeping Brains Young by Making Music, explains.

RESEARCH FOCUS 8-3

Keeping Brains Young by Making Music Music is a widespread leisure activity that is known to increase brain plasticity and can lead to a wide range of benefits, including enhanced motor skills, increased intelligence, and increased verbal skills—especially when music training begins in childhood. Music is also known to have beneficial rehabilitative effects in stroke patients and those with Parkinson disease. There are now data suggesting that musical training is beneficial in forestalling the effects of aging on the brain (see review by Herholz & Zatorre, 2012). For example, musical practice reduces age-related declines in a variety of cognitive processes, including nonverbal memory and frontal lobe functions. Lars Rogenmoser and colleagues (2018) used a novel MRI-based procedure known as BrainAGE to investigate the impact of musical training on brain maturation. BrainAGE is based on a database of structural MRI data that aggregates brain structure across the whole brain to one single value— estimated brain age. Rogenmoser and colleagues found that, compared to amateur or professional musicians, nonmusicians exhibited higher BrainAGE scores, even in relatively young participants (mean ages of approximately 25 years). Thus, making music early in life appears to modulate the effect of aging on the brain. The BrainAGE procedure has applications beyond music.

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Using this procedure, Katje Franke and colleagues have shown in a series of papers that older estimated brain age is predictive of dementia (see Franke et al., 2014).

Depiction of the BrainAGE Concept MRI images of healthy brains at different ages provides a model of normal age-related changes. This graph shows a comparison of new brains with the archived brains to get an estimate of individual brain ages.

Not only does early musical training act to keep the brain young, but music can also be used as a therapy in old brains to make them act like younger brains. You may have noticed that young children often spontaneously break into dance when they hear music. The ability of music to stimulate movement has been used as a therapy to restore behaviors such as walking in patients with Parkinson disease. By hearing, or even mentally remembering, the tune of songs, such patients can move with the music rather than being frozen in place and unable to move.

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Like early exposure to language during development, early exposure to music alters the brain. Perfect (absolute) pitch, or the ability to recreate a musical note without external reference, is believed to require musical training during an early period, when brain development is most sensitive to this experience. Similarly, adults exposed only to Western music since childhood usually find Eastern music peculiar, even nonmusical, on first encountering it. Not only does early musical training alter brain development, it also acts to enhance healthy brain aging, much like learning a second language early in life. These examples demonstrate that early exposure to music alters neurons in the auditory system (see Levitin & Rogers, 2005). Figure 15-12 shows enhanced nerve tract connectivity in people with perfect pitch.

Such loss of plasticity does not mean that the adult human brain grows fixed and unchangeable. Adults’ brains are influenced by exposure to new environments and experiences, although more slowly and less extensively than children’s brains are. In fact, evidence reveals that experience affects the brain well into old age—good news for those of us who are no longer children (Kolb et al., 2003). We will return to the discussion of the impact of experience and environment in the context of abnormal brain development in the next section.

Experience and Neural Connectivity Experience can actually sculpt the brain prenatally, as studies of the developing visual system show clearly. A simple analogy will illustrate

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the anatomical challenge of connecting the visual receptors in the eyes to the rest of the visual system. Imagine that students in a large lecture hall are each viewing the front of the room (the visual field) through a small cardboard tube, such as an empty paper towel roll. If each student looks directly ahead, he or she will see only a small bit of the total visual field. Essentially, this is how the photoreceptor neurons in the eyes act. Each cell sees only a small bit of the visual field. The problem is putting all of the bits together to form a complete picture. To do so, analogously to students sitting side by side, receptors that see adjacent views must send their information to adjacent regions in the various parts of the brain’s visual system, such as the midbrain. How do they accomplish this feat? Section 9-2 describes visual system anatomy. Figure 2-19 details midbrain structures.

Roger Sperry (1963) suggested the chemoaffinity hypothesis, the idea that specific molecules in different cells in various midbrain regions give each cell a distinctive chemical identity. Each cell has an identifiable biochemical label. Presumably, incoming axons seek out a specific chemical, such as the tropic factors discussed in Section 8-2, and consequently land in the correct general midbrain region. Many experiments have shown this process to take place prenatally as the eye and brain are developing. But the problem is that chemical affinity directs incoming axons only to a general location. To return to

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our two adjacent retinal cells, how do they now place themselves in precisely the correct position? Here is where postnatal experience comes in: fine-tuning of neural placement is believed to be activity dependent. Because adjacent receptors tend to be activated at the same time, they tend to form synapses on the same neurons in the midbrain after chemoaffinity has drawn them to a general midbrain region. Figure 8-25 illustrates this process. Neurons A and G are unlikely to be activated by the same stimulus, so they seldom fire synchronously. Neurons A and B, in contrast, are apt to be activated by the same stimuli, as are B and C. Through this simultaneous activity and with the passage of time, cells eventually line up correctly in the connections they form.

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FIGURE 8-25 Chemoaffinity in the Visual System Neurons A through G project from the retina to the tectum in the midbrain. The activities of adjacent neurons (C and D, say) are more likely to coincide than are the activities of widely separated neurons such as A and G. As a result, adjacent retinal neurons are more likely to establish permanent synapses on the same tectal neurons. By using chemical signals, axons grow to the approximate location in the tectum (top). The connections become more precise with the passage of time (bottom).

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Now consider what happens to axons coming from different eyes. Although the neural inputs from the two eyes may be active simultaneously, neurons in the same eye are more likely to be active together than are cells in different eyes. The net effect is that inputs from the two eyes tend to organize themselves into neural bands, called columns, that represent the same region of space in each eye, as shown on the left in Figure 8-26. Formation of these segregated cortical columns therefore depends on the patterns of coinciding electrical activity on the incoming axons.

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FIGURE 8-26 Ocular Dominance Columns Typically in the postnatal development of the cat brain, axons from each eye enter the cortex, where they grow large terminal arborizations. (L, left eye; R, right eye).

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If experience is abnormal—for example, if one eye is covered during a crucial time in development—the neural connections will not be guided appropriately by experience. As shown at the right in Figure 826, the effect of suturing one eye closed has the most disruptive effect on cortical organization in kittens between 30 and 60 days after birth. In a child who has a “lazy eye,” visual input from that eye does not contribute to fine-tuning the neural connections as it should. So the details of those connections develop abnormally, much as if the eye had been covered. The resulting loss of sharpness in vision is amblyopia. To summarize, an organism’s genetic blueprint is vague in regard to exactly which connections in the brain go to exactly which neurons. Experience fine-tunes neural connectivity by modifying those details.

Critical Periods for Experience and Brain Development The preceding examples of perfect pitch and visual connectivity show that for healthy development, specific sensory experiences occurring at particular times are especially important. A time during which brain development is most sensitive to a specific experience is called either a critical period or a sensitive period. The absence of appropriate sensory experience during a critical period may result in abnormal brain development, leading to abnormal behavior that endures even into adulthood. Our colleague Richard Tees offered an analogy to help explain the concept. He pictured the developing animal as a little train traveling past an environmental setting, perhaps the Rocky Mountains. All the windows are closed at the beginning of the journey (prenatal development), but at particular 923

stages of the trip, the windows in certain cars open, exposing the occupants (different parts of the brain) to the outside world. Some windows open to expose the brain to specific sounds, others to certain smells, others to particular sights, and so on. This exposure affects the brain’s development, and the absence of any exposure through an open window severely disturbs that development. As the journey continues, the windows become harder to open, and finally they close permanently. This does not mean that the brain can no longer change, but changes become much harder to induce. Now imagine two different trains, one headed through the Rocky Mountains and another, the Orient Express, traveling across Eastern Europe. The views from the windows are very different, and the effects on the brain are correspondingly different. In other words, not only is the brain altered by the experiences it has during a critical period, but the particular kinds of experiences encountered matter, too. An extensively studied example of a behavior occurring during a critical period is the phenomenon of imprinting, whereby an animal learns to restrict its social preferences to a specific class of objects, usually the members of its own species. In birds, such as chickens and waterfowl, the critical period for imprinting often comes shortly after hatching. Typically, the first moving object a young hatchling sees is a parent or sibling, so the hatchling’s brain appropriately imprints to its own species. Appropriate imprinting is not inevitable, however. Konrad Lorenz (1970) demonstrated that if the first animal or object that baby goslings encounter is a person, the goslings imprint to that person as though he

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or she were their mother. Figure 8-27 shows a flock of goslings that imprinted to Lorenz and followed him wherever he went. Incorrect imprinting has long-term consequences for the hatchlings. They often direct their subsequent sexual behavior toward humans. A Barbary dove that had become imprinted to Lorenz directed its courtship toward his hand and even tried to copulate with the hand if it was held in a certain orientation.

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FIGURE 8-27 Strength of Imprinting Ethologist Konrad Lorenz followed by goslings that imprinted on him. He was the first object that the geese encountered after hatching, so he became their “mother.”

This quick acquisition and its permanent behavioral consequences suggest that during imprinting, the brain makes a rapid change of some

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kind, probably a structural change, given the permanence of the new behavior. Indeed, such a change does happen. Gabriel Horn and his colleagues at Cambridge University (1985) showed that synapses in a specific forebrain region enlarge with imprinting. Thus, imprinting seems a good model for studying brain plasticity during development, in part because the changes are rapid, related to specific experience, and localized in the brain. But why do critical periods end? Takao Hensch (2017) hypothesizes that two types of molecular brakes act in tandem to terminate critical periods. One type of brake is epigenetic and leads to increased expression of certain genes during development, which act to limit plasticity. The second type of brake involves perineuronal nets, which are specialized structures in the extracellular matrix that act as a molecular latticework over a neuron (much like the netting that surrounds neuronal cell bodies), such as GABAergic interneurons containing the calcium-binding protein parvalbumin (known as PV cells). Perineuronal nets reach maturity at the end of the critical period and can act as a physical barrier to morphological plasticity by blocking the generation of new synapses. There is growing evidence that disruption of perineuronal nets in adulthood can allow a reopening of critical periods. Temporarily removing perineuronal nets on PV cells may provide a promising avenue for the development of brain therapies.

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Perineuronal net that covers PV neurons and limits plasticity.

The Adolescent Brain as a Critical Period There is a growing consensus that adolescence is a period of heightened neural plasticity relative to the juvenile and adult brain (e.g., Fuhrmann et al., 2015). The onset of enhanced plasticity likely coincides with the

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release of gonadal hormones, but the timing of the reduction in plasticity at the end of adolescence has not been well studied. Several clear brain changes occur during adolescence, including increased production of astrocytes and myelin, decreased cortical thickness, and, most importantly, active changes in connectivity. Connections with the amygdala, striatum, hippocampus, and prefrontal cortex are changing throughout this period. Casey and colleagues (2015) provided an oversimplified illustration (presented in Figure 8-28) of the types of changes in prefrontal-subcortical circuitry: the interconnections and their relative strength change with development, providing insight into the emotional, social, and other nonemotional behaviors of adolescents. These studies support the important principle that changes in connectivity must be precise enough for an altered circuit to process information differently and carry out the altered (or new) function.

FIGURE 8-28 Changes in Prefrontal-Subcortical Circuitry Simplistic illustration of hierarchical age-related changes in connectivity from subcortico-subcortical to cortico-subcortical circuits. Regional changes in connectivity are indicated with dotted and bolded lines. Relative strength of the connections is indicated by the dashed lines (weaker), solid lines (stronger), and bold lines (strongest). Abbreviations: mPFC: medial prefrontal cortex; lPFC: lateral prefrontal cortex; OFC: orbitofrontal cortex; VS: ventral striatum; Amy: amygdala; VTA: ventral tegmental area. Research from Casey et al., 2015.

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The fact that adolescence is a critical period for changing neural circuit connectivity is likely adaptive. Considerable learning about the environment, especially the social environment, takes place during this period. But enhanced plasticity also renders the brain vulnerable to a wide range of experiences, such as stress, psychoactive drugs, brain trauma (for example, concussion), and harmful peer relationships, which influence brain organization and function differently in adolescents than in adults. It is no accident that many forms of mental illness become apparent in adolescence (e.g., Tottenham & Galvan, 2016).

Hormones and Brain Development The determination of sex is largely genetic. In mammals, the Y chromosome in males controls the process by which an undifferentiated, primitive gonad develops into testes, as illustrated in Figure 8-29. The genitals begin to form in the seventh week after conception, but they appear identical (indifferent) in the two sexes at this early stage. No sexual dimorphism, or structural difference, yet exists. The testes subsequently secrete the sex hormone testosterone, which stimulates development of male reproductive organs and later, in puberty, the appearance of male secondary sexual characteristics such as facial hair and deepening of the voice.

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FIGURE 8-29 Sexual Differentiation in the Human Infant Early in the indifferent stage, male and female human embryos are identical (top). In the absence of testosterone, female structures emerge (left). In response to testosterone, genitalia begin to develop into male structures at about 60 days (right). Parallel changes take place in the embryonic brain in response to the absence or presence of testosterone.

Gonadal (sex) hormones change the genetic activity of certain cells, most obviously those that form the genitals, but neural cells also respond to them. Regions of the embryonic brain thus also may begin to show sexual dimorphism as testosterone secretion begins, about 60 days

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after conception. What does sexual differentiation have to do with brain development? Although the answer is largely hormonal, genetic influences contribute, too. Section 12-5 detail the actions of gonadal hormones, including testosterone.

Testosterone stimulates sexual differentiation in male embryos. In its absence, female embryos develop. Prenatal exposure to gonadal hormones shapes male and female brains differently because these hormones activate different genes in the two sexes. Experience, then, affects male and female brains differently. Clearly, genes and experience begin to shape the developing brain very early.

Gonadal Hormones and Brain Development Testosterone, the best-known androgen (the class of hormones that stimulates or controls masculine characteristics), is released during a brief period of prenatal brain development. Subsequently, it alters the brain much as it alters the sex organs. This process is masculinization. Testosterone does not affect all body organs or all brain regions, but it does affect many brain regions in many ways. It affects the number of neurons formed in certain brain areas, reduces the number of neurons that die, increases cell growth, increases or reduces dendritic branching and synaptic growth, and regulates synaptic activity, among other effects. Estrogens, the sex hormones responsible for the female’s distinguishing characteristics, also influence postnatal brain

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development. Jill Goldstein and her colleagues found sex differences in the volume of cortical regions known to have differential levels of receptors for testosterone (androgen receptors) and estrogen, respectively, as shown in Figure 8-30 (Goldstein et al., 2001). Orange areas in the figure are larger in females, and green areas are larger in males. Clearly, a male brain and a female brain are not the same. Hormones alter brain development, and clear sex differences appear in the rate of brain development (see Figure 8-19).

FIGURE 8-30 Sex Differences in Brain Volume Cerebral areas related to sex differences in the distribution of estrogen (orange) and androgen (green) receptors in the developing brain correspond to areas of relatively larger cerebral volumes in adult women and men. Information from Goldstein et al., 2001.

Testosterone’s effects on brain development were once believed to be unimportant because this hormone was thought primarily to influence brain regions related to sexual behavior, not regions of higher functions. That belief is false. Testosterone changes cell structure in many cortical regions, with diverse behavioral consequences that include influences on cognitive processes. Although postnatal experiences may influence sex differences in the brain, an MRI study of the brains of newborns by Douglas Dean and his colleagues (2018) has shown that sex differences 933

in brain structure exist at 1 month of life, suggesting that the sex differences emerge in the prenatal period and in the first month of life. Jocelyne Bachevalier adapted her method, shown in Experiment 8-1, by training infant male and female monkeys in the concurrent discrimination task, as well as in an object reversal learning task, in which one object always conceals a food reward, whereas another object never does. After the animal learns this pattern, the reward contingencies are reversed so that the particular object that has always been rewarded is now never rewarded, and the formerly unrewarded object now conceals the reward. When the animal learns this new pattern, the contingencies are reversed again, and so on for five reversals. Bachevalier found that 2½-month-old male monkeys were superior to female monkeys on the object reversal task, but females did better on the concurrent task. Apparently, the different brain areas required for these two tasks mature at different rates in male and female monkeys. Bachevalier and her colleague William Overman (Overman et al., 1996) repeated the experiment with children 15 to 30 months old. The results were the same: boys were superior at the object reversal task, and girls were superior at the concurrent task. At 32 to 55 months of age, there was no longer a difference. Presumably, by that point, the brain regions required for both tasks had matured in both boys and girls. At the earlier age, however, gonadal hormones seemed to influence the maturation rate in certain brain regions, just as they had in the baby monkeys.

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Although gonadal hormones’ biggest effects on the brain may come during early development, their role is by no means finished in infancy. Both testosterone and estrogen (which females’ ovaries produce in large quantities) continue to influence brain structure throughout an animal’s life. In fact, removal of the ovaries in middle-aged laboratory rats leads to marked growth of dendrites and glial cells in the cortex. This finding of widespread neural change in the cortex associated with estrogen loss has implications for treating postmenopausal women with hormone replacement therapy, which may reverse the plastic changes. Gonadal hormones also affect how the brain responds to environmental events. For instance, among rats housed in complex environments, males show more dendritic growth in neurons of the visual cortex than do females (Juraska, 1990). In contrast, females housed in this setting show more dendritic growth in the hippocampus than males do. Apparently, the same experience can affect the male and female brain differently, due to the mediating influence of gonadal hormones. As females and males develop, then, their brains continue to diverge more and more, much like a fork in a road. After you set out on one path, your direction is forever changed, as the roads increasingly course farther apart. To summarize, gonadal hormones alter basic neuronal development, shape experience-dependent changes in the brain, and influence neuronal structure throughout our lifetimes. Those who believe that behavioral differences between males and females are solely the result of environmental experiences must consider these neural effects of sex hormones. 935

Details on sexual orientation and gender identity appear in Section 12-5.

In part, it is true that environmental factors exert a major influence. But one reason they do so may be that male and female brains are different to start with. Even the same events experienced by structurally different brains may lead to different effects on those brains. Evidence shows that significant experiences, such as prenatal stress, produce markedly different changes in gene expression in the frontal cortex of male and female rats (Mychasiuk et al., 2011). Another key question related to hormonal influences on brain development is whether any sex differences in brain organization might be independent of hormonal action. In other words, are differences in the action of sex chromosome genes unrelated to sex hormones? Although little is known about such genetic effects in humans, studies of birds clearly show that genetic effects on brain cells may indeed contribute to sex differentiation. Songbirds have an especially interesting brain dimorphism: in most species, males sing and females do not. This behavioral difference between the sexes is directly related to a neural birdsong circuit present in males but not in females. Robert Agate and his colleagues (2003) studied the brain of a rare gynandromorph zebra finch, shown in Figure 8-31. This bird exhibits physical characteristics of both sexes.

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FIGURE 8-31 Gynandromorph This rare zebra finch has dull female plumage on one side of the body and bright male plumage on the other side. Neural, not gonadal, origin of brain sex differences in a gynandromorphic finch. Agate RJ, Grisham W, Wade J, Mann S, Wingfield J, Schanen C, Palotie A, Arnold AP. Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4873-8.

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Genetic analysis shows that cells on one-half of the bird’s brain and body are genetically female and on the other half are genetically male. The two sides of the gynandromorph’s body and brain were exposed to the same hormones during prenatal development. Thus, the effect of male and female genes on the birdsong circuit can be examined to determine how the genes and hormones might interact. If the sex difference in the birdsong circuit were totally related to the presence of hormones prenatally, then the two sides of the brain should be equally masculine or feminine. Agate’s results confirm the opposite: the neural song circuit is masculine on the male side of the brain. Only a genetic difference that was at least partly independent of hormonal effects could explain such a structural difference in the brain.

Gut Bacteria and Brain Development We have emphasized factors that affect CNS development directly, but a less direct route exerts itself via the enteric nervous system. The ENS sends information to the brain that affects our mental state. The brain, in turn, can modify gut function. An important component of the ENS is the microbiome, the bacteria in the gut with which the ENS interacts. About 1014 microbiota populate the adult gut, which means that microbiota outnumber the host body cells by a factor of 10. But in utero, the fetus’s gut is sterile. It is only at birth that trillions of microbes from the mother’s vaginal and anal fluids, and later from her skin, invade the baby’s body and start to grow.

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Many

Section 2-5 introduces the ENS and microbiome.

neurodevelopmental disorders, including autism, may be related to an atypical microbiome early in life (e.g., Kelly et al., 2017). Psychobiotics is a term that refers to the use of live bacteria (probiotics) or compounds that enhance the growth of gut bacteria (prebiotics) to confer mental health benefits. Although there are not yet many human clinical trials, animal laboratory studies have proven encouraging. For example, a series of studies using a rodent model of early-life stress showed that untreated stressed animals exhibited cognitive deficits in adulthood, whereas animals whose mothers received a probiotic formulation in their drinking water while the pups were nursing displayed no such effects in adulthood (e.g., Cowan et al., 2016). Other studies have shown that certain bacteria can enhance emotional learning and reduce anxiety and the effects of stress (see review by Foster et al., 2017).

8-4 Review Before you continue, check your understanding. You can find answers to the self test in Answers to Section Review Self-Tests. 1. The idea that specific molecules in different cells in various midbrain regions give each cell a distinctive chemical identity is known as the . 2. Subnormal visual stimulation to one eye during early development can lead to a loss of acuity, known as 3. The hormone development.

masculinizes the brain during

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4. The brain’s sensitivity to experience is highest during . 5. Why do so many mental disorders appear during adolescence?

For additional study tools, visit

launchpadworks.com

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8-5 Abnormal Experience and Brain Development As we have shown, both pre- and postnatal experience and environment play a significant role in modifying brain development. In this section, we discuss how many aversive experiences, as well as injury and exposure to drugs, can lead to abnormal brain development and neurodevelopmental disorders.

Early Life Experience and Brain Development If complex or enriched experiences early in life can stimulate brain growth and influence later behavior, severely restricted experiences early in life seem likely to retard both brain growth and behavior. To study the effects of such restrictions, Donald Hebb and his colleagues (Clarke et al., 1951) placed young Scottish terriers in the dark with as little stimulation as possible and compared their behavior to that of dogs raised in a typical environment. When the dogs raised in the barren environment, obviously unethical by today’s standards, were later removed from it, their behavior was highly unusual. They showed virtually no reaction to people or other dogs and appeared to have lost any pain sensation. Even sticking pins in them (also unethical) produced no response. When given a dog version of the Hebb–Williams intelligence test for rats, these dogs performed

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terribly and were unable to learn tasks that dogs raised in more stimulating settings learned easily. Results of subsequent studies show that depriving young animals of visual input or of maternal contact, specifically, has devastating consequences for their behavioral development and presumably for their brain development. Austin Riesen (1982) and his colleagues extensively studied animals raised in the dark. They found that after early visual deprivation, even though the animals’ eyes still work, they may be functionally blind. An absence of visual stimulation results in the atrophy of dendrites on cortical neurons, essentially the opposite of the results observed in the brains of animals raised in complex and stimulating environments. Not only does the absence of specific sensory inputs adversely affect brain development; so too does the absence of more complex typical experiences. In the 1950s, Harry Harlow (1971) began the first systematic laboratory studies of analogous deprivation in laboratory animals. Harlow showed that infant monkeys raised without maternal (or paternal) contact develop grossly atypical intellectual and social behaviors in adulthood. Harlow separated baby monkeys from their mothers shortly after birth and raised them in individual cages. Perhaps the most stunning effect occurred in adulthood, when these animals were totally unable to establish normal relations with other animals. Unfortunately, Harlow did not analyze the deprived monkeys’ brains. We would predict atrophy of cortical neurons, especially in the frontal lobe regions related to social behavior. Harlow’s student Stephen Suomi has found a wide variety of hormonal and neurological abnormalities among motherless 942

monkeys, including epigenetic changes (see the review by Dettmer & Suomi, 2014). Children who are raised in a barren environment or are abused or neglected are at a serious disadvantage later in life. In the previous section, we discussed the impact of an impoverished environment on the language development of children. Proof is also evident in the hampered intellectual and motor development displayed by children raised in dreadful circumstances, such as those described in Clinical Focus 8-4, Romanian Orphans. Although some argue that children can succeed in school and in life if they really want to, abnormal developmental experiences can clearly alter the brain irrevocably. As a society, we cannot ignore the effects of the environment to which our children are exposed.

CLINICAL FOCUS 8-4

Romanian Orphans In the 1970s, Romania’s Communist regime outlawed all forms of birth control and abortion. The natural result was more than 100,000 unwanted children in state-run orphanages. The conditions were appalling. The children were housed and clothed but given virtually no environmental stimulation. Mostly they were confined to cots with few, if any, playthings and virtually no personal interaction with overworked caregivers, who looked after 20 to 25 children at once. Bathing often consisted of being hosed down with cold water.

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Romanian orphans warehoused in the 1970s and 1980s endured the conditions shown in this photograph. The utter absence of stimuli h

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