Neuroscience - Purves' Third Edition PDF

Purves3/eFM 5/13/04 12:59 PM Page i NEUROSCIENCE Third Edition Purves3/eFM 5/13/04 12:59 PM Page ii Purves3/eFM 5/13/04 12:59 PM Page iii NEUROSCIEN...

Purves3/eFM 5/13/04 12:59 PM Page i NEUROSCIENCE Third Edition Purves3/eFM 5/13/04 12:59 PM Page ii Purves3/eFM 5/13/04 12:59 PM Page iii NEUROSCIENCE THIRD EDITION Edited by DALE PURVES GEORGE J. AUGUSTINE DAVID FITZPATRICK WILLIAM C. HALL ANTHONY-SAMUEL LAMANTIA JAMES O. MCNAMARA S. MARK WILLIAMS Sinauer Associates, Inc. Publishers Sunderland, Massachusetts U.S.A. Purves3/eFM 5/13/04 12:59 PM Page iv THE COVER Dorsal view of the human brain. (Courtesy of S. Mark Williams.) NEUROSCIENCE: Third Edition Copyright © 2004 by Sinauer Associates, Inc. All rights reserved. This book may not be reproduced in whole or in part without permission. Address inquiries and orders to Sinauer Associates, Inc. 23 Plumtree Road Sunderland, MA 01375 U.S.A. www.sinauer.com FAX: 413-549-1118 [email protected] [email protected] Library of Congress Cataloging-in-Publication Data Neuroscience / edited by Dale Purves... [et al.].— 3rd ed. p. ; cm. Includes bibliographical references and index. ISBN 0-87893-725-0 (casebound : alk. paper) 1. Neurosciences. [DNLM: 1. Nervous System Physiology. 2. Neurochemistry. WL 102 N50588 2004] I. Purves, Dale. QP355.2.N487 2004 612.8—dc22 2004003973 Printed in U.S.A. 5 4 3 2 1 Purves3/eFM 5/13/04 12:59 PM Page v Contributors George J. Augustine, Ph.D. Dona M. Chikaraishi, Ph.D. Michael D. Ehlers, M.D., Ph.D. Gillian Einstein, Ph.D. David Fitzpatrick, Ph.D. William C. Hall, Ph.D. Erich Jarvis, Ph.D. Lawrence C. Katz, Ph.D. Julie Kauer, Ph.D. Anthony-Samuel LaMantia, Ph.D. James O. McNamara, M.D. Richard D. Mooney, Ph.D. Miguel A. L. Nicolelis, M.D., Ph.D. Dale Purves, M.D. Peter H. Reinhart, Ph.D. Sidney A. Simon, Ph.D. J. H. Pate Skene, Ph.D. James Voyvodic, Ph.D. Leonard E. White, Ph.D. S. Mark Williams, Ph.D. UNIT EDITORS UNIT I: George J. Augustine UNIT II: David Fitzpatrick UNIT III: William C. Hall UNIT IV: Anthony-Samuel LaMantia UNIT V: Dale Purves Purves3/eFM 5/13/04 12:59 PM Page vi Purves3/eFM 5/13/04 12:59 PM Page vii Contents in Brief 1. Studying the Nervous Systems of Humans and Other Animals 1 UNIT I NEURAL SIGNALING 2. Electrical Signals of Nerve Cells 31 3. Voltage-Dependent Membrane Permeability 47 4. Channels and Transporters 69 5. Synaptic Transmission 93 6. Neurotransmitters, Receptors, and Their Effects 129 7. Molecular Signaling within Neurons 165 UNIT II SENSATION AND SENSORY PROCESSING 8. The Somatic Sensory System 189 9. Pain 209 10. Vision: The Eye 229 11. Central Visual Pathways 259 12. The Auditory System 283 13. The Vestibular System 315 14. The Chemical Senses 337 UNIT III MOVEMENT AND ITS CENTRAL CONTROL 15. Lower Motor Neuron Circuits and Motor Control 371 16. Upper Motor Neuron Control of the Brainstem and Spinal Cord 393 17. Modulation of Movement by the Basal Ganglia 417 18. Modulation of Movement by the Cerebellum 435 19. Eye Movements and Sensory Motor Integration 453 20. The Visceral Motor System 469 UNIT IV THE CHANGING BRAIN 21. Early Brain Development 501 22. Construction of Neural Circuits 521 23. Modification of Brain Circuits as a Result of Experience 557 24. Plasticity of Mature Synapses and Circuits 575 UNIT V COMPLEX BRAIN FUNCTIONS 25. The Association Cortices 613 26. Language and Speech 637 27. Sleep and Wakefulness 659 28. Emotions 687 29. Sex, Sexuality, and the Brain 711 30. Memory 733 APPENDIX A THE BRAINSTEM AND CRANIAL NERVES 755 APPENDIX B VASCULAR SUPPLY, THE MENINGES, AND THE VENTRICULAR SYSTEM 763 Purves3/eFM 5/13/04 12:59 PM Page viii Contents Preface xvi Acknowledgments xvii Supplements to Accompany NEUROSCIENCE xviii Chapter 1 Studying the Nervous Systems of Humans and Other Animals 1 Overview 1 Overall Organization of the Human Nervous Genetics, Genomics, and the Brain 1 System 14 The Cellular Components of the Nervous System 2 Neuroanatomical Terminology 16 Neurons 4 The Subdivisions of the Central Nervous System 18 Neuroglial Cells 8 Organizational Principles of Neural Systems 20 Cellular Diversity in the Nervous System 9 Functional Analysis of Neural Systems 23 Neural Circuits 11 Analyzing Complex Behavior 24 BOX A Brain Imaging Techniques 25 Summary 26 Unit I NEURAL SIGNALING Chapter 2 Electrical Signals Chapter 3 Voltage-Dependent Membrane of Nerve Cells 31 Permeability 47 Overview 31 Overview 47 Electrical Potentials across Nerve Cell Membranes 31 Ionic Currents Across Nerve Cell Membranes 47 How Ionic Movements Produce Electrical Signals 34 BOX A The Voltage Clamp Method 48 The Forces That Create Membrane Potentials 36 Two Types of Voltage-Dependent Ionic Current 49 Electrochemical Equilibrium in an Environment with Two Voltage-Dependent Membrane Conductances 52 More Than One Permeant Ion 38 Reconstruction of the Action Potential 54 The Ionic Basis of the Resting Membrane Potential 40 Long-Distance Signaling by Means of Action BOX A The Remarkable Giant Nerve Cells Potentials 56 of Squid 41 BOX B Threshold 57 The Ionic Basis of Action Potentials 43 BOX C Passive Membrane Properties 60 BOX B Action Potential Form The Refractory Period 61 and Nomenclature 44 Increased Conduction Velocity as a Result Summary 45 of Myelination 63 Summary 65 BOX D Multiple Sclerosis 66 Purves3/eFM 5/13/04 12:59 PM Page ix Contents ix Chapter 4 Channels and Transporters 69 Chapter 6 Neurotransmitters and Their Overview 69 Receptors 129 Ion Channels Underlying Action Potentials 69 Overview 129 BOX A The Patch Clamp Method 70 Categories of Neurotransmitters 129 The Diversity of Ion Channels 73 Acetylcholine 129 BOX B Expression of Ion Channels in Xenopus BOX A Addiction 134 Oocytes 75 BOX B Neurotoxins that Act on Postsynaptic Voltage-Gated Ion Channels 76 Receptors 136 Ligand-Gated Ion Channels 78 Glutamate 137 Stretch- and Heat-Activated Channels 78 BOX C Myasthenia Gravis: An Autoimmune The Molecular Structure of Ion Channels 79 Disease of Neuromuscular Synapses 140 BOX C Toxins That Poison Ion Channels 82 GABA and Glycine 143 BOX D Diseases Caused by Altered Ion BOX D Excitotoxicity Following Acute Brain Channels 84 Injury 145 Active Transporters Create and Maintain Ion The Biogenic Amines 147 Gradients 86 Functional Properties of the Na+/K+ Pump 87 BOX E Biogenic Amine Neurotransmitters and Psychiatric Disorders 148 The Molecular Structure of the Na+/K+ Pump 89 ATP and Other Purines 152 Summary 90 Peptide Neurotransmitters 153 Chapter 5 Synaptic Transmission 93 Unconventional Neurotransmitters 157 Overview 93 BOX F Marijuana and the Brain 160 Electrical Synapses 93 Summary 161 Signal Transmission at Chemical Synapses 96 Properties of Neurotransmitters 96 Chapter 7 Molecular Signaling within BOX A Criteria That Define a Neurons 165 Neurotransmitter 99 Overview 165 Quantal Release of Neurotransmitters 102 Strategies of Molecular Signaling 165 Release of Transmitters from Synaptic Vesicles 103 The Activation of Signaling Pathways 167 Local Recycling of Synaptic Vesicles 105 Receptor Types 168 The Role of Calcium in Transmitter Secretion 107 G-Proteins and Their Molecular Targets 170 BOX B Diseases That Affect the Presynaptic Second Messengers 172 Terminal 108 Second Messenger Targets: Protein Kinases and Molecular Mechanisms of Transmitter Secretion 110 Phosphatases 175 Neurotransmitter Receptors 113 Nuclear Signaling 178 BOX C Toxins That Affect Transmitter Examples of Neuronal Signal Transduction 181 Release 115 Summary 184 Postsynaptic Membrane Permeability Changes during Synaptic Transmission 116 Excitatory and Inhibitory Postsynaptic Potentials 121 Summation of Synaptic Potentials 123 Two Families of Postsynaptic Receptors 124 Summary 126 Purves3/eFM 5/13/04 12:59 PM Page x x Contents Unit II SENSATION AND SENSORY PROCESSING Chapter 8 The Somatic Sensory System 189 Chapter 10 Vision: The Eye 229 Overview 189 Overview 229 Cutaneous and Subcutaneous Somatic Sensory Anatomy of the Eye 229 Receptors 189 The Formation of Images on the Retina 231 Mechanoreceptors Specialized to Receive Tactile BOX A Myopia and Other Refractive Errors 232 Information 192 The Retina 234 Differences in Mechanosensory Discrimination across Phototransduction 236 the Body Surface 193 BOX B Retinitis Pigmentosa 239 BOX A Receptive Fields and Sensory Maps Functional Specialization of the Rod and Cone in the Cricket 195 Systems 240 BOX B Dynamic Aspects of Somatic Sensory BOX C Macular Degeneration 243 Receptive Fields 196 Anatomical Distribution of Rods and Cones 244 Mechanoreceptors Specialized for Proprioception 197 Cones and Color Vision 245 Active Tactile Exploration 199 BOX D The Importance of Context in Color The Major Afferent Pathway for Mechanosensory Perception 247 Information: The Dorsal Column–Medial Lemniscus System 199 Retinal Circuits for Detecting Luminance Change 249 The Trigeminal Portion of the Mechanosensory System 202 BOX E The Perception of Light Intensity 250 BOX C Dermatomes 202 Contribution of Retinal Circuits to Light Adaptation 254 The Somatic Sensory Components of the Thalamus 203 Summary 257 The Somatic Sensory Cortex 203 Higher-Order Cortical Representations 206 Chapter 11 Central Visual Pathways 259 BOX D Patterns of Organization within the Sensory Cortices: Brain Modules 207 Overview 259 Summary 208 Central Projections of Retinal Ganglion Cells 259 BOX A The Blind Spot 262 Chapter 9 Pain 209 The Retinotopic Representation of the Visual Field 263 Overview 209 Visual Field Deficits 267 Nociceptors 209 The Functional Organization of the Striate Cortex 269 Transduction of Nociceptive Signals 211 The Columnar Organization of the Striate Cortex 271 BOX A Capsaicin 212 BOX B Random Dot Stereograms and Related Amusements 272 Central Pain Pathways 213 Division of Labor within the Primary Visual BOX B Referred Pain 215 Pathway 275 BOX C A Dorsal Column Pathway for Visceral BOX C Optical Imaging of Functional Domains in Pain 218 the Visual Cortex 276 Sensitization 220 The Functional Organization of Extrastriate Visual BOX D Phantom Limbs and Phantom Pain 222 Areas 278 Descending Control of Pain Perception 224 Summary 281 The Placebo Effect 224 The Physiological Basis of Pain Modulation 225 Chapter 12 The Auditory System 283 Summary 227 Overview 283 Sound 283 The Audible Spectrum 284 Purves3/eFM 5/13/04 12:59 PM Page xi Contents xi A Synopsis of Auditory Function 285 How Semicircular Canal Neurons Sense Angular BOX A Four Causes of Acquired Hearing Loss 285 Accelerations 325 BOX B Music 286 BOX C Throwing Cold Water on the Vestibular The External Ear 287 System 326 The Middle Ear 289 Central Pathways for Stabilizing Gaze, Head, and Posture 328 The Inner Ear 289 Vestibular Pathways to the Thalamus and Cortex 331 BOX C Sensorineural Hearing Loss and Cochlear Implants 290 BOX D Mauthner Cells in Fish 332 BOX D The Sweet Sound of Distortion 295 Summary 333 Hair Cells and the Mechanoelectrical Transduction of Sound Waves 294 Chapter 14 The Chemical Senses 337 Two Kinds of Hair Cells in the Cochlea 300 Overview 337 Tuning and Timing in the Auditory Nerve 301 The Organization of the Olfactory System 337 How Information from the Cochlea Reaches Targets in Olfactory Perception in Humans 339 the Brainstem 303 Physiological and Behavioral Responses to Integrating Information from the Two Ears 303 Odorants 341 Monaural Pathways from the Cochlear Nucleus to the The Olfactory Epithelium and Olfactory Receptor Lateral Lemniscus 307 Neurons 342 Integration in the Inferior Colliculus 307 BOX A Olfaction, Pheromones, and Behavior in The Auditory Thalamus 308 the Hawk Moth 344 The Auditory Cortex 309 The Transduction of Olfactory Signals 345 BOX E Representing Complex Sounds in the Odorant Receptors 346 Brains of Bats and Humans 310 Olfactory Coding 348 Summary 313 The Olfactory Bulb 350 BOX B Temporal “Coding” of Olfactory Information in Insects 350 Chapter 13 The Vestibular System 315 Central Projections of the Olfactory Bulb 353 Overview 315 The Organization of the Taste System 354 The Vestibular Labyrinth 315 Taste Perception in Humans 356 Vestibular Hair Cells 316 Idiosyncratic Responses to Tastants 357 The Otolith Organs: The Utricle and Saccule 317 The Organization of the Peripheral Taste System 359 BOX A A Primer on Vestibular Navigation 318 Taste Receptors and the Transduction of Taste BOX B Adaptation and Tuning of Vestibular Hair Signals 360 Cells 320 Neural Coding in the Taste System 362 How Otolith Neurons Sense Linear Forces 322 Trigeminal Chemoreception 363 The Semicircular Canals 324 Summary 366 Unit III MOVEMENT AND ITS CENTRAL CONTROL Chapter 15 Lower Motor Neuron Circuits Motor Neuron–Muscle Relationships 373 and Motor Control 371 The Motor Unit 375 Overview 371 The Regulation of Muscle Force 377 Neural Centers Responsible for Movement 371 The Spinal Cord Circuitry Underlying Muscle Stretch Reflexes 379 Purves3/eFM 5/13/04 12:59 PM Page xii xii Contents The Influence of Sensory Activity on Motor Behavior Circuits within the Basal Ganglia System 424 381 BOX A Huntington’s Disease 426 Other Sensory Feedback That Affects Motor BOX B Parkinson’s Disease: An Opportunity for Performance 382 Novel Therapeutic Approaches 429 BOX A Locomotion in the Leech and the Lamprey BOX C Basal Ganglia Loops and Non-Motor 384 Brain Functions 432 Flexion Reflex Pathways 387 Summary 433 Spinal Cord Circuitry and Locomotion 387 BOX B The Autonomy of Central Pattern Chapter 18 Modulation of Movement by Generators: Evidence from the Lobster the Cerebellum 435 Stomatogastric Ganglion 388 Overview 435 The Lower Motor Neuron Syndrome 389 Organization of the Cerebellum 435 BOX C Amyotrophic Lateral Sclerosis 391 Projections to the Cerebellum 438 Summary 391 Projections from the Cerebellum 440 Circuits within the Cerebellum 441 Chapter 16 Upper Motor Neuron Control of the Brainstem and Spinal BOX A Prion Diseases 444 Cord 393 Cerebellar Circuitry and the Coordination of Ongoing Overview 393 Movement 445 Descending Control of Spinal Cord Circuitry: Futher Consequences of Cerebellar Lesions 448 General Information 393 Summary 449 Motor Control Centers in the Brainstem: Upper Motor BOX B Genetic Analysis of Cerebellar Function 450 Neurons That Maintain Balance and Posture 397 BOX A The Reticular Formation 398 Chapter 19 Eye Movements and Sensory The Corticospinal and Corticobulbar Pathways: Motor Integration 453 Upper Motor Neurons That Initiate Complex Overview 453 Voluntary Movements 402 What Eye Movements Accomplish 453 BOX B Descending Projections to Cranial Nerve The Actions and Innervation of Extraocular Muscles Motor Nuclei and Their Importance 454 in Diagnosing the Cause of Motor BOX A The Perception of Stabilized Retinal Deficits 404 Images 456 Functional Organization of the Primary Motor Cortex Types of Eye Movements and Their Functions 457 405 Neural Control of Saccadic Eye Movements 458 BOX C What Do Motor Maps Represent? 408 BOX B Sensory Motor Integration in the The Premotor Cortex 411 Superior Colliculus 462 BOX D Sensory Motor Talents and Cortical Neural Control of Smooth Pursuit Movements 466 Space 410 Neural Control of Vergence Movements 466 Damage to Descending Motor Pathways: The Upper Summary 467 Motor Neuron Syndrome 412 BOX E Muscle Tone 414 Summary 415 Chapter 20 The Visceral Motor System 469 Overview 469 Early Studies of the Visceral Motor System 469 Chapter 17 Modulation of Movement by the Basal Ganglia 417 Distinctive Features of the Visceral Motor System 470 Overview 417 The Sympathetic Division of the Visceral Motor System 471 Projections to the Basal Ganglia 417 The Parasympathetic Division of the Visceral Motor Projections from the Basal Ganglia to Other Brain System 476 Regions 422 The Enteric Nervous System 479 Evidence from Studies of Eye Movements 423 Sensory Components of the Visceral Motor System 480 Purves3/eFM 5/13/04 12:59 PM Page xiii Contents xiii Central Control of Visceral Motor Functions 483 Visceral Motor Reflex Functions 491 BOX A The Hypothalamus 484 Autonomic Regulation of Cardiovascular Function 491 Neurotransmission in the Visceral Motor System 487 Autonomic Regulation of the Bladder 493 BOX B Horner’s Syndrome 488 Autonomic Regulation of Sexual Function 496 BOX C Obesity and the Brain 490 Summary 498 Unit IV THE CHANGING BRAIN Chapter 21 Early Brain Development 501 BOX B Molecular Signals That Promote Synapse Overview 501 Formation 542 The Initial Formation of the Nervous System: Trophic Interactions and the Ultimate Size of Neuronal Gastrulation and Neurulation 501 Populations 543 The Molecular Basis of Neural Induction 503 Further Competitive Interactions in the Formation of Neuronal Connections 545 BOX A Stem Cells: Promise and Perils 504 Molecular Basis of Trophic Interactions 547 BOX B Retinoic Acid: Teratogen and Inductive Signal 506 BOX C Why Do Neurons Have Dendrites? 548 Formation of the Major Brain Subdivisions 510 BOX D The Discovery of BDNF and the Neurotrophin Family 552 BOX C Homeotic Genes and Human Brain Development 513 Neurotrophin Signaling 553 BOX D Rhombomeres 514 Summary 554 Genetic Abnormalities and Altered Human Brain Development 515 Chapter 23 Modification of Brain Circuits The Initial Differentiation of Neurons and Glia 516 as a Result of Experience 557 BOX E Neurogenesis and Neuronal Birthdating Overview 557 517 Critical Periods 557 The Generation of Neuronal Diversity 518 BOX A Built-In Behaviors 558 Neuronal Migration 520 The Development of Language: BOX F Mixing It Up: Long-Distance Neuronal Example of a Human Critical Period 559 Migration 524 BOX B Birdsong 560 Summary 525 Critical Periods in Visual System Development 562 Effects of Visual Deprivation on Ocular Dominance 563 Chapter 22 Construction of Neural BOX C Transneuronal Labeling with Radioactive Circuits 527 Amino Acids 564 Overview 527 Visual Deprivation and Amblyopia in Humans 568 The Axonal Growth Cone 527 Mechanisms by which Neuronal Activity Affects the Non-Diffusible Signals for Axon Guidance 528 Development of Neural Circuits 569 BOX A Choosing Sides: Axon Guidance at the Cellular and Molecular Correlates of Activity- Optic Chiasm 530 Dependent Plasticity during Critical Periods 572 Diffusible Signals for Axon Guidance: Evidence for Critical Periods in Other Sensory Chemoattraction and Repulsion 534 Systems 572 The Formation of Topographic Maps 537 Summary 573 Selective Synapse Formation 539 Purves3/eFM 5/13/04 12:59 PM Page xiv xiv Contents Chapter 24 Plasticity of Mature Synapses Long-Term Synaptic Depression 592 and Circuits 575 BOX C Silent Synapses 594 Overview 575 Changes in Gene Expression Cause Enduring Synaptic Plasticity Underlies Behavioral Modification Changes in Synaptic Function during LTP and in Invertebrates 575 LTD 597 BOX A Genetics of Learning and Memory in the Plasticity in the Adult Cerebral Cortex 599 Fruit Fly 581 BOX D Epilepsy: The Effect of Pathological Short-Term Synaptic Plasticity in the Mammalian Activity on Neural Circuitry 600 Nervous System 582 Recovery from Neural Injury 602 Long-Term Synaptic Plasticity in the Mammalian Generation of Neurons in the Adult Brain 605 Nervous System 583 BOX E Why Aren’t We More Like Fish and Long-Term Potentiation of Hippocampal Synapses 584 Frogs? 606 Molecular Mechanisms Underlying LTP 587 Summary 609 BOX B Dendritic Spines 590 Unit V COMPLEX BRAIN FUNCTIONS Chapter 25 The Association Cortices 613 Chapter 26 Language and Speech 637 Overview 613 Overview 637 The Association Cortices 613 Language Is Both Localized and Lateralized 637 An Overview of Cortical Structure 614 Aphasias 638 Specific Features of the Association Cortices 615 BOX A Speech 640 BOX A A More Detailed Look at Cortical BOX B Do Other Animals Have Language? 642 Lamination 617 BOX C Words and Meaning 645 Lesions of the Parietal Association Cortex: Deficits of A Dramatic Confirmation of Language Lateralization Attention 619 646 Lesions of the Temporal Association Cortex: Anatomical Differences between the Right and Left Deficits of Recognition 622 Hemispheres 648 Lesions of the Frontal Association Cortex: Deficits of Mapping Language Functions 649 Planning 623 BOX D Language and Handedness 650 BOX B Psychosurgery 625 The Role of the Right Hemisphere in Language 654 “Attention Neurons” in the Monkey Parietal Cortex 626 Sign Language 655 “Recognition Neurons” in the Monkey Temporal Summary 656 Cortex 627 “Planning Neurons” in the Monkey Frontal Cortex 630 BOX C Neuropsychological Testing 632 Chapter 27 Sleep and Wakefulness 659 BOX D Brain Size and Intelligence 634 Overview 659 Summary 635 Why Do Humans (and Many Other Animals) Sleep? 659 BOX A Styles of Sleep in Different Species 661 Purves3/eFM 5/13/04 12:59 PM Page xv Contents xv The Circadian Cycle of Sleep and Wakefulness 662 BOX C The Actions of Sex Hormones 718 Stages of Sleep 665 Other Central Nervous System Dimorphisms BOX B Molecular Mechanisms of Biological Specifically Related to Reproductive Behaviors 720 Clocks 666 Brain Dimorphisms Related to Cognitive Function 728 BOX C Electroencephalography 668 Hormone-Sensitive Brain Circuits in Adult Animals 729 Physiological Changes in Sleep States 671 Summary 731 The Possible Functions of REM Sleep and Dreaming 671 Chapter 30 Memory 733 Neural Circuits Governing Sleep 674 Overview 733 BOX D Consciousness 675 Qualitative Categories of Human Memory 733 Thalamocortical Interactions 679 Temporal Categories of Memory 734 Sleep Disorders 681 BOX A Phylogenetic Memory 735 BOX E Drugs and Sleep 682 The Importance of Association in Information Storage Summary 684 736 Forgetting 738 Chapter 28 Emotions 687 BOX B Savant Syndrome 739 Overview 687 Brain Systems Underlying Declarative Memory Physiological Changes Associated with Emotion 687 Formation 741 The Integration of Emotional Behavior 688 BOX C Clinical Cases That Reveal the Anatomical BOX A Facial Expressions: Pyramidal and Substrate for Declarative Memories 742 Extrapyramidal Contributions 690 Brain Systems Underlying Long-Term Storage of The Limbic System 693 Declarative Memory 746 BOX B The Anatomy of the Amygdala 696 Brain Systems Underlying Nondeclarative Learning The Importance of the Amygdala 697 and Memory 748 BOX C The Reasoning Behind an Important Memory and Aging 749 Discovery 698 BOX D Alzheimer’s Disease 750 The Relationship between Neocortex and Amygdala Summary 753 701 BOX D Fear and the Human Amygdala: Appendix A The Brainstem and Cranial A Case Study 702 Nerves 755 BOX E Affective Disorders 704 Cortical Lateralization of Emotional Functions 705 Appendix B Vascular Supply, the Meninges, Emotion, Reason, and Social Behavior 707 and the Ventricular System 763 Summary 708 The Blood Supply of the Brain and Spinal Cord 763 The Blood-Brain Barrier 766 Chapter 29 Sex, Sexuality, and the Brain 711 BOX A Stroke 767 Overview 711 The Meninges 768 Sexually Dimorphic Behavior 711 What Is Sex? 712 The Ventricular System 770 BOX A The Development of Male and Female Phenotypes 714 Glossary Hormonal Influences on Sexual Dimorphism 715 Illustration Source References BOX B The Case of Bruce/Brenda 716 Index The Effect of Sex Hormones on Neural Circuitry 718 Purves3/eFM 5/13/04 12:59 PM Page xvi Preface Whether judged in molecular, cellular, systemic, behavioral, or cogni- tive terms, the human nervous system is a stupendous piece of bio- logical machinery. Given its accomplishments—all the artifacts of human culture, for instance—there is good reason for wanting to understand how the brain and the rest of the nervous system works. The debilitating and costly effects of neurological and psychiatric dis- ease add a further sense of urgency to this quest. The aim of this book is to highlight the intellectual challenges and excitement—as well as the uncertainties—of what many see as the last great frontier of bio- logical science. The information presented should serve as a starting point for undergraduates, medical students, graduate students in the neurosciences, and others who want to understand how the human nervous system operates. Like any other great challenge, neuro- science should be, and is, full of debate, dissension, and considerable fun. All these ingredients have gone into the construction of the third edition of this book; we hope they will be conveyed in equal measure to readers at all levels. Purves3/eFM 5/13/04 12:59 PM Page xvii Acknowledgments We are grateful to numerous colleagues who provided helpful contri- butions, criticisms and suggestions to this and previous editions. We particularly wish to thank Ralph Adolphs, David Amaral, Eva Anton, Gary Banker, Bob Barlow, Marlene Behrmann, Ursula Bellugi, Dan Blazer, Bob Burke, Roberto Cabeza, Nell Cant, Jim Cavanaugh, John Chapin, Milt Charlton, Michael Davis, Rob Deaner, Bob Desimone, Allison Doupe, Sasha du Lac, Jen Eilers, Anne Fausto-Sterling, Howard Fields, Elizabeth Finch, Nancy Forger, Jannon Fuchs, Michela Gallagher, Dana Garcia, Steve George, the late Patricia Gold- man-Rakic, Mike Haglund, Zach Hall, Kristen Harris, Bill Henson, John Heuser, Jonathan Horton, Ron Hoy, Alan Humphrey, Jon Kaas, Jagmeet Kanwal, Herb Killackey, Len Kitzes, Arthur Lander, Story Landis, Simon LeVay, Darrell Lewis, Jeff Lichtman, Alan Light, Steve Lisberger, Donald Lo, Arthur Loewy, Ron Mangun, Eve Marder, Robert McCarley, Greg McCarthy, Jim McIlwain, Chris Muly, Vic Nadler, Ron Oppenheim, Larysa Pevny, Michael Platt, Franck Polleux, Scott Pomeroy, Rodney Radtke, Louis Reichardt, Marnie Rid- dle, Jamie Roitman, Steve Roper, John Rubenstein, Ben Rubin, David Rubin, Josh Sanes, Cliff Saper, Lynn Selemon, Carla Shatz, Bill Snider, Larry Squire, John Staddon, Peter Strick, Warren Strittmatter, Joe Takahashi, Richard Weinberg, Jonathan Weiner, Christina Williams, Joel Winston, and Fulton Wong. It is understood, of course, that any errors are in no way attributable to our critics and advisors. We also thank the students at Duke University Medical School as well as many other students and colleagues who provided sugges- tions for improvement of the last edition. Finally, we owe special thanks to Robert Reynolds and Nate O’Keefe, who labored long and hard to put the third edition together, and to Andy Sinauer, Graig Donini, Carol Wigg, Christopher Small, Janice Holabird, and the rest of the staff at Sinauer Associates for their outstanding work and high standards. Purves3/eFM 5/13/04 1:00 PM Page xviii Supplements to Accompany NEUROSCIENCE Third Edition For the Student Sylvius for Neuroscience: A Visual Glossary of Human Neuroanatomy (CD-ROM) S. Mark Williams, Leonard E. White, and Andrew C. Mace Sylvius for Neuroscience: A Visual Glossary of Human Neuroanatomy, included in every copy of the textbook, is an interactive CD reference guide to the structure of the human nervous system. By entering a corresponding page number from the textbook, students can quickly search the CD for any neuroanatomical structure or term and view corresponding images and animations. Descriptive information is provided with all images and animations. Additionally, students can take notes on the content and share these with other Sylvius users. Sylvius is an essential study aid for learning basic human neuro- anatomy. Sylvius for Neuroscience features: Over 400 neuroanatomical structures and terms. High-resolution images. Animations of pathways and 3-D reconstructions. Definitions and descriptions. Audio pronunciations. A searchable glossary. Categories of anatomical structures and terms (e.g., cranial nerves, spinal cord tracts, lobes, cortical areas, etc.), that can be easily browsed. In addition, structures can be browsed by text- book chapter. Purves3/eFM 5/13/04 1:00 PM Page xix Supplements xix Images and text relevant to the textbook: Icons in the textbook indicate specific content on the CD. By entering a textbook page number, students can automatically load the relevant images and text. A history feature that allows the student to quickly reload recently viewed structures. A bookmark feature that adds bookmarks to structures of in- terest; bookmarks are automatically stored on the student’s computer. A notes feature that allows students to type notes for any selected structure; notes are automatically saved on the stu- dent’s computer and can be shared among students and instructors (i.e., imported and exported). A self-quiz mode that allows for testing on structure identifica- tion and functional information. A print feature that formats images and text for printed output. An image zoom tool. For the Instructor Instructor’s Resource CD (ISBN 0-87893-750-1) This expanded resource includes all the figures and tables from the textbook in JPEG format, reformatted and relabeled for optimal read- ability. Also included are ready-to-use PowerPoint® presentations of all figures and tables. In addition, new for the Third Edition, the Instructor’s Resource CD includes a set of short-answer study ques- tions for each chapter in Microsoft® Word® format. Overhead Transparencies (ISBN 0-87893-751-X) This set includes 100 illustrations (approximately 150 transparencies), selected from throughout the textbook for teaching purposes. These are relabeled and optimized for projection in classrooms. Purves3/eFM 5/13/04 1:00 PM Page xx Purves01 5/13/04 1:02 PM Page 1 Chapter 1 Studying the Nervous Systems Overview of Humans and Neuroscience encompasses a broad range of questions about how nervous Other Animals systems are organized, and how they function to generate behavior. These questions can be explored using the analytical tools of genetics, molecular and cell biology, systems anatomy and physiology, behavioral biology, and psychology. The major challenge for a student of neuroscience is to integrate the diverse knowledge derived from these various levels of analysis into a more or less coherent understanding of brain structure and function (one has to qualify this statement because so many questions remain unan- swered). Many of the issues that have been explored successfully concern how the principal cells of any nervous system—neurons and glia—perform their basic functions in anatomical, electrophysiological, and molecular terms. The varieties of neurons and supporting glial cells that have been identified are assembled into ensembles called neural circuits, and these cir- cuits are the primary components of neural systems that process specific types of information. Neural systems comprise neurons and circuits in a number of discrete anatomical locations in the brain. These systems subserve one of three general functions. Sensory systems represent information about the state of the organism and its environment, motor systems organize and generate actions; and associational systems link the sensory and motor sides of the nervous system, providing the basis for “higher-order” functions such as perception, attention, cognition, emotions, rational thinking, and other complex brain functions that lie at the core of understanding human beings, their history and their future. Genetics, Genomics, and the Brain The recently completed sequencing of the genome in humans, mice, the fruit fly Drosophila melanogaster, and the nematode worm Caenorhabditis elegans is perhaps the logical starting point for studying the brain and the rest of the nervous system; after all, this inherited information is also the starting point of each individual organism. The relative ease of obtaining, analyzing, and correlating gene sequences with neurobiological observations has facilitated a wealth of new insights into the basic biology of the nervous system. In par- allel with studies of normal nervous systems, the genetic analysis of human pedigrees with various brain diseases has led to a widespread sense that it will soon be possible to understand and treat disorders long considered beyond the reach of science and medicine. A gene consists of DNA sequences called exons that are transcribed into a messenger RNA and subsequently a protein. The set of exons that defines 1 Purves01 5/13/04 1:02 PM Page 2 2 Chapter One Figure 1.1 Estimates of the number of genes in the human genome, as well as Human in the genomes of the mouse, the fruit fly Drosophila melanogaster, and the nematode worm Caenorhabditis elegans. Mouse D. melanogaster C. elegans 0 10,000 20,000 30,000 40,000 50,000 Number of genes the transcript of any gene is flanked by upstream (or 5′) and downstream (or 3′) regulatory sequences that control gene expression. In addition, sequences between exons—called introns—further influence transcription. Of the approximately 35,000 genes in the human genome, a majority are expressed in the developing and adult brain; the same is true in mice, flies, and worms—the species commonly used in modern genetics (and increasingly in neuroscience) (Figure 1.1). Nevertheless, very few genes are uniquely ex- pressed in neurons, indicating that nerve cells share most of the basic struc- tural and functional properties of other cells. Accordingly, most “brain- specific” genetic information must reside in the remainder of nucleic acid sequences—regulatory sequences and introns—that control the timing, quantity, variability and cellular specificity of gene expression. One of the most promising dividends of sequencing the human genome has been the realization that one or a few genes, when altered (mutated), can begin to explain some aspects of neurological and psychiatric diseases. Before the “postgenomic era” (which began following completion of the sequencing of the human genome), many of the most devastating brain dis- eases remained largely mysterious because there was little sense of how or why the normal biology of the nervous system was compromised. The iden- tification of genes correlated with disorders such as Huntington’s disease, Parkinson’s disease, Alzheimer’s disease, major depression, and schizophre- nia has provided a promising start to understanding these pathological processes in a much deeper way (and thus devising rational therapies). Genetic and genomic information alone do not completely explain how the brain normally works or how disease processes disrupt its function. To achieve these goals it is equally essential to understand the cell biology, anatomy, and physiology of the brain in health as well as disease. The Cellular Components of the Nervous System Early in the nineteenth century, the cell was recognized as the fundamental unit of all living organisms. It was not until well into the twentieth century, however, that neuroscientists agreed that nervous tissue, like all other organs, is made up of these fundamental units. The major reason was that the first generation of “modern” neurobiologists in the nineteenth century had difficulty resolving the unitary nature of nerve cells with the micro- scopes and cell staining techniques that were then available. This inade- Purves01 5/13/04 1:02 PM Page 3 Studying the Ner vous Systems of Humans and O ther Animals 3 (A) Neurons in mesencephalic (B) Retinal (C) Retinal ganglion cell (D) Retinal amacrine cell nucleus of cranial nerve V bipolar cell Dendrites Dendrites Dendrites Cell Cell body Cell body bodies Axon Axon Cell body * Axons (E) Cortical pyramidal cell (F) Cerebellar Purkinje cells * Dendrites Dendrites Cell body Cell body Axon Axon * * Figure 1.2 Examples of the rich variety of nerve cell morphologies found in the human nervous system. Tracings are quacy was exacerbated by the extraordinarily complex shapes and extensive from actual nerve cells stained by branches of individual nerve cells, which further obscured their resemblance impregnation with silver salts (the so- to the geometrically simpler cells of other tissues (Figures 1.2–1.4). As a called Golgi technique, the method used result, some biologists of that era concluded that each nerve cell was con- in the classical studies of Golgi and nected to its neighbors by protoplasmic links, forming a continuous nerve Cajal). Asterisks indicate that the axon cell network, or reticulum. The “reticular theory” of nerve cell communica- runs on much farther than shown. Note tion, which was championed by the Italian neuropathologist Camillo Golgi that some cells, like the retinal bipolar (for whom the Golgi apparatus in cells is named), eventually fell from favor cell, have a very short axon, and that and was replaced by what came to be known as the “neuron doctrine.” The others, like the retinal amacrine cell, major proponents of this new perspective were the Spanish neuroanatomist have no axon at all. The drawings are not all at the same scale. Santiago Ramón y Cajal and the British physiologist Charles Sherrington. The contrasting views represented by Golgi and Cajal occasioned a spir- ited debate in the early twentieth century that set the course of modern neu- roscience. Based on light microscopic examination of nervous tissue stained with silver salts according to a method pioneered by Golgi, Cajal argued persuasively that nerve cells are discrete entities, and that they communicate Purves01 5/13/04 1:02 PM Page 4 4 Chapter One with one another by means of specialized contacts that Sherrington called “synapses.” The work that framed this debate was recognized by the award of the Nobel Prize for Physiology or Medicine in 1906 to both Golgi and Cajal ( the joint award suggests some ongoing concern about just who was correct, despite Cajal’s overwhelming evidence). The subsequent work of Sherrington and others demonstrating the transfer of electrical signals at synaptic junctions between nerve cells provided strong support of the “neu- ron doctrine,” but challenges to the autonomy of individual neurons remained. It was not until the advent of electron microscopy in the 1950s that any lingering doubts about the discreteness of neurons were resolved. The high-magnification, high-resolution pictures that could be obtained with the electron microscope clearly established that nerve cells are functionally independent units; such pictures also identified the specialized cellular junc- tions that Sherrington had named synapses (see Figures 1.3 and 1.4). The histological studies of Cajal, Golgi, and a host of successors led to the further consensus that the cells of the nervous system can be divided into two broad categories: nerve cells (or neurons), and supporting cells called neuroglia (or simply glia; see Figure 1.5). Nerve cells are specialized for elec- trical signaling over long distances, and understanding this process repre- sents one of the more dramatic success stories in modern biology (and the subject of Unit I of this book). Supporting cells, in contrast, are not capable of electrical signaling; nevertheless, they have several essential functions in the developing and adult brain. Neurons Neurons and glia share the complement of organelles found in all cells, including the endoplasmic reticulum and Golgi apparatus, mitochondria, and a variety of vesicular structures. In neurons, however, these organelles are often more prominent in distinct regions of the cell. In addition to the distribution of organelles and subcellular components, neurons and glia are in some measure different from other cells in the specialized fibrillar or tubular proteins that constitute the cytoskeleton (Figures 1.3 and 1.4). Although many of these proteins—isoforms of actin, tubulin, and myosin, as well as several others—are found in other cells, their distinctive organization in neurons is critical for the stability and function of neuronal processes and synaptic junctions. The filaments, tubules, vesicular motors, and scaffolding proteins of neurons orchestrate the growth of axons and dendrites; the traf- ficking and appropiate positioning of membrane components, organelles, and vesicles; and the active processes of exocytosis and endocytosis that underlie synaptic communication. Understanding the ways in which these molecular components are used to insure the proper development and func- tion of neurons and glia remains a primary focus of modern neurobiology. The basic cellular organization of neurons resembles that of other cells; however, they are clearly distinguished by specialization for intercellular communication. This attribute is apparent in their overall morphology, in the specific organization of their membrane components for electrical signaling, and in the structural and functional intricacies of the synaptic contacts between neurons (see Figures 1.3 and 1.4). The most obvious sign of neu- ronal specialization for communication via electrical signaling is the exten- sive branching of neurons. The most salient aspect of this branching for typ- ical nerve cells is the elaborate arborization of dendrites that arise from the neuronal cell body (also called dendritic branches or dendritic processes). Den- drites are the primary target for synaptic input from other neurons and are Purves01 5/13/04 1:02 PM Page 5 Studying the Ner vous Systems of Humans and O ther Animals 5 (A) (B) Axon (C) Synaptic endings (terminal boutons) Endoplasmic Mitochondrion reticulum F E Nucleus Soma Dendrite Golgi (D) Myelinated axons apparatus C B Ribosomes Axons G D (E) Dendrites (F) Neuronal cell body (soma) (G) Myelinated axon and node of Ranvier Figure 1.3 The major light and electron microscopical features of neurons. (A) Dia- gram of nerve cells and their component parts. (B) Axon initial segment (blue) entering a myelin sheath (gold). (C) Terminal boutons (blue) loaded with synaptic vesicles (arrowheads) forming synapses (arrows) with a dendrite (purple). (D) Transverse section of axons (blue) ensheathed by the processes of oligodendro- cytes (gold). (E) Apical dendrites (purple) of cortical pyramidal cells. (F) Nerve cell bodies (purple) occupied by large round nuclei. (G) Portion of a myelinated axon (blue) illustrating the intervals between adjacent segments of myelin (gold) referred to as nodes of Ranvier (arrows). (Micrographs from Peters et al., 1991.) Purves01 5/13/04 1:02 PM Page 6 6 Chapter One Figure 1.4 Distinctive arrangement of (A) (B) (C) cytoskeletal elements in neurons. (A) The cell body, axons, and dendrites are distinguished by the distribution of tubulin (green throughout cell) versus other cytoskeletal elements—in this case, Tau (red), a microtubule-binding protein found only in axons. (B) The strikingly distinct localization of actin (red) to the growing tips of axonal and (D) dendritic processes is shown here in cultured neuron taken from the hip- pocampus. (C) In contrast, in a cultured epithelial cell, actin (red) is distributed in fibrils that occupy most of the cell body. (D) In astroglial cells in culture, actin (red) is also seen in fibrillar bun- dles. (E) Tubulin (green) is seen throughout the cell body and dendrites (E) (G) of neurons. (F) Although tubulin is a major component of dendrites, extend- ing into spines, the head of the spine is enriched in actin (red). (G) The tubulin component of the cytoskeleton in non- neuronal cells is arrayed in filamentous networks. (H–K) Synapses have a dis- tinct arrangement of cytoskeletal ele- ments, receptors, and scaffold proteins. (H) Two axons (green; tubulin) from motor neurons are seen issuing two (F) branches each to four muscle fibers. The red shows the clustering of postsynaptic receptors (in this case for the neuro- transmitter acetylcholine). (I) A higher power view of a single motor neuron (H) (I) synapse shows the relationship between the axon (green) and the postsynaptic receptors (red). (J) The extracellular space between the axon and its target muscle is shown in green. (K) The clus- tering of scaffolding proteins (in this case, dystrophin) that localize receptors and link them to other cytoskeletal ele- ments is shown in green. (A courtesy of Y. N. Jan; B courtesy of E. Dent and F. Gertler; C courtesy of D. Arneman and C. Otey; D courtesy of A. Gonzales and (J) (K) R. Cheney; E from Sheng, 2003; F from Matus, 2000; G courtesy of T. Salmon et al.; H–K courtesy of R. Sealock.) Purves01 5/13/04 1:02 PM Page 7 Studying the Ner vous Systems of Humans and O ther Animals 7 also distinguished by their high content of ribosomes as well as specific cytoskeletal proteins that reflect their function in receiving and integrating information from other neurons. The spectrum of neuronal geometries ranges from a small minority of cells that lack dendrites altogether to neu- rons with dendritic arborizations that rival the complexity of a mature tree (see Figure 1.2). The number of inputs that a particular neuron receives depends on the complexity of its dendritic arbor: nerve cells that lack den- drites are innervated by (thus, receive electrical signals from) just one or a few other nerve cells, whereas those with increasingly elaborate dendrites are innervated by a commensurately larger number of other neurons. The synaptic contacts made on dendrites (and, less frequently, on neu- ronal cell bodies) comprise a special elaboration of the secretory apparatus found in most polarized epithelial cells. Typically, the presynaptic terminal is immediately adjacent to a postsynaptic specialization of the target cell (see Figure 1.3). For the majority of synapses, there is no physical continuity between these pre- and postsynaptic elements. Instead, pre- and postsynap- tic components communicate via secretion of molecules from the presynap- tic terminal that bind to receptors in the postsynaptic specialization. These molecules must traverse an interval of extracellular space between pre- and postsynaptic elements called the synaptic cleft. The synaptic cleft, however, is not simply a space to be traversed; rather, it is the site of extracellular pro- teins that influence the diffusion, binding, and degradation of molecules secreted by the presynaptic terminal (see Figure 1.4). The number of synap- tic inputs received by each nerve cell in the human nervous system varies from 1 to about 100,000. This range reflects a fundamental purpose of nerve cells, namely to integrate information from other neurons. The number of synaptic contacts from different presynaptic neurons onto any particular cell is therefore an especially important determinant of neuronal function. The information conveyed by synapses on the neuronal dendrites is inte- grated and “read out” at the origin of the axon, the portion of the nerve cell specialized for signal conduction to the next site of synaptic interaction (see Figures 1.2 and 1.3). The axon is a unique extension from the neuronal cell body that may travel a few hundred micrometers (µm; usually called microns) or much farther, depending on the type of neuron and the size of the species. Moreover, the axon also has a distinct cytoskeleton whose ele- ments are central for its functional integrity (see Figure 1.4). Many nerve cells in the human brain (as well as that of other species) have axons no more than a few millimeters long, and a few have no axons at all. Relatively short axons are a feature of local circuit neurons or interneu- rons throughout the brain. The axons of projection neurons, however, extend to distant targets. For example, the axons that run from the human spinal cord to the foot are about a meter long. The electrical event that carries sig- nals over such distances is called the action potential, which is a self-regen- erating wave of electrical activity that propagates from its point of initiation at the cell body (called the axon hillock) to the terminus of the axon where synaptic contacts are made. The target cells of neurons include other nerve cells in the brain, spinal cord, and autonomic ganglia, and the cells of mus- cles and glands throughout the body. The chemical and electrical process by which the information encoded by action potentials is passed on at synaptic contacts to the next cell in a path- way is called synaptic transmission. Presynaptic terminals (also called syn- aptic endings, axon terminals, or terminal boutons) and their postsynaptic spe- cializations are typically chemical synapses, the most abundant type of Purves01 5/13/04 1:03 PM Page 8 8 Chapter One synapse in the nervous system. Another type, the electrical synapse, is far more rare (see Chapter 5). The secretory organelles in the presynaptic termi- nal of chemical synapses are synaptic vesicles (see Figure 1.3), which are generally spherical structures filled with neurotransmitter molecules. The positioning of synaptic vesicles at the presynaptic membrane and their fusion to initiate neurotransmitter release is regulated by a number of pro- teins either within or associated with the vesicle. The neurotransmitters released from synaptic vesicles modify the electrical properties of the target cell by binding to neurotransmitter receptors (Figure 1.4), which are local- ized primarily at the postsynaptic specialization. The intricate and concerted activity of neurotransmitters, receptors, related cytoskeletal elements, and signal transduction molecules are thus the basis for nerve cells communicating with one another, and with effector cells in muscles and glands. Figure 1.5 Varieties of neuroglial Neuroglial Cells cells. Tracings of an astrocyte (A), an Neuroglial cells—also referred to as glial cells or simply glia—are quite dif- oligodendrocyte (B), and a microglial ferent from nerve cells. Glia are more numerous than neurons in the brain, cell (C) visualized using the Golgi outnumbering them by a ratio of perhaps 3 to 1. The major distinction is that method. The images are at approxi- glia do not participate directly in synaptic interactions and electrical signal- mately the same scale. (D) Astrocytes in tissue culture, labeled (red) with an ing, although their supportive functions help define synaptic contacts and antibody against an astrocyte-specific maintain the signaling abilities of neurons. Although glial cells also have protein. (E) Oligodendroglial cells in complex processes extending from their cell bodies, these are generally less tissue culture labeled with an antibody prominent than neuronal branches, and do not serve the same purposes as against an oligodendroglial-specific axons and dendrites (Figure 1.5). protein. (F) Peripheral axon are en- sheathed by myelin (labeled red) except at a distinct region called the node of Ranvier. The green label indicates ion channels concentrated in the node; the (A) Astrocyte (B) Oligodendrocyte (C) Microglial cell blue label indicates a molecularly dis- tinct region called the paranode. (G) Microglial cells from the spinal cord, labeled with a cell type-specific anti- body. Inset: Higher-magnification image of a single microglial cell labeled with a macrophage-selective marker. (A–C after Jones and Cowan, 1983; D, E courtesy of A.-S. LaMantia; F courtesy Cell of M. Bhat; G courtesy of A. Light; inset body Glial processes courtesy of G. Matsushima.) (D) (E) (F) (G) Purves01 5/13/04 1:03 PM Page 9 Studying the Ner vous Systems of Humans and O ther Animals 9 The term glia (from the Greek word meaning “glue”) reflects the nine- teenth-century presumption that these cells held the nervous system together in some way. The word has survived, despite the lack of any evi- dence that binding nerve cells together is among the many functions of glial cells. Glial roles that are well-established include maintaining the ionic milieu of nerve cells, modulating the rate of nerve signal propagation, mod- ulating synaptic action by controlling the uptake of neurotransmitters at or near the synaptic cleft, providing a scaffold for some aspects of neural devel- opment, and aiding in (or impeding, in some instances) recovery from neural injury. There are three types of glial cells in the mature central nervous system: astrocytes, oligodendrocytes, and microglial cells (see Figure 1.5). Astro- cytes, which are restricted to the brain and spinal cord, have elaborate local processes that give these cells a starlike appearance (hence the prefix “astro”). A major function of astrocytes is to maintain, in a variety of ways, an appropriate chemical environment for neuronal signaling. Oligodendro- cytes, which are also restricted to the central nervous system, lay down a laminated, lipid-rich wrapping called myelin around some, but not all, axons. Myelin has important effects on the speed of the transmission of elec- trical signals (see Chapter 3). In the peripheral nervous system, the cells that elaborate myelin are called Schwann cells. Finally, microglial cells are derived primarily from hematopoietic precur- sor cells (although some may be derived directly from neural precursor cells). They share many properties with macrophages found in other tissues, and are primarily scavenger cells that remove cellular debris from sites of injury or normal cell turnover. In addition, microglia, like their macrophage counterparts, secrete signaling molecules—particularly a wide range of cytokines that are also produced by cells of the immune system—that can modulate local inflammation and influence cell survival or death. Indeed, some neurobiologists prefer to categorize microglia as a type of macrophage. Following brain damage, the number of microglia at the site of injury increases dramatically. Some of these cells proliferate from microglia resident in the brain, while others come from macrophages that migrate to the injured area and enter the brain via local disruptions in the cerebral vasculature. Cellular Diversity in the Nervous System Although the cellular constituents of the human nervous system are in many ways similar to those of other organs, they are unusual in their extraordi- nary numbers: the human brain is estimated to contain 100 billion neurons and several times as many supporting cells. More importantly, the nervous system has a greater range of distinct cell types—whether categorized by morphology, molecular identity, or physiological activity—than any other organ system (a fact that presumably explains why so many different genes are expressed in the nervous system; see above). The cellular diversity of any nervous system—including our own—undoubtedly underlies the the capac- ity of the system to form increasingly complicated networks to mediate increasingly sophisticated behaviors. For much of the twentieth century, neuroscientists relied on the same set of techniques developed by Cajal and Golgi to describe and categorize the diversity of cell types in the nervous system. From the late 1970s onward, however, new technologies made possible by the advances in cell and mole- cular biology provided investigators with many additional tools to discern the properties of neurons (Figure 1.6). Whereas general cell staining methods Purves01 5/13/04 1:03 PM Page 10 10 Chapter One (A) (B) (C) (D) (E) (F) (G) (H) (I) (J) (K) (L) (M) (N) (O) (P) showed mainly differences in cell size and distribution, antibody stains and probes for messenger RNA added greatly to the appreciation of distinctive types of neurons and glia in various regions of the nervous system. At the same time, new tract tracing methods using a wide variety of tracing sub- stances allowed the interconnections among specific groups of neurons to be Purves01 5/13/04 1:03 PM Page 11 Studying the Ner vous Systems of Humans and O ther Animals 11 ▲ Figure 1.6 Structural diversity in the nervous system demonstrated with cellular and molecular markers. First row: Cellular organization of different brain regions demonstrated with Nissl stains, which label nerve and glial cell bodies. (A) The cerebral cortex at the boundary between the primary and secondary visual areas. (B) The olfactory bulbs. (C) Differences in cell density in cerebral cortical layers. (D) Individual Nissl-stained neurons and glia at higher magnification. Second row: Clas- sical and modern approaches to seeing individual neurons and their processes. (E) Golgi-labeled cortical pyramidal cells. (F) Golgi-labeled cerebellar Purkinje cells. (G) Cortical interneuron labeled by intracellular injection of a fluorescent dye. (H) Reti- nal neurons labeled by intracellular injection of fluorescent dye. Third row: Cellular and molecular approaches to seeing neural connections and systems. (I) At top, an antibody that detects synaptic proteins in the olfactory bulb; at bottom, a fluorescent label shows the location of cell bodies. (J) Synaptic zones and the location of Purk- inje cell bodies in the cerebellar cortex labeled with synapse-specific antibodies (green) and a cell body marker (blue). (K) The projection from one eye to the lateral geniculate nucleus in the thalamus, traced with radioactive amino acids (the bright label shows the axon terminals from the eye in distinct layers of the nucleus). (L) The map of the body surface of a rat in the somatic sensory cortex, shown with a marker that distinguishes zones of higher synapse density and metabolic activity. Fourth row: Peripheral neurons and their projections. (M) An autonomic neuron labeled by intracellular injection of an enzyme marker. (N) Motor axons (green) and neuromuscular synapses (orange) in transgenic mice genetically engineered to express fluorescent proteins. (O) The projection of dorsal root ganglia to the spinal cord, demonstrated by an enzymatic tracer. (P) Axons of olfactory receptor neurons from the nose labeled in the olfactory bulb with a vital fluorescent dye. (G courtesy of L. C. Katz; H courtesy of C. J. Shatz; N,O courtesy of W. Snider and J. Lichtman; all others courtesy of A.-S. LaMantia and D. Purves.) explored much more fully. Tracers can be introduced into either living or fixed tissue, and are transported along nerve cell processes to reveal their origin and termination. More recently, genetic and neuroanatomical meth- ods have been combined to visualize the expression of fluorescent or other tracer molecules under the control of regulatory sequences of neural genes. This approach, which shows individual cells in fixed or living tissue in remarkable detail, allows nerve cells to be identified by both their transcrip- tional state and their structure. Finally, ways of determining the molecular identity and morphology of nerve cells can be combined with measurements of their physiological activity, thus illuminating structure–function relation- ships. Examples of these various approaches are shown in Figure 1.6. Neural Circuits Neurons never function in isolation; they are organized into ensembles or neural circuits that process specific kinds of information and provide the foundation of sensation, perception and behavior. The synaptic connections that define such circuits are typically made in a dense tangle of dendrites, axons terminals, and glial cell processes that together constitute what is called neuropil (the suffix -pil comes from the Greek word pilos, meaning “felt”; see Figure 1.3). The neuropil is thus the region between nerve cell bodies where most synaptic connectivity occurs. Although the arrangement of neural circuits varies greatly according to the function being served, some features are characteristic of all such ensem- bles. Preeminent is the direction of information flow in any particular circuit, which is obviously essential to understanding its purpose. Nerve cells that Purves01 5/13/04 1:03 PM Page 12 12 Chapter One Sensory (afferent) Muscle axon sensory 3A receptor Extensor muscle 2B 2A 1 Flexor muscle 3B Interneuron Motor 2C 4 (efferent) axons 1 Hammer tap stretches 2 (A) Sensory neuron synapses 3 (A) Motor neuron conducts 4 Leg tendon, which, in turn, with and excites motor action potential to extends stretches sensory neuron in the spinal cord synapses on extensor receptors in leg extensor muscle fibers, causing muscle (B) Sensory neuron also contraction excites spinal interneuron (C) Interneuron synapse (B) Flexor muscle relaxes inhibits motor neuron because the activity of its to flexor muscles motor neurons has been inhibited Figure 1.7 A simple reflex circuit, the knee-jerk response (more formally, the myotatic reflex), illustrates several carry information toward the brain or spinal cord (or farther centrally within points about the functional organization the spinal cord and brain) are called afferent neurons; nerve cells that carry of neural circuits. Stimulation of periph- information away from the brain or spinal cord (or away from the circuit in eral sensors (a muscle stretch receptor in question) are called efferent neurons. Interneurons or local circuit neurons this case) initiates receptor potentials only participate in the local aspects of a circuit, based on the short distances that trigger action potentials that travel over which their axons extend. These three functional classes—afferent neu- centrally along the afferent axons of the rons, efferent neurons, and interneurons—are the basic constituents of all sensory neurons. This information stim- neural circuits. ulates spinal motor neurons by means A simple example of a neural circuit is the ensemble of cells that subserves of synaptic contacts. The action poten- tials triggered by the synaptic potential the myotatic spinal reflex (the “knee-jerk” reflex; Figure 1.7). The afferent in motor neurons travel peripherally in neurons of the reflex are sensory neurons whose cell bodies lie the dorsal efferent axons, giving rise to muscle con- root ganglia and whose peripheral axons terminate in sensory endings in traction and a behavioral response. One skeletal muscles (the ganglia that serve this same of function for much of the of the purposes of this particular reflex head and neck are called cranial nerve ganglia; see Appendix A). The central is to help maintain an upright posture in axons of these afferent sensory neurons enter the the spinal cord where they the face of unexpected changes. terminate on a variety of central neurons concerned with the regualtion of muscle tone, most obviously the motor neurons that determine the activity of the related muscles. These neurons constitute the efferent neurons as well as interneurons of the circuit. One group of these efferent neurons in the ventral horn of the spinal cord projects to the flexor muscles in the limb, and the other to extensor muscles. Spinal cord interneurons are the third element of this circuit. The interneurons receive synaptic contacts from sensory afferent neurons and make synapses on the efferent motor neurons that project to the Purves01 5/13/04 1:03 PM Page 13 Studying the Ner vous Systems of Humans and O ther Animals 13 Sensory Hammer Figure 1.8 Relative frequency of action (afferent) tap