Neuron to Brain

FIFTH EDITION

From

John G. Nicholls
International School for Advanced Studies, Trieste, Italy

A. Robert Martin
Emeritus, University of Colorado School of Medicine

Paul A. Fuchs
The Johns Hopkins University School of Medicine

David A. Brown
University College London

Mathew E. Diamond
International School for Advanced Studies, Trieste, Italy

David A. Weisblat
University of California, Berkeley

Sinauer Associates, Inc. Publishers Sunderland, Massachusetts USA

Brief Table of Contents

PART I
CHAPTER 1 CHAPTER 2 CHAPTER 3

Introduction to the Nervous System 1

Principles of Signaling and Organization 3 Signaling in the Visual System 23 Functional Architecture of the Visual Cortex 43

PART IV

Integrative Mechanisms 335

337

CHAPTER 17 Autonomic Nervous System

CHAPTER 18 Cellular Mechanisms of Behavior in Ants, Bees, and Leeches 355

PART V

Sensation and Movement 383

385

CHAPTER 19 Sensory Transduction

PART II
CHAPTER 4 CHAPTER 5 CHAPTER 6 CHAPTER 7 CHAPTER 8 CHAPTER 9

Electrical Properties of Neurons and Glia 61

Ion Channels and Signaling 63 Structure of Ion Channels 77 Ionic Basis of the Resting Potential Ionic Basis of the Action Potential Electrical Signaling in Neurons Ion Transport across Cell Membranes 143 99 113

CHAPTER 20 Transduction and Transmission in the Retina 407 CHAPTER 21 Touch, Pain, and Texture Sensation 433 CHAPTER 22 Auditory and Vestibular Sensation CHAPTER 23 Constructing Perception 475 453

129

CHAPTER 24 Circuits Controlling Reflexes, Respiration, and Coordinated Movements 497

PART VI

CHAPTER 10 Properties and Functions of Neuroglial Cells 159

Development and Regeneration of the Nervous System 529

PART III

Intercellular Communication

CHAPTER 25 Development of the Nervous System 531

183

CHAPTER 11 Mechanisms of Direct Synaptic Transmission 185 CHAPTER 12 Indirect Mechanisms of Synaptic Transmission 213 CHAPTER 13 Release of Neurotransmitters 243

CHAPTER 26 Critical Periods in Sensory Systems 565 CHAPTER 27 Regeneration of Synaptic Connections after Injury 589

PART VII

Conclusion

613
615

CHAPTER 14 Neurotransmitters in the Central Nervous System 273 CHAPTER 15 Transmitter Synthesis, Transport, Storage, and Inactivation 299 CHAPTER 16 Synaptic Plasticity 317

CHAPTER 28 Open Questions

Contents

PART I INTRODUCTION TO THE NERVOUS SYSTEM 1

CHAPTER 1 Principles of Signaling and Organization 3
Signaling in Simple Neuronal Circuits 4 Complex Neuronal Circuitry in Relation to Higher Functions 4
Organization of the Retina 5

Integrative Mechanisms 18 Complexity of the Information Conveyed by Action Potentials 19 Reverse Traffic of Signals from Higher to Lower Centers 19 Higher Functions of the Brain 20
Cellular and Molecular Biology of Neurons 20 Signals for Development of the Nervous System 20 Regeneration of the Nervous System after Injury 21

Shapes and Connections of Neurons 5 Cell Body, Axons, and Dendrites 7 Techniques for Identifying Neurons and Tracing Their Connections 7 Non-Neuronal Cells 8 Grouping of Cells According to Function 9 Complexity of Connections 9
Signaling in Nerve Cells 10

CHAPTER 2 Signaling in the Visual System 23

Pathways in the Visual System 24

Convergence and Divergence of Connections 25

Receptive Fields of Ganglion and Geniculate Cells 26

Universality of Electrical Signals 10 Techniques for Recording Signals from Neurons with Electrodes 11 Noninvasive Techniques for Recording and Stimulating Neuronal Activity 11 Spread of Local Graded Potentials and Passive Electrical Properties of Neurons 13 Spread of Potential Changes in Photoreceptors and Bipolar Cells 14 Properties of Action Potentials 14 Propagation of Action Potentials along Nerve Fibers 15 Action Potentials as the Neural Code 15 Synapses: The Sites for Cell-to-Cell Communication 15 Chemically Mediated Synaptic Transmission 15 Excitation and Inhibition 16 Electrical Transmission 17 Modulation of Synaptic Efficacy 17

Concept of Receptive Fields 26 The Output of the Retina 26 Ganglion and Geniculate Cell Receptive Field Organization 27 Sizes of Receptive Fields 28 Classification of Ganglion and Geniculate Cells 29 What Information Do Ganglion and Geniculate Cells Convey? 29
Box 2.1 Strategies for Exploring the Cortex 30

Cortical Receptive Fields 31 Responses of Simple Cells 31 Synthesis of the Simple Receptive Field 33 Responses of Complex Cells 35 Synthesis of the Complex Receptive Field 37 Receptive Fields: Units for Form Perception 38

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CHAPTER 3 Functional Architecture of the Visual Cortex 43

Retinotopic Maps 44 From Lateral Geniculate Nucleus to Visual Cortex 45

Cell Groupings for Color 52

Connections of Magnocellular and Parvocellular Pathways between V1 and Visual Area 2 (V2) 53
Relations between Ocular Dominance and Orientation Columns 54

Segregation of Retinal Inputs to the Lateral Geniculate Nucleus 45 Cytoarchitecture of the Visual Cortex 45 Inputs, Outputs, and Layering of Cortex 47
Ocular Dominance Columns 48

Horizontal Intracortical Connections 55 Construction of a Single, Unified Visual Field from Inputs Arising in Two Eyes 56
Box 3.1 Corpus Callosum 57

Demonstration of Ocular Dominance Columns by Imaging 50

Orientation Columns 50

Association Areas of Visual Cortex 57 Where Do We Go from Here? 58

PART II ELECTRICAL PROPERTIES OF NEURONS AND GLIA 61

CHAPTER 4 Ion Channels and Signaling 63
Properties of Ion Channels 64
Box 5.1 Classication of Amino Acids 81

A Receptor Superfamily 81

The Nerve Cell Membrane 64 What Does an Ion Channel Look Like? Channel Selectivity 65 Open and Closed States 65 Modes of Activation 66

64

Receptor Structure and Function 82 Structure of the Pore Lining 82 High-Resolution Imaging of the AChR Receptor Activation 84 Ion Selectivity and Conductance 84
Voltage-Activated Channels 86

83

Measurement of Single-Channel Currents 67

Intracellular Recording with Microelectrodes Channel Noise 67 Patch Clamp Recording 68 Single-Channel Currents 69 Channel Conductance 70 Conductance and Permeability 72 Equilibrium Potential 72 The Nernst Equation 73 Nonlinear CurrentVoltage Relations 73 Ion Permeation through Channels 74
Box 4.1 Measuring Channel Conductance

67

The Voltage-Activated Sodium Channel 86 Amino Acid Sequence and Tertiary Structure of the Sodium Channel 86 Voltage-Activated Calcium Channels 88 Voltage-Activated Potassium Channels 88 Pore Formation in Voltage-Activated Channels 89 High-Resolution Imaging of the Potassium Channel 90 Selectivity and Conductance 90 Gating of Voltage-Activated Channels 91
Other Channels 92

74

CHAPTER 5 Structure of Ion Channels 77

Ligand-Activated Channels 78

The Nicotinic Acetylcholine Receptor 78 Amino Acid Sequence of AChR Subunits 79 Higher Order Chemical Structure 79 Other Nicotinic ACh Receptors 79

Glutamate Receptors 92 ATP-Activated Channels 94 Channels Activated by Cyclic Nucleotides 94 Calcium-Activated Potassium Channels 94 Voltage-Sensitive Chloride Channels 94 Inward-Rectifying Potassium Channels 95 2P Channels 95 Transient Receptor Potential (TRP) Channels 95
Diversity of Subunits 95 Conclusion 96

Contents xv

CHAPTER 6 Ionic Basis of the Resting Potential 99

A Model Cell 100

CHAPTER 8 Electrical Signaling in Neurons 129

Specic Electrical Properties of Cell Membranes 131 Flow of Current in a Nerve Fiber 131
Box 8.1 Relation between Cable Constants and Specic Membrane Properties 133

Ionic Equilibrium 100 Electrical Neutrality 101

The Effect of Extracellular Potassium and Chloride on Membrane Potential 102 Membrane Potentials in Squid Axons 103

Action Potential Propagation 134

The Effect of Sodium Permeability

The Constant Field Equation 105

104

Myelinated Nerves and Saltatory Conduction

134

The Resting Membrane Potential 106 Chloride Distribution 107 An Electrical Model of the Membrane 107 Predicted Values of Membrane Potential 108

Box 8.2 Classication of Vertebrate Nerve Fibers 135

Distribution of Channels in Myelinated Fibers

Geometry and Conduction Block 137 Conduction in Dendrites 137 Pathways for Current Flow between Cells 139

136

Contribution of the SodiumPotassium Pump to the Membrane Potential 109 What Ion Channels Are Associated with the Resting Potential? 109 Changes in Membrane Potential 110

CHAPTER 9 Ion Transport across Cell Membranes 143

The SodiumPotassium Exchange Pump 144

CHAPTER 7 Ionic Basis of the Action Potential 113

Voltage Clamp Experiments 114

Capacitative and Leak Currents 114 Ionic Currents Carried by Sodium and Potassium 114 Selective Poisons for Sodium and Potassium Channels 115
Box 7.1 The Voltage Clamp 116

Biochemical Properties of SodiumPotassium ATPase 144 Experimental Evidence that the Pump Is Electrogenic 144 Mechanism of Ion Translocation 146
Calcium Pumps 147

Endoplasmic and Sarcoplasmic Reticulum Calcium ATPase 147 Plasma Membrane Calcium ATPase 147
SodiumCalcium Exchange 147

Dependence of Ion Currents on Membrane Potential 116 Inactivation of the Sodium Current 117 Sodium and Potassium Conductances as Functions of Potential 118
Quantitative Description of Sodium and Potassium Conductances 119

The NCX Transport System 148 Reversal of SodiumCalcium Exchange 148 SodiumCalcium Exchange in Retinal Rods 149
Chloride Transport 150

Reconstruction of the Action Potential 120 Threshold and Refractory Period 120
Gating Currents 122 Mechanisms of Activation and Inactivation 123 Activation and Inactivation of Single Channels 124 Afterpotentials 125 The Role of Calcium in Excitation 127

Inward Chloride Transport 150 Outward PotassiumChloride Cotransport 150 ChlorideBicarbonate Exchange 150
Transport of Neurotransmitters 151

Transport into Presynaptic Vesicles 151 Transmitter Uptake 152

Molecular Structure of Transporters 153

Calcium Action Potentials 127 Calcium Ions and Excitability 128

ATPases 154 SodiumCalcium Exchangers 155 Chloride Transporters 155 Transport Molecules for Neurotransmitters 155
Signicance of Transport Mechanisms 156

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CHAPTER 10 Properties and Functions of Neuroglial Cells 159

Historical Perspective 160 Appearance and Classification of Glial Cells 160 Structural Relations between Neurons, Glia, and Capillaries 163
Physiological Properties of Neuroglial Cell Membranes 164

A Cautionary Note 171

Effects of Neuronal Activity on Glial Cells 172

Ion Channels, Pumps, and Receptors in Glial Cell Membranes 165 Electrical Coupling between Glial Cells 165
Functions of Neuroglial Cells 165

Potassium Accumulation in Extracellular Space 172 Potassium and Calcium Movement through Glial Cells 172 Calcium Waves in Glial Cells 173 Spatial Buffering of Extracellular Potassium Concentration by Glia 174 Glial Cells and Neurotransmitters 174 Release of Transmitters by Glial Cells 174 Immediate Effects of Glial Cells on Synaptic Transmission 176
Glial Cells and the BloodBrain Barrier 176

Myelin and the Role of Neuroglial Cells in Axonal Conduction 166 Glial Cells and Development 168 Role of Microglial Cells in CNS Repair and Regeneration 169 Schwann Cells as Pathways for Outgrowth in Peripheral Nerves 170

Astrocytes and Blood Flow through the Brain

Box 10.1 The BloodBrain Barrier 177

177

Transfer of Metabolites from Glial Cells to Neurons 179

Glial Cells and Immune Responses of the CNS 179

PART III INTERCELLULAR COMMUNICATION 183

CHAPTER 11 Mechanisms of Direct Synaptic Transmission 185
Synaptic Transmission 186 Chemical Synaptic Transmission 186
Box 11.1 Electrical or Chemical Transmission? 187 Box 11.4 Electrical Model of the Motor End Plate 198

Excitatory Synaptic Potentials in the CNS 199

Direct Synaptic Inhibition 201

Reversal of Inhibitory Potentials 201 Presynaptic Inhibition 203

Transmitter Receptor Localization 205 Electrical Synaptic Transmission 207

Synaptic Structure 188 Synaptic Potentials at the Neuromuscular Junction 188

Box 11.2 Drugs and Toxins Acting at the Neuromuscular Junction 190 Box 11.3 Action of Tubocurarine at the Motor End Plate 191

Identification and Characterization of Electrical Synapses 207 Comparison of Electrical and Chemical Transmission 208

Mapping the Region of the Muscle Fiber Receptive to ACh 192 Morphological Demonstration of the Distribution of ACh Receptors 194 Measurement of Ionic Currents Produced by ACh 195 Significance of the Reversal Potential 196 Relative Contributions of Sodium, Potassium, and Calcium to the End-Plate Potential 196 Resting Membrane Conductance and Synaptic Potential Amplitude 196 Kinetics of Currents through Single ACh Receptor Channels 197

CHAPTER 12 Indirect Mechanisms of Synaptic Transmission 213

Direct Versus Indirect Transmission 214 G ProteinCoupled Metabotropic Receptors and G Proteins 215

Structure of G ProteinCoupled Receptors 215

Box 12.1 Receptors, G Proteins, and Effectors: Convergence and Divergence in G Protein Signaling 216

G Proteins 216

Contents xvii

Modulation of Ion Channel Function by ReceptorActivated G Proteins: Direct Actions 217

Statistical Analysis of the End-Plate Potential 252

Box 13.1 Statistical Fluctuation in Quantal Release 253

G Protein Activation of Potassium Channels 217

Box 12.2 Identifying Responses Mediated by G Proteins 218

G Protein Inhibition of Calcium Channels Involved in Transmitter Release 221

G Protein Activation of Cytoplasmic Second Messenger Systems 222

Quantum Content at Neuronal Synapses 255 Number of Molecules in a Quantum 255 Number of Channels Activated by a Quantum 256 Changes in Mean Quantal Size at the Neuromuscular Junction 257 Nonquantal Release 257
Vesicles and Transmitter Release 258

-Adrenergic Receptors Activate Calcium Channels via a G Proteinthe Adenylyl Cyclase Pathway 223
Box 12.3 Cyclic AMP as a Second Messenger 225 Box 12.4 Phosphatidylinositol-4,5-bisphosphate (PIP2) and the phosphoinositide (PI) Cycle 227

G Protein Activation of Phospholipase C 228 Direct Actions of PIP2 229 G Protein Activation of Phospholipase A2 230
Convergence and Divergence of Signals Generated by Indirectly Coupled Receptors 230 Retrograde Signaling via Endocannabinoids 231
Box 12.5 Formation and Metabolism of Endocannabinoids 233

Ultrastructure of Nerve Terminals 258 Morphological Evidence for Exocytosis 259 Release of Vesicle Contents by Exocytosis 261 Monitoring Exocytosis and Endocytosis in Living Cells 262 Mechanism of Exocytosis 264 High-Resolution Structure of Synaptic Vesicle Attachments 264 Reuptake of Synaptic Vesicles 266 Vesicle Recycling Pathways 267 Ribbon Synapses 269 Vesicle Pools 270

Signaling via Nitric Oxide and Carbon Monoxide 234 Calcium as an Intracellular Second Messenger 235

CHAPTER 14 Neurotransmitters in the Central Nervous System 273

Chemical Transmission in the CNS 274 Mapping Neurotransmitter Pathways 274
Box 14.1 The Discovery of Central Transmitters: I. The Amino Acids 275 Box 14.2 The Discovery of Central Transmitters: II. Neuropeptides 277

Actions of Calcium 237

Box 12.6 Measuring Intracellular Calcium 238

Prolonged Time Course of Indirect Transmitter Action 239

CHAPTER 13 Release of Neurotransmitters 243

Characteristics of Transmitter Release 244

Visualizing Transmitter-Specific Neurons in Living Brain Tissue 278

Key Transmitters 278

Axon Terminal Depolarization and Release 244 Synaptic Delay 245 Evidence that Calcium Is Required for Release 246 Measurement of Calcium Entry into Presynaptic Nerve Terminals 246 Localization of Calcium Entry Sites 248 Transmitter Release by Intracellular Concentration Jumps 249 Other Factors Regulating Transmitter Release 249
Quantal Release 250

Glutamate 279 GABA (-Aminobutyric acid) and glycine 279 Acetylcholine 281 Biogenic Amines 287 Adenosine Triphosphate (ATP) 290
Peptides 292

Spontaneous Release of Multimolecular Quanta Fluctuations in the End-Plate Potential 252

251

Substance P 293 Opioid Peptides 293 Orexins (Hypocretins) 294 Vasopressin and Oxytocin: The Social Brain 296

xviii Contents

CHAPTER 15 Transmitter Synthesis, Transport, Storage, and Inactivation 299

Neurotransmitter Synthesis 300

Removal of ATP by Hydrolysis 314 Removal of Transmitters by Uptake 314

Synthesis of ACh 300 Synthesis of Dopamine and Norepinephrine 302 Synthesis of 5-Hydroxytryptamine (5-HT) 304 Synthesis of GABA 305 Synthesis of Glutamate 305 Short- and Long-Term Regulation of Transmitter Synthesis 305 Synthesis of Neuropeptides 306
Storage of Transmitters in Synaptic Vesicles 307

CHAPTER 16 Synaptic Plasticity 317

Short-Term Changes in Signaling 318

Facilitation and Depression of Transmitter Release 318 Post-Tetanic Potentiation and Augmentation 319 Mechanisms Underlying Short-Term Synaptic Changes 320
Long-Term Changes in Signaling 323

Co-Storage and Co-Release 308

Axonal Transport 310

Rate and Direction of Axonal Transport 311 Microtubules and Fast Transport 311 Mechanism of Slow Axonal Transport 311
Removal of Transmitters from the Synaptic Cleft 313

Removal of ACh by Acetylcholinesterase

313

Long-Term Potentiation 323 Associative LTP in Hippocampal Pyramidal Cells 323 Mechanisms Underlying the Induction of LTP 326 Silent Synapses 326 Presynaptic LTP 328 Long-Term Depression 329 LTD in the Cerebellum 331 Mechanisms Underlying LTD 331 Presynaptic LTD 332 Significance of Changes in Synaptic Efficacy 332

PART IV INTEGRATIVE MECHANISMS 335

CHAPTER 17 Autonomic Nervous System 337
Functions under Involuntary Control 338 From Behavior to Neurons and Vice Versa 356 Navigation by Ants and Bees 357

Sympathetic and Parasympathetic Nervous Systems 338 Synaptic Transmission in Autonomic Ganglia M-Currents in Autonomic Ganglia 342 Purinergic Transmission 344

340

Transmitter Release by Postganglionic Axons 343

Box 17.1 The Path to Understanding Sympathetic Mechanisms 344

The Desert Ants Pathway Home 357 Polarized Light Detection by the Ants Eye 359 Strategies for Finding the Nest 361 Polarized Light and Twisted Photoreceptors 361 Additional Mechanisms for Navigation by Ants and Bees 362 Neural Mechanisms for Navigation 364
Behavioral Analysis at the Level of Individual Neurons in the CNS of the Leech 365

Sensory Inputs to the Autonomic Nervous System 345 The Enteric Nervous System 346 Regulation of Autonomic Functions by the Hypothalamus 347 Hypothalamic Neurons That Release Hormones 347 Distribution and Numbers of GnRH Cells 349 Circadian Rhythms 349

Leech Ganglia: Semiautonomous Units 365 Sensory Cells in Leech Ganglia 367 Motor Cells 370 Connections of Sensory and Motor Cells 371
Higher Order Behaviors in the Leech 373

CHAPTER 18 Cellular Mechanisms of Behavior in Ants, Bees, and Leeches 355

Habituation, Sensitization, and Conduction Block 374 Circuits Responsible for the Production of Rhythmical Swimming 377 To Swim or to Crawl? Neurons that Determine Behavioral Choices in the Leech 378
Why Should One Work on Invertebrate Nervous Systems? 381

Contents xix

PART V SENSATION AND MOVEMENT 383

CHAPTER 19 Sensory Transduction 385
Stimulus Coding by Mechanoreceptors 386

Structure of Rhodopsin 413 Cones and Color Vision 413 Color Blindness 415
Transduction 415

Short and Long Receptors 386 Encoding Stimulus Parameters by Stretch Receptors 387 The Crayfish Stretch Receptor 388 Muscle Spindles 389 Responses to Static and Dynamic Muscle Stretch 390 Mechanisms of Adaptation in Mechanoreceptors 391 Adaptation in the Pacinian Corpuscle 391
Direct Transduction by Mechanosensory Hair Cells 392

Properties of the Photoreceptor Channels 415 Molecular Structure of Cyclic GMPGated Channels 416 The cGMP Cascade 416 Amplification through the cGMP Cascade 417 Responses to Single Quanta of Light 417
Box 20.1 Adaptation of Photoreceptors 418

Circadian Photoreceptors in the Mammalian Retina 420

Synaptic Organization of the Retina 420

Mechanosensory Hair Cells of the Vertebrate Ear 392 Structure of Hair Cell Receptors 393
Transduction by Hair Bundle Deection 394

Tip Links and Gating Springs 395 Transduction Channels in Hair Cells Adaptation of Hair Cells 396
Olfaction 397

395

Olfactory Receptors 397 The Olfactory Response 398 Cyclic Nucleotide-Gated Channels in Olfactory Receptors 399 Coupling the Receptor to Ion Channels 399 Odorant Specificity 400
Mechanisms of Taste (Gustation) 401

Bipolar, Horizontal, and Amacrine cells 420 Molecular Mechanisms of Synaptic Transmission in the Retina 421 Receptive Fields of Retinal Neurons 422 Responses of Bipolar Cells 423 Receptive Field Organization of Bipolar Cells 424 Rod Bipolar Cells 424 Horizontal Cells and Surround Inhibition 424 Significance of Receptive Field Organization of Bipolar Cells 426
Receptive Fields of Ganglion Cells 426

Taste Receptor Cells 401 Taste Modalities 402

Pain and Temperature Sensation in Skin 403

Activation and Sensitization of Nociceptors

404

CHAPTER 20 Transduction and Transmission in the Retina 407

The Eye 408

The Output of the Retina 426 Ganglion Cell Receptive Field Organization 427 Sizes of Receptive Fields 427 Classification of Ganglion Cells 427 Synaptic Inputs to Ganglion Cells Responsible for Receptive Field Organization 428 Amacrine Cell Control of Ganglion Cell Responses 429 What Information Do Ganglion Cells Convey? 429

Anatomical Pathways in the Visual System 408 Layering of Cells in the Retina 408
Phototransduction in Retinal Rods and Cones 409

CHAPTER 21 Touch, Pain, and Texture Sensation 433

From Receptors to Cortex 434

Arrangement and Morphology of Photoreceptors 410 Electrical Responses of Vertebrate Photoreceptors to Light 411
Visual Pigments 412

Absorption of Light by Visual Pigments 412

Receptors in the Skin 434 Anatomy of Receptor Neurons 436 Sensations Evoked by Afferent Signals 436 Ascending Pathways 437 Somatosensory Cortex 438 Pain Perception and its Modulation 439

xx Contents
Somatosensory System Organization and Texture Sensation in Rats and Mice 440

The Vestibulo-Ocular Reflex 471 Higher Order Vestibular Function 471

The Whiskers of Mice and Rats 440 Magnification Factor 440 Topographic Map of the Whiskers and Columnar Organization 441 Map Development and Plasticity 441
Box 21.1 Variation across Species in Cortical Maps 443

CHAPTER 23 Constructing Perception 475

What Is the Function of Cortical Processing? 476 Tactile Working Memory Task and its Representation in Primary Somatosensory Cortex 476

Texture Sensation through the Whiskers: Peripheral Mechanisms 444 Texture Sensation through the Whiskers: Cortical Mechanisms 445
Somatosensory System Organization and Texture Sensation in Primates 446

Behavioral Task 476 Neuronal Representation of Vibration Sensations in SI 478 Replacement of Vibrations by Artificial Stimuli 479
Transformation from Sensation to Action 480

Magnification Factor 446 Topographic Map of the Skin and Columnar Organization 446 Map Plasticity 447 Texture Sensation through the Fingertip: Peripheral Mechanisms 447 Texture Sensation through the Fingertip: Cortical Mechanisms 450

Activity in SI across Successive Stages of the Task Activity in Regions beyond SI 481 Neurons Associated with Decision Making 483
Visual Object Perception in Primates 484

480

Object Perception and the Ventral Visual Pathway Deficits in Object Perception 485
Images that Activate Neurons in the Ventral Stream 485

484

CHAPTER 22 Auditory and Vestibular Sensation 453

The Auditory System: Encoding the Frequency Composition of Sound 455

Discovery of Responses to Complex Stimuli in Monkeys 485 The Special Case of Faces 485
Box 23.1 Functional Magnetic Resonance Imaging 487

The Cochlea 456 Frequency Selectivity: Mechanical Tuning 456 Electromotility of Mammalian Cochlear Hair Cells 457 Efferent Inhibition of the Cochlea 458 Frequency Selectivity in Nonmammalian Vertebrates: Electrical Tuning of Hair Cells 461 Hair Cell Potassium Channels and Electrical Tuning 461 The Auditory Pathway: Transmission between Hair Cells and Eighth Nerve Fibers 463 Stimulus Coding by Primary Afferent Neurons 464 Brainstem and Thalamus 464 Sound Localization 464 Auditory Cortex 466
The Vestibular System: Encoding Head Motion and Position 467

Perceptual Invariance and Neuronal Response Invariance 487

Dorsal Intracortical Visual Pathways and Motion Detection 489 Transformation from Elements to Percepts 492

Merging of Features 492 Speed of Processing 493 Forms of Coding 493 TopDown Inputs 494 Further Processing 495

CHAPTER 24 Circuits Controlling Reexes, Respiration, and Coordinated Movements 497

The Motor Unit 498

Vestibular Hair Cells and Neurons 467 The Adequate Stimulus for the Saccule and Utricle 469 The Adequate Stimulus for the Semicircular Canals 470

Synaptic Inputs to Motoneurons 499 Unitary Synaptic Potentials in Motoneurons 500 The Size Principle and Graded Contractions 500
Spinal Reexes 501

Reciprocal Innervation 501

Contents xxi

Central Nervous System Control of Muscle Spindles 503 Flexor Reflexes 506
Generation of Coordinated Movements 506

Neural Control of Respiration 506 Locomotion 509 Sensory Feedback and Central Pattern Generator Programs 511
Organization of Descending Motor Control 512

What Do Motor Maps Mean? 515 Cellular Activity and Movement 516 Cortical Cell Activity Related to Direction of Arm Movements 516 Higher Control of Movement 517
Cerebellum and Basal Ganglia 519

Terminology 512 Supraspinal Control of Motoneurons 512 Lateral Motor Pathways 512 Medial Motor Pathways 513
Motor Cortex and the Execution of Voluntary Movement 514

The Cerebellum 519 Connections of the Cerebellum 519 Synaptic Organization of the Cerebellar Cortex 521 What Does the Cerebellum Do and How Does It Do It? 523 The Basal Ganglia 524 Circuitry of the Basal Ganglia 525 Diseases of the Basal Ganglia 525

PART VI DEVELOPMENT AND REGENERATION

OF THE NERVOUS SYSTEM
CHAPTER 25 Development of the Nervous System 531
Development: General Considerations 532

529

Control of Transmitter Choice in the Peripheral Nervous System 547 Changes in Receptors during Development 549
Axon Outgrowth and Growth Cone Navigation 550

Genomic Equivalence and Cell Type Diversity 532 Cell Fate Maps Provide a Description of Normal Development 533
Box 25.1 Conserved Signaling Pathways for Early Development and Neurogenesis 534

Early Morphogenesis of the Nervous System 535 Patterning along Anteroposterior and Dorsoventral Axes 537

Growth Cones, Axon Elongation, and the Role of Actin 550 Cell and Extracellular Matrix Adhesion Molecules and Axon Outgrowth 550 Growth Cone Guidance: Target-Dependent and Target-Independent Navigation 552 Target-Dependent Navigation via Guidepost Cells Growth Cone Navigation along Gradients 553
Growth Factors and Survival of Neurons 555

552

Anteroposterior Patterning and Segmentation in Hindbrain 538 Dorsoventral Patterning in the Spinal Cord 539
Cell Proliferation 541

Cell Proliferation in the Ventricular Zone 541 Cell Proliferation via Radial Glia 541 When Do Neurons Stop Dividing? Adult Neurogenesis 543
Migration 545

Cell Death in the Developing Nervous System 555 Nerve Growth Factor 555 NGF in the Central Nervous System 556 The Neurotrophins and other Families of Growth Factors 556
Formation of Connections 558

Migration of Cortical Neurons 545 Genetic Abnormalities of Cortical Layers in Reeler Mice 547
Determination of Cell Phenotype 547

Establishment of the Retinotectal Map 558 Synapse Formation 559 Pruning and the Removal of Polyneuronal Innervation 560 Neuronal Activity and Synapse Elimination 561
General Considerations of Neural Specicity and Development 561

Lineage of Neurons and Glial Cells 547

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CHAPTER 26 Critical Periods in Sensory Systems 565

The Visual System in Newborn Monkeys and Kittens 566

Critical Periods in the Auditory System of Barn Owls 581

Receptive Fields and Response Properties of Cortical Cells in Newborn Animals 566 Ocular Dominance Columns in Newborn Monkeys and Kittens 567 Postnatal Development of Ocular Dominance Columns 568
Effects of Abnormal Visual Experience in Early Life 569

Effects of Enriched Sensory Experience in Early Life 583 Critical Periods in Humans and Clinical Consequences 585

CHAPTER 27 Regeneration of Synaptic Connections after Injury 589

Regeneration in the Peripheral Nervous System 590

Wallerian Degeneration and Removal of Debris 590 Retrograde Transsynaptic Effects of Axotomy 591
Effects of Denervation on Postsynaptic Cells 592

Blindness after Lid Closure 569 Responses of Cortical Cells after Monocular Deprivation 569 Relative Importance of Diffuse Light and Form for Maintaining Normal Responses 569 Morphological Changes in the Lateral Geniculate Nucleus after Visual Deprivation 569 Morphological Changes in the Cortex after Visual Deprivation 570 Critical Period for Susceptibility to Lid Closure 570 Recovery during the Critical Period 571
Requirements for Maintenance of Functioning Connections in the Visual System 573

Binocular Lid Closure and the Role of Competition 573 Effects of Strabismus (Squint) 573 Changes in Orientation Preference 574 Segregation of Visual Inputs without Competition 574 Effects of Impulse Activity on the Developing Visual System 575 Synchronized Spontaneous Activity in the Absence of Inputs during Development 576 Role of -Aminobutyric Acid (GABA) and Trophic Molecules in Development of Columnar Architecture 577 Critical Periods in Somatosensory and Olfactory Systems 578
Sensory Deprivation and Critical Periods in the Auditory System 578

The Denervated Muscle Membrane 592 Appearance of New ACh Receptors (AChRs) after Denervation or Prolonged Inactivity of Muscle 592 Synthesis and Degradation of Receptors in Denervated Muscle 592 Role of Muscle Inactivity in Denervation Supersensitivity 593 Role of Calcium in Development of Supersensitivity in Denervated Muscle 595 Supersensitivity of Peripheral Nerve Cells after Removal of Synaptic Inputs 596 Susceptibility of Normal and Denervated Muscles to New Innervation 597 Role of Schwann Cells and Microglia in Axon Outgrowth after Injury 597 Denervation-Induced Axonal Sprouting 598 Appropriate and Inappropriate Reinnervation 598
Basal Lamina, Agrin, and the Formation of Synaptic Specializations 599

Identification of Agrin 601 The Role of Agrin in Synapse Formation 602 Mechanism of Action of Agrin 603
Regeneration in the Mammalian CNS 605

Regulation of Synapse Formation by Activity in the Cochlear Nucleus 580

Box 26.1 The Cochlear Implant 581

Glial Cells and CNS Regeneration 605 Schwann Cell Bridges and Regeneration 606 Formation of Synapses by Axons Regenerating in the Mammalian CNS 607 Regeneration in Immature Mammalian CNS 607 Neuronal Transplants 609 Prospects for Developing Treatment of Spinal Cord Injury in Patients 610

Contents xxiii

PART VII CONCLUSION 613

CHAPTER 28 Open Questions 615
Cellular and Molecular Studies of Neuronal Functions 616 Functional Importance of Intercellular Transfer of Materials 616 Development and Regeneration 617 Genetic Approaches to Understanding the Nervous System 617 Sensory and Motor Integration 618 Rhythmicity 618 Input from Clinical Neurology to Studies of the Brain 619 Input from Basic Neuroscience to Neurology 620 The Rate of Progress 621 Conclusions 621

APPENDIX A Current Flow in Electrical Circuits A1 APPENDIX B Metabolic Pathways for the Synthesis and Inactivation of Low-Molecular-Weight Transmitters B1 APPENDIX C Structures and Pathways of the Brain C1 Glossary G1 BB1

Bibliography Index I1