From

Neuron
to Brain
FIFTH EDITION

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

© Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured

or disseminated in any form without express written permission from the publisher.
Brief Table of Contents

PART I Introduction to the Nervous PART IV Integrative Mechanisms 335

System 1 CHAPTER 17 Autonomic Nervous System 337
CHAPTER 1 Principles of Signaling and
CHAPTER 18 Cellular Mechanisms of Behavior
Organization 3
in Ants, Bees, and Leeches 355
CHAPTER 2 Signaling in the Visual System 23

CHAPTER 3 Functional Architecture of the Visual PART V Sensation and Movement 383
Cortex 43 CHAPTER 19 Sensory Transduction 385

CHAPTER 20 Transduction and Transmission

PART II Electrical Properties of in the Retina 407
Neurons and Glia 61
CHAPTER 21 Touch, Pain, and Texture
CHAPTER 4 Ion Channels and Signaling 63
Sensation 433
CHAPTER 5 Structure of Ion Channels 77
CHAPTER 22 Auditory and Vestibular Sensation 453
CHAPTER 6 Ionic Basis of the Resting Potential 99
CHAPTER 23 Constructing Perception 475
CHAPTER 7 Ionic Basis of the Action Potential 113
CHAPTER 24 Circuits Controlling Reflexes,
CHAPTER 8 Electrical Signaling in Neurons 129 Respiration, and Coordinated
Movements 497
CHAPTER 9 Ion Transport across Cell
Membranes 143
PART VI Development and
CHAPTER 10 Properties and Functions of Neuroglial Regeneration of the
Cells 159 Nervous System 529
CHAPTER 25 Development of the Nervous
PART III Intercellular System 531
Communication 183
CHAPTER 26 Critical Periods in Sensory
CHAPTER 11 Mechanisms of Direct Synaptic Systems 565
Transmission 185
CHAPTER 27 Regeneration of Synaptic Connections
CHAPTER 12 Indirect Mechanisms of Synaptic after Injury 589
Transmission 213

CHAPTER 13 Release of Neurotransmitters 243 PART VII Conclusion 613

CHAPTER 14 Neurotransmitters in the Central CHAPTER 28 Open Questions 615
Nervous System 273

CHAPTER 15 Transmitter Synthesis, Transport,

Storage, and Inactivation 299

CHAPTER 16 Synaptic Plasticity 317

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Contents

PART I INTRODUCTION TO THE NERVOUS SYSTEM 1

■ CHAPTER 1 Principles of Signaling Integrative Mechanisms 18
and Organization 3 Complexity of the Information Conveyed by Action
Potentials 19
Signaling in Simple Neuronal Circuits 4
Reverse Traffic of Signals from Higher to Lower
Complex Neuronal Circuitry in Relation to Higher
Centers 19
Functions 4
Higher Functions of the Brain 20
Organization of the Retina 5
Cellular and Molecular Biology of Neurons 20
Shapes and Connections of Neurons 5
Cell Body, Axons, and Dendrites 7 Signals for Development of the Nervous System 20
Techniques for Identifying Neurons and Tracing Their Regeneration of the Nervous System after Injury 21
Connections 7
Non-Neuronal Cells 8 ■ CHAPTER 2 Signaling in the
Grouping of Cells According to Function 9 Visual System 23
Complexity of Connections 9 Pathways in the Visual System 24
Signaling in Nerve Cells 10 Convergence and Divergence of Connections 25
Universality of Electrical Signals 10 Receptive Fields of Ganglion and
Techniques for Recording Signals from Neurons with Geniculate Cells 26
Electrodes 11 Concept of Receptive Fields 26
Noninvasive Techniques for Recording The Output of the Retina 26
and Stimulating Neuronal Activity 11 Ganglion and Geniculate Cell Receptive Field
Spread of Local Graded Potentials and Passive Organization 27
Electrical Properties of Neurons 13 Sizes of Receptive Fields 28
Spread of Potential Changes in Photoreceptors and Classification of Ganglion and Geniculate Cells 29
Bipolar Cells 14
What Information Do Ganglion and Geniculate Cells
Properties of Action Potentials 14 Convey? 29
Propagation of Action Potentials along Nerve
■ Box 2.1 Strategies for Exploring the Cortex 30
Fibers 15
Action Potentials as the Neural Code 15 Cortical Receptive Fields 31
Synapses: The Sites for Cell-to-Cell Responses of Simple Cells 31
Communication 15 Synthesis of the Simple Receptive Field 33
Chemically Mediated Synaptic Transmission 15 Responses of Complex Cells 35
Excitation and Inhibition 16 Synthesis of the Complex Receptive Field 37
Electrical Transmission 17 Receptive Fields: Units for Form Perception 38
Modulation of Synaptic Efficacy 17

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xiv Contents
■ CHAPTER 3 Functional Architecture of
the Visual Cortex 43
Retinotopic Maps 44
From Lateral Geniculate Nucleus to Visual Cortex 45
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
Demonstration of Ocular Dominance Columns by
Imaging 50
Orientation Columns 50
PART II ELECTRICAL PROPERTIES OF NEURONS AND GLIA 61
■ CHAPTER 4 Ion Channels and
Signaling 63
Properties of Ion Channels 64
The Nerve Cell Membrane 64
What Does an Ion Channel Look Like? 64
Channel Selectivity 65
Open and Closed States 65
Modes of Activation 66
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 Current–Voltage Relations 73
Ion Permeation through Channels 74
■ Box 4.1 Measuring Channel Conductance
■ 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
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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
Horizontal Intracortical Connections 55
Construction of a Single, Unified Visual Field from
Inputs Arising in Two Eyes 56
■ Box 3.1 Corpus Callosum 57
Association Areas of Visual Cortex 57
Where Do We Go from Here? 58
■ Box 5.1 Classification of Amino Acids 81
A Receptor Superfamily 81
Receptor Structure and Function 82
Structure of the Pore Lining 82
High-Resolution Imaging of the AChR 83
Receptor Activation 84
Ion Selectivity and Conductance 84
Voltage-Activated Channels 86
The Voltage-Activated Sodium Channel 86
67 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
Glutamate Receptors 92
74
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 ■ CHAPTER 8 Electrical Signaling in

Resting Potential 99
A Model Cell 100
Ionic Equilibrium 100
Electrical Neutrality 101
The Effect of Extracellular Potassium and Chloride on
Membrane Potential 102
Membrane Potentials in Squid Axons 103
The Effect of Sodium Permeability
The Constant Field Equation 105
The Resting Membrane Potential 106
Neurons 129
Specific Electrical Properties of Cell Membranes 131
Flow of Current in a Nerve Fiber 131
■ Box 8.1 Relation between Cable Constants and
Specific Membrane Properties 133
Action Potential Propagation 134
Myelinated Nerves and
104 Saltatory Conduction 134
■ Box 8.2 Classification of Vertebrate Nerve
Fibers 135

Chloride Distribution 107 Distribution of Channels in Myelinated Fibers 136

An Electrical Model of the Membrane 107
Predicted Values of Membrane Potential 108
Contribution of the Sodium–Potassium Pump
to the Membrane Potential 109
What Ion Channels Are Associated with the Resting
Potential? 109
Changes in Membrane Potential 110
Geometry and Conduction Block 137
Conduction in Dendrites 137
Pathways for Current Flow between Cells 139
■ CHAPTER 9 Ion Transport across Cell
Membranes 143
The Sodium–Potassium Exchange Pump 144

■ CHAPTER 7 Ionic Basis of the Action Biochemical Properties of Sodium–Potassium

ATPase 144
Potential 113
Experimental Evidence that the Pump Is
Voltage Clamp Experiments 114 Electrogenic 144
Capacitative and Leak Currents 114 Mechanism of Ion Translocation 146
Ionic Currents Carried by Sodium and Calcium Pumps 147
Potassium 114
Endoplasmic and Sarcoplasmic Reticulum Calcium
Selective Poisons for Sodium ATPase 147
and Potassium Channels 115
Plasma Membrane Calcium ATPase 147
■ Box 7.1 The Voltage Clamp 116
Sodium–Calcium Exchange 147
Dependence of Ion Currents on Membrane The NCX Transport System 148
Potential 116
Reversal of Sodium–Calcium Exchange 148
Inactivation of the Sodium Current 117
Sodium–Calcium Exchange in Retinal Rods 149
Sodium and Potassium Conductances as Functions of
Potential 118 Chloride Transport 150
Inward Chloride Transport 150
Quantitative Description of Sodium
and Potassium Conductances 119 Outward Potassium–Chloride Cotransport 150
Reconstruction of the Action Potential 120 Chloride–Bicarbonate Exchange 150
Threshold and Refractory Period 120 Transport of Neurotransmitters 151
Gating Currents 122 Transport into Presynaptic Vesicles 151
Mechanisms of Activation and Transmitter Uptake 152
Inactivation 123 Molecular Structure of Transporters 153
Activation and Inactivation of Single Channels 124 ATPases 154
Afterpotentials 125 Sodium–Calcium Exchangers 155
The Role of Calcium in Excitation 127 Chloride Transporters 155
Calcium Action Potentials 127 Transport Molecules for Neurotransmitters 155
Calcium Ions and Excitability 128 Significance of Transport Mechanisms 156

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xvi Contents
■ 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
Ion Channels, Pumps, and Receptors in Glial Cell
Membranes 165
Electrical Coupling between Glial Cells 165
Functions of Neuroglial Cells 165
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
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
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
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
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A Cautionary Note 171
Effects of Neuronal Activity on Glial Cells 172
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 Blood–Brain Barrier 176
Astrocytes and Blood Flow through the Brain 177
■ Box 10.1 The Blood–Brain Barrier 177
Transfer of Metabolites from Glial Cells to
Neurons 179
Glial Cells and Immune Responses of the CNS 179
■ 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
Identification and Characterization of Electrical
Synapses 207
Comparison of Electrical and Chemical
Transmission 208
■ CHAPTER 12 Indirect Mechanisms of
Synaptic Transmission 213
Direct Versus Indirect Transmission 214
G Protein–Coupled Metabotropic Receptors and
G Proteins 215
Structure of G Protein–Coupled Receptors 215
■ Box 12.1 Receptors, G Proteins, and Effectors:
Convergence and Divergence in G Protein
Signaling 216
G Proteins 216

Modulation of Ion Channel Function by Receptor-
Activated G Proteins: Direct Actions 217
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
β-Adrenergic Receptors Activate Calcium Channels via
a G Protein—the 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
Signaling via Nitric Oxide and Carbon Monoxide 234
Calcium as an Intracellular Second Messenger 235
Actions of Calcium 237
■ Box 12.6 Measuring Intracellular Calcium
Prolonged Time Course of Indirect Transmitter
Action 239
■ CHAPTER 13 Release of
Neurotransmitters 243
Characteristics of Transmitter Release 244
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
Spontaneous Release of Multimolecular Quanta
Fluctuations in the End-Plate Potential 252
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Contents xvii
Statistical Analysis of the End-Plate Potential 252
■ Box 13.1 Statistical Fluctuation in Quantal
Release 253
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
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
■ CHAPTER 14 Neurotransmitters in the
Central Nervous System 273
Chemical Transmission in the CNS 274
238 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
Visualizing Transmitter-Specific Neurons in Living
Brain Tissue 278
Key Transmitters 278
Glutamate 279
GABA (γ-Aminobutyric acid) and glycine 279
Acetylcholine 281
Biogenic Amines 287
Adenosine Triphosphate (ATP) 290
Peptides 292
Substance P 293
Opioid Peptides 293
Orexins (Hypocretins) 294
251 Vasopressin and Oxytocin: The Social Brain 296
xviii Contents
■ CHAPTER 15 Transmitter Synthesis,
Transport, Storage, and Inactivation 299
Neurotransmitter Synthesis 300
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
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
PART IV INTEGRATIVE MECHANISMS 335
■ CHAPTER 17 Autonomic Nervous
System 337
Functions under Involuntary Control 338
Sympathetic and Parasympathetic Nervous
Systems 338
Synaptic Transmission in Autonomic Ganglia 340
M-Currents in Autonomic Ganglia 342
Transmitter Release by Postganglionic Axons 343
Purinergic Transmission 344
■ Box 17.1 The Path to Understanding Sympathetic
Mechanisms 344
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
■ CHAPTER 18 Cellular Mechanisms
of Behavior in Ants, Bees, and
Leeches 355
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Removal of ATP by Hydrolysis 314
Removal of Transmitters by Uptake 314
■ 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
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
From Behavior to Neurons and Vice Versa 356
Navigation by Ants and Bees 357
The Desert Ant’s Pathway Home 357
Polarized Light Detection by the Ant’s 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
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
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

PART V SENSATION AND MOVEMENT 383
■ CHAPTER 19 Sensory
Transduction 385
Stimulus Coding by Mechanoreceptors 386
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
Mechanosensory Hair Cells of the Vertebrate Ear 392
Structure of Hair Cell Receptors 393
Transduction by Hair Bundle Deflection 394
Tip Links and Gating Springs 395
Transduction Channels in Hair Cells 395
Adaptation of Hair Cells 396
Olfaction 397
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
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
Anatomical Pathways in the Visual System 408
Layering of Cells in the Retina 408
Phototransduction in Retinal Rods and Cones 409
Arrangement and Morphology of Photoreceptors 410
Electrical Responses of Vertebrate Photoreceptors to
Light 411
Visual Pigments 412
Absorption of Light by Visual Pigments 412
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Contents xix
Structure of Rhodopsin 413
Cones and Color Vision 413
Color Blindness 415
Transduction 415
Properties of the Photoreceptor Channels 415
Molecular Structure of Cyclic GMP–Gated
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
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
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
■ CHAPTER 21 Touch, Pain, and Texture
Sensation 433
From Receptors to Cortex 434
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 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
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
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
■ CHAPTER 22 Auditory and Vestibular
Sensation 453
The Auditory System: Encoding the Frequency
Composition of Sound 455
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
Vestibular Hair Cells and Neurons 467
The Adequate Stimulus for the Saccule and Utricle 469
The Adequate Stimulus for the Semicircular Canals 470
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The Vestibulo-Ocular Reflex 471
Higher Order Vestibular Function 471
■ 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
Behavioral Task 476
Neuronal Representation of Vibration Sensations
in SI 478
Replacement of Vibrations by Artificial Stimuli 479
Transformation from Sensation to Action 480
Activity in SI across Successive Stages of the Task 480
Activity in Regions beyond SI 481
Neurons Associated with Decision Making 483
Visual Object Perception in Primates 484
Object Perception and the Ventral Visual Pathway 484
Deficits in Object Perception 485
Images that Activate Neurons in the Ventral
Stream 485
Discovery of Responses to Complex Stimuli in
Monkeys 485
The Special Case of Faces 485
■ Box 23.1 Functional Magnetic Resonance
Imaging 487
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
Top–Down Inputs 494
Further Processing 495
■ CHAPTER 24 Circuits Controlling
Reflexes, Respiration, and Coordinated
Movements 497
The Motor Unit 498
Synaptic Inputs to Motoneurons 499
Unitary Synaptic Potentials in Motoneurons 500
The Size Principle and Graded Contractions 500
Spinal Reflexes 501
Reciprocal Innervation 501

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
Terminology 512
Supraspinal Control of Motoneurons 512
Lateral Motor Pathways 512
Medial Motor Pathways 513
Motor Cortex and the Execution of Voluntary
Movement 514
PART VI DEVELOPMENT AND REGENERATION
OF THE NERVOUS SYSTEM
■ CHAPTER 25 Development of the
Nervous System 531
Development: General Considerations 532
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
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
Migration of Cortical Neurons 545
Genetic Abnormalities of Cortical Layers in Reeler
Mice 547
Determination of Cell Phenotype 547
Lineage of Neurons and Glial Cells 547
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Contents xxi
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
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
529
Control of Transmitter Choice in the Peripheral
Nervous System 547
Changes in Receptors during Development 549
Axon Outgrowth and Growth Cone Navigation 550
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 552
Growth Cone Navigation along Gradients 553
Growth Factors and Survival of Neurons 555
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
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 Specificity
and Development 561
xxii Contents
■ CHAPTER 26 Critical Periods in
Sensory Systems 565
The Visual System in Newborn Monkeys and
Kittens 566
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
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 γ-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
Regulation of Synapse Formation by Activity in the
Cochlear Nucleus 580
■ Box 26.1 The Cochlear Implant 581
© Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured
or disseminated in any form without express written permission from the publisher.
Critical Periods in the Auditory System of Barn
Owls 581
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
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
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 A–1

■ APPENDIX B Metabolic Pathways for

the Synthesis and Inactivation of
Low-Molecular-Weight
Transmitters B–1

■ APPENDIX C Structures and Pathways

of the Brain C–1

Glossary G–1

Bibliography BB–1

Index I–1

© Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured

or disseminated in any form without express written permission from the publisher.