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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


System 1

CHAPTER 1

Principles of Signaling and


Organization 3

CHAPTER 2

Signaling in the Visual System

CHAPTER 3

Functional Architecture of the Visual


Cortex 43

PART IV

CHAPTER 17 Autonomic Nervous System

PART V

Sensation and Movement 383

CHAPTER 19 Sensory Transduction

385

CHAPTER 20 Transduction and Transmission


in the Retina 407

CHAPTER 4

Ion Channels and Signaling

CHAPTER 5

Structure of Ion Channels

CHAPTER 6

Ionic Basis of the Resting Potential

99

CHAPTER 7

Ionic Basis of the Action Potential

113

CHAPTER 8

Electrical Signaling in Neurons

CHAPTER 9

Ion Transport across Cell


Membranes 143

CHAPTER 21 Touch, Pain, and Texture


Sensation 433

63
77

CHAPTER 22 Auditory and Vestibular Sensation

129

CHAPTER 23 Constructing Perception

453

475

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

CHAPTER 25 Development of the Nervous


System 531

183

CHAPTER 26 Critical Periods in Sensory


Systems 565

CHAPTER 11 Mechanisms of Direct Synaptic


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

243

CHAPTER 14 Neurotransmitters in the Central


Nervous System 273

CHAPTER 27 Regeneration of Synaptic Connections


after Injury 589

PART VII

Conclusion

CHAPTER 28 Open Questions

613
615

CHAPTER 15 Transmitter Synthesis, Transport,


Storage, and Inactivation 299
CHAPTER 16 Synaptic Plasticity

337

23

Electrical Properties of
Neurons and Glia 61

Intercellular
Communication

335

CHAPTER 18 Cellular Mechanisms of Behavior


in Ants, Bees, and Leeches 355

PART II

PART III

Integrative Mechanisms

317

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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

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

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

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

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

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

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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30

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

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

Orientation Columns 50

PART II ELECTRICAL PROPERTIES OF NEURONS AND GLIA 61


CHAPTER 4 Ion Channels and
Signaling 63

Box 5.1 Classication of Amino Acids

A Receptor Superfamily 81

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

Properties of Ion Channels 64

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

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

83

Voltage-Activated Channels 86

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

81

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

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

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Contents xv

CHAPTER 6 Ionic Basis of the


Resting Potential 99

CHAPTER 8 Electrical Signaling in


Neurons 129

A Model Cell 100

Specic Electrical Properties of Cell Membranes 131

Ionic Equilibrium 100


Electrical Neutrality 101

Flow of Current in a Nerve Fiber 131

The Effect of Extracellular Potassium and Chloride on


Membrane Potential 102
Membrane Potentials in Squid Axons 103

The Effect of Sodium Permeability

104

The Constant Field Equation 105


The Resting Membrane Potential 106

Box 8.1 Relation between Cable Constants and


Specic Membrane Properties 133

Action Potential Propagation 134

Myelinated Nerves and


Saltatory Conduction

134

Box 8.2 Classication of Vertebrate Nerve


Fibers 135

Distribution of Channels in Myelinated Fibers

Chloride Distribution 107


An Electrical Model of the Membrane 107

Geometry and Conduction Block 137

Predicted Values of Membrane Potential 108

Conduction in Dendrites 137

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 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

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

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

Calcium Action Potentials 127


Calcium Ions and Excitability 128

136

Pathways for Current Flow between Cells 139

CHAPTER 9 Ion Transport across Cell


Membranes 143
The SodiumPotassium Exchange Pump 144

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

The NCX Transport System 148


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

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

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

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 BloodBrain Barrier 176

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

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

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 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

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Contents xvii

Statistical Analysis of the End-Plate Potential 252

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

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

-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

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

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

Prolonged Time Course of Indirect Transmitter


Action 239

Box 14.2 The Discovery of Central Transmitters:


II. Neuropeptides 277

CHAPTER 13 Release of
Neurotransmitters 243

Visualizing Transmitter-Specific Neurons in Living


Brain Tissue 278

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

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

251

Key Transmitters 278

Glutamate 279
GABA (-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
Vasopressin and Oxytocin: The Social Brain 296

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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

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

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
M-Currents in Autonomic Ganglia 342

340

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

From Behavior to Neurons and Vice Versa 356


Navigation by Ants and Bees 357

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

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

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Contents xix

PART V SENSATION AND MOVEMENT 383


CHAPTER 19 Sensory
Transduction 385

Structure of Rhodopsin 413


Cones and Color Vision 413
Color Blindness 415

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

Mechanosensory Hair Cells of the Vertebrate Ear 392


Structure of Hair Cell Receptors 393
Transduction by Hair Bundle Deection 394

395

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

415

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

Direct Transduction by Mechanosensory Hair


Cells 392

Tip Links and Gating Springs 395


Transduction Channels in Hair Cells
Adaptation of Hair Cells 396

Transduction

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

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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

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


Activity in Regions beyond SI 481
Neurons Associated with Decision Making 483

480

Visual Object Perception in Primates 484

Object Perception and the Ventral Visual Pathway


Deficits in Object Perception 485

484

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
TopDown Inputs 494
Further Processing 495

CHAPTER 24 Circuits Controlling


Reexes, 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 Reexes 501

Reciprocal Innervation 501

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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

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

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

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

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
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 Specicity
and Development 561

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552

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 -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

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

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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

Bibliography
Index

BB1

I1

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