Principles of Neural Science, Sixth Edition
By Eric R. Kandel, John D. Koester, Sarah H. Mack and Steven A. Siegelbaum
Contents
Preface xli
Acknowledgments xliii
Contributors xlv
Part I
Overall Perspective
1 The Brain and Behavior. . . . . . . . . . . . . . .7
Eric R. Kandel, Michael N. Shadlen
Two Opposing Views Have Been Advanced on the
Relationship Between Brain and Behavior 8
The Brain Has Distinct Functional Regions 10
The First Strong Evidence for Localization of Cognitive
Abilities Came From Studies of Language Disorders 16
Mental Processes Are the Product of Interactions Between
Elementary Processing Units in the Brain 21
Highlights 23
Selected Reading 23
References 24
2 Genes and Behavior. . . . . . . . . . . . . . . . .26
Matthew W. State, Cornelia I. Bargmann, Conrad Gilliam
An Understanding of Molecular Genetics and Heritability
Is Essential to the Study of Human Behavior 27
The Understanding of the Structure and Function of the
Genome Is Evolving 27
Genes Are Arranged on Chromosomes 30
The Relationship Between Genotype and Phenotype Is
Often Complex 31
Genes Are Conserved Through Evolution 32
Genetic Regulation of Behavior Can Be Studied
in Animal Models 34
A Transcriptional Oscillator Regulates Circadian
Rhythm in Flies, Mice, and Humans 34
Natural Variation in a Protein Kinase Regulates Activity
in Flies and Honeybees 42
Neuropeptide Receptors Regulate the Social Behaviors
of Several Species 44
Studies of Human Genetic Syndromes Have
Provided Initial Insights Into the Underpinnings
of Social Behavior 46
Brain Disorders in Humans Result From Interactions
Between Genes and the Environment 46
Rare Neurodevelopmental Syndromes Provide Insights
Into the Biology of Social Behavior, Perception, and
Cognition 46
Psychiatric Disorders Involve Multigenic Traits 48
Advances in Autism Spectrum Disorder Genetics
Highlight the Role of Rare and De Novo Mutations in
Neurodevelopmental Disorders 48
Identification of Genes for Schizophrenia Highlights the
Interplay of Rare and Common Risk Variants 49
Perspectives on the Genetic Bases of Neuropsychiatric
Disorders 51
Highlights 51
Glossary 52
Selected Reading 53
References 53
3 Nerve Cells, Neural Circuitry, and Behavior . . . . . . . . . . . . . . . . . . . . . . .56
Michael N. Shadlen, Eric R. Kandel
The Nervous System Has Two Classes of Cells 57
Nerve Cells Are the Signaling Units of the Nervous
System 57
Glial Cells Support Nerve Cells 61
Each Nerve Cell Is Part of a Circuit That Mediates
Specific Behaviors 62
Signaling Is Organized in the Same Way in All
Nerve Cells 64
The Input Component Produces Graded
Local Signals 65
The Trigger Zone Makes the Decision to Generate an
Action Potential 67
The Conductive Component Propagates an All-or-None
Action Potential 67
The Output Component Releases Neurotransmitter 68
The Transformation of the Neural Signal From
Sensory to Motor Is Illustrated by the Stretch-Reflex
Pathway 68
Nerve Cells Differ Most at the Molecular Level 69
The Reflex Circuit Is a Starting Point for Understanding
the Neural Architecture of Behavior 70
Neural Circuits Can Be Modified by Experience 71
Highlights 71
Selected Reading 72
References 72
4 The Neuroanatomical Bases by Which Neural Circuits Mediate Behavior. . . . .73
David G. Amaral
Local Circuits Carry Out Specific Neural Computations
That Are Coordinated to Mediate Complex Behaviors 74
Sensory Information Circuits Are Illustrated in the
Somatosensory System 74
Somatosensory Information From the Trunk and Limbs
Is Conveyed to the Spinal Cord 76
The Primary Sensory Neurons of the Trunk and Limbs
Are Clustered in the Dorsal Root Ganglia 79
The Terminals of Central Axons of Dorsal Root
Ganglion Neurons in the Spinal Cord Produce a
Map of the Body Surface 81
Each Somatic Submodality Is Processed in a Distinct
Subsystem From the Periphery to the Brain 81
The Thalamus Is an Essential Link Between Sensory
Receptors and the Cerebral Cortex 82
Sensory Information Processing Culminates in the
Cerebral Cortex 84
Voluntary Movement Is Mediated by Direct Connections
Between the Cortex and Spinal Cord 89
Modulatory Systems in the Brain Influence Motivation,
Emotion, and Memory 89
The Peripheral Nervous System Is Anatomically Distinct
From the Central Nervous System 92
Memory Is a Complex Behavior Mediated by Structures
Distinct From Those That Carry Out Sensation
or Movement 93
The Hippocampal System Is Interconnected With the
Highest-Level Polysensory Cortical Regions 94
The Hippocampal Formation Comprises Several
Different but Highly Integrated Circuits 94
The Hippocampal Formation Is Made Up Mainly of
Unidirectional Connections 95
Highlights 95
Selected Reading 96
References 96
5 The Computational Bases of Neural Circuits That Mediate Behavior. . . . . . .97
Larry F. Abbott, Attila Losonczy, Nathaniel B. Sawtell
Neural Firing Patterns Provide a Code
for Information 98
Sensory Information Is Encoded by Neural Activity 98
Information Can Be Decoded From Neural Activity 99
Hippocampal Spatial Cognitive Maps Can Be Decoded
to Infer Location 99
Neural Circuit Motifs Provide a Basic Logic for
Information Processing 102
Visual Processing and Object Recognition Depend on a
Hierarchy of Feed-Forward Representations 103
Diverse Neuronal Representations in the Cerebellum
Provide a Basis for Learning 104
Recurrent Circuitry Underlies Sustained Activity and
Integration 105
Learning and Memory Depend on
Synaptic Plasticity 107
Dominant Patterns of Synaptic Input Can be Identified
by Hebbian Plasticity 107
Synaptic Plasticity in the Cerebellum Plays a Key Role
in Motor Learning 108
Highlights 110
Selected Reading 110
References 110
6 Imaging and Behavior. . . . . . . . . . . . . .111
Daphna Shohamy, Nick Turk-Browne
Functional MRI Experiments Measure Neurovascular
Activity 112
fMRI Depends on the Physics of Magnetic
Resonance 112
fMRI Depends on the Biology of Neurovascular
Coupling 115
Functional MRI Data Can Be Analyzed in Several
Ways 115
fMRI Data First Need to Be Prepared for Analysis by
Following Preprocessing Steps 115
fMRI Can Be Used to Localize Cognitive Functions to
Specific Brain Regions 118
fMRI Can Be Used to Decode What Information Is
Represented in the Brain 118
fMRI Can Be Used to Measure Correlated Activity
Across Brain Networks 119
Functional MRI Studies Have Led to Fundamental
Insights 120
fMRI Studies in Humans Have Inspired
Neurophysiological Studies in Animals 120
fMRI Studies Have Challenged Theories From Cognitive
Psychology and Systems Neuroscience 121
fMRI Studies Have Tested Predictions From Animal
Studies and Computational Models 122
Functional MRI Studies Require
Careful Interpretation 122
Future Progress Depends on Technological
and Conceptual Advances 123
Highlights 125
Suggested Reading 126
References 126
Part II
Cell and Molecular Biology of Cells of the Nervous System
7 The Cells of the Nervous System. . . . .133
Beth Stevens, Franck Polleux, Ben A. Barres
Neurons and Glia Share Many Structural and Molecular
Characteristics 134
The Cytoskeleton Determines Cell Shape 139
Protein Particles and Organelles Are Actively Transported
Along the Axon and Dendrites 142
Fast Axonal Transport Carries Membranous
Organelles 143
Slow Axonal Transport Carries Cytosolic Proteins and
Elements of the Cytoskeleton 146
Proteins Are Made in Neurons as in Other
Secretory Cells 147
Secretory and Membrane Proteins Are Synthesized and
Modified in the Endoplasmic Reticulum 147
Secretory Proteins Are Modified in the Golgi
Complex 149
Surface Membrane and Extracellular Substances Are
Recycled in the Cell 150
Glial Cells Play Diverse Roles in Neural
Function 151
Glia Form the Insulating Sheaths for
Axons 151
Astrocytes Support Synaptic Signaling 154
Microglia Have Diverse Functions
in Health and Disease 159
Choroid Plexus and Ependymal Cells Produce
Cerebrospinal Fluid 160
Highlights 162
Selected Reading 163
References 163
8 Ion Channels. . . . . . . . . . . . . . . . . . . . . .165
John D. Koester, Bruce P. Bean
Ion Channels Are Proteins That Span the Cell
Membrane 166
Ion Channels in All Cells Share Several Functional
Characteristics 169
Currents Through Single Ion Channels Can Be
Recorded 169
The Flux of Ions Through a Channel Differs From
Diffusion in Free Solution 171
The Opening and Closing of a Channel Involve
Conformational Changes 172
The Structure of Ion Channels Is Inferred From
Biophysical, Biochemical, and Molecular Biological
Studies 174
Ion Channels Can Be Grouped Into Gene
Families 177
X-Ray Crystallographic Analysis of Potassium Channel
Structure Provides Insight Into Mechanisms of Channel
Permeability and Selectivity 180
X-Ray Crystallographic Analysis of Voltage-Gated
Potassium Channel Structures Provides Insight into
Mechanisms of Channel Gating 182
The Structural Basis of the Selective Permeability of
Chloride Channels Reveals a Close Relation Between
Channels and Transporters 185
Highlights 187
Selected Reading 188
References 188
9 Membrane Potential and the Passive Electrical Properties of the Neuron. . . . . . . . . . . . . . . . . . . . . . . .190
John D. Koester, Steven A. Siegelbaum
The Resting Membrane Potential Results From the
Separation of Charge Across the Cell Membrane 191
The Resting Membrane Potential Is Determined by
Nongated and Gated Ion Channels 191
Open Channels in Glial Cells Are Permeable to
Potassium Only 193
Open Channels in Resting Nerve Cells Are Permeable to
Three Ion Species 194
The Electrochemical Gradients of Sodium, Potassium,
and Calcium Are Established by Active Transport
of the Ions 195
Chloride Ions Are Also Actively Transported 198
The Balance of Ion Fluxes in the Resting Membrane Is
Abolished During the Action Potential 198
The Contributions of Different Ions to the Resting
Membrane Potential Can Be Quantified by the
Goldman Equation 199
The Functional Properties of the Neuron Can Be
Represented as an Electrical Equivalent Circuit 199
The Passive Electrical Properties of the Neuron Affect
Electrical Signaling 201
Membrane Capacitance Slows the Time Course of
Electrical Signals 203
Membrane and Cytoplasmic Resistance Affect the
Efficiency of Signal Conduction 204
Large Axons Are More Easily Excited
Than Small Axons 206
Passive Membrane Properties and Axon Diameter
Affect the Velocity of Action Potential
Propagation 207
Highlights 208
Selected Reading 209
References 210
10 Propagated Signaling: The Action Potential . . . . . . . . . . . . . . . . . . . . . . . . .211
Bruce P. Bean, John D. Koester
The Action Potential Is Generated by the Flow of Ions
Through Voltage-Gated Channels 212
Sodium and Potassium Currents Through
Voltage-Gated Channels Are Recorded With the
Voltage Clamp 212
Voltage-Gated Sodium and Potassium Conductances
Are Calculated From Their Currents 217
The Action Potential Can Be Reconstructed
From the Properties of Sodium and Potassium
Channels 219
The Mechanisms of Voltage Gating Have Been Inferred
From Electrophysiological Measurements 220
Voltage-Gated Sodium Channels Select for Sodium
on the Basis of Size, Charge, and Energy of Hydration of
the Ion 222
Individual Neurons Have a Rich Variety of
Voltage-Gated Channels That Expand Their Signaling
Capabilities 224
The Diversity of Voltage-Gated Channel Types Is
Generated by Several Genetic Mechanisms 225
Voltage-Gated Sodium Channels 225
Voltage-Gated Calcium Channels 227
Voltage-Gated Potassium Channels 227
Voltage-Gated Hyperpolarization-Activated Cyclic
Nucleotide-Gated Channels 228
Gating of Ion Channels Can Be Controlled by
Cytoplasmic Calcium 228
Excitability Properties Vary Between Types of
Neurons 229
Excitability Properties Vary Between Regions of the
Neuron 231
Neuronal Excitability Is Plastic 233
Highlights 233
Selected Reading 234
References 234
Part III
Synaptic Transmission
11 Overview of Synaptic Transmission . . . . . . . . . . . . . . . . . . . . .241
Steven A. Siegelbaum, Gerald D. Fischbach
Synapses Are Predominantly Electrical or
Chemical 241
Electrical Synapses Provide Rapid Signal
Transmission 242
Cells at an Electrical Synapse Are Connected by
Gap-Junction Channels 244
Electrical Transmission Allows Rapid and Synchronous
Firing of Interconnected Cells 247
Gap Junctions Have a Role in Glial Function and
Disease 248
Chemical Synapses Can Amplify Signals 248
The Action of a Neurotransmitter Depends on the
Properties of the Postsynaptic Receptor 249
Activation of Postsynaptic Receptors Gates Ion
Channels Either Directly or Indirectly 250
Electrical and Chemical Synapses Can Coexist and
Interact 251
Highlights 252
Selected Reading 252
References 253
12 Directly Gated Transmission: The Nerve-Muscle Synapse . . . . . . . .254
Gerald D. Fischbach, Steven A. Siegelbaum
The Neuromuscular Junction Has Specialized Presynaptic
and Postsynaptic Structures 255
The Postsynaptic Potential Results From a Local Change
in Membrane Permeability 255
The Neurotransmitter Acetylcholine
Is Released in Discrete Packets 260
Individual Acetylcholine Receptor-Channels
Conduct All-or-None Currents 260
The Ion Channel at the End-Plate Is Permeable to Both
Sodium and Potassium Ions 260
Four Factors Determine the End-Plate
Current 262
The Acetylcholine Receptor-Channels Have Distinct
Properties That Distinguish Them From the
Voltage-Gated Channels That Generate the Muscle
Action Potential 262
Transmitter Binding Produces a Series of
State Changes in the Acetylcholine
Receptor-Channel 263
The Low-Resolution Structure of the Acetylcholine
Receptor Is Revealed by Molecular and
Biophysical Studies 264
The High-Resolution Structure of the Acetylcholine
Receptor-Channel Is Revealed by X-Ray
Crystal Studies 267
Highlights 268
Postscript: The End-Plate Current Can Be Calculated From
an Equivalent Circuit 269
Selected Reading 272
References 272
13 Synaptic Integration in the Central Nervous System. . . . . . . . . . . . . . . . . . .273
Rafael Yuste, Steven A. Siegelbaum
Central Neurons Receive Excitatory and Inhibitory
Inputs 274
Excitatory and Inhibitory Synapses Have Distinctive
Ultrastructures and Target Different Neuronal
Regions 274
Excitatory Synaptic Transmission Is Mediated by
Ionotropic Glutamate Receptor-Channels Permeable to
Cations 277
The Ionotropic Glutamate Receptors Are Encoded by a
Large Gene Family 278
Glutamate Receptors Are Constructed From a Set of
Structural Modules 279
NMDA and AMPA Receptors Are Organized by a
Network of Proteins at the Postsynaptic
Density 281
NMDA Receptors Have Unique Biophysical and
Pharmacological Properties 283
The Properties of the NMDA Receptor Underlie
Long-Term Synaptic Plasticity 284
NMDA Receptors Contribute to
Neuropsychiatric Disease 284
Fast Inhibitory Synaptic Actions Are Mediated by
Ionotropic GABA and Glycine Receptor-Channels
Permeable to Chloride 287
Ionotropic Glutamate, GABA, and Glycine Receptors Are
Transmembrane Proteins Encoded by Two Distinct Gene
Families 287
Chloride Currents Through GABAA and Glycine
Receptor-Channels Normally Inhibit the
Postsynaptic Cell 288
Some Synaptic Actions in the Central Nervous System
Depend on Other Types of Ionotropic Receptors 291
Excitatory and Inhibitory Synaptic Actions Are Integrated
by Neurons Into a Single Output 291
Synaptic Inputs Are Integrated at the Axon
Initial Segment 292
Subclasses of GABAergic Neurons Target Distinct
Regions of Their Postsynaptic Target Neurons
to Produce Inhibitory Actions With Different
Functions 293
Dendrites Are Electrically Excitable Structures That Can
Amplify Synaptic Input 295
Highlights 298
Selected Reading 299
References 299
14 Modulation of Synaptic Transmission and Neuronal Excitability: Second Messengers. . . . . . . . . . . . . . . .301
Steven A. Siegelbaum, David E. Clapham, Eve Marder
The Cyclic AMP Pathway Is the Best Understood
Second-Messenger Signaling Cascade Initiated by
G Protein–Coupled Receptors 303
The Second-Messenger Pathways Initiated by G
Protein–Coupled Receptors Share a Common Molecular
Logic 305
A Family of G Proteins Activates Distinct
Second-Messenger Pathways 305
Hydrolysis of Phospholipids by Phospholipase C
Produces Two Important Second Messengers,
IP3 and Diacylglycerol 305
Receptor Tyrosine Kinases Compose the Second Major
Family of Metabotropic Receptors 308
Several Classes of Metabolites Can Serve as Transcellular
Messengers 309
Hydrolysis of Phospholipids by Phospholipase A2
Liberates Arachidonic Acid to Produce Other Second
Messengers 310
Endocannabinoids Are Transcellular Messengers That
Inhibit Presynaptic Transmitter Release 310
The Gaseous Second Messenger Nitric Oxide Is a
Transcellular Signal That Stimulates Cyclic GMP
Synthesis 310
The Physiological Actions of Metabotropic
Receptors Differ From Those of Ionotropic
Receptors 312
Second-Messenger Cascades Can Increase or
Decrease the Opening of Many Types of Ion
Channels 312
G Proteins Can Modulate Ion Channels
Directly 315
Cyclic AMP–Dependent Protein Phosphorylation Can
Close Potassium Channels 317
Second Messengers Can Endow Synaptic Transmission
with Long-Lasting Consequences 317
Modulators Can Influence Circuit Function by Altering
Intrinsic Excitability or Synaptic Strength 317
Multiple Neuromodulators Can Converge
Onto the Same Neuron and Ion Channels 320
Why So Many Modulators? 320
Highlights 321
Selected Reading 322
References 322
15 Transmitter Release . . . . . . . . . . . . . . .324
Steven A. Siegelbaum, Thomas C. Südhof,
Richard W. Tsien
Transmitter Release Is Regulated by Depolarization of the
Presynaptic Terminal 324
Release Is Triggered by Calcium Influx 327
The Relation Between Presynaptic Calcium
Concentration and Release 329
Several Classes of Calcium Channels Mediate
Transmitter Release 329
Transmitter Is Released in Quantal Units 332
Transmitter Is Stored and Released by
Synaptic Vesicles 333
Synaptic Vesicles Discharge Transmitter by Exocytosis
and Are Recycled by Endocytosis 337
Capacitance Measurements Provide Insight Into
the Kinetics of Exocytosis and Endocytosis 338
Exocytosis Involves the Formation of a
Temporary Fusion Pore 338
The Synaptic Vesicle Cycle Involves Several Steps 341
Exocytosis of Synaptic Vesicles Relies on a Highly
Conserved Protein Machinery 343
The Synapsins Are Important for Vesicle Restraint and
Mobilization 345
SNARE Proteins Catalyze Fusion of Vesicles With the
Plasma Membrane 345
Calcium Binding to Synaptotagmin Triggers Transmitter
Release 347
The Fusion Machinery Is Embedded in a Conserved
Protein Scaffold at the Active Zone 347
Modulation of Transmitter Release Underlies Synaptic
Plasticity 350
Activity-Dependent Changes in Intracellular Free
Calcium Can Produce Long-Lasting Changes in
Release 351
Axo-axonic Synapses on Presynaptic Terminals Regulate
Transmitter Release 351
Highlights 354
Selected Reading 356
References 356
16 Neurotransmitters. . . . . . . . . . . . . . . . .358
Jonathan A. Javitch, David Sulzer
A Chemical Messenger Must Meet Four Criteria to Be
Considered a Neurotransmitter 358
Only a Few Small-Molecule Substances Act as
Transmitters 360
Acetylcholine 360
Biogenic Amine Transmitters 361
Amino Acid Transmitters 364
ATP and Adenosine 364
Small-Molecule Transmitters Are Actively Taken Up Into
Vesicles 364
Many Neuroactive Peptides Serve as Transmitters 367
Peptides and Small-Molecule Transmitters Differ in
Several Ways 370
Peptides and Small-Molecule Transmitters Can Be
Co-released 370
Removal of Transmitter From the Synaptic Cleft
Terminates Synaptic Transmission 371
Highlights 376
Selected Reading 377
References 378
Part IV
Perception
17 Sensory Coding. . . . . . . . . . . . . . . . . . .385
Esther P. Gardner, Daniel Gardner
Psychophysics Relates Sensations to the Physical
Properties of Stimuli 387
Psychophysics Quantifies the Perception of Stimulus
Properties 387
Stimuli Are Represented in the Nervous System by the
Firing Patterns of Neurons 388
Sensory Receptors Respond to Specific Classes of
Stimulus Energy 390
Multiple Subclasses of Sensory Receptors Are Found in
Each Sense Organ 393
Receptor Population Codes Transmit Sensory
Information to the Brain 395
Sequences of Action Potentials Signal the Temporal
Dynamics of Stimuli 396
The Receptive Fields of Sensory Neurons Provide
Spatial Information About Stimulus Location 397
Central Nervous System Circuits Refine Sensory
Information 398
The Receptor Surface Is Represented Topographically in
the Early Stages of Each Sensory System 400
Sensory Information Is Processed in Parallel Pathways
in the Cerebral Cortex 402
Feedback Pathways From the Brain Regulate Sensory
Coding Mechanisms 403
Top-Down Learning Mechanisms Influence
Sensory Processing 404
Highlights 405
Selected Reading 406
References 406
18 Receptors of the Somatosensory System. . . . . . . . . . . . . . . . . . . . . . . . . . .408
Esther P. Gardner
Dorsal Root Ganglion Neurons Are the Primary Sensory
Receptor Cells of the Somatosensory System 409
Peripheral Somatosensory Nerve Fibers Conduct Action
Potentials at Different Rates 410
A Variety of Specialized Receptors Are Employed by the
Somatosensory System 414
Mechanoreceptors Mediate Touch and
Proprioception 414
Specialized End Organs Contribute to
Mechanosensation 416
Proprioceptors Measure Muscle Activity
and Joint Positions 421
Thermal Receptors Detect Changes in
Skin Temperature 422
Nociceptors Mediate Pain 424
Itch Is a Distinctive Cutaneous Sensation 425
Visceral Sensations Represent the Status of
Internal Organs 426
Action Potential Codes Transmit Somatosensory
Information to the Brain 426
Sensory Ganglia Provide a Snapshot of Population
Responses to Somatic Stimuli 427
Somatosensory Information Enters the Central Nervous
System Via Spinal or Cranial Nerves 427
Highlights 432
Selected Reading 433
References 433
19 Touch. . . . . . . . . . . . . . . . . . . . . . . . . . . .435
Esther P. Gardner
Active and Passive Touch Have Distinct Goals 436
The Hand Has Four Types of Mechanoreceptors 437
A Cell’s Receptive Field Defines Its Zone of
Tactile Sensitivity 438
Two-Point Discrimination Tests Measure
Tactile Acuity 439
Slowly Adapting Fibers Detect Object
Pressure and Form 444
Rapidly Adapting Fibers Detect Motion
and Vibration 446
Both Slowly and Rapidly Adapting Fibers Are
Important for Grip Control 446
Tactile Information Is Processed in the Central Touch
System 450
Spinal, Brain Stem, and Thalamic Circuits Segregate
Touch and Proprioception 450
The Somatosensory Cortex Is Organized Into
Functionally Specialized Columns 452
Cortical Columns Are Organized Somatotopically 454
The Receptive Fields of Cortical Neurons Integrate
Information From Neighboring Receptors 457
Touch Information Becomes Increasingly Abstract in
Successive Central Synapses 460
Cognitive Touch Is Mediated by Neurons in the
Secondary Somatosensory Cortex 460
Active Touch Engages Sensorimotor Circuits in the
Posterior Parietal Cortex 463
Lesions in Somatosensory Areas of the Brain Produce
Specific Tactile Deficits 464
Highlights 466
Selected Reading 467
References 467
20 Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . .470
Allan I. Basbaum
Noxious Insults Activate Thermal, Mechanical, and
Polymodal Nociceptors 471
Signals From Nociceptors Are Conveyed to Neurons in
the Dorsal Horn of the Spinal Cord 474
Hyperalgesia Has Both Peripheral and
Central Origins 476
Four Major Ascending Pathways Convey Nociceptive
Information From the Spinal Cord to the Brain 484
Several Thalamic Nuclei Relay Nociceptive Information
to the Cerebral Cortex 484
The Perception of Pain Arises From and Can Be
Controlled by Cortical Mechanisms 485
Anterior Cingulate and Insular Cortex Are Associated
With the Perception of Pain 485
Pain Perception Is Regulated by a Balance of Activity in
Nociceptive and Nonnociceptive Afferent Fibers 488
Electrical Stimulation of the Brain
Produces Analgesia 488
Opioid Peptides Contribute to Endogenous Pain
Control 489
Endogenous Opioid Peptides and Their Receptors Are
Distributed in Pain-Modulatory Systems 489
Morphine Controls Pain by Activating
Opioid Receptors 490
Tolerance to and Dependence on Opioids Are Distinct
Phenomena 493
Highlights 493
Selected Reading 494
References 494
21 The Constructive Nature of Visual Processing . . . . . . . . . . . . . . . . .496
Charles D. Gilbert, Aniruddha Das
Visual Perception Is a Constructive Process 496
Visual Processing Is Mediated by the Geniculostriate
Pathway 499
Form, Color, Motion, and Depth Are Processed in Discrete
Areas of the Cerebral Cortex 502
The Receptive Fields of Neurons at Successive Relays
in the Visual Pathway Provide Clues to How the Brain
Analyzes Visual Form 506
The Visual Cortex Is Organized Into Columns of
Specialized Neurons 508
Intrinsic Cortical Circuits Transform
Neural Information 512
Visual Information Is Represented by a Variety of Neural
Codes 517
Highlights 518
Selected Reading 519
References 519
22 Low-Level Visual Processing: The Retina . . . . . . . . . . . . . . . . . . . . . . .521
Markus Meister, Marc Tessier-Lavigne
The Photoreceptor Layer Samples the
Visual Image 522
Ocular Optics Limit the Quality of the Retinal
Image 522
There Are Two Types of Photoreceptors:
Rods and Cones 524
Phototransduction Links the Absorption of a Photon to a
Change in Membrane Conductance 526
Light Activates Pigment Molecules in the
Photoreceptors 528
Excited Rhodopsin Activates a Phosphodiesterase
Through the G Protein Transducin 529
Multiple Mechanisms Shut Off the Cascade 530
Defects in Phototransduction Cause Disease 530
Ganglion Cells Transmit Neural Images
to the Brain 530
The Two Major Types of Ganglion Cells Are ON Cells
and OFF Cells 530
Many Ganglion Cells Respond Strongly
to Edges in the Image 531
The Output of Ganglion Cells Emphasizes Temporal
Changes in Stimuli 531
Retinal Output Emphasizes Moving Objects 531
Several Ganglion Cell Types Project to the Brain
Through Parallel Pathways 531
A Network of Interneurons Shapes the
Retinal Output 536
Parallel Pathways Originate in Bipolar Cells 536
Spatial Filtering Is Accomplished by
Lateral Inhibition 536
Temporal Filtering Occurs in Synapses and Feedback
Circuits 537
Color Vision Begins in Cone-Selective Circuits 538
Congenital Color Blindness Takes Several Forms 538
Rod and Cone Circuits Merge in the Inner Retina 540
The Retina’s Sensitivity Adapts to Changes in
Illumination 540
Light Adaptation Is Apparent in Retinal Processing and
Visual Perception 540
Multiple Gain Controls Occur Within the Retina 541
Light Adaptation Alters Spatial Processing 543
Highlights 543
Selected Reading 543
References 544
23 Intermediate-Level Visual Processing and Visual Primitives. . . . . . . . . . . . . .545
Charles D. Gilbert
Internal Models of Object Geometry Help the Brain
Analyze Shapes 547
Depth Perception Helps Segregate Objects From
Background 550
Local Movement Cues Define Object Trajectory and
Shape 554
Context Determines the Perception of
Visual Stimuli 555
Brightness and Color Perception Depend on
Context 555
Receptive-Field Properties Depend on Context 558
Cortical Connections, Functional Architecture, and
Perception Are Intimately Related 558
Perceptual Learning Requires Plasticity in
Cortical Connections 559
Visual Search Relies on the Cortical Representation of
Visual Attributes and Shapes 559
Cognitive Processes Influence Visual Perception 560
Highlights 562
Selected Reading 563
References 563
24 High-Level Visual Processing: From Vision to Cognition. . . . . . . . . .564
Thomas D. Albright, Winrich A. Freiwald
High-Level Visual Processing Is Concerned With Object
Recognition 564
The Inferior Temporal Cortex Is the Primary Center for
Object Recognition 565
Clinical Evidence Identifies the Inferior Temporal
Cortex as Essential for Object Recognition 566
Neurons in the Inferior Temporal Cortex Encode
Complex Visual Stimuli and Are Organized in
Functionally Specialized Columns 568
The Primate Brain Contains Dedicated Systems for Face
Processing 569
The Inferior Temporal Cortex Is Part of a Network of
Cortical Areas Involved in Object Recognition 570
Object Recognition Relies on Perceptual
Constancy 571
Categorical Perception of Objects Simplifies
Behavior 572
Visual Memory Is a Component of High-Level Visual
Processing 573
Implicit Visual Learning Leads to Changes in the
Selectivity of Neuronal Responses 573
The Visual System Interacts With Working Memory and
Long-Term Memory Systems 573
Associative Recall of Visual Memories Depends on
Top-Down Activation of the Cortical Neurons That
Process Visual Stimuli 578The Cerebellum Adjusts the Vestibulo-Ocular
Reflex 643
The Thalamus and Cortex Use Vestibular Signals
for Spatial Memory and Cognitive and Perceptual
Functions 645
Vestibular Information Is Present in the Thalamus 645
Vestibular Information Is Widespread in the
Cortex 645
Vestibular Signals Are Essential for Spatial Orientation
and Spatial Navigation 646
Clinical Syndromes Elucidate Normal Vestibular
Function 647
Caloric Irrigation as a Vestibular Diagnostic
Tool 647
Bilateral Vestibular Hypofunction Interferes With
Normal Vision 647
Highlights 648
Selected Reading 649
References 649
28 Auditory Processing by the Central Nervous System. . . . . . . . . . . . . . . . . . .651
Donata Oertel, Xiaoqin Wang
Sounds Convey Multiple Types of Information to Hearing
Animals 652
The Neural Representation of Sound in Central Pathways
Begins in the Cochlear Nuclei 652
The Cochlear Nerve Delivers Acoustic Information
in Parallel Pathways to the Tonotopically Organized
Cochlear Nuclei 655
The Ventral Cochlear Nucleus Extracts Temporal and
Spectral Information About Sounds 655
The Dorsal Cochlear Nucleus Integrates Acoustic With
Somatosensory Information in Making Use of Spectral
Cues for Localizing Sounds 656
The Superior Olivary Complex in Mammals Contains
Separate Circuits for Detecting Interaural Time and
Intensity Differences 657
The Medial Superior Olive Generates a Map of
Interaural Time Differences 657
The Lateral Superior Olive Detects Interaural Intensity
Differences 659
The Superior Olivary Complex Provides Feedback to the
Cochlea 662
Ventral and Dorsal Nuclei of the Lateral Lemniscus
Shape Responses in the Inferior Colliculus With
Inhibition 663
Afferent Auditory Pathways Converge in the Inferior
Colliculus 664
Sound Location Information From the Inferior
Colliculus Creates a Spatial Map of Sound in the
Superior Colliculus 665
The Inferior Colliculus Transmits Auditory Information to
the Cerebral Cortex 665
Stimulus Selectivity Progressively Increases Along the
Ascending Pathway 665
The Auditory Cortex Maps Numerous Aspects of
Sound 668
A Second Sound-Localization Pathway From the
Inferior Colliculus Involves the Cerebral Cortex in Gaze
Control 669
Auditory Circuits in the Cerebral Cortex Are Segregated
Into Separate Processing Streams 670
The Cerebral Cortex Modulates Sensory Processing in
Subcortical Auditory Areas 670
The Cerebral Cortex Forms Complex
Sound Representations 671
The Auditory Cortex Uses Temporal and Rate Codes to
Represent Time-Varying Sounds 671
Primates Have Specialized Cortical Neurons That
Encode Pitch and Harmonics 673
Insectivorous Bats Have Cortical Areas Specialized for
Behaviorally Relevant Features of Sound 675
The Auditory Cortex Is Involved in Processing Vocal
Feedback During Speaking 677
Highlights 679
Selected Reading 680
References 680
29 Smell and Taste: The Chemical Senses. . . . . . . . . . . . . . . . . .682
Linda Buck, Kristin Scott, Charles Zuker
A Large Family of Olfactory Receptors Initiate the Sense
of Smell 683
Mammals Share a Large Family of Odorant
Receptors 684
Different Combinations of Receptors Encode Different
Odorants 685
Olfactory Information Is Transformed Along the Pathway
to the Brain 686
Odorants Are Encoded in the Nose by Dispersed
Neurons 686
Sensory Inputs in the Olfactory Bulb Are Arranged by
Receptor Type 687
The Olfactory Bulb Transmits Information to the
Olfactory Cortex 688
Output From the Olfactory Cortex Reaches Higher
Cortical and Limbic Areas 690
Olfactory Acuity Varies in Humans 691
Odors Elicit Characteristic Innate Behaviors 691
Pheromones Are Detected in Two Olfactory
Structures 691
Invertebrate Olfactory Systems Can Be Used to Study
Odor Coding and Behavior 691
Olfactory Cues Elicit Stereotyped Behaviors and
Physiological Responses in the Nematode 694
Strategies for Olfaction Have Evolved Rapidly 695
The Gustatory System Controls the Sense
of Taste 696
Taste Has Five Submodalities That Reflect Essential
Dietary Requirements 696
Tastant Detection Occurs in Taste Buds 696
Each Taste Modality Is Detected by Distinct Sensory
Receptors and Cells 698
Gustatory Information Is Relayed From the Periphery to
the Gustatory Cortex 702
Perception of Flavor Depends on Gustatory, Olfactory,
and Somatosensory Inputs 702
Insects Have Modality-Specific Taste Cells That Drive
Innate Behaviors 702
Highlights 703
Selected Reading 704
References 705
Part V
Movement
30 Principles of Sensorimotor Control. . . . . . . . . . . . . . . . . . . . . . . . . . .713
Daniel M. Wolpert, Amy J. Bastian
The Control of Movement Poses Challenges for the
Nervous System 714
Actions Can Be Controlled Voluntarily, Rhythmically, or
Reflexively 715
Motor Commands Arise Through a Hierarchy of
Sensorimotor Processes 715
Motor Signals Are Subject to Feedforward and Feedback
Control 716
Feedforward Control Is Required for Rapid
Movements 716
Feedback Control Uses Sensory Signals to
Correct Movements 719
Estimation of the Body’s Current State Relies on Sensory
and Motor Signals 719
Prediction Can Compensate for Sensorimotor
Delays 723
Sensory Processing Can Differ for Action and
Perception 724
Motor Plans Translate Tasks Into
Purposeful Movement 725
Stereotypical Patterns Are Employed in
Many Movements 725
Motor Planning Can Be Optimal at Reducing Costs 726
Optimal Feedback Control Corrects for Errors in a
Task-Dependent Manner 728
Multiple Processes Contribute to
Motor Learning 729
Error-Based Learning Involves Adapting Internal
Sensorimotor Models 730
Skill Learning Relies on Multiple Processes
for Success 732
Sensorimotor Representations Constrain Learning 734
Highlights 735
Selected Reading 735
References 735
31 The Motor Unit and Muscle Action. . . . . . . . . . . . . . . . . . . .737
Roger M. Enoka
The Motor Unit Is the Elementary Unit of Motor
Control 737
A Motor Unit Consists of a Motor Neuron and Multiple
Muscle Fibers 737
The Properties of Motor Units Vary 739
Physical Activity Can Alter Motor Unit Properties 742
Muscle Force Is Controlled by the Recruitment and
Discharge Rate of Motor Units 742
The Input–Output Properties of Motor Neurons Are
Modified by Input From the Brain Stem 745
Muscle Force Depends on the Structure
of Muscle 745
The Sarcomere Is the Basic Organizational Unit of
Contractile Proteins 745
Noncontractile Elements Provide Essential Structural
Support 747
Contractile Force Depends on Muscle Fiber Activation,
Length, and Velocity 747
Muscle Torque Depends on Musculoskeletal
Geometry 750
Different Movements Require Different Activation
Strategies 754
Contraction Velocity Can Vary in Magnitude and
Direction 754
Movements Involve the Coordination of Many
Muscles 755
Muscle Work Depends on the Pattern of Activation 758
Highlights 758
Selected Reading 759
References 759
32 Sensory-Motor Integration in the Spinal Cord . . . . . . . . . . . . . . . . . . . . . .761
Jens Bo Nielsen, Thomas M. Jessell
Reflex Pathways in the Spinal Cord Produce Coordinated
Patterns of Muscle Contraction 762
The Stretch Reflex Acts to Resist the
Lengthening of a Muscle 762
Neuronal Networks in the Spinal Cord Contribute to the
Coordination of Reflex Responses 762
The Stretch Reflex Involves a Monosynaptic Pathway 762
Gamma Motor Neurons Adjust the Sensitivity of Muscle
Spindles 766
The Stretch Reflex Also Involves Polysynaptic
Pathways 767
Golgi Tendon Organs Provide Force-Sensitive Feedback
to the Spinal Cord 769
Cutaneous Reflexes Produce Complex Movements That
Serve Protective and Postural Functions 770
Convergence of Sensory Inputs on Interneurons
Increases the Flexibility of Reflex Contributions
to Movement 772
Sensory Feedback and Descending Motor Commands
Interact at Common Spinal Neurons to Produce Voluntary
Movements 773
Muscle Spindle Sensory Afferent Activity Reinforces
Central Commands for Movements Through the Ia
Monosynaptic Reflex Pathway 773
Modulation of Ia inhibitory Interneurons and Renshaw
Cells by Descending Inputs Coordinate Muscle Activity
at Joints 775
Transmission in Reflex Pathways May Be Facilitated or
Inhibited by Descending Motor Commands 776
Descending Inputs Modulate Sensory Input to the
Spinal Cord by Changing the Synaptic Efficiency of
Primary Sensory Fibers 777
Part of the Descending Command for Voluntary
Movements Is Conveyed Through Spinal
Interneurons 778
Propriospinal Neurons in the C3–C4 Segments Mediate
Part of the Corticospinal Command for Movement of
the Upper Limb 778
Neurons in Spinal Reflex Pathways Are Activated Prior
to Movement 779
Proprioceptive Reflexes Play an Important
Role in Regulating Both Voluntary and Automatic
Movements 779
Spinal Reflex Pathways Undergo
Long-Term Changes 779
Damage to the Central Nervous System Produces
Characteristic Alterations in
Reflex Responses 780
Interruption of Descending Pathways to the Spinal Cord
Frequently Produces Spasticity 780
Lesion of the Spinal Cord in Humans Leads to a Period
of Spinal Shock Followed by Hyperreflexia 780
Highlights 781
Selected Reading 781
References 781
33 Locomotion. . . . . . . . . . . . . . . . . . . . . . .783
Trevor Drew, Ole Kiehn
Locomotion Requires the Production of a Precise and
Coordinated Pattern of Muscle Activation 786
The Motor Pattern of Stepping Is Organized
at the Spinal Level 790
The Spinal Circuits Responsible for Locomotion Can Be
Modified by Experience 792
Spinal Locomotor Networks Are Organized Into
Rhythm- and Pattern-Generation Circuits 792
Somatosensory Inputs From Moving Limbs Modulate
Locomotion 795
Proprioception Regulates the Timing and Amplitude of
Stepping 795
Mechanoreceptors in the Skin Allow Stepping to Adjust
to Unexpected Obstacles 798
Supraspinal Structures Are Responsible for Initiation and
Adaptive Control of Stepping 799
Midbrain Nuclei Initiate and Maintain Locomotion and
Control Speed 800
Midbrain Nuclei That Initiate Locomotion Project to
Brain Stem Neurons 800
The Brain Stem Nuclei Regulate Posture During
Locomotion 802
Visually Guided Locomotion Involves the Motor
Cortex 804
Planning of Locomotion Involves the Posterior Parietal
Cortex 806
The Cerebellum Regulates the Timing and Intensity of
Descending Signals 806
The Basal Ganglia Modify Cortical and Brain Stem
Circuits 807
Computational Neuroscience Provides Insights Into
Locomotor Circuits 809
Neuronal Control of Human Locomotion Is Similar to
That of Quadrupeds 809
Highlights 811
Suggested Reading 812
References 812
34 Voluntary Movement: Motor Cortices. . . . . . . . . . . . . . . . . . . .815
Stephen H. Scott, John F. Kalaska
Voluntary Movement Is the Physical Manifestation of an
Intention to Act 816
Theoretical Frameworks Help Interpret Behavior and
the Neural Basis of Voluntary Control 816
Many Frontal and Parietal Cortical Regions Are
Involved in Voluntary Control 818
Descending Motor Commands Are Principally
Transmitted by the Corticospinal Tract 819
Imposing a Delay Period Before the Onset of Movement
Isolates the Neural Activity Associated With Planning
From That Associated With Executing the Action 821
Parietal Cortex Provides Information About the World and
the Body for State Estimation to Plan and Execute Motor
Actions 823
The Parietal Cortex Links Sensory Information to Motor
Actions 824
Body Position and Motion Are Represented in Several
Areas of Posterior Parietal Cortex 824
Spatial Goals Are Represented in Several Areas of
Posterior Parietal Cortex 825
Internally Generated Feedback May Influence Parietal
Cortex Activity 827
Premotor Cortex Supports Motor Selection
and Planning 828
Medial Premotor Cortex Is Involved in the Contextual
Control of Voluntary Actions 829
Dorsal Premotor Cortex Is Involved in Planning
Sensory-Guided Movement of the Arm 831
Dorsal Premotor Cortex Is Involved in Applying Rules
(Associations) That Govern Behavior 833
Ventral Premotor Cortex Is Involved in Planning Motor
Actions of the Hand 835
Premotor Cortex May Contribute to Perceptual
Decisions That Guide Motor Actions 835
Several Cortical Motor Areas Are Active When the
Motor Actions of Others Are Being Observed 837
Many Aspects of Voluntary Control Are Distributed
Across Parietal and Premotor Cortex 840
The Primary Motor Cortex Plays an Important Role in
Motor Execution 841
The Primary Motor Cortex Includes a Detailed Map of
the Motor Periphery 841
Some Neurons in the Primary Motor Cortex Project
Directly to Spinal Motor Neurons 841
Activity in the Primary Motor Cortex Reflects
Many Spatial and Temporal Features of Motor
Output 844
Primary Motor Cortical Activity Also Reflects
Higher-Order Features of Movement 851
Sensory Feedback Is Transmitted Rapidly to the Primary
Motor Cortex and Other Cortical Regions 852
The Primary Motor Cortex Is Dynamic and
Adaptable 852
Highlights 856
Selected Reading 858
References 858
35 The Control of Gaze. . . . . . . . . . . . . . .860
Michael E. Goldberg, Mark F. Walker
The Eye Is Moved by the Six Extraocular Muscles 860
Eye Movements Rotate the Eye in the Orbit 860
The Six Extraocular Muscles Form Three
Agonist–Antagonist Pairs 862
Movements of the Two Eyes Are Coordinated 862
The Extraocular Muscles Are Controlled by
Three Cranial Nerves 862
Six Neuronal Control Systems Keep the Eyes on
Target 866
An Active Fixation System Holds the Fovea on a
Stationary Target 866
The Saccadic System Points the Fovea Toward Objects of
Interest 866
The Motor Circuits for Saccades Lie in the Brain
Stem 868
Horizontal Saccades Are Generated in the Pontine
Reticular Formation 868
Vertical Saccades Are Generated in the Mesencephalic
Reticular Formation 870
Brain Stem Lesions Result in Characteristic Deficits in
Eye Movements 870
Saccades Are Controlled by the Cerebral Cortex Through
the Superior Colliculus 871
The Superior Colliculus Integrates Visual and Motor
Information into Oculomotor Signals for the Brain
Stem 871
The Rostral Superior Colliculus Facilitates Visual
Fixation 873
The Basal Ganglia and Two Regions of Cerebral Cortex
Control the Superior Colliculus 873
The Control of Saccades Can Be Modified by
Experience 877
Some Rapid Gaze Shifts Require Coordinated Head and
Eye Movements 877
The Smooth-Pursuit System Keeps Moving Targets on the
Fovea 878
The Vergence System Aligns the Eyes to
Look at Targets at Different Depths 879
Highlights 880
Selected Reading 881
References 881
36 Posture. . . . . . . . . . . . . . . . . . . . . . . . . . .883
Fay B. Horak, Gammon M. Earhart
Equilibrium and Orientation Underlie
Posture Control 884
Postural Equilibrium Controls the Body’s
Center of Mass 884
Postural Orientation Anticipates Disturbances
to Balance 886
Postural Responses and Anticipatory
Postural Adjustments Use Stereotyped Strategies and
Synergies 886
Automatic Postural Responses Compensate for Sudden
Disturbances 887
Anticipatory Postural Adjustments Compensate for
Voluntary Movement 892
Posture Control Is Integrated With Locomotion 894
Somatosensory, Vestibular, and Visual Information Must
Be Integrated and Interpreted to Maintain Posture 894
Somatosensory Signals Are Important for Timing and
Direction of Automatic Postural Responses 894
Vestibular Information Is Important for Balance on
Unstable Surfaces and During Head Movements 895
Visual Inputs Provide the Postural System With
Orientation and Motion Information 897
Information From a Single Sensory Modality Can Be
Ambiguous 897
The Postural Control System Uses a Body Schema That
Incorporates Internal Models for Balance 898
Control of Posture Is Task Dependent 900
Task Requirements Determine the Role of
Each Sensory System in Postural Equilibrium
and Orientation 900
Control of Posture Is Distributed in the Nervous
System 900
Spinal Cord Circuits Are Sufficient for Maintaining
Antigravity Support but Not Balance 900
The Brain Stem and Cerebellum Integrate
Sensory Signals for Posture 901
The Spinocerebellum and Basal Ganglia Are Important
in Adaptation of Posture 902
Cerebral Cortex Centers Contribute to Postural
Control 905
Highlights 906
Suggested Reading 906
References 906
37 The Cerebellum. . . . . . . . . . . . . . . . . . .908
Amy J. Bastian, Stephen G. Lisberger
Damage of the Cerebellum Causes Distinctive Symptoms
and Signs 909
Damage Results in Characteristic Abnormalities of
Movement and Posture 909
Damage Affects Specific Sensory and Cognitive
Abilities 909
The Cerebellum Indirectly Controls Movement Through
Other Brain Structures 911
The Cerebellum Is a Large Subcortical
Brain Structure 911
The Cerebellum Connects With the Cerebral
Cortex Through Recurrent Loops 911
Different Movements Are Controlled by
Functional Longitudinal Zones 911
The Cerebellar Cortex Comprises Repeating Functional
Units Having the Same
Basic Microcircuit 918
The Cerebellar Cortex Is Organized Into Three
Functionally Specialized Layers 918
The Climbing-Fiber and Mossy-Fiber Afferent Systems
Encode and Process Information Differently 918
The Cerebellar Microcircuit Architecture
Suggests a Canonical Computation 920
The Cerebellum Is Hypothesized to Perform Several
General Computational Functions 922
The Cerebellum Contributes to Feedforward
Sensorimotor Control 922
The Cerebellum Incorporates an Internal Model of
the Motor Apparatus 922
The Cerebellum Integrates Sensory Inputs and Corollary
Discharge 923
The Cerebellum Contributes to Timing Control 923
The Cerebellum Participates in Motor
Skill Learning 923
Climbing-Fiber Activity Changes the Synaptic Efficacy
of Parallel Fibers 924
The Cerebellum Is Necessary for Motor Learning in
Several Different Movement Systems 925
Learning Occurs at Several Sites in the Cerebellum 928
Highlights 929
Selected Reading 929
References 930
38 The Basal Ganglia. . . . . . . . . . . . . . . . .932
Peter Redgrave, Rui M. Costa
The Basal Ganglia Network Consists of Three Principal
Input Nuclei, Two Main Output Nuclei, and One Intrinsic
Nucleus 934
The Striatum, Subthalamic Nucleus, and Substantia
Nigra Pars Compacta/Ventral Tegmental Area Are the
Three Principal Input Nuclei of the Basal Ganglia 934
The Substantia Nigra Pars Reticulata and the Internal
Globus Pallidus Are the Two Principal Output Nuclei of
the Basal Ganglia 935
The External Globus Pallidus Is Mostly an Intrinsic
Structure of the Basal Ganglia 935
The Internal Circuitry of the Basal Ganglia Regulates
How the Components Interact 935
The Traditional Model of the Basal Ganglia Emphasizes
Direct and Indirect Pathways 935
Detailed Anatomical Analyses Reveal a More Complex
Organization 936
Basal Ganglia Connections With External Structures Are
Characterized by Reentrant Loops 937
Inputs Define Functional Territories in the
Basal Ganglia 937
Output Neurons Project to the External
Structures That Provide Input 937
Reentrant Loops Are a Cardinal Principle
of Basal Ganglia Circuitry 937
Physiological Signals Provide Further Clues
to Function in the Basal Ganglia 939
The Striatum and Subthalamic Nucleus Receive Signals
Mainly from the Cerebral Cortex,
Thalamus, and Ventral Midbrain 939
Ventral Midbrain Dopamine Neurons Receive
Input From External Structures and Other
Basal Ganglia Nuclei 939
Disinhibition Is the Final Expression of Basal Ganglia
Output 940
Throughout Vertebrate Evolution, the Basal Ganglia Have
Been Highly Conserved 940
Action Selection Is a Recurring Theme in Basal Ganglia
Research 941
All Vertebrates Face the Challenge of Choosing
One Behavior From Several Competing
Options 941
Selection Is Required for Motivational, Affective,
Cognitive, and Sensorimotor Processing 941
The Neural Architecture of the Basal Ganglia Is
Configured to Make Selections 942
Intrinsic Mechanisms in the Basal Ganglia
Promote Selection 943
Selection Function of the Basal Ganglia
Questioned 943
Reinforcement Learning Is an Inherent Property of a
Selection Architecture 944
Intrinsic Reinforcement Is Mediated by Phasic
Dopamine Signaling Within the Basal
Ganglia Nuclei 944
Extrinsic Reinforcement Could Bias Selection by
Operating in Afferent Structures 946
Behavioral Selection in the Basal Ganglia Is Under
Goal-Directed and Habitual Control 946
Diseases of the Basal Ganglia May Involve Disorders of
Selection 947
A Selection Mechanism Is Likely to Be Vulnerable to
Several Potential Malfunctions 947
Parkinson Disease Can Be Viewed in Part as a Failure to
Select Sensorimotor Options 948
Huntington Disease May Reflect a Functional Imbalance
Between the Direct and Indirect Pathways 948
Schizophrenia May Be Associated With a General
Failure to Suppress Nonselected Options 948
Attention Deficit Hyperactivity Disorder and Tourette
Syndrome May Also Be Characterized by Intrusions of
Nonselected Options 949
Obsessive-Compulsive Disorder Reflects the Presence of
Pathologically Dominant Options 949
Addictions Are Associated With Disorders of
Reinforcement Mechanisms and Habitual Goals 949
Highlights 950
Suggested Reading 951
References 951
39 Brain–Machine Interfaces. . . . . . . . . .953
Krishna V. Shenoy, Byron M. Yu
BMIs Measure and Modulate Neural Activity to Help
Restore Lost Capabilities 954
Cochlear Implants and Retinal Prostheses Can Restore
Lost Sensory Capabilities 954
Motor and Communication BMIs Can Restore Lost
Motor Capabilities 954
Pathological Neural Activity Can Be Regulated by Deep
Brain Stimulation and Antiseizure BMIs 956
Replacement Part BMIs Can Restore Lost Brain
Processing Capabilities 956
Measuring and Modulating Neural Activity Rely on
Advanced Neurotechnology 956
BMIs Leverage the Activity of Many Neurons to Decode
Movements 958
Decoding Algorithms Estimate Intended Movements
From Neural Activity 960
Discrete Decoders Estimate Movement Goals 961
Continuous Decoders Estimate Moment-by-Moment
Details of Movements 961
Increases in Performance and Capabilities of Motor and
Communication BMIs Enable Clinical Translation 962
Subjects Can Type Messages Using
Communication BMIs 964
Subjects Can Reach and Grasp Objects Using
BMI-Directed Prosthetic Arms 965
Subjects Can Reach and Grasp Objects Using
BMI-Directed Stimulation of Paralyzed Arms 965
Subjects Can Use Sensory Feedback Delivered by Cortical
Stimulation During BMI Control 967
BMIs Can Be Used to Advance
Basic Neuroscience 968
BMIs Raise New Neuroethics Considerations 970
Highlights 971
Selected Reading 972
References 972
Part VI
The Biology of Emotion, Motivation, and Homeostasis
40 The Brain Stem . . . . . . . . . . . . . . . . . . .981
Clifford B. Saper, Joel K. Elmquist
The Cranial Nerves Are Homologous to the Spinal
Nerves 982
Cranial Nerves Mediate the Sensory and Motor
Functions of the Face and Head and the Autonomic
Functions of the Body 982
Cranial Nerves Leave the Skull in Groups and Often Are
Injured Together 985
The Organization of the Cranial Nerve Nuclei Follows the
Same Basic Plan as the Sensory and Motor Areas of the
Spinal Cord 986
Embryonic Cranial Nerve Nuclei Have a
Segmental Organization 987
Adult Cranial Nerve Nuclei Have a
Columnar Organization 987
The Organization of the Brain Stem Differs From the
Spinal Cord in Three Important Ways 992
Neuronal Ensembles in the Brain Stem Reticular
Formation Coordinate Reflexes and Simple Behaviors
Necessary for Homeostasis and Survival 992
Cranial Nerve Reflexes Involve Mono- and Polysynaptic
Brain Stem Relays 992
Pattern Generators Coordinate More Complex
Stereotypic Behaviors 994
Control of Breathing Provides an Example of How
Pattern Generators Are Integrated Into More Complex
Behaviors 994
Monoaminergic Neurons in the Brain Stem Modulate
Sensory, Motor, Autonomic, and Behavioral
Functions 998
Many Modulatory Systems Use Monoamines as
Neurotransmitters 998
Monoaminergic Neurons Share Many
Cellular Properties 1001
Autonomic Regulation and Breathing Are Modulated by
Monoaminergic Pathways 1002
Pain Perception Is Modulated by Monoamine
Antinociceptive Pathways 1002
Motor Activity Is Facilitated by
Monoaminergic Pathways 1004
Ascending Monoaminergic Projections Modulate
Forebrain Systems for Motivation and Reward 1004
Monoaminergic and Cholinergic Neurons Maintain
Arousal by Modulating Forebrain Neurons 1006
Highlights 1007
Selected Reading 1008
References 1008
41 The Hypothalamus: Autonomic, Hormonal, and Behavioral Control of Survival. . . . . . . . . . . . . . .1010
Bradford B. Lowell, Larry W. Swanson,
John P. Horn
Homeostasis Keeps Physiological Parameters Within a
Narrow Range and Is Essential
for Survival 1011
The Hypothalamus Coordinates
Homeostatic Regulation 1013
The Hypothalamus Is Commonly Divided Into Three
Rostrocaudal Regions 1013
Modality-Specific Hypothalamic Neurons Link
Interoceptive Sensory Feedback With Outputs That
Control Adaptive Behaviors and Physiological
Responses 1015
Modality-Specific Hypothalamic Neurons Also Receive
Descending Feedforward Input Regarding Anticipated
Homeostatic Challenges 1015
The Autonomic System Links the Brain to Physiological
Responses 1015
Visceral Motor Neurons in the Autonomic System Are
Organized Into Ganglia 1015
Preganglionic Neurons Are Localized in Three Regions
Along the Brain Stem and Spinal Cord 1016
Sympathetic Ganglia Project to Many Targets
Throughout the Body 1016
Parasympathetic Ganglia Innervate Single Organs 1018
The Enteric Ganglia Regulate the Gastrointestinal
Tract 1019
Acetylcholine and Norepinephrine Are the Principal
Transmitters of Autonomic Motor Neurons 1019
Autonomic Responses Involve Cooperation Between the
Autonomic Divisions 1021
Visceral Sensory Information Is Relayed to the Brain Stem
and Higher Brain Structures 1023
Central Control of Autonomic Function Can Involve
the Periaqueductal Gray, Medial Prefrontal Cortex, and
Amygdala 1025
The Neuroendocrine System Links the Brain to
Physiological Responses Through Hormones 1026
Hypothalamic Axon Terminals in the Posterior Pituitary
Release Oxytocin and Vasopressin Directly Into the
Blood 1027
Endocrine Cells in the Anterior Pituitary Secrete
Hormones in Response to Specific Factors Released by
Hypothalamic Neurons 1028
Dedicated Hypothalamic Systems Control Specific
Homeostatic Parameters 1029
Body Temperature Is Controlled by Neurons in the
Median Preoptic Nucleus 1029
Water Balance and the Related Thirst Drive Are
Controlled by Neurons in the Vascular Organ of the
Lamina Terminalis, Median Preoptic Nucleus, and
Subfornical Organ 1031
Energy Balance and the Related Hunger Drive Are
Controlled by Neurons in the Arcuate Nucleus 1033
Sexually Dimorphic Regions in the Hypothalamus
Control Sex, Aggression, and Parenting 1039
Sexual Behavior and Aggression Are Controlled by
the Preoptic Hypothalamic Area and a Subarea of the
Ventromedial Hypothalamic Nucleus 1040
Parental Behavior Is Controlled by the Preoptic
Hypothalamic Area 1041
Highlights 1041
Selected Reading 1042
References 1043
42 Emotion. . . . . . . . . . . . . . . . . . . . . . . . .1045
Daniel Salzman, Ralph Adolphs
The Modern Search for the Neural Circuitry of Emotion
Began in the Late 19th Century 1047
The Amygdala Has Been Implicated in Both Learned and
Innate Fear 1050
The Amygdala Has Been Implicated in Innate Fear in
Animals 1052
The Amygdala Is Important for Fear in Humans 1053
The Amygdala’s Role Extends to Positive
Emotions 1055
Emotional Responses Can Be Updated Through Extinction
and Regulation 1055
Emotion Can Influence Cognitive Processes 1056
Many Other Brain Areas Contribute to Emotional
Processing 1056
Functional Neuroimaging Is Contributing to Our
Understanding of Emotion in Humans 1059
Functional Imaging Has Identified Neural Correlates of
Feelings 1060
Emotion Is Related to Homeostasis 1060
Highlights 1062
Selected Reading 1063
References 1063
43 Motivation, Reward, and Addictive States. . . . . . . . . . . . . . . . . .1065
Eric J. Nestler, C. Daniel Salzman
Motivational States Influence Goal-Directed
Behavior 1065
Both Internal and External Stimuli Contribute to
Motivational States 1065
Rewards Can Meet Both Regulatory and Nonregulatory
Needs on Short and Long Timescales 1066
The Brain’s Reward Circuitry Provides a Biological
Substrate for Goal Selection 1066
Dopamine May Act as a Learning Signal 1068
Drug Addiction Is a Pathological Reward State 1069
All Drugs of Abuse Target Neurotransmitter Receptors,
Transporters, or Ion Channels 1070
Repeated Exposure to a Drug of Abuse Induces Lasting
Behavioral Adaptations 1071
Lasting Molecular Adaptations Are Induced in Brain
Reward Regions by Repeated Drug Exposure 1074
Lasting Cellular and Circuit Adaptations Mediate
Aspects of the Drug-Addicted State 1075
Natural Addictions Share Biological Mechanisms With
Drug Addictions 1077
Highlights 1078
Selected Reading 1079
References 1079
44 Sleep and Wakefulness. . . . . . . . . . .1080
Clifford B. Saper, Thomas E. Scammell
Sleep Consists of Alternating Periods of REM Sleep and
Non-REM Sleep 1081
The Ascending Arousal System Promotes Wakefulness 1082
The Ascending Arousal System in the Brain Stem and
Hypothalamus Innervates the Forebrain 1084
Damage to the Ascending Arousal System
Causes Coma 1085
Circuits Composed of Mutually Inhibitory Neurons
Control Transitions From Wake to Sleep and From Non-
REM to REM Sleep 1085
Sleep Is Regulated by Homeostatic and Circadian
Drives 1086
The Homeostatic Pressure for Sleep Depends on
Humoral Factors 1086
Circadian Rhythms Are Controlled by a Biological Clock
in the Suprachiasmatic Nucleus 1087
Circadian Control of Sleep Depends on Hypothalamic
Relays 1090
Sleep Loss Impairs Cognition and Memory 1091
Sleep Changes With Age 1092
Disruptions in Sleep Circuitry Contribute to Many Sleep
Disorders 1092
Insomnia May Be Caused by Incomplete Inhibition of
the Arousal System 1092
Sleep Apnea Fragments Sleep and Impairs
Cognition 1093
Narcolepsy Is Caused by a Loss of
Orexinergic Neurons 1093
REM Sleep Behavior Disorder Is Caused by Failure of
REM Sleep Paralysis Circuits 1095
Restless Legs Syndrome and Periodic Limb Movement
Disorder Disrupt Sleep 1095
Non-REM Parasomnias Include Sleepwalking, Sleep
Talking, and Night Terrors 1095
Sleep Has Many Functions 1096
Highlights 1097
Selected Reading 1098
References 1098
Part VII
Development and the Emergence of Behavior
45 Patterning the Nervous
System. . . . . . . . . . . . . . . . . . . . . . . . . .1107
Joshua R. Sanes, Thomas M. Jessell
The Neural Tube Arises From the Ectoderm 1108
Secreted Signals Promote Neural Cell Fate 1108
Development of the Neural Plate Is Induced by Signals
From the Organizer Region 1108
Neural Induction Is Mediated by Peptide Growth
Factors and Their Inhibitors 1110
Rostrocaudal Patterning of the Neural Tube Involves
Signaling Gradients and Secondary Organizing
Centers 1112
The Neural Tube Becomes Regionalized
Early in Development 1112
Signals From the Mesoderm and Endoderm Define the
Rostrocaudal Pattern of the Neural Plate 1112
Signals From Organizing Centers Within the
Neural Tube Pattern the Forebrain, Midbrain,
and Hindbrain 1113
Repressive Interactions Divide the Hindbrain
Into Segments 1115
Dorsoventral Patterning of the Neural Tube Involves
Similar Mechanisms at Different Rostrocaudal
Levels 1115
The Ventral Neural Tube Is Patterned by Sonic
Hedgehog Protein Secreted from the Notochord and
Floor Plate 1117
The Dorsal Neural Tube Is Patterned by Bone
Morphogenetic Proteins 1119
Dorsoventral Patterning Mechanisms Are Conserved
Along the Rostrocaudal Extent of the Neural Tube 1119
Local Signals Determine Functional Subclasses of
Neurons 1119
Rostrocaudal Position Is a Major Determinant
of Motor Neuron Subtype 1120
Local Signals and Transcriptional Circuits Further
Diversify Motor Neuron Subtypes 1121
The Developing Forebrain Is Patterned by Intrinsic and
Extrinsic Influences 1123
Inductive Signals and Transcription Factor Gradients
Establish Regional Differentiation 1123
Afferent Inputs Also Contribute to
Regionalization 1124
Highlights 1128
Selected Reading 1129
References 1129
46 Differentiation and Survival of Nerve Cells . . . . . . . . . . . . . . . . . . .1130
Joshua R. Sanes, Thomas M. Jessell
The Proliferation of Neural Progenitor Cells Involves
Symmetric and Asymmetric Cell Divisions 1131
Radial Glial Cells Serve as Neural Progenitors and
Structural Scaffolds 1131
The Generation of Neurons and Glial Cells Is Regulated
by Delta-Notch Signaling and Basic Helix-Loop-Helix
Transcription Factors 1131
The Layers of the Cerebral Cortex Are Established by
Sequential Addition of Newborn Neurons 1135
Neurons Migrate Long Distances From Their Site of
Origin to Their Final Position 1137
Excitatory Cortical Neurons Migrate Radially
Along Glial Guides 1137
Cortical Interneurons Arise Subcortically and Migrate
Tangentially to Cortex 1138
Neural Crest Cell Migration in the Peripheral Nervous
System Does Not Rely on Scaffolding 1141
Structural and Molecular Innovations Underlie the
Expansion of the Human Cerebral Cortex 1141
Intrinsic Programs and Extrinsic Factors Determine the
Neurotransmitter Phenotypes of Neurons 1143
Neurotransmitter Choice Is a Core Component
of Transcriptional Programs of Neuronal
Differentiation 1143
Signals From Synaptic Inputs and Targets Can Influence
the Transmitter Phenotypes of Neurons 1146
The Survival of a Neuron Is Regulated by Neurotrophic
Signals From the Neuron’s Target 1147
The Neurotrophic Factor Hypothesis Was Confirmed by
the Discovery of Nerve Growth Factor 1147
Neurotrophins Are the Best-Studied
Neurotrophic Factors 1147
Neurotrophic Factors Suppress a Latent Cell Death
Program 1151
Highlights 1153
Selected Reading 1154
References 1154
47 The Growth and Guidance of Axons . . . . . . . . . . . . . . . . . . . . . . . .1156
Joshua R. Sanes
Differences Between Axons and Dendrites Emerge Early
in Development 1156
Dendrites Are Patterned by Intrinsic and Extrinsic
Factors 1157
The Growth Cone Is a Sensory Transducer
and a Motor Structure 1161
Molecular Cues Guide Axons to Their Targets 1166
The Growth of Retinal Ganglion Axons Is Oriented in a
Series of Discrete Steps 1168
Growth Cones Diverge at the Optic Chiasm 1171
Gradients of Ephrins Provide Inhibitory
Signals in the Brain 1172
Axons From Some Spinal Neurons Are
Guided Across the Midline 1176
Netrins Direct Developing Commissural Axons Across
the Midline 1176
Chemoattractant and Chemorepellent Factors Pattern
the Midline 1176
Highlights 1179
Selected Reading 1179
References 1180
48 Formation and Elimination
of Synapses. . . . . . . . . . . . . . . . . . . . . .1181
Joshua R. Sanes
Neurons Recognize Specific Synaptic Targets 1182
Recognition Molecules Promote Selective Synapse
Formation in the Visual System 1182
Sensory Receptors Promote Targeting of
Olfactory Neurons 1184
Different Synaptic Inputs Are Directed to Discrete
Domains of the Postsynaptic Cell 1186
Neural Activity Sharpens Synaptic Specificity 1187
Principles of Synaptic Differentiation Are Revealed at the
Neuromuscular Junction 1189
Differentiation of Motor Nerve Terminals Is Organized
by Muscle Fibers 1190
Differentiation of the Postsynaptic Muscle Membrane Is
Organized by the Motor Nerve 1194
The Nerve Regulates Transcription of Acetylcholine
Receptor Genes 1196
The Neuromuscular Junction Matures in a Series of
Steps 1197
Central Synapses and Neuromuscular Junctions Develop
in Similar Ways 1198
Neurotransmitter Receptors Become Localized
at Central Synapses 1198
Synaptic Organizing Molecules Pattern Central Nerve
Terminals 1199
Some Synapses Are Eliminated After Birth 1204
Glial Cells Regulate Both Formation and Elimination of
Synapses 1205
Highlights 1207
Selected Reading 1208
References 1208
49 Experience and the Refinement of
Synaptic Connections. . . . . . . . . . . . .1210
Joshua R. Sanes
Development of Human Mental Function
Is Influenced by Early Experience 1211
Early Experience Has Lifelong Effects on Social
Behaviors 1211
Development of Visual Perception Requires Visual
Experience 1212
Development of Binocular Circuits in the Visual Cortex
Depends on Postnatal Activity 1213
Visual Experience Affects the Structure and Function of
the Visual Cortex 1213
Patterns of Electrical Activity Organize Binocular
Circuits 1215
Reorganization of Visual Circuits During a
Critical Period Involves Alterations in Synaptic
Connections 1219
Cortical Reorganization Depends on Changes in Both
Excitation and Inhibition 1219
Synaptic Structures Are Altered During the
Critical Period 1221
Thalamic Inputs Are Remodeled During
the Critical Period 1221
Synaptic Stabilization Contributes to Closing
the Critical Period 1223
Experience-Independent Spontaneous Neural Activity
Leads to Early Circuit Refinement 1224
Activity-Dependent Refinement of Connections Is a
General Feature of Brain Circuitry 1225
Many Aspects of Visual System Development
Are Activity-Dependent 1225
Sensory Modalities Are Coordinated During a Critical
Period 1227
Different Functions and Brain Regions Have Different
Critical Periods of Development 1228
Critical Periods Can Be Reopened in Adulthood 1229
Visual and Auditory Maps Can Be Aligned in
Adults 1230
Binocular Circuits Can Be Remodeled in Adults 1231
Highlights 1233
Selected Reading 1234
References 123450 Repairing the Damaged Brain. . . . .1236
Joshua R. Sanes
Damage to the Axon Affects Both the Neuron and
Neighboring Cells 1237
Axon Degeneration Is an Active Process 1237
Axotomy Leads to Reactive Responses
in Nearby Cells 1240
Central Axons Regenerate Poorly After Injury 1241
Therapeutic Interventions May Promote Regeneration of
Injured Central Neurons 1242
Environmental Factors Support the Regeneration
of Injured Axons 1243
Components of Myelin Inhibit Neurite
Outgrowth 1244
Injury-Induced Scarring Hinders Axonal
Regeneration 1246
An Intrinsic Growth Program Promotes
Regeneration 1246
Formation of New Connections by Intact Axons Can
Lead to Recovery of Function Following Injury 1247
Neurons in the Injured Brain Die but New Ones Can Be
Born 1248
Therapeutic Interventions May Retain or Replace Injured
Central Neurons 1250
Transplantation of Neurons or Their Progenitors Can
Replace Lost Neurons 1250
Stimulation of Neurogenesis in Regions of Injury May
Contribute to Restoring Function 1254
Transplantation of Nonneuronal Cells or Their
Progenitors Can Improve Neuronal Function 1255
Restoration of Function Is the Aim of
Regenerative Therapies 1255
Highlights 1256
Selected Reading 1257
References 1257
51 Sexual Differentiation of the Nervous System. . . . . . . . . . . . . . . . . . . . . . . . . .1260
Nirao M. Shah, Joshua R. Sanes
Genes and Hormones Determine Physical Differences
Between Males and Females 1261
Chromosomal Sex Directs the Gonadal Differentiation of
the Embryo 1261
Gonads Synthesize Hormones That Promote
Sexual Differentiation 1262
Disorders of Steroid Hormone Biosynthesis
Affect Sexual Differentiation 1263
Sexual Differentiation of the Nervous System Generates
Sexually Dimorphic Behaviors 1264
Erectile Function Is Controlled by a Sexually Dimorphic
Circuit in the Spinal Cord 1266
Song Production in Birds Is Controlled by Sexually
Dimorphic Circuits in the Forebrain 1267
Mating Behavior in Mammals Is Controlled
by a Sexually Dimorphic Neural Circuit in the
Hypothalamus 1272
Environmental Cues Regulate Sexually Dimorphic
Behaviors 1272
Pheromones Control Partner Choice in Mice 1272
Early Experience Modifies Later Maternal
Behavior 1274
A Set of Core Mechanisms Underlies Many Sexual
Dimorphisms in the Brain and Spinal Cord 1275
The Human Brain Is Sexually Dimorphic 1277
Sexual Dimorphisms in Humans May Arise From
Hormonal Action or Experience 1279
Dimorphic Structures in the Brain Correlate with
Gender Identity and Sexual Orientation 1279
Highlights 1281
Selected Reading 1282
References 1283
Part VIII
Learning, Memory, Language
and Cognition
52 Learning and Memory. . . . . . . . . . . .1291
Daphna Shohamy, Daniel L. Schacter,
Anthony D. Wagner
Short-Term and Long-Term Memory Involve Different
Neural Systems 1292
Short-Term Memory Maintains Transient
Representations of Information Relevant to Immediate
Goals 1292
Information Stored in Short-Term Memory Is Selectively
Transferred to Long-Term Memory 1293
The Medial Temporal Lobe Is Critical for Episodic
Long-Term Memory 1294
Episodic Memory Processing Involves Encoding,
Storage, Retrieval, and Consolidation 1297
Episodic Memory Involves Interactions Between the
Medial Temporal Lobe and Association Cortices 1298
Episodic Memory Contributes to Imagination and
Goal-Directed Behavior 1300
The Hippocampus Supports Episodic Memory by
Building Relational Associations 1300
Implicit Memory Supports a Range of Behaviors in
Humans and Animals 1303
Different Forms of Implicit Memory Involve Different
Neural Circuits 1303
Implicit Memory Can Be Associative or
Nonassociative 1304
Operant Conditioning Involves Associating a Specific
Behavior With a Reinforcing Event 1306
Associative Learning Is Constrained by the Biology of
the Organism 1307
Errors and Imperfections in Memory Shed Light on
Normal Memory Processes 1308
Highlights 1309
Suggested Reading 1310
References 1310
53 Cellular Mechanisms of Implicit Memory Storage and the Biological Basis of Individuality. . . . . . . . . . . . .1312
Eric R. Kandel, Joseph LeDoux
Storage of Implicit Memory Involves Changes in the
Effectiveness of Synaptic Transmission 1313
Habituation Results From Presynaptic Depression of
Synaptic Transmission 1314
Sensitization Involves Presynaptic Facilitation of
Synaptic Transmission 1316
Classical Threat Conditioning Involves Facilitation of
Synaptic Transmission 1317
Long-Term Storage of Implicit Memory Involves
Synaptic Changes Mediated by the cAMP-PKA-CREB
Pathway 1319
Cyclic AMP Signaling Has a Role in
Long-Term Sensitization 1319
The Role of Noncoding RNAs in the
Regulation of Transcription 1323
Long-Term Synaptic Facilitation Is Synapse
Specific 1324
Maintaining Long-Term Synaptic Facilitation Requires
a Prion-Like Protein Regulator of Local Protein
Synthesis 1327
Memory Stored in a Sensory-Motor Synapse Becomes
Destabilized Following Retrieval but
Can Be Restabilized 1330
Classical Threat Conditioning of Defensive Responses in
Flies Also Uses the cAMP-PKA-CREB Pathway 1330
Memory of Threat Learning in Mammals Involves the
Amygdala 1331
Learning-Induced Changes in the Structure
of the Brain Contribute to the Biological Basis of
Individuality 1336
Highlights 1336
Selected Reading 1337
References 1337
54 The Hippocampus and the Neural Basis of Explicit Memory Storage . . . . . . . . . . . . . . . . .1339
Edvard I. Moser, May-Britt Moser,
Steven A. Siegelbaum
Explicit Memory in Mammals Involves Synaptic Plasticity
in the Hippocampus 1340
Long-Term Potentiation at Distinct Hippocampal
Pathways Is Essential for Explicit Memory
Storage 1342
Different Molecular and Cellular Mechanisms
Contribute to the Forms of Expression of
Long-Term Potentiation 1345
Long-Term Potentiation Has Early and Late
Phases 1347
Spike-Timing-Dependent Plasticity Provides a
More Natural Mechanism for Altering Synaptic
Strength 1349
Long-Term Potentiation in the Hippocampus Has
Properties That Make It Useful as A Mechanism for
Memory Storage 1349
Spatial Memory Depends on Long-Term
Potentiation 1350
Explicit Memory Storage Also Depends on Long-Term
Depression of Synaptic Transmission 1353
Memory Is Stored in Cell Assemblies 1357
Different Aspects of Explicit Memory Are Processed in
Different Subregions of the Hippocampus 1358
The Dentate Gyrus Is Important for Pattern
Separation 1359
The CA3 Region Is Important for Pattern
Completion 1360
The CA2 Region Encodes Social Memory 1360
A Spatial Map of the External World Is Formed in the
Hippocampus 1360
Entorhinal Cortex Neurons Provide a Distinct
Representation of Space 1361
Place Cells Are Part of the Substrate for
Spatial Memory 1365
Disorders of Autobiographical Memory Result From
Functional Perturbations in the Hippocampus 1367
Highlights 1367
Selected Reading 1368
References 1368
55 Language. . . . . . . . . . . . . . . . . . . . . . . .1370
Patricia K. Kuhl
Language Has Many Structural Levels: Phonemes,
Morphemes, Words, and Sentences 1371
Language Acquisition in Children Follows a Universal
Pattern 1372
The “Universalist” Infant Becomes Linguistically
Specialized by Age 1 1373
The Visual System Is Engaged in Language Production
and Perception 1376
Prosodic Cues Are Learned as Early as In Utero 1376
Transitional Probabilities Help Distinguish Words in
Continuous Speech 1376
There Is a Critical Period for Language
Learning 1377
The “Parentese” Speaking Style Enhances
Language Learning 1377
Successful Bilingual Learning Depends on the Age at
Which the Second Language Is Learned 1378
A New Model for the Neural Basis of Language Has
Emerged 1378
Numerous Specialized Cortical Regions Contribute to
Language Processing 1378
The Neural Architecture for Language Develops
Rapidly During Infancy 1380
The Left Hemisphere Is Dominant for Language 1381
Prosody Engages Both Right and Left Hemispheres
Depending on the Information Conveyed 1382
Studies of the Aphasias Have Provided Insights into
Language Processing 1382
Broca’s Aphasia Results From a Large
Lesion in the Left Frontal Lobe 1382
Wernicke’s Aphasia Results From Damage to Left
Posterior Temporal Lobe Structures 1384
Conduction Aphasia Results From Damage to a Sector
of Posterior Language Areas 1384
Global Aphasia Results From Widespread Damage to
Several Language Centers 1386
Transcortical Aphasias Result From Damage to Areas
Near Broca’s and Wernicke’s Areas 1386
Less Common Aphasias Implicate Additional
Brain Areas Important for Language 1386
Highlights 1388
Selected Reading 1389
References 1390
56 Decision-Making and Consciousness. . . . . . . . . . . . . . . . . . .1392
Michael N. Shadlen, Eric R. Kandel
Perceptual Discriminations Require a Decision
Rule 1393
A Simple Decision Rule Is the Application of a
Threshold to a Representation of the
Evidence 1393
Perceptual Decisions Involving Deliberation Mimic
Aspects of Real-Life Decisions Involving Cognitive
Faculties 1395
Neurons in Sensory Areas of the Cortex Supply
the Noisy Samples of Evidence to
Decision-Making 1397
Accumulation of Evidence to a Threshold Explains the
Speed Versus Accuracy Trade-Off 1401
Neurons in the Parietal and Prefrontal Association Cortex
Represent a Decision Variable 1401
Perceptual Decision-Making Is a Model for Reasoning
From Samples of Evidence 1404
Decisions About Preference Use Evidence About
Value 1408
Decision-Making Offers a Framework for Understanding
Thought Processes, States of Knowing, and States of
Awareness 1409
Consciousness Can be Understood Through the Lens of
Decision Making 1412
Highlights 1415
Selected Reading 1415
References 1416
Part IX
Diseases of the Nervous System
57 Diseases of the Peripheral Nerve and Motor Unit . . . . . . . . . . . . . . . . . .1421
Robert H. Brown, Stephen C. Cannon,
Lewis P. Rowland
Disorders of the Peripheral Nerve, Neuromuscular Junction,
and Muscle Can Be Distinguished Clinically 1422
A Variety of Diseases Target Motor Neurons and
Peripheral Nerves 1426
Motor Neuron Diseases Do Not Affect Sensory Neurons
(Amyotrophic Lateral Sclerosis) 1426
Diseases of Peripheral Nerves Affect Conduction of the
Action Potential 1428
The Molecular Basis of Some Inherited Peripheral
Neuropathies Has Been Defined 1430
Disorders of Synaptic Transmission at the Neuromuscular
Junction Have Multiple Causes 1432
Myasthenia Gravis Is the Best-Studied Example of a
Neuromuscular Junction Disease 1433
Treatment of Myasthenia Is Based on the Physiological
Effects and Autoimmune Pathogenesis of the Disease 1435
There Are Two Distinct Congenital Forms of Myasthenia
Gravis 1435
Lambert-Eaton Syndrome and Botulism Also Alter
Neuromuscular Transmission 1436
Diseases of Skeletal Muscle Can Be Inherited or
Acquired 1437
Dermatomyositis Exemplifies Acquired
Myopathy 1437
Muscular Dystrophies Are the Most Common Inherited
Myopathies 1437
Some Inherited Diseases of Skeletal Muscle Arise From
Genetic Defects in Voltage-Gated Ion Channels 1441
Highlights 1445
Selected Reading 1445
References 1445
58 Seizures and Epilepsy . . . . . . . . . . . .1447
Gary Westbrook
Classification of Seizures and the Epilepsies Is Important
for Pathogenesis and Treatment 1448
Seizures Are Temporary Disruptions of
Brain Function 1448
Epilepsy Is a Chronic Condition of
Recurrent Seizures 1449
The Electroencephalogram Represents the Collective
Activity of Cortical Neurons 1450
Focal Onset Seizures Originate Within a Small Group of
Neurons 1454
Neurons in a Seizure Focus Have Abnormal Bursting
Activity 1454
The Breakdown of Surround Inhibition Leads to
Synchronization 1456
The Spread of Seizure Activity Involves Normal Cortical
Circuitry 1460
Generalized Onset Seizures Are Driven by
Thalamocortical Circuits 1461
Locating the Seizure Focus Is Critical to the Surgical
Treatment of Epilepsy 1463
Prolonged Seizures Can Cause Brain Damage 1465
Repeated Convulsive Seizures Are a
Medical Emergency 1465
Excitotoxicity Underlies Seizure-Related
Brain Damage 1466
The Factors Leading to Development of Epilepsy Are
Poorly Understood 1467
Mutations in Ion Channels Are Among the
Genetic Causes of Epilepsy 1467
The Genesis of Acquired Epilepsies Is a Maladaptive
Response to Injury 1469
Highlights 1470
Selected Reading 1471
References 1471
59 Disorders of Conscious and Unconscious Mental Processes. . . . .1473
Christopher D. Frith
Conscious and Unconscious Cognitive Processes Have
Distinct Neural Correlates 1474
Differences Between Conscious and Unconscious
Processes in Perception Can Be Seen in Exaggerated Form
After Brain Damage 1476
The Control of Action Is Largely Unconscious 1479
The Conscious Recall of Memories Is a
Creative Process 1482
Behavioral Observation Needs to Be Supplemented With
Subjective Reports 1483
Verification of Subjective Reports Is Challenging 1484
Malingering and Hysteria Can Lead to Unreliable
Subjective Reports 1485
Highlights 1485
Selected Reading 1486
References 1486
60 Disorders of Thought and Volition in Schizophrenia . . . . . . . . . . . . . . . . . . .1488
Steven E. Hyman, Joshua Gordon
Schizophrenia Is Characterized by Cognitive
Impairments, Deficit Symptoms, and
Psychotic Symptoms 1489
Schizophrenia Has a Characteristic Course of
Illness With Onset During the Second and Third
Decades of Life 1490
The Psychotic Symptoms of Schizophrenia
Tend to Be Episodic 1490
The Risk of Schizophrenia Is Highly Influenced by
Genes 1490
Schizophrenia Is Characterized by Abnormalities in Brain
Structure and Function 1492
Loss of Gray Matter in the Cerebral Cortex Appears to
Result From Loss of Synaptic Contacts Rather Than Loss
of Cells 1494
Abnormalities in Brain Development
During Adolescence May Be Responsible for
Schizophrenia 1494
Antipsychotic Drugs Act on Dopaminergic Systems in the
Brain 1497
Highlights 1499
Selected Reading 1499
References 1499
61 Disorders of Mood and Anxiety . . . . . . . . . . . . . . . . . . . . .1501
Steven E. Hyman, Carol Tamminga
Mood Disorders Can Be Divided Into Two General
Classes: Unipolar Depression and Bipolar Disorder 1501
Major Depressive Disorder Differs Significantly From
Normal Sadness 1502
Major Depressive Disorder Often Begins Early in Life 1503
A Diagnosis of Bipolar Disorder Requires an Episode of
Mania 1503
Anxiety Disorders Represent Significant Dysregulation of
Fear Circuitry 1504
Both Genetic and Environmental Risk Factors Contribute
to Mood and Anxiety Disorders 1506
Depression and Stress Share Overlapping Neural
Mechanisms 1508
Dysfunctions of Human Brain Structures and Circuits
Involved in Mood and Anxiety Disorders Can Be
Identified by Neuroimaging 1509
Identification of Abnormally Functioning Neural
Circuits Helps Explain Symptoms and May Suggest
Treatments 1509
A Decrease in Hippocampal Volume Is Associated With
Mood Disorders 1512
Major Depression and Anxiety Disorders
Can Be Treated Effectively 1512
Current Antidepressant Drugs Affect Monoaminergic
Neural Systems 1512
Ketamine Shows Promise as a Rapidly Acting Drug to
Treat Major Depressive Disorder 1515
Psychotherapy Is Effective in the Treatment of Major
Depressive Disorder and Anxiety Disorders 1515
Electroconvulsive Therapy Is Highly Effective Against
Depression 1518
Newer Forms of Neuromodulation Are Being
Developed to Treat Depression 1518
Bipolar Disorder Can Be Treated With Lithium and
Several Anticonvulsant Drugs 1519
Second-Generation Antipsychotic Drugs Are Useful
Treatments for Bipolar Disorder 1520
Highlights 1520
Selected Reading 1521
References 1521
62 Disorders Affecting Social Cognition: Autism Spectrum Disorder . . . . . . . . . . . . . . . . . . . . . . . .1523
Matthew W. State
Autism Spectrum Disorder Phenotypes Share
Characteristic Behavioral Features 1524
Autism Spectrum Disorder Phenotypes Also Share
Distinctive Cognitive Abnormalities 1525
Social Communication Is Impaired in Autism
Spectrum Disorder: The Mind Blindness
Hypothesis 1525
Other Social Mechanisms Contribute to Autism
Spectrum Disorder 1527
People With Autism Show a Lack of
Behavioral Flexibility 1528
Some Individuals With Autism Have Special
Talents 1528
Genetic Factors Increase Risk for Autism Spectrum
Disorder 1529
Rare Genetic Syndromes Have Provided Initial Insights
Into the Biology of Autism Spectrum Disorders 1531
Fragile X Syndrome 1531
Rett Syndrome 1531
Williams Syndrome 1532
Angelman Syndrome and Prader-Willi Syndrome 1533
Neurodevelopmental Syndromes Provide Insight Into
the Mechanisms of Social Cognition 1534
The Complex Genetics of Common Forms of Autism
Spectrum Disorder Are Being Clarified 1534
Genetics and Neuropathology Are Illuminating the
Neural Mechanisms of Autism Spectrum Disorder 1537
Genetic Findings Can Be Interpreted Using
Systems Biological Approaches 1537
Autism Spectrum Disorder Genes Have Been Studied in
a Variety of Model Systems 1538
Postmortem and Brain Tissue Studies Provide Insight
Into Autism Spectrum Disorder Pathology 1539
Advances in Basic and Translational Science Provide
a Path to Elucidate the Pathophysiology of Autism
Spectrum Disorder 1540
Highlights 1540
Selected Reading 1541
References 1541
63 Genetic Mechanisms in Neurodegenerative Diseases of the Nervous System. . . . . . . . . . . . . . . . . .1544
Huda Y. Zoghbi
Huntington Disease Involves Degeneration
of the Striatum 1545
Spinobulbar Muscular Atrophy Is Caused by Androgen
Receptor Dysfunction 1546
Hereditary Spinocerebellar Ataxias Share Similar
Symptoms but Have Distinct Etiologies 1546
Parkinson Disease Is a Common Degenerative Disorder of
the Elderly 1548
Selective Neuronal Loss Occurs After Damage to
Ubiquitously Expressed Genes 1550
Animal Models Are Productive Tools for Studying
Neurodegenerative Diseases 1552
Mouse Models Reproduce Many Features of
Neurodegenerative Diseases 1552
Invertebrate Models Manifest Progressive
Neurodegeneration 1553
The Pathogenesis of Neurodegenerative Diseases Follows
Several Pathways 1553
Protein Misfolding and Degradation Contribute to
Parkinson Disease 1553
Protein Misfolding Triggers Pathological
Alterations in Gene Expression 1555
Mitochondrial Dysfunction Exacerbates
Neurodegenerative Disease 1556
Apoptosis and Caspases Modify the Severity
of Neurodegeneration 1556
Understanding the Molecular Dynamics of
Neurodegenerative Diseases Suggests Approaches to
Therapeutic Intervention 1556
Highlights 1558
Selected Reading 1558
References 1558
64 The Aging Brain . . . . . . . . . . . . . . . . .1561
Joshua R. Sanes, David M. Holtzman
The Structure and Function of the Brain Change With
Age 1561
Cognitive Decline Is Significant and Debilitating in a
Substantial Fraction of the Elderly 1566
Alzheimer Disease Is the Most Common Cause of
Dementia 1567
The Brain in Alzheimer Disease Is Altered by Atrophy,
Amyloid Plaques, and Neurofibrillary Tangles 1568
Amyloid Plaques Contain Toxic Peptides That
Contribute to Alzheimer Pathology 1570
Neurofibrillary Tangles Contain Microtubule-Associated
Proteins 1573
Risk Factors for Alzheimer Disease Have Been
Identified 1574
Alzheimer Disease Can Now Be Diagnosed Well but
Available Treatments Are Unsatisfactory 1576
Highlights 1579
Selected Reading 1580
References 1580
Index 1583