Handbook of Basal Ganglia Structure and Function (eBook)

Front Cover 1
Handbook of Basal Ganglia Structure and Function 4
Copyright Page 5
Dedication 6
Contents 8
Contributors 20
Preface 24
Acknowledgements 26
Part A: The Basal Ganglia System and its Evolution 28
Chapter 1. The Neuroanatomical Organization of the Basal Ganglia 30
I. Introduction 30
II. Overview of Basal Ganglia Organization 31
III. The Corticostriatal System 33
A. Subtypes of Corticostriatal Neurons 33
B. Patterns of Organization of Corticostriatal Afferents 34
IV. Striatum 35
A. Medium Spiny Projection Neurons 35
B. Synaptic Inputs to Medium Spiny Neurons 36
C. Striatal Interneurons 38
V. Output Systems of the Striatum 39
A. The Direct and Indirect Pathways 39
B. Other Nuclei of the Indirect Pathway 41
C. Dual Projections within Basal Ganglia Circuits 43
VI. Basal Ganglia Output Nuclei: Internal Segment of Globus Pallidus and Substantia Nigra 44
A. Cell Types 45
B. Inputs 45
C. Outputs 46
VII. The Nigrostriatal Dopamine System 46
A. Dorsal Tier Versus Ventral Tier Dopamine Neurons 46
B. Inputs to Dopamine Neurons 48
VIII. Striatal Patch-Matrix Compartments 48
A. Markers Defining the Patch-Matrix Compartments 48
B. Dopamine Inputs to Patches Versus Matrix 48
C. Cortical and Thalamic Inputs 49
D. Outputs of Patches Versus Matrix 50
References 50
Chapter 2. The Conservative Evolution of the Vertebrate Basal Ganglia 56
I. Introduction 56
A. Defining Traits of Basal Ganglia in Mammals 56
Box 2.1 Brain Evolution and the Term Homology 57
II. Basal Ganglia in Anamniotes 58
A. Agnathans 58
B. Chondroicthyans 59
C. Osteicthyes – Ray-Finned Fish 61
D. Osteicthyes – Lobe-Finned Fish 64
E. Amphibians 65
F. Summary and Overview of Basal Ganglia Evolution in Anamniotes 68
III. Basal Ganglia in Amniotes 68
A. Reptiles 68
B. Birds 71
C. Overview of Basal Ganglia Evolution in Amniotes 76
IV. Basal Ganglia Evolution – Outdated Concepts and Terminology 77
Acknowledgments 77
References 77
Chapter 3. Cell Types in the Different Nuclei of the Basal Ganglia 90
I. Introduction 90
A. Overview of the Basal Ganglia Nuclei in Rodents and Higher Vertebrates 90
B. Overview of Recent Findings on the Circuitry and Nuclei of the Basal Ganglia 91
II. Projection Neurons Within the Different Nuclei of the Basal Ganglia 93
III. Interneurons Within the Nuclei of the Basal Ganglia 94
IV. Absolute Numbers of Neurons in the Basal Ganglia: Functional Implications 95
A. Absolute Number of Projection Neurons in the Striatum and its Targets 95
B. Absolute Number of GPe, GPi, SNr and STN Neurons 96
C. Absolute Number of Interneurons 97
V. Glial Cell Types Within the Different Nuclei 97
A. Absolute Number of Glial Cells: Neuron-to-Astrocyte Ratios in Some of the Basal Ganglia Nuclei of the Rat 98
VI. Conclusions: The Past and the Next 10–15 Years 98
Acknowledgments 99
References 99
Chapter 4. Neurotransmitter Receptors in the Basal Ganglia 102
I. Introduction 102
II. Ionotropic Receptors 107
A. Glutamate Receptor Ion Channels 107
B. Ligand-Gated Ion Channels 109
III. Metabotropic Receptors 111
A. Family 1 112
B. Family 3 116
IV. Conclusions 117
Acknowledgments 118
References 118
Part B: Anatomy and Physiology of the Striatum 124
Chapter 5. The Striatal Skeleton: Medium Spiny Projection Neurons and their Lateral Connections 126
I. Introduction 126
II. The Striatal Medium Spiny Neuron 126
A. General Morphology of the Medium Spiny Neuron 126
B. Dendritic Spines 128
C. Glutamate Receptor-Mediated Responses 128
D. Neurophysiology of Medium Spiny Neurons 130
E. Dopaminergic Modulation of Ion Channels 131
III. Anatomical Connectivity of the Striatal Skeleton 132
A. Quantitative Neuroanatomical Consideration of Local Connectivity 133
IV. Synaptic Physiology of Lateral Interactions 134
V. Functional Implications, Models and Outlook 135
Acknowledgment 136
References 136
Chapter 6. D1 and D2 Dopamine Receptor Modulation of Glutamatergic Signaling in Striatal Medium Spiny Neurons 140
I. Introduction 140
II. The "Classical" Model of Dopaminergic Modulation 141
III. Modulation of Intrinsic Excitability and Glutamatergic Signaling by D1 Receptors 141
Box 6.1 D1 and D2 MSNs Differ in Dendritic Morphology 143
IV. Modulation of Intrinsic Excitability and Glutamatergic Signaling by D2 Receptors 144
V. Dopaminergic Modulation of Long-Term Synaptic Plasticity 144
Box 6.2 MSN Dendrites are Active 145
VI. The Indirect Players – Striatal Interneurons 151
VII. Dopaminergic Modulation of Glutamatergic Signaling in Parkinson's Disease 151
VIII. Functional Implications for the Pathophysiology in Parkinson's Disease 155
IX. Concluding Remarks 155
References 156
Chapter 7. The Cholinergic Interneurons of the Striatum: Intrinsic Properties Underlie Multiple Discharge Patterns 160
I. Introduction 160
II. Autonomous Firing Patterns in Cholinergic Interneurons 162
A. Biophysical Mechanism of Autonomous Firing 162
B. Influence of Neurotransmitters on Autonomous Firing 165
III. Influence of the Cholinergic Interneurons on the Striatal Network 167
A. Neuronal Excitability 167
B. Synaptic Transmission 168
C. Synaptic Plasticity 169
IV. The Cholinergic Interneurons are the Tonically Active Neurons of the Striatum 170
A. The Pause Response 170
B. Spontaneous Firing Patterns and Synchronization of TANs 170
V. Summary and Conclusions 172
References 173
Chapter 8. GABAergic Interneurons of the Striatum 178
I. Introduction 178
II. Parvalbumin-Immunoreactive Interneurons 179
A. Neurocytology 179
B. Afferents and Efferents 179
C. Basic Membrane Properties 179
D. Firing Characteristics 181
E. Synaptic Connectivity 181
F. In Vivo Recordings 182
G. Pharmacology 183
III. Somatostatin/NOS/Neuropeptide Y Interneurons 183
A. Neurocytology 183
B. Afferents and Efferents 185
C. Basic Membrane Properties 185
D. Synaptic Connectivity 185
E. Spontaneous Activity 185
F. Pharmacology 187
IV. LTS Neurons 187
A. Synaptic Connectivity 187
V. Calretinin Interneurons 187
VI. Other GABAergic Interneurons: Tyrosine Hydroxylase-Immunoreactive Neurons 187
A. Striatal EGFP-TH+ Interneurons 189
VII. Summary and Conclusions 190
Acknowledgments 190
References 190
Chapter 9. Endocannabinoid Signaling in the Striatum 194
I. Introduction: The Endocannabinoid System 194
II. Endocannabinoids and Cannabinoid Receptors in the Striatum 195
A. The CB1 Receptor 195
B. The CB2 Receptor 197
C. TRPV1 197
D. Endocannabinoids in Striatum 197
E. Biosynthetic Enzymes 198
F. Degrading Enzymes 199
III. CB1 Receptor Function in the Striatum 200
IV. Endocannabinoid-Mediated Synaptic Plasticity in the Striatum 201
A. Short-Term Depression 201
B. Long-Term Depression 202
V. Endocannabinoid Roles in Striatum-Dependent Behavior 205
References 208
Chapter 10. Nitric Oxide Signaling in the Striatum 214
I. Introduction: The Nitric Oxide System 214
A. Biosynthesis of NO 214
B. nNOS-Expressing Interneurons and NO Effector Pathways 215
II. Afferent Regulation of Striatal NO Synthesis 216
A. Role of Corticostriatal Afferents and Glutamate Receptors 216
B. Regulation of Striatal NO Synthesis by Dopamine 216
III. Effects of NO Signaling on Neurotransmitter Release 218
A. Regulation of Glutamate Release 218
B. Regulation of Dopamine Release 219
C. Regulation of Acetylcholine Release 219
IV. Regulation of Striatal Neuron Activity and Output by NO Signaling 219
A. Tonic NO Signaling 219
B. Phasic NO Signaling 220
C. Regulation of Short- and Long-Term Synaptic Plasticity 220
D. Regulation of Striatal Neuronal Synchrony and Output 220
V. Role of Striatal NO-sGC Signaling in Motor Behavior 222
VI. Impact of Dopamine Depletion on Striatal NO-sGC Signaling 222
Acknowledgments 223
References 223
Chapter 11. Role of Adenosine in the Basal Ganglia 228
I. Introduction: The Adenosine System 228
II. Adenosine Receptor Localization and Function 229
A. A[sub(1)] Receptors 229
B. A[sub(2A)] Receptors 229
III. Adenosine Receptor Interactions 230
A. Biochemical Interactions: Postsynaptic Modulation of BG Neurotransmission 230
B. Biochemical Interactions: Presynaptic Modulation of BG Neurotransmission 233
IV. A[sub(2A)] Receptors in Parkinson's Disease: Biochemical Studies 233
A. Postsynaptic Interactions with the Dopamine System 233
B. Postsynaptic Interactions with the Glutamate System 234
C. Presynaptic Interactions 234
D. A[sub(2A)] Receptor Control of Striatal GAD67 and Neuropeptides 235
V. A[sub(2A)]-Dopamine Interactions in Parkinson's Disease: Behavioral Studies 235
A. Studies in Rodents 236
B. Studies in Primates 236
C. Clinical Trials with A[sub(2A)] Receptor Antagonists in PD Patients 237
VI. A[sub(2A)] Receptors in Huntington's Disease 237
VII. Neuroprotective Potential of A[sub(2A)] Receptor Antagonists 238
VIII. Adenosine Receptors and Cognitive Processes: Any Role? 238
IX. Conclusions 240
References 240
Chapter 12. Regulation of Corticostriatal Synaptic Plasticity in Physiological and Pathological Conditions 246
I. Introduction 246
II. Physiological and Pharmacological Characterization of Corticostriatal Long-Term Depression (LTD) and Long-Term Potentiation (LTP) 247
A. Role of Glutamate Receptors in LTD and LTP 247
B. Role of Dopamine Receptors 248
C. Role of Acetylcholine 249
D. Role of Endogenous Cannabinoids 250
E. Synaptic Plasticity Expressed by Striatal Interneurons 250
III. Synaptic Depotentiation at Corticostriatal Synapses: A Mechanism of Physiological "Forgetting"? 250
IV. Corticostriatal Synaptic Plasticity in Experimental Models of Parkinson's Disease 251
V. Corticostriatal Synaptic Plasticity in Experimental Models of Hyperkinetic Disorders 251
A. Huntington's Disease 251
B. L-DOPA-Induced Dyskinesia 252
VI. Striatal Synaptic Plasticity and Neuronal Ischemia 253
VII. Conclusions and Future Perspectives 253
References 254
Part C: Anatomy and Physiology of Globus Pallidus, Subthalamic Nucleus and Substantia Nigra 258
Chapter 13. Organization of the Globus Pallidus 260
I. Introduction: The Globus Pallidus in the Basal Ganglia Circuitry 260
II. Anatomy of the Striatum and the Globus Pallidus 260
A. Functional Territories of the GPe and GPi 261
B. Morphological Characteristics of GPe Neurons 264
C. Projection Sites of GPe Axons 264
D. Morphological Characteristics of GPi Neurons 265
E. Projection Sites of GPi Axons 266
III. Physiology of the Globus Pallidus 266
A. Physiological Properties of GPe Neurons 266
B. Physiological Properties of GPi Neurons 267
C. Synaptic Inputs to GPe and GPi Neurons 267
IV. Functional Considerations 270
Acknowledgments 271
References 271
Chapter 14. Projections from Pallidum to Striatum 276
I. Introduction 276
II. General Anatomy of Pallidostriatal Projections 276
III. Topography 278
IV. Characteristics of Pallidostriatal Neurons 279
V. Striatal Targets of Pallidostriatal Neurons 280
VI. Chemical Neuroanatomy and Regulation of Pallidostriatal Neurons 281
VII. Functional Considerations 281
References 282
Chapter 15. The Subthalamic Nucleus: From In Vitro to In Vivo Mechanisms 286
I. Introduction 286
II. Synaptic Organization of the Subthalamic Nucleus and Responses to Cortical Stimulation 288
A. Inputs 288
B. Outputs 288
C. Responses to Cortical Stimulation 289
III. Cellular Basis of Single-Spike and Burst Firing in Subthalamic Nucleus Neurons In Vitro 289
A. Burst Firing 289
B. Single-Spike Activity 290
C. In Vivo Activities of STN Neurons and their Relation to Cortical Patterns 292
D. Anesthesia-Dependent Slow Oscillations 292
E. Natural Patterns 293
IV. Subthalamic Nucleus, Dopamine and Parkinsonism 293
A. Dopaminergic Control of STN Activity 293
B. Aberrant Oscillations in the GPe-STN Network in Parkinsonism 293
V. The Subthalamic Nucleus as a Remote Control System for Cortical Seizures 294
A. Pharmacological and Deep-Brain Stimulation Studies in Generalized Epilepsy 294
B. Propagation of SWDs in Basal Ganglia Networks: Functional Imbalance Between Cortico-Subthalamo-Nigral and Cortico-Striato-Nigral Pathways 296
C. Rhythmic Bursting in STN and GPe Neurons During Seizures and its Repercussion on SNr Cells 296
D. Control of Ictogenesis by the Subthalamo-Nigro-Thalamo-Cortical Pathway 297
E. Is There an On-line Control of Cortical Seizures by the STN? 298
Acknowledgments 298
References 298
Chapter 16. Neurophysiology of Substantia Nigra Dopamine Neurons: Modulation by GABA 302
I. Introduction 302
II. Neurocytology of Nigrostriatal Dopamine Neurons 303
III. Electrophysiological Properties of Nigrostriatal Dopamine Neurons 304
A. Extracellular Recordings 304
B. Intracellular Recordings 306
IV. Neuroanatomy of GABA Afferents to Nigral Dopamine Neurons 307
V. Neurophysiology of GABA Afferents 308
A. Responses to Striatal Stimulation 308
B. Responses to Pallidal Stimulation 308
C. Responses to SNr Stimulation 311
D. Why are SNr Neurons so Much More Sensitive to GABA than Nigrostriatal Neurons? 312
E. Pharmacology of GABAergic Synaptic Responses in Nigrostriatal Neurons In Vivo 312
F. Why are Postsynaptic GABA[sub(B)] Responses Seen in Response to Stimulation of GABA Afferents in Mice In Vivo, but not in Rats? 313
G. Effects of GABA Receptor Antagonists on Spontaneous Activity in Nigrostriatal Neurons 314
H. Afferent Regulation of Burst Firing in Nigrostriatal Neurons 316
VI. Concluding Remarks 317
Acknowledgments 318
References 318
Chapter 17. Regulation of Extracellular Dopamine: Release and Reuptake 324
I. Introduction 324
II. Regulation of Dopamine Release 324
A. Exocytotic Processes 324
B. Regulation of Quantal Size 326
C. Regulation of Release by Autoreceptors 328
D. Regulation of Release by Heteroreceptors 330
E. Relationship Between Impulse Flow and Vesicular Release 332
III. Dopamine Reuptake 334
A. Reuptake Replenishes the Releasable Pool 334
B. Extracellular Elimination of the Released Dopamine is Achieved by Reuptake 334
C. Reuptake Limits Dopamine Diffusion in the Extracellular Fluid 334
D. Regulation of Dopamine Reuptake by D2 Autoreceptors 337
IV. Relationship Between the Firing of Dopamine Neurons and Extracellular Dopamine 337
A. The Tonic Extracellular Dopamine Level 337
B. Phasic Changes in Extracellular Dopamine 337
V. Conclusions 339
References 339
Part D: Network Integration 348
Chapter 18. Organization of Corticostriatal Projection Neuron Types 350
I. Introduction 350
II. Cortical Projections to Basal Ganglia – Historical Overview 350
III. Corticostriatal Neuron Types 352
IV. Ultrastructure of Cortical Input to Striatum 355
V. Differential Input of Cortex to Striatal Neurons 357
A. Anatomical Evidence 357
B. Electrophysiological Evidence 360
C. Open Questions 361
VI. Functional Considerations 361
A. Motor Control 361
B. Motor Learning, Corticostriatal Plasticity and the Differential Cortical Input to Striatum 362
Acknowledgments 364
References 364
Chapter 19. Gating of Cortical Input to the Striatum 368
I. Introduction 368
II. Anatomy of Corticostriatal Input Pathways 369
III. Corticostriatal Mapping 369
IV. Cortical Cells of Origin 369
V. Terminal Distribution of Corticostriatal Axons 370
VI. Significance of Corticostriatal Statistics 371
A. Lack of Output Flexibility 372
B. Broad Tuning 372
VII. Synaptic Plasticity in the Corticostriatal Pathway 373
VIII. Synthesis and Conclusions 375
Acknowledgment 375
References 375
Chapter 20. Organization of Prefrontal-Striatal Connections 380
I. Introduction: Prefrontal Cortex-Basal Ganglia Circuits 380
II. Prefrontal Cortex and Striatum 381
III. Topographical Organization of Prefrontal-Striatal Projections 382
A. Medial Prefrontal and Agranular Insular Projections to the Striatum 382
B. Orbital-Prefrontal Projections to the Striatum 384
IV. Relationships of the Prefrontal-Striatal Projections with the Compartmental Structure of the Striatum 384
A. Striatal Compartments: Patch-Matrix and Shell-Core 384
B. Prefrontal Cortical Lamination and Striatal Compartments 385
V. Cortico-Cortical and Corticostriatal Relationships 386
VI. Relationships of the Prefrontal-Striatal Topography with Other Striatal Inputs 388
A. Triadic Relationships of the Thalamic and Limbic Projections with the Prefrontal-Striatal System 388
VII. Medium-Sized Spiny Projection Neurons: Integrators of Striatal Inputs 390
References 390
Chapter 21. Gating of Limbic Input to the Ventral Striatum 394
I. Introduction 394
II. The Nucleus Accumbens: A Forebrain Gateway 395
III. Electrophysiological Properties of MSNs that Shape Input Integration 395
A. Up and Down Membrane Potential States and Ensemble Coding in the NAc 395
B. Up States Depend on Glutamatergic Inputs 397
C. Dopamine Modulation of Up States 398
IV. Hippocampal Gating of Prefrontocortical Throughput 400
V. Other Inputs Can also Drive Up States and Command Neuronal Activity in the Nucleus Accumbens 401
VI. The Nucleus Accumbens, a Behavioral Switchboard 402
References 404
Chapter 22. Anatomical and Functional Organization of the Thalamostriatal Systems 408
I. Introduction 408
II. Anatomy of the Thalamostriatal Systems 409
A. Sources of Thalamostriatal Projections 409
B. Thalamostriatal versus Thalamocortical Systems: Segregated or Collateralized Origins 411
C. Afferents to Thalamostriatal Neurons: Sources of Basal Ganglia-Thalamostriatal Loops 411
III. Synaptic Organization of Thalamostriatal Systems 412
A. Synaptic Organization of CM/Pf Projections to the Striatum 412
B. Synaptic Organization of non-CM/Pf Thalamostriatal Projections 413
C. Plasticity of the Synaptic Connectivity of the Thalamostriatal and Corticostriatal Systems in Parkinsonism 413
IV. Physiology of CM/Pf Neurons and Related Thalamostriatal Projections 414
A. Functional Characteristics of CM/Pf Neurons 414
B. Physiological Effects of CM/Pf Activation Upon Striatal Neurons 415
V. Extrastriatal Basal Ganglia Targets of CM/Pf 416
VI. Pathophysiology of CM/Pf Neurons in Parkinson's Disease and Related Disorders 416
VII. Neurosurgical CM/Pf Interventions for Movement Disorders 417
A. Ablative Surgeries of CM/Pf 417
B. CM/Pf Deep-Brain Stimulation and Tourette's Syndrome 417
C. CM/Pf Deep-Brain Stimulation and Parkinson's Disease 418
VIII. Conclusions 419
Abbreviations 419
References 419
Chapter 23. Subcortical Connections of the Basal Ganglia 424
I. Introduction 424
II. Cortical and Subcortical Loops Through the Basal Ganglia 425
III. Functions of Pedunculopontine Tegmental Nucleus and its Connections with Basal Ganglia 425
A. Anatomical Connections 425
B. Functions 427
IV. Functions of Superior Colliculus and its Connections with Basal Ganglia 428
A. Background 428
B. Connections with the Basal Ganglia 428
V. Function of Basal Ganglia in Relation to Cortico-Basal Ganglia-Thalamo-Cortical Loops and their Dopaminergic Afferents 429
A. Internal Circuitry of Basal Ganglia Could Aid Selection 430
B. Basal Ganglia Can Compress Information Aiding Selection 430
C. Dopamine Can Modulate Selection Mechanisms within the Basal Ganglia 430
VI. Comparison of Functional Connections of Pedunculopontine Tegmental Nucleus and Superior Colliculus with Basal Ganglia and Midbrain Dopamine Neurons 431
A. Why are there Subcortical Connections with the Basal Ganglia? 431
B. How might the Input from Subcortical Structures to the Basal Ganglia Function? 431
C. How might the Output from the Basal Ganglia to Subcortical Structures Function? 432
D. Subcortical-Basal Ganglia Connections within a Heterarchical Layered Network 432
VII. Conclusions 433
References 433
Chapter 24. Integrative Networks Across Basal Ganglia Circuits 436
I. Introduction 436
II. Parallel Processing 437
A. Functional Organization of Frontal Cortex 437
B. General Topography of Cortico-Striatal Projections 437
C. General Topography of Thalamo-Striatal Projections 438
D. Pathways Through the Basal Ganglia and Back to Cortex 439
III. Integrative Pathways 440
A. Cortico-Striatal Connections 440
B. Integration Through Connections of the Pallidum 443
C. The Striato-Nigro-Striatal Projection System 444
D. The Place of the Thalamus in Basal Ganglia Circuitry 448
IV. Functional Considerations 449
Abbreviations 450
References 450
Chapter 25. Synchronous Activity in Basal Ganglia Circuits 456
I. Introduction 456
II. Testing Predictions of the Rate-Based Model: Effects of Increased Dopamine Receptor Stimulation 456
III. Testing Predictions of the Rate-Based Model: Effects of Dopamine Loss 457
IV. Synchronous Firing Patterns in Basal Ganglia Circuits 458
A. Multisecond Oscillations 459
B. 1 Hz Oscillations 460
C. 4–30 Hz Oscillations 463
D. Gamma Frequency Oscillations 463
V. Conclusions 463
References 465
Part E: Molecular Signaling in the Basal Ganglia 472
Chapter 26. Second-Messenger Cascades 474
I. Introduction 474
II. Second-Messenger Pathways 475
A. G-Protein-Coupled Receptors 475
B. Ionotropic Receptors 481
C. Ca[sup(2+)] Signaling 482
D. Ras/MAP Kinase Signaling 484
III. Conclusions and Outlook 485
References 485
Chapter 27. Neurotransmitter Regulation of Basal Ganglia Gene Expression 488
I. Introduction 488
II. Regulation by Glutamate 490
A. & #945
B. N-Methyl-D-aspartate (NMDA) Receptors 492
C. Metabotropic Glutamate Receptors 495
III. Regulation by Dopamine 496
A. D1 Receptors 496
B. D2 Receptors 498
C. "D1–D2 Receptor Synergy" 498
D. Gene Expression in the Globus Pallidus 499
IV. Regulation by Adenosine 500
A. A1 Receptors 500
B. A2a Receptors 500
C. A1–A2a Receptor Interactions 501
D. Gene Expression in the Globus Pallidus 501
V. Regulation by Acetylcholine 501
A. Muscarinic Receptors 501
B. Nicotinic Receptors 502
VI. Regulation by Serotonin 502
A. 5-HT[sub(1)] Receptors 503
B. 5-HT[sub(2)] Receptors 503
C. 5-HT[sub(3)] Receptors 503
D. 5-HT[sub(4)] Receptors 504
E. 5-HT[sub(6)] Receptors 504
F. 5-HT[sub(7)] Receptors 504
VII. Regulation by Neuropeptides 504
A. Opioids 504
B. Tachykinins 507
C. Neurotensin 507
References 508
Chapter 28. D1 Dopamine Receptor Supersensitivity in the Dopamine-Depleted Striatum: Aberrant ERK1/2 Signaling 518
I. Introduction: D1 and D2 Dopamine Receptors in Direct and Indirect Striatal Projections 518
II. Dopamine Receptor Supersensitivity in Parkinson's Disease 520
III. Aberrant Activation of ERK1/2 Involving Serotonin 5-HT2 Receptors in the Dorsal Striatum 521
IV. Functional Significance of Aberrant Activation of ERK1/2 in Direct Pathway Neurons 524
References 526
Chapter 29. Psychostimulant-Induced Gene Regulation in Corticostriatal Circuits 528
I. Introduction 528
II. Gene Regulation in the Striatum Occurs Mostly in Direct Pathway Neurons and is Mediated by D1 Dopamine Receptors 530
Box 29.1 Role of Cortical Activity in Striatal Gene Regulation – Effect of Context 531
III. Neuroadaptations After Repeated Psychostimulant Treatments 532
A. Increased Dynorphin Expression 532
Box 29.2 Opioid Peptides as Negative Feedback Mechanisms that Regulate Striatal Output 533
B. Blunted Gene Inducibility 534
C. Alternative Splicing: Accumulation of deltaFosB 535
IV. Topography of Psychostimulant-Induced Gene Regulation: Sensorimotor Corticostriatal Circuits are Mostly Affected 536
A. Mapping of Striatal Gene Regulation 536
Box 29.3 Mapping of Affected Functional Domains in the Striatum 537
B. Relationship Between Cortical and Striatal Gene Regulation 539
V. Functional Consequences of Psychostimulant-Induced Molecular Changes in the Striatum 540
A. Behavioral Stereotypies 540
B. Effects of Psychostimulants on Procedural Learning – Role in Addiction? 541
Box 29.4 Effects of Cocaine on Procedural Learning in a Motor-Skill Paradigm 542
C. Facilitatory Role of Serotonin in Striatal Gene Regulation: Possible Clinical Implications 543
VI. Summary and Conclusions 544
Acknowledgments 545
References 545
Chapter 30. Chromatin Remodeling: Role in Neuropathologies of the Basal Ganglia 554
I. Introduction 554
II. Chromatin Remodeling and Histone Modifications 555
A. Histone Acetylation 556
B. Histone Phosphorylation 559
C. Histone Methylation 562
III. Chromatin Remodeling and Striatal Dysfunctions 562
A. Chromatin Remodeling in Drug Addiction 562
B. Chromatin Remodeling in Human Neurological Disease 564
IV. Conclusions 566
References 566
Part F: Basal Ganglia Function and Dysfunction 574
Chapter 31. Phasic Dopamine Signaling and Basal Ganglia Function 576
I. Introduction 576
II. Selection: A Fundamental Problem 576
III. Reinforcement Learning 577
IV. Role of Dopamine in Reinforcement Learning 578
A. Phasic Dopamine Signaling 578
B. Inconvenient Observations 579
C. The Reinforcing Function of Phasic Dopamine: Reward Prediction? 580
D. An Alternative Proposal: Reinforcement of Agency Assessment 580
V. The Agency Hypothesis 581
A. A Neural Network for Determining Agency 581
B. Signal Timing and the Determination of Agency 582
C. Aversive Stimuli and Failures of Predicted Reward 582
D. Why are Short-Latency Dopamine Reinforcement Signals so Short? 583
VI. Summary and Conclusions 584
Acknowledgments 584
References 584
Chapter 32. Role of Basal Ganglia in Habit Learning and Memory: Rats, Monkeys, and Humans 588
I. Introduction 588
II. Evidence from Rat Studies 588
III. Evidence from Monkey Studies 591
IV. Evidence from Human Studies 592
V. Conclusions, Modifications, and Implications 593
References 594
Chapter 33. Drug Addiction: the Neural and Psychological Basis of a Compulsive Incentive Habit 598
I. Introduction 598
II. Drug Addiction: A Neuropsychiatric Disorder Dependent Upon the Basal Ganglia and their Cortical Inputs 599
III. Neurophysiological Mapping of the Consequences of Psychostimulant Exposure in the Basal Ganglia 600
IV. Drug Reinforcement: A Mechanism Dependent upon Ventral Cortico-Striato-Pallidal Loops 600
A. From Reward to Reinforcement, the Dopamine Hypothesis 600
B. From Positive to Negative Reinforcement: Reduced Striatal Dopamine Transmission and Beyond 601
C. Neurochemical Sensitization of Striatal Dopamine Transmission by Repeated Exposure to Psychostimulants 602
V. Striatal-Dependent Pavlovian and Instrumental Learning Mechanisms in the Development of Drug Addiction 603
A. Instrumental Learning Processes: the Acquisition of Drug Taking Behavior 603
B. Goal-Directed and Habitual Drug Seeking Behavior 603
C. Pavlovian Conditioning: the Establishment of Drug "Cues" 604
D. Conditioned Approach 604
E. Pavlovian-to-Instrumental Transfer 605
F. Conditioned Reinforcement 605
VI. Cellular and Molecular Substrates of Drug Addiction: Role of Corticostriatal Mechanisms 607
A. Psychostimulant-Induced Plasticity in the Corticostriatal Circuitry: When Addictive Drugs Usurp Basal Ganglia-Dependent Learning Mechanisms, such as Striatal LTP and LTD 607
B. Psychostimulant-Induced Molecular Adaptations within the Basal Ganglia: Implications for Drug Addiction 608
VII. Towards an Understanding of Psychostimulant Addiction: Dysregulation of Corticostriatal Circuitry and Incentive Habits 610
A. Parallel Mechanisms 610
B. Integrative Mechanisms 610
C. Addiction: Towards the View of an Incentive Habit 612
D. Top–down Inhibitory or "Executive" Control 612
Acknowledgments 613
References 613
Chapter 34. Parkinson's Disease: Cross-Talk Between Environmental Factors and Gene Defects 620
I. Introduction 620
II. Environmental Hypothesis of Parkinson's Disease 620
A. Toxin Exposure and Animal Models 620
B. Toxin Exposure and Human Susceptibility to PD 623
C. Toxins and Oxidative Stress 623
D. Inclusion Formation 624
Box 34.1 Lewy Bodies 625
III. Environmental Toxins and Inflammation 626
IV. Environmental Toxins and Genetic Vulnerability 627
Box 34.2 Parkinson's Disease Mutations 628
V. Summary and Conclusions 629
References 629
Chapter 35. Alterations in Corticostriatal Synaptic Function in Huntington's and Parkinson's Diseases 634
I. Introduction 634
II. Striatal Organization 635
A. Electrophysiological Properties of Striatal D1 and D2 Dopamine Receptor-Containing MSNs 635
B. Dopamine Functions in Striatum 636
C. Presynaptic Modulation of Striatal Glutamatergic Inputs by Dopamine 636
D. Other Receptors Regulating Glutamate Release in the Corticostriatal Pathway 636
III. The Corticostriatal Pathway in Huntington's Disease 637
A. Genetic Mouse Models of HD 637
B. Biphasic Alterations in Glutamatergic Neurotransmission 639
C. Dopamine Receptor Modulation of Corticostriatal Transmission in HD 640
D. Consequences of Corticostriatal Pathway Dysfunction in HD 640
E. Some Unresolved Questions 641
IV. The Corticostriatal Pathway in Parkinson's Disease 641
A. Mouse Models of Parkinsonism 641
B. Alterations in Glutamatergic Neurotransmission and Dopamine Modulation 643
C. Comparison Between Dopamine-Depletion and Genetic Models of PD 644
D. Some Unresolved Questions 644
V. Conclusions 645
Acknowledgments 645
References 645
Chapter 36. Molecular Mechanisms of L-DOPA-Induced Dyskinesia 652
I. Introduction 652
II. Molecular and Cellular Changes Following Dopamine Denervation 653
A. Presynaptic Alterations 653
B. Postsynaptic Signal-Transduction Mechanisms 654
C. Structural and Synaptic Alterations in Striatal Microcircuits 655
III. Molecular and Cellular Changes Caused by L-Dopa Treatment 656
A. Signaling-Pathway Activation in Striatal Neurons 656
B. Altered Glutamate Receptor Function and Corticostriatal Synaptic Plasticity 657
C. Changes in Striatal Gene and Protein Expression: Hypothesis-Driven Studies 658
D. Changes in Striatal Gene and Protein Expression: Discovery-Based Studies 660
IV. System-Level Adaptations and Structural Plasticity in the Basal Ganglia 661
A. Increased Activity in Striatofugal GABAergic Pathways 661
B. Structural Plasticity 661
V. Concluding Remarks 662
References 662
Chapter 37. Compensatory Mechanisms in Experimental and Human Parkinsonism: Potential for New Therapies 668
I. Introduction 668
II. Overview of Compensation, Classic Concepts 669
III. Striatal Mechanisms 669
A. Pre- and Postsynaptic Changes in Dopaminergic Activity 669
B. Re-Innervation 671
C. Serotonin Compensation 672
D. Volume Transmission and Passive Stabilization 672
IV. Basal Ganglia-Mediated Compensation 672
V. Thalamo-Cortical-Mediated Compensation 674
VI. Dopamine Compensation Reappraised 675
VII. Conclusions – Compensation vs. Sensing Dopamine Depletion 676
Acknowledgments 676
References 676
Chapter 38. Pathological Synchrony of Basal Ganglia-Cortical Networks in the Systemic MPTP Primate Model of Parkinson's Disease 680
I. Introduction: Parkinson's Disease – Prevalence, Symptoms and Therapy 680
II. Anatomical and Physiological Organization of the Basal Ganglia 681
III. The MPTP Primate Model of Parkinson's Disease 681
IV. Excessive Synchrony and Oscillations in Parkinson's Disease 682
A. Results from Animal Models 682
B. Observations in Human Patients 683
V. How Might Excessive Synchrony Impair Basal Ganglia Processing? 683
VI. Conclusions and Future Directions 684
Acknowledgments 684
References 684
Chapter 39. Deep-Brain Stimulation for Neurologic and Psychiatric Disorders 686
I. Introduction 686
II. Basal Ganglia-Thalamocortical Circuits 687
A. Circuit Anatomy 687
B. Basal Ganglia Anatomy and Circuitry 687
C. Basal Ganglia Output 688
D. Normal Functions of the Motor Circuit 688
III. "Circuit Disorders" Involving the Basal Ganglia 690
A. Parkinsonism 690
B. Dystonia 691
IV. Deep-Brain Stimulation 692
A. Historical Aspects 692
B. Technical Aspects 693
C. Mechanism of Action 693
D. Ablation vs. DBS 694
V. DBS Treatment of Movement Disorders 694
A. Parkinson's Disease 694
B. Dystonia 696
VI. DBS Treatment of Other Hyperkinetic Disorders 697
A. Hemiballism 697
B. Huntington's Chorea 697
VII. DBS Treatment of Neuropsychiatric Disorders 697
A. Tourette's Syndrome 698
B. Obsessive Compulsive Disorder 699
C. Treatment-Resistant Depression 699
D. Lesch–Nyhan Disease 700
VIII. Conclusions 701
References 701
Index 710
A 710
B 710
C 711
D 712
E 713
F 713
G 714
H 714
I 714
K 714
L 715
M 715
N 715
O 716
P 716
Q 717
R 717
S 718
T 719
U 719
V 719
Y 720
Z 720
Color Plates 722