Handbook of Basal Ganglia Structure and Function

By Academic Press

Handbook of Basal Ganglia Structure and Function, Second Edition, offers an integrated overview of the structural and functional aspects of the basal ganglia, highlighting clinical relevance. The basal ganglia, a group of forebrain nuclei interconnected with the cerebral cortex, thalamus, and brainstem, are involved in numerous brain functions, such as motor control and learning, sensorimotor integration, reward, and cognition.

These nuclei are essential for normal brain function and behavior, and their importance is further emphasized by the numerous and diverse disorders associated with basal ganglia dysfunction, including Parkinson’s disease, Tourette’s syndrome, Huntington’s disease, obsessive-compulsive disorder, dystonia, and psychostimulant addiction.

This updated edition has been thoroughly revised to provide the most up-to-date account of this critical brain structure. Edited and authored by internationally acclaimed basal ganglia researchers, the new edition contains ten entirely new chapters that offer expanded coverage of anatomy and physiology, detailed accounts of recent advances in cellular/molecular mechanisms and cellular/physiological mechanisms, and critical, deeper insights into the behavioral and clinical aspects of basal ganglia function and dysfunction.

• Synthesizes widely dispersed information on the behavioral neurobiology of the basal ganglia, including advances in the understanding of anatomy, cellular/molecular and cellular/physiological mechanisms, and behavioral and clinical aspects of function and dysfunction
• Written by international authors who are preeminent researchers in the field
• Explores, in full, the clinically relevant impact of the basal ganglia on various psychiatric and neurological diseases

• Language: English
• Publisher: Academic Press
• Release date: Sep 15, 2016
• ISBN: 9780128025260

Book preview

Handbook of Basal Ganglia Structure and Function, Second Edition

24C

Heinz Steiner

Kuei Y.Tseng

Department of Cellular and Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, USA

Table of Contents

Cover image

Title page

Copyright

Dedication

List of Contributors

Preface

References

Acknowledgments

List of Abbreviations

Part A. The Basal Ganglia System and Its Evolution

Chapter 1. The Neuroanatomical Organization of the Basal Ganglia

I Introduction

II Overview of Basal Ganglia Organization

III The Corticostriatal System

IV Striatum

V Output Systems of the Striatum

VI Basal Ganglia Output Nuclei: GPi and Substantia Nigra

VII The Nigrostriatal Dopamine System

VIII Striatal Patch–Matrix Compartments

IX Summary

References

Chapter 2. The History of the Basal Ganglia: The Nuclei

I Introduction

II The Core Structures of the Basal Ganglia: Striatum and Pallidum

III Two Control Structures of the Basal Ganglia

IV Conclusion

References

Chapter 3. The History of the Basal Ganglia: Cells and Circuits

I Introduction

II Ramon y Cajal's Basal Ganglia

III Unification

IV Spiny-Cell Revolution

V The Electro-Anatomists

VI The Indirect Pathway

VII The Dopamine Connection

VIII Recurrent Striatopetal Pathways

IX Are We There Yet?

References

Chapter 4. The Conservative Evolution of the Vertebrate Basal Ganglia

I Introduction

II Basal Ganglia in Anamniotes

III Basal Ganglia in Amniotes

Acknowledgments

References

Chapter 5. Cell Types in the Different Nuclei of the Basal Ganglia

I Introduction

II Projection Neurons in the Different Nuclei of the Basal Ganglia

III Interneurons in the Nuclei of the Basal Ganglia

IV Absolute Numbers of Neurons in the Basal Ganglia: Functional Implications

V Glial Cell Types in the Different Nuclei

VI Conclusion: the Past and the Next 10–15 Years

Acknowledgments

References

Part B. Anatomy and Physiology of the Striatum

Chapter 6. The Striatal Skeleton: Medium Spiny Projection Neurons and Their Lateral Connections

I The Medium-Sized Spiny Projection Neuron

II Anatomical Connectivity of the Striatal Skeleton

III Synaptic Physiology of Lateral Interactions

IV Functional Implications, Models, and Outlook

V Further Reading

Acknowledgments

References

Chapter 7. The Cholinergic Interneuron of the Striatum

I Introduction

II Autonomous Firing Patterns in Cholinergic Interneurons

III The Cholinergic Interneurons Are TANs in the Striatum

IV Inputs to Striatal Cholinergic Interneurons

V Influence of the Cholinergic Interneuron on the Striatal Network

VI Cholinergic Interneurons Co-release Glutamate and Induce Di-synaptic Release of Various Neurotransmitters

VII Summary and Conclusions

References

Chapter 8. GABAergic Interneurons of the Striatum

I Introduction

II Theoretical Issues: What Constitutes a Cell Type?

III PV-Immunoreactive Interneurons

IV NPY Interneurons

V NPY-Neurogliaform Interneurons

VI Striatal Tyrosine Hydroxylase Interneurons

VII Fast Adapting Interneurons

VIII Calretinin Interneurons

IX Recurrent Interneurons

X Functional Considerations

XI Summary and Conclusions

Acknowledgments

References

Chapter 9. Dopaminergic Modulation of Glutamatergic Signaling in Striatal Spiny Projection Neurons

I Introduction

II Acute Dopaminergic Modulation of Excitability in Striatal Direct-Pathway Neurons

III Acute Dopaminergic Modulation of Excitability in Striatal Indirect-Pathway Neurons

IV LTD at Glutamatergic Synapses on Striatal Projection Neurons

V LTP at Glutamatergic Synapses on Striatal Projection Neurons

VI An Indirect Player—ChIs

VII Homeostatic Plasticity in Striatal Circuitry in PD Models

VIII Conclusions

Acknowledgments

References

Chapter 10. Endocannabinoid Signaling in the Striatum

I Introduction to the Endocannabinoid System

II The Endocannabinoid System in the Striatum

III CB1 Receptor Function in the Striatum

IV Conclusion

References

Chapter 11. Nitric Oxide Signaling in the Striatum

I Introduction

II Afferent Regulation of Striatal NO Synthesis

III Effects of NO Signaling on Neurotransmitter Release

IV Regulation of Striatal Neuron Activity and Output by NO Signaling

V Role of Striatal NO-sGC Signaling in Motor Behavior

VI Impact of DA Depletion on Striatal NO-sGC Signaling

Acknowledgments

References

Chapter 12. Role of Adenosine in the Basal Ganglia

I The Adenosine System: Adenosine Receptor Localization and Function

II Adenosine Receptor Interactions

III A2A Receptors in Models of Parkinson's Disease

IV Adenosine A2A–DA Interactions: Behavioral Studies in Models of PD

V Clinical Trials With Adenosine A2A Receptor Antagonists in PD Patients

VI Adenosine A2A Receptors in Huntington's Disease

VII Neuroprotective Potential of A2A Receptor Antagonists

VIII Adenosine Receptors and Modulation of Cognitive Processes

IX Conclusions

References

Part C. Anatomy and Physiology of Globus Pallidus, Subthalamic Nucleus, and Substantia Nigra

Chapter 13. Organization of the Globus Pallidus

I Introduction

II Major Afferent Projections and Functional Territories of the GPe and GPi

III Subtypes and Efferent Projections of GPe Neurons

IV Physiological Properties and Subtypes of GPe Neurons

V Efferent Projections of GPi

VI Morphological and Physiological Properties of GPi Neurons

VII Functional Considerations

Acknowledgments

References

Chapter 14. The Subthalamic Nucleus

I Introduction

II Intrinsic Properties of STN Neurons

III Synaptic Inputs to STN Neurons

IV Synaptic Integration in STN Neurons

V Synaptic Outputs of STN Neurons

VI Normal Activity Patterns and Functions of the STN

VII Abnormal Activity Patterns and Dysfunction of the STN

VIII Future Directions

Acknowledgments

References

Chapter 15. The Substantia Nigra Pars Reticulata

I Introduction

II Neurocytology

III General Neurophysiological Characteristics of SNr Gaba Projection Neurons

IV Intrinsic Ion Channels Critical to the Sustained Autonomous High Frequency Firing in SNr Gaba Neurons

V Synaptic Inputs to SNr Gaba Projection Neurons and Their Regulation

VI Synaptic Outputs from SNr Gaba Projection Neurons and Their Functions

VII Summary and Conclusions

References

Chapter 16. Subtypes of Midbrain Dopamine Neurons

I Introduction

II Origin and Characterization of the Subtypes of Midbrain DA Neurons

III Conclusions

References

Chapter 17. Neurophysiology of Substantia Nigra Dopamine Neurons: Modulation by GABA and Glutamate

I Introduction

II Neurocytology of Nigrostriatal DA Neurons

III Electrophysiological Properties of Nigrostriatal DA Neurons

IV Neuroanatomy of GABAergic Afferents to Nigral DA Neurons

V Neurophysiology of GABAergic Afferents

VI Glutamate Afferents to Nigral DA Neurons

VII Concluding Remarks

Acknowledgments

References

Chapter 18. Plasticity in Dopamine Neurons

I Plasticity as a Substrate for Learning Associations

II Synaptic Plasticity in Dopamine Neurons

III Intrinsic Plasticity in Dopamine Neurons

IV Input-Specific Plasticity

V Conclusion

Acknowledgments

References

Chapter 19. Regulation of Extracellular Dopamine: Release and Uptake

I Regulation of Dopamine Release

II DA Uptake

III Relationship Between DA Neuron Firing and Extracellular DA

IV Summary and Conclusions

Acknowledgments

References

Part D. Network Integration

Chapter 20. Organization of Corticostriatal Projection Neuron Types

I Introduction

II Cortical Projections to Basal Ganglia—Historical Overview

III Corticostriatal Neurons: IT-Types Versus PT-Types

IV Ultrastructure of Cortical Input to Striatum

V Differential Input of Cortex to Striatal Neurons

VI Comparison to Other Studies on Cortical Input to MSN Types

VII Functional Considerations

Acknowledgments

References

Chapter 21. Organization of Prefrontal-Striatal Connections

I Prefrontal Cortex-Basal Ganglia Circuits

II Relationships of the Prefrontal Cortical-Striatal Projections With the Compartmental Structure of the Striatum

III Cortico-Cortical and Corticostriatal Relationships

IV Relationships of the Prefrontal-Corticostriatal Topography With Other Striatal Inputs

V Medium-Sized Spiny Projection Neurons: Integrators of Striatal Inputs

VI Conclusions

References

Chapter 22. Gating of Cortical Input Through the Striatum

I Introduction

II The Mechanisms of Gating

III The Significance of Up-States

IV Concluding Remarks

References

Chapter 23. Regulation of Corticostriatal Synaptic Plasticity in Physiological and Pathological Conditions

I Introduction

II Physiological and Pharmacological Characterization of Corticostriatal LTD and LTP

III Synaptic Depotentiation at Corticostriatal Synapses: A Mechanism of Physiological Forgetting?

IV Other Forms of Synaptic Plasticity

V Corticostriatal Synaptic Plasticity in Experimental Models of Parkinson's Disease

VI Corticostriatal Synaptic Plasticity in Experimental Models of Hyperkinetic Disorders

VII Striatal Synaptic Plasticity and Neuronal Ischemia

VIII Conclusions and Future Perspectives

References

Chapter 24. The Thalamostriatal Systems in Normal and Disease States

I Introduction

II Dual Origin of the Thalamostriatal Systems: CM/Pf and Other Thalamic Nuclei

III Differences Between Thalamostriatal and Corticostriatal Systems

IV Physiology of the Thalamostriatal Systems

V Behavioral Functions of the CM/Pf-Striatal System

VI CM/Pf Neuronal Loss in Neurodegenerative Diseases

VII The CM/Pf as a Target for Neurosurgical Interventions in Brain Disorders

VIII Conclusion

References

Chapter 25. The Tail of the Ventral Tegmental Area/Rostromedial Tegmental Nucleus: A Modulator of Midbrain Dopamine Systems

I Introduction

II The tVTA/RMTg in Responses to Drugs of Abuse

III The tVTA/RMTg in Avoidance Behaviors

IV The tVTA/RMTg in Reward Prediction

V Motor-Related Functions of the tVTA/RMTg

VI Conclusions

References

Chapter 26. The Rostromedial Tegmental Nucleus: Connections With the Basal Ganglia

I Introduction

II Neuroanatomy and Connections of the RMTg

III Focus on RMTg in Relation to the Basal Ganglia

IV Behavioral and Neuropsychiatric Implications

V Summary and Conclusions

Acknowledgments

References

Chapter 27. Integrative Networks Across Basal Ganglia Circuits

I Introduction

II Basal Ganglia Circuitry

III Integrative Pathways

IV Functional Considerations

References

Part E. Molecular Signaling in the Basal Ganglia

Chapter 28. Receptors and Second Messengers in the Basal Ganglia

I Introduction

II Receptors

III Second Messengers

IV Conclusions and Outlook

References

Chapter 29. Regulation of Striatal Signaling by Protein Phosphatases

I Introduction

II MSNs Express Specific Sets of Signaling Proteins

III Protein Phosphatases in MSNs

IV Striatal-Enriched Regulators of Ser/Thr Protein Phosphatases

V Conclusions: Integrated Regulation of Protein Phosphatases in MSNs

References

Chapter 30. Neurotransmitter Regulation of Striatal Gene Expression

I Introduction

II Regulation by Glutamate

III Regulation by Dopamine

IV Regulation by Adenosine

V Regulation by Acetylcholine

VI Regulation by Serotonin

VII Regulation by Neuropeptides

VIII Regulation by Neurotrophins

IX Conclusions

References

Chapter 31. Psychostimulant-Induced Gene Regulation in Striatal Circuits

I Introduction

II Mechanisms of Psychostimulant-Induced Gene Regulation in the Striatum

III Neuroadaptations After Repeated Psychostimulant Treatments

IV Topography of Psychostimulant-Induced Gene Regulation in the Striatum

V Behavioral Consequences of Striatal Gene Regulation and Potential Clinical Significance

VI Summary and Conclusions

Acknowledgments

References

Chapter 32. Epigenetics in Neuropathologies of the Basal Ganglia

I Introduction

II Molecular Mechanisms of Epigenetic Modulation

III Epigenetic Mechanisms in Drug Addiction

IV Epigenetic Mechanisms in L-DOPA-Induced Dyskinesia

V Epigenetic Dysregulation in Huntington's Disease

VI Epigenetic Dysregulation in Dentatorubral–Pallidoluysian Atrophy

VII Epigenetic Dysregulation in Myoclonus–Dystonia

VIII Summary and Conclusion

References

Part F. Basal Ganglia Function and Dysfunction

Chapter 33. Investigating Basal Ganglia Function With Cell-Type-Specific Manipulations

I Introduction

II Early Methods of Investigating the Organization and Function of the Basal Ganglia

III Inferring Function of Specific Cell Types Through Pharmacology and Dopamine Receptor Manipulation

IV New Technologies Enable New Insights

V Applying Cell-Type-Specific Manipulations to the Midbrain

VI Cell-Type-Specific Manipulations in the Striatum

VII Cell-Type-Specific Manipulations in Other Basal Ganglia Structures

VIII Observing the Activity of Specific Basal Ganglia Cell Types

IX Conclusion: Insights From Cell-Type-Specific Manipulations of the Basal Ganglia

References

Chapter 34. Phasic Dopamine Signaling in Action Selection and Reinforcement Learning

I Introduction

II Selection: A Fundamental Problem

III Reinforcement Learning

IV Role of DA in Reinforcement Learning

V The Agency Hypothesis

VI Summary and Conclusions

Acknowledgments

References

Chapter 35. Memory Systems of the Basal Ganglia

I Introduction

II Mnemonic Function of the DLS

III Mnemonic Function of the DMS

IV Mnemonic Function of the Nucleus Accumbens

V Conclusions

References

Chapter 36. Abnormal Activities in Cortico-Basal Ganglia Circuits in Movement Disorders

I Introduction

II Testing Predictions of the Rate-Based Model

III Synchronous Firing Patterns in Basal Ganglia Circuits

IV Conclusions

References

Chapter 37. Morphological Plasticity in the Striatum Associated With Dopamine Dysfunction

I Introduction

II Role of Dopamine in Dendritic Spine Formation

III Morphological Changes in PD and in Animals Models of PD

IV L-DOPA-Induced Morphological Plasticity

V Morphological Changes in Drug Abuse and Addiction

VI Concluding Remarks

References

Chapter 38. Neuroinflammation in Movement Disorders

I Introduction

II Inflammatory Component in Movement Disorders and Aging

III PD as a Paradigm

IV Neuroinflammation and Huntington's Disease

V The Inflammatory Factor in Other Movement Disorders

VI Therapeutic Perspectives Targeting Inflammation to Avert Movement Disorders

Acknowledgments

References

Chapter 39. Disease-Associated Changes in the Striosome and Matrix Compartments of the Dorsal Striatum

I Introduction

II Compulsive Behavior Disorders

III Dystonia

IV Huntington's Disease

V Summary

Acknowledgments

References

Chapter 40. Etiology and Progression of Parkinson's Disease: Cross-Talk Between Environmental Factors and Genetic Vulnerability

I Introduction

II Environmental Hypothesis of Parkinson's Disease

III Environmental Toxins and Inflammation

IV Routes of Environmental Exposure and the Pathogenesis of Parkinson's Disease

V Environmental Toxins and Genetic Vulnerability

VI Summary and Conclusions

Acknowledgments

References

Chapter 41. Determinants of Selective Vulnerability of Dopamine Neurons in Parkinson's Disease

I Introduction

II Does Dopamine Drive Pathogenesis?

III Does the Selective Vulnerability of DA Neurons in the SNc Arise from Their Structure?

IV Are SNc DA Neurons Worked to Death?

V Are SNc DA Neurons Murdered by Their Colleagues?

VI Are Mitochondria the Convergence Point of Mechanisms Governing Selective Vulnerability?

VII What are the Prospects for a Neuroprotective Therapy in Parkinson's Disease?

References

Chapter 42. Parkinson's Disease: Genetics

I Introduction

II Autosomal-Dominant Forms of Inherited Parkinson's Disease

III Autosomal-Recessive, Early-Onset Typical Parkinsonism

IV Autosomal-Recessive, Juvenile Atypical Parkinsonism

V Associated Genes (Risk Factors)

VI Implications for Basic Research and Therapeutics

VII Summary and Conclusions

References

Chapter 43. Molecular Mechanisms of L-DOPA-Induced Dyskinesia

I Introduction

II Molecular and Cellular Changes Following DA Denervation

III Molecular and Cellular Changes Caused by L-DOPA Treatment

IV The Cortical-Basal Ganglia Network in LID

V Additional Mechanisms and Concluding Remarks

References

Chapter 44. Cell Therapy in Parkinson's Disease: Understanding the Challenge

I Overview

II Studies in Animal Models

III Clinical Trials of Dopamine Neuron Transplantation

IV A Brief History of Lessons Learned

V Stem Cells in the Future of Cell Therapy for Parkinson's Disease

VI Moving Forward: Implications of Basal Ganglia Basics for Cell Therapy

VII Cell Therapy: Lessons from the Levodopa Story

References

Chapter 45. Cellular and Molecular Mechanisms of Neuronal Dysfunction in Huntington's Disease

I Introduction

II Transcriptional Dysregulation in Huntington's Disease

III Mitochondrial Dysfunctions and Energy Deficits in Huntington's Disease

IV Lack of Trophic Support

V Alterations of Striatal Signaling and Excitotoxicity in Huntington's Disease

VI Striatal Vulnerability: The Dopamine Hypothesis

VII Dysregulation of Cholesterol Metabolism in Huntington's Disease

VIII Summary and Conclusion

References

Chapter 46. Alterations of Synaptic Function in Huntington's Disease

I Introduction

II Huntington's Disease

III Animal Models of Huntington's Disease

IV Striatal Circuits

V Glutamate Neurotransmission in Huntington's Disease

VI GABA Neurotransmission in Huntington's Disease

VII Dopaminergic Alterations in Huntington's Disease

VIII Conclusions

Acknowledgments

References

Chapter 47. Pathophysiology of Dystonia

I Introduction

II The Anatomical and Clinical Framework of Dystonia

III Linking Striatal Dysfunction to Dystonia

IV The Microcircuitry of Dystonia

V The Role of Other Brain Regions: The Cerebellar Circuitry and the Network Disease

VI Conclusions

References

Chapter 48. Tourette Syndrome and Tic Disorders

I Introduction

II Clinical Overview

III Neuroanatomy

IV Neurophysiology

V Neurochemistry

VI Neuroimmunology

VII Animal Models

VIII Conclusions

References

Chapter 49. Deep-Brain Stimulation for Neurologic and Neuropsychiatric Disorders

I Introduction

II Basal Ganglia–Thalamocortical Circuits and Associated Disorders

III General Aspects of DBS

IV DBS Treatment of Movement Disorders

V DBS Treatment of Neuropsychiatric Disorders

VI Future Developments

VII Conclusion

References

Index

Copyright

Dedication

List of Contributors

Preface

The basal ganglia are a group of forebrain nuclei that are interconnected with the cerebral cortex, thalamus, and brainstem. Since the first anatomical description of its biggest component, the corpus striatum, in 1664 by the English anatomist Thomas Willis, the modern view of the basal ganglia system was slow in arising. For more than 250 years, the term corpus striatum (striated body, for the many passing fiber bundles) stood for a set of subcortical nuclei, including some that were eventually found to be functionally unrelated. The principal parts of the corpus striatum comprised the caudate nucleus and the lenticular nucleus (nucleus lentiformis, named for its lens-shape), which itself consisted of the putamen and the external and internal segments of the globus pallidus. Other nuclei, such as the substantia nigra (locus niger crurum cerebri, discovered by Vicq d’Azyr, 1784; termed substantia nigra by Soemmerring, 1792) and the subthalamic nucleus (body of Luys; Luys, 1865) were included in the functional organization of the basal ganglia only after the introduction of tract tracing techniques in the 1960s (see chapter: The History of the Basal Ganglia: The Nuclei in this Volume).

Willis (1664) was the first to consider the corpus striatum as an important brain structure related to sensory and motor functions due to its anatomical proximity to prominent ascending and descending fiber bundles. However, the role of the corpus striatum was obscured for another 100–200 years because anatomists and neurologists of the 18th and 19th centuries turned their attention toward the cerebral cortex and cerebellum. A turning point in the history of the basal ganglia was reached at the beginning of the 20th century with the publication of several pathophysiological reports showing that brain lesions involving the corpus striatum resulted in movement disorders (eg, Wilson, 1912; Vogt and Vogt, 1920). These findings returned attention to the basal ganglia, which then began to gain importance once again. Modern basal ganglia terminology such as striatum (for caudate nucleus and putamen) and pallidum was introduced by Cécile and Oskar Vogt (1941) in their attempt to simplify forebrain anatomical nomenclature.

Two major expansions of scientific knowledge that propelled the basal ganglia to the prominence they hold today occurred decades later (see chapter: The History of the Basal Ganglia: Cells and Circuits). The first was the result of a revolution in neuroanatomical methodologies that included the development of tract tracing techniques to delineate neuronal pathways and connections, and of histochemical methods to localize neurotransmitters, enzymes, and receptor binding sites. The second expansion was enabled by the advances in neurophysiological recording techniques that went hand in hand with the molecular revolution that swept the biological sciences during the last decade of the 20th century. These innovations, together with the 21st century development of optogenetic and chemogenetic techniques (see chapter: Investigating Basal Ganglia Function With Cell-Type-Specific Manipulations), further clarified the molecular and functional characteristics of individual neuron types and their interactions in basal ganglia circuits and related networks. From a mere 23-line paragraph in an exemplary early review 200 years ago (Bell, The anatomy of the human body, Vol 3: Nervous System, 1809), our knowledge on basal ganglia structure and function has expanded to the volume at hand.

The present volume provides and integrates basal ganglia knowledge from molecular to systems to clinical levels. Part A presents an overview over the neuroanatomical organization of the basal ganglia, offering the general organizational principles and cell types and serving as a guide and reference tool for the remainder of the book. Part A also includes historical accounts on the discovery of the basal ganglia and an overview over the evolution of this brain system. Part B provides chapters on anatomical and physiological aspects of the striatum, including reviews of the various neuronal types and the regulation of striatal activity by the different neurotransmitter and neuromodulator systems. Part C addresses anatomy and physiology of the other basal ganglia nuclei, globus pallidus, subthalamic nucleus, and substantia nigra, including their cellular composition, neurotransmitters, and connections. Part D provides reviews on the network integration of the basal ganglia, especially on the organization of the connections with cortex, thalamus, and other brain regions. Part D also contains two complementary reviews of a newly discovered afferent structure and regulator of midbrain dopamine neurons, the rostromedial tegmental nucleus. Part E offers accounts of advances in second-messenger signaling and gene regulation by neurotransmitter receptors in the basal ganglia, with an emphasis on the striatum. Part F provides reviews on various aspects of basal ganglia function and dysfunction. These include chapters on dopamine function, learning and memory processes, and neuroinflammation, as well as papers addressing the role of the basal ganglia in movement disorders (eg, Parkinson's disease, Huntington's disease, dyskinesia, dystonia, Tourette syndrome, and tics) and the utility of deep-brain stimulation and other advances in the treatment of such disorders.

References

1. Vogt C, Vogt O. Zur Lehre der Erkrankungen des striären Systems. J Psychol Neurol (Leipzig). 1920;25:631–659.

2. Vogt C, Vogt O. Thalamusstudien I-III. J Psychol Neurol. 1941;50:31–154.

3. Willis T. Cerebri anatome cui accessit nervorum descriptio et usus London: Martyn & Allestry; 1664.

4. Wilson SAK. Progressive lenticular degeneration: A familial nervous disease associated with cirrhosis of the liver. Brain. 1912;34:295–507.

Acknowledgments

We are again grateful for the enthusiasm and willingness to contribute a chapter shown by so many of our colleagues in the field of basal ganglia research. Most contributors also served as expert reviewers for chapters. In addition, we thank the following reviewers for their valuable criticisms and suggestions: N.S. Bamford, M. Benoit-Marand, J.D. Berke, E. Brouillet, C.S. Chan, J.F. Cheer, A.Y. Deutch, A. Gonzalez Gallegos, A.J. Gruber, P. Gubellini, A. Leblois, M.K. Lobo, P.R. Lowenstein, P.J. Magill, N. Mallet, M. Mameli, F.P. Manfredsson, M. Marinelli, J.E. McCutcheon, D.S. McGehee, E.J. Nestler, F. Pedata, J.A. Potashkin, M.A. Schwarzschild, A. Sharrott, G. Silberberg, J.R. Sladek Jr., D.G. Standaert, E. Valjent, R.P. Vertes, J.Q. Wang, and J.A. Wolf.

We received tireless support from our Acquisition Editor, April Farr, and our Editorial Project Manager, Timothy Bennett, at Elsevier, and our editorial assistant, David Alter, at Chicago Medical School/Rosalind Franklin University of Medicine and Science. Last but not least, we would like to thank the Series Editor, Joseph P. Huston, for inviting us to prepare this expanded second edition of the handbook.

List of Abbreviations

Part A. The Basal Ganglia System and Its Evolution

Outline

Chapter 1 The Neuroanatomical Organization of the Basal Ganglia

Chapter 2 The History of the Basal Ganglia: The Nuclei

Chapter 3 The History of the Basal Ganglia: Cells and Circuits

Chapter 4 The Conservative Evolution of the Vertebrate Basal Ganglia

Chapter 5 Cell Types in the Different Nuclei of the Basal Ganglia

Chapter 1

The Neuroanatomical Organization of the Basal Ganglia

C.R. Gerfen¹ and J.P. Bolam²,    ¹Laboratory of Systems Neuroscience, National Institute of Mental Health, Bethesda, MD, United States,    ²MRC Anatomical Neuropharmacology Unit, Oxford University, Oxford, United Kingdom

The basal ganglia comprise a subcortical brain system through which the cerebral cortex affects behavior. The principal input structure is the striatum, whose GABAergic medium spiny neurons (MSNs) are the target of excitatory cortical and thalamic inputs. The output of the basal ganglia are GABAergic neurons in the internal segment of the globus pallidus and substantia nigra pars reticulata, which provide inhibition to the thalamus and midbrain motor areas including the superior colliculus and pedunculopontine nucleus. Activity in these output pathways is regulated by opponent effects of the two main MSN subtypes, those expressing the D1 dopamine receptor, which project directly to the output nuclei, and those expressing the D2 dopamine receptor, which project indirectly through the external segment of the globus pallidus and subthalamic nucleus. In addition, the striatum is organized into patch and matrix compartments, which differentially regulate substantia nigra pars compacta dopamine neurons and GABAergic output pathways.

Keywords

Cortex; striatum; globus pallidus; substantia nigra; subthalamic nucleus; thalamus; dopamine; GABA; medium spiny neuron; cholinergic interneuron

Outline

I. Introduction 3

II. Overview of Basal Ganglia Organization 5

III. The Corticostriatal System 6

A. Subtypes of Corticostriatal Neurons 7

B. Organization Patterns of Corticostriatal Afferents 8

IV. Striatum 9

A. Medium Spiny Projection Neurons 9

B. Synaptic Inputs to Medium Spiny Neurons 9

C. Striatal Interneurons 12

V. Output Systems of the Striatum 13

A. The Direct and Indirect Pathways 13

B. Other Nuclei of the Indirect Pathway 16

C. Dual Projections Within Basal Ganglia Circuits 18

VI. Basal Ganglia Output Nuclei: GPi and Substantia Nigra 19

A. Cell Types 20

B. Inputs 20

C. Outputs 20

VII. The Nigrostriatal Dopamine System 21

A. Dorsal Tier Versus Ventral Tier Dopamine Neurons 21

B. Inputs to Dopamine Neurons 23

VIII. Striatal Patch–Matrix Compartments 23

A. Cortical Inputs 23

B. Thalamic Inputs 24

C. Striatal Outputs 24

D. General Patch–Matrix Organization 26

IX. Summary 26

References 27

I Introduction

The basal ganglia connect the cerebral cortex with neuronal systems that transform activity in the cortex into directed behavior. Functions attributed to the basal ganglia include motor learning, habit formation, and the selection of actions based on desirable outcomes (Cisek and Kalaska, 2010; Graybiel et al., 1994; Hikosaka et al., 2000; Mink, 1996; Redgrave et al., 1999; Wichmann and DeLong, 2003; Yin and Knowlton, 2006). Most cortical areas provide inputs to the basal ganglia, which in turn provide outputs to brain systems that are involved in the generation of behavior. Among the behavior effector systems targeted are thalamic nuclei that project to those frontal cortical areas involved in the planning and execution of movement; midbrain regions including the superior colliculus, which contributes to the generation of eye movements; the pedunculopontine nucleus, which is involved in orienting movements; and hypothalamic systems associated with autonomic functions.

Two points concerning the function of the basal ganglia are emphasized. First, while the basal ganglia connect the cerebral cortex with a wide range of behavior effector systems, the basal ganglia operate in parallel with other output systems of the cerebral cortex. These other corticofugal systems may have a more primary role in the actual generation of behavior. For example, the frontal cortical areas involved in the planning and execution of movement behavior provide direct output, via direct corticospinal projections, that is responsible for the generation of movement. Thus, it remains unclear whether the basal ganglia should be thought of as playing a direct or modulatory role in specifying behavior. Second, while the basal ganglia are connected with a wide range of behavior effector systems, not all regions of the basal ganglia are connected with all of the output systems. In other words, there is a conservation of regional functional organization of the cerebral cortex in the connections of the basal ganglia. In considering the neuroanatomical organization of the basal ganglia, there are differing views. On the one hand, the basal ganglia have been proposed to provide for interactions between disparate functional circuits, for example, between the so-called limbic and nonlimbic functions. Another view holds that there are parallel functional circuits, in which distinct functions are for the most part maintained, or segregated, one from the other. This review is biased toward the view that there is maintenance of functional parallel circuits in the organization of the basal ganglia, with considerable interactions between adjacent circuits (see also chapter: Integrative Networks Across Basal Ganglia Circuits).

Most details of the neuroanatomical and neurophysiological organization of basal ganglia circuits have first been established in rodents and confirmed in primates. Accordingly, the present review is mainly based on studies in rodents (as are the schemes used to illustrate the organizational principles). Several of the following chapters provide detailed information on the functional organization of the primate basal ganglia. What are the most significant differences in the organization between rodents and other mammals, notably primates? The most obvious differences between rodents and primates are those involving the gross anatomy of the nuclei of the basal ganglia. There are two major examples. The first is the striatum, which in the primate is subdivided into caudate nucleus and putamen by the internal capsule that provides a structural separation between these two nuclei. This structural separation does provide a gross separation of functional regions in the striatum in that the caudate nucleus is mainly the target of prefrontal cortical inputs, whereas the putamen is the target of motor and somatosensory inputs. As the cortical input to the striatum is in a large part responsible for its function, the caudate nucleus and putamen in the primate are to a major extent functionally distinct. However, the internal capsule does not provide a precise divider of functional zones and there is some overlap of inputs from prefrontal cortex to the putamen. In the rodent, which lacks such a distinct structural separation, there are nonetheless regional differences in the striatum that are comparable to those of the caudate and putamen, again determined by the regional distribution of inputs from different cortical areas.

The second major gross anatomical difference between rats and primates involves the globus pallidus (GP) (see chapter: Organization of the Globus Pallidus). In primates, the internal segment of the globus pallidus (GPi) is situated immediately adjacent to the external segment (GPe), whereas in rodents, the homologous nucleus is separated from the GPe and is embedded in the fiber tract of the internal capsule. In rodents, this nucleus has historically been termed the entopeduncular nucleus, which reflects its location. However, as this nucleus is functionally comparable to the GPi in primates, this nomenclature, GPi, is adopted for the present volume. Both nuclei represent, along with the substantia nigra pars reticulata (SNr) (see chapter: The Substantia Nigra Pars Reticulata), which is nearly identical in both rodents and primates, the output structures of the basal ganglia.

Despite the gross anatomical differences noted, the major connectional organization of the basal ganglia in rodents and primates is remarkably similar. Three of the major features of basal ganglia organization that will be dealt with in some depth in this review, the organization of direct and indirect output pathways of the striatum, the patch–matrix compartmental organization of the striatum, and the dual projections of individual striatal neurons have been demonstrated in both rodents and primates, and appear, in the main, nearly identical in organization.

Differences in the organization of the basal ganglia between rodents and primates may for the most part be attributed to the expanded cortex in primates. In primates, cortical fields are considerably elaborated and more precisely defined in terms of functional segregation of different cortical areas. While the organization of corticostriatal patterns appears to follow the same general principles in rodents and primates, the elaboration of more detailed precise mapping patterns predominate in the primate. Thus, in summary, the major organizational principles of the basal ganglia appear for the most part nearly identical in rodents and primates.

II Overview of Basal Ganglia Organization

The organization of the basal ganglia is intimately linked to that of the cerebral cortex, with distinct differences between those regions of the basal ganglia that receive inputs from neocortical, six-layered cortex, compared with those receiving inputs from allocortical areas. This review focuses primarily on the neocortical part of the basal ganglia. A general canonical organizational plan of the neocortical-related basal ganglia is described in Fig. 1.1. The components of this canonical basal ganglia system include the neocortex, the striatum, which includes the caudate–putamen and the core of the nucleus accumbens, the GPe, the subthalamic nucleus (STN), the GPi, the SNr, and the substantia nigra pars compacta (SNc).

Figure 1.1 Diagram of basal ganglia circuits. (A) The striatum receives excitatory corticostriatal and thalamic inputs. Outputs of the basal ganglia arise from the GPi and the SNr, which are directed to the thalamus, superior colliculus, and pedunculopontine nucleus (PPN). The striatum has two output pathways. The direct pathway is formed by D1 dopamine receptor (Drd1a)-expressing medium spiny neurons (D1-MSNs) that project to the GPi and SNr output nuclei. The indirect pathway originates from D2 receptor (Drd2)-expressing MSNs (D2-MSNs) that project only to the GPe, which together with the STN connects to the basal output nuclei. The direct and indirect pathways provide opponent regulation of the basal ganglia output interface. (B) Fluorescent image of a sagittal brain section from a mouse expressing eGFP under the control of the Drd1a promoter shows D1-MSNs in the striatum that project axons through the GPe, which terminate in the GPi/SNr and to some degree in the GPe. (C) Fluorescent image of a sagittal section from a Drd2-eGFP mouse shows that labeled MSNs (D2-MSNs) provide axonal projections that terminate in the GPe, but do not extend to the GPi or SNr. Source: From Gerfen, C.R., Surmeier, D.J., 2011. Modulation of striatal projection systems by dopamine. Annu. Rev. Neurosci. 34, 441–466 (Gerfen and Surmeier, 2011).

The major input to this system comes from layer 5 glutamatergic neurons from nearly all areas of the neocortex. The output of this system is provided by the GABAergic projection neurons in the GPi and the SNr. These outputs target thalamic nuclei that project to frontal cortical areas involved in the planning and execution of movement behavior; the intralaminar thalamic nuclei, which provide inputs to the neocortex and the striatum; the intermediate layers of the superior colliculus, which are involved in the generation of eye and head movements; and the pedunculopontine nucleus, which is involved in orienting movements of the body. In between the cortical inputs and the GABAergic output systems are the neuroanatomical circuits that comprise the prototypical basal ganglia.

The main input structure of the basal ganglia is the striatum (see Part B). The regions of the striatum that receive inputs from neocortical areas are the caudate–putamen and core of the nucleus accumbens. The principal targets of the cortical input are medium-sized spiny GABAergic projection neurons (MSNs), which account for over 90% of neurons in the striatum (see chapter: The Striatal Skeleton: Medium Spiny Projection Neurons and Their Lateral Connections). These neurons are divided into two types, which give rise to the two main components of the prototypical basal ganglia circuit, the direct and indirect striatal output pathways (Fig. 1.1). The direct striatal projection system (called d-MSNs in some chapters) is so-named because these neurons provide direct inputs to the output neurons of the basal ganglia in the GPi and SNr. Indirect striatal projection neurons (i-MSNs) provide inputs to the GPe, which, together with the STN, comprises the main components of the indirect basal ganglia pathway. GABAergic neurons in the GPe (see chapter: Organization of the Globus Pallidus) project back to the striatum, to the output neurons of the basal ganglia in the GPi and SNr, and to the STN. The STN (see chapter: The Subthalamic Nucleus), which itself receives inputs from the neocortex, provides excitatory projections to the output neurons of the basal ganglia.

The cortex provides excitatory inputs to the striatum, which in turn, through the direct and indirect pathways, provides both inhibitory and excitatory regulation of the output of the basal ganglia. The output neurons of the basal ganglia, GABAergic neurons in the GPi and SNr, display a relatively high level of tonic activity (see chapters: Organization of the Globus Pallidus and The Substantia Nigra Pars Reticulata). In a long held model of basal ganglia function, excitatory input from the cortex has been demonstrated to function through a disinhibitory mechanism. Thus, activation of the direct output neurons of the striatum by the excitatory input from the cortex results in inhibition of the tonic inhibitory output of the basal ganglia. The role of the indirect pathway is more complex. On the one hand, the target of the indirect striatal output neurons are GABAergic neurons in the GPe, which project to the output neurons of the basal ganglia and to the STN. Thus, cortical excitation of the indirect pathway inhibits the GABAergic GPe output, resulting in disinhibition of the output neurons of the basal ganglia and the STN. The STN, which also receives direct excitatory inputs from the cerebral cortex, provides excitatory inputs to the output neurons of the basal ganglia. Additionally, it has been demonstrated that the interconnections between the GPe and STN generate an oscillatory pattern of activity that is conveyed to the output neurons of the basal ganglia. Given the complexities of the organization of these circuits at this time, the specific mechanisms responsible for regulating the output of the basal ganglia remain to be established. However, in general terms, the activity in the direct and indirect striatal output pathways may be viewed as providing counterbalanced or antagonistic regulation of the output of the basal ganglia.

Overlain on the canonical basal ganglia circuits discussed above are a number of additional neuroanatomical features that add to the complexity of the organization of this system. Notable among these is the dopaminergic nigrostriatal system, which provides a massive dopaminergic input to the striatum from the midbrain dopamine neurons in the ventral tegmental area and SNc (see chapters: Subtypes of Midbrain Dopamine Neurons and Neurophysiology of Substantia Nigra Dopamine Neurons: Modulation by GABA and Glutamate). In addition, this review describes the following features of basal ganglia organization: (1) the organization of the striatal system, which incorporates a general topographic organization with considerable overlap of corticostriatal inputs from cortical areas that are interconnected; (2) the patch and matrix compartmental organization of the striatum, which is related to the laminar organization of the cerebral cortex and provides differential inputs to the output systems of the basal ganglia and the nigrostriatal dopaminergic system (see chapter: Disease-Associated Changes in the Striosome and Matrix Compartments of the Dorsal Striatum); and (3) the dual representation of striatal outputs in the GPe and output nuclei of the basal ganglia.

III The Corticostriatal System

The striatum is the main input structure of the basal ganglia and the vast majority of its neurons are MSNs, whose activity is determined by excitatory inputs from the cerebral cortex and thalamus. Consequently, the information that striatal projection neurons transmit within the circuits of the basal ganglia is largely determined by the activity of corticostriatal (and thalamostriatal) inputs. Cortical neurons providing striatal inputs are located mostly in layer 5, and in some cases layer 3, of most cortical areas. All corticostriatal neurons are pyramidal neurons and utilize glutamate as a neurotransmitter. The following sections provide an overview of the corticostriatal system. More detailed information on specific aspects of this system is provided in chapters Organization of Corticostriatal Projection Neuron Types, Organization of Prefrontal–Striatal Connections, Gating of Cortical Input Through the Striatum, Regulation of Corticostriatal Synaptic Plasticity in Physiological and Pathological Conditions, Integrative Networks Across Basal Ganglia Circuits, and Abnormal Activities in Cortico-Basal Ganglia Circuits in Movement Disorders.

A Subtypes of Corticostriatal Neurons

Two main subtypes of corticostriatal neurons are recognized based on the distribution of their subcortical axon collaterals (Fig. 1.2) (see chapter: Organization of Corticostriatal Projection Neuron Types). One type, termed the intratelencephalic (IT-type) corticostriatal neuron, provides axon collaterals that distribute only within the striatum and cerebral cortex (Cowan and Wilson, 1994; Wilson, 1987; Wise and Jones, 1977; Zheng and Wilson, 2002). These neurons are located in the superficial half of layer 5 with some distributed in layers 2/3. A second type of corticostriatal neuron is classified as a pyramidal tract (PT-type) corticostriatal neuron. These neurons are located primarily in frontal cortical areas and give rise to PT projections to the brainstem or spinal cord, but have been shown to also contribute axon collaterals to the striatum (Cowan and Wilson, 1994; Donoghue and Kitai, 1981; Landry et al., 1984). Within the cortex, these neurons are distributed, for the most part, deeper than the first type of corticostriatal neuron, in the deeper parts of layer 5, and occasionally in layer 6. The striatal projection of this cell is formed by a very fine collateral branching off the much larger main axon in the course of its trajectory through the internal capsule. In addition to collateral branches distributing in the striatum, axon collaterals of these neurons also extend to the thalamus, STN, zona incerta, GPi, SNr, superior colliculus, and pontine nuclei. While PT corticostriatal neurons projecting to these other subcortical areas have been thought to arise from different populations of neurons, a recent study has shown that individual PT corticostriatal neurons may extend collaterals to each of these areas (Kita and Kita, 2012). This finding raises the question as to whether most PT corticostriatal neurons project to each of these subcortical areas, or whether there are subtypes that have more select subcortical projection targets. Recent studies in which PT corticostriatal neurons have been identified in BAC-Cre transgenic lines suggest that these neurons are widely distributed in somatosensory, sensorimotor, and prefrontal cortical areas with collaterals projecting to each of the subcortical targets (Gerfen et al., 2013; Gong et al., 2007). Thus, while the striatum is a major target of PT corticostriatal projections, the same information is directly provided to multiple components of the basal ganglia circuits.

Figure 1.2 Subtypes of corticostriatal neurons. Tracings of dendrites (black) and cortical (A and B) and striatal axons (A′ and B′) (gray) show the two subtypes of corticostriatal neurons, which had been intracellularly labeled. (A) The corticostriatal neuron depicted provides an axonal projection to the PT-type neuron. Axon collaterals within the cortex are distributed in relatively close proximity to the parent neuron. (A′) The PT axon (arrow) of this neuron gives off collaterals in the striatum, which display focal terminal arborizations. (B) The corticostriatal neuron shown, located in the medial agranular cortex (AGm), is a bilaterally projecting cortico-cortical neuron that also extends axon collaterals bilaterally into the striatum (intratelencephalically projecting neuron, IT-type). Axon collaterals within the ipsilateral cortex both distribute locally around the parent neuron in AGm and extend to the adjacent lateral agranular (motor) cortical area (AGl). (B′) This neuron has an axon that provides an extensive arborization pattern within the striatum, but does not extend collaterals beyond the striatum. Source: These neuronal tracings are modified from Cowan, R.L., Wilson, C.J., 1994. Spontaneous firing patterns and axonal projections of single corticostriatal neurons in the rat medial agranular cortex. J. Neurophysiol. 71, 17–32.

Different subtypes of corticostriatal neurons display some degree of specificity in their targets within the striatum. One example of this is the organization of corticostriatal inputs to the two striatal compartments, with cortical neurons from more superficial and from deeper cortical layers projecting, respectively, to the patch and matrix compartments (Gerfen, 1989). Whether the corticostriatal inputs to the patch and matrix compartments correspond to the more superficial IT and deeper PT neurons remain to be determined. Other studies have suggested that there is a differential targeting from corticostriatal IT-type and PT-type neurons to direct and indirect striatal neurons, respectively (Lei et al., 2004) (see chapter: Organization of Corticostriatal Projection Neuron Types). However, recent work provided evidence that both direct and indirect neurons to some degree receive inputs from both IT and PT neurons (Kress et al., 2013). Other work suggests that the cortical origins of input to direct and indirect striatal neurons are organized by cortical area, with somatosensory and limbic areas providing inputs preferentially to the direct pathway and motor cortical areas providing inputs preferentially to the indirect pathway neurons (Wall et al., 2013). Resolving the organization of cortical inputs to the direct and indirect pathways is critical to developing models of how activity in the direct and indirect pathways affects behavior (Morita et al., 2012).

Overall, these studies suggest that there are functional channels originating in the cerebral cortex that extend on the one hand through the macroscopic patch and matrix compartments and on the other hand through the direct and indirect striatal pathways to differentially affect the output of the basal ganglia.

B Organization Patterns of Corticostriatal Afferents

A distinct feature of corticostriatal projections is that the axons of individual neurons are distributed in manner such that they contact a maximum number of neurons but make minimal contacts with each postsynaptic neuron (ie, MSNs) (Zheng and Wilson, 2002). Quantitative data from Wilson and his colleagues provide informative boundaries for the type of information processing that may be taking place within the basal ganglia of the rat. First, there appears to be roughly a 6:1 ratio in terms of the numbers of corticostriatal neurons (17,000,000) and striatal MSNs (2,800,000; Oorschot, 1996) (see chapter: Cell Types in the Different Nuclei of the Basal Ganglia). Second, the volume over which the dendrites of a single MSN spread (400 μm in diameter) contains approximately 2850 other neurons. Third, approximately 380,000 corticostriatal neurons innervate the volume of the dendritic field of a single MSN, which contains 2850 neurons. Fourth, a single corticostriatal axon traversing this area has on average 40 synaptic boutons. If, as is estimated, each axon makes only a single or a few contacts with a single MSN, then each corticostriatal input makes contact with about 1% of the striatal neurons in the area across which it extends.

Taken together, these quantitative estimates indicate that the cortical input to a single striatal MSN is rather unique, that is, no two striatal neurons share common inputs from the cortex. Thus, postsynaptic excitatory activation of individual striatal MSNs is dependent on convergent input from multiple corticostriatal neurons. Consequently, the pattern of convergence of corticostriatal inputs is critical to understanding the information that is transmitted from the cerebral cortex into the basal ganglia. Note that the pattern of innervation of parvalbumin-positive striatal interneurons is different from that of MSNs. An individual cortical axon can give rise to multiple inputs to an individual parvalbumin neuron and, interestingly, cortical afferents to these neurons can arise in different functional territories (Ramanathan et al., 2002).

Cortical input to the striatum originates from most cortical areas—including primary and higher order sensory areas: motor, premotor, and prefrontal regions—as well as from limbic cortical areas (see also chapters: Organization of Prefrontal–Striatal Connections and Integrative Networks Across Basal Ganglia Circuits). It is well established that this input is organized in a general topographic manner in that the spatial relationships between cortical areas are maintained in the projections to the striatum (Carman et al., 1963; Kemp and Powell, 1970; Webster, 1961). For example, projections from prefrontal areas are directed mainly to the rostral caudate nucleus, while cortical inputs from motor cortex terminate primarily in the rostral putamen (Künzle, 1975). This pattern of the topographic organization of corticostriatal projections was embodied in the concept of functional regions within the striatum being dependent on the cortical origin of inputs to these regions (Alexander et al., 1986). Thus, dorsal regions of the striatum receiving inputs from premotor and motor cortical areas are characterized as motor regions of the striatum, whereas more ventral regions receiving inputs from limbic cortical areas are characterized as limbic.

More complex is the issue of overlapping projections from functionally related areas. While it is clear that, in general, cortical areas provide input to a much broader area of the striatum than accounted for on the basis of topography alone, the varied and sometimes intricate pattern of this organization have led to a variety of interpretations as to the functional significance. While the widespread nature of corticostriatal organization is not in doubt, where some have seen patterns of overlap related to patterns of cortical connectivity (Yeterian and Van Hoesen, 1978), others have seen interdigitation (Selemon and Goldman-Rakic, 1985). Detailed mapping of the organization of corticostriatal inputs has begun to resolve these issues, showing, in some cases, the overlap of inputs from interconnected cortical areas that are organized fairly precisely by the somatotopic organization within such areas (Flaherty and Graybiel, 1991, 1993; Parthasarathy et al., 1992).

IV Striatum

The striatum comprises the caudate nucleus, putamen, and nucleus accumbens. The striatum is composed of one principal neuron type, the MSN (Bishop et al., 1982; DiFiglia et al., 1976; Wilson and Groves, 1980) (see chapter: The Striatal Skeleton: Medium Spiny Projection Neurons and Their Lateral Connections). This neuron type makes up as much as 95% or more of the neuron population (Kemp and Powell, 1971) (see chapter: Cell Types in the Different Nuclei of the Basal Ganglia); these neurons are rather homogeneously distributed such that the striatum lacks a distinct cytoarchitectural organization, as contrasted with the laminar organization of the cortex, for example. Using retrograde axonal transport methods, Grofová (1975) established that these neurons are the projection neuron of the striatum. Cortical input to the striatum targets primarily spiny projection neurons, the MSNs (Somogyi et al., 1981). Thus, the MSN is the major input target and the major output neuron of the striatum.

The remaining striatal neurons are interneurons (Bishop et al., 1982; DiFiglia et al., 1976), in that they do not provide projection axons out of the striatum, but rather distribute axons within the striatum, most of which make synaptic contact with projection neurons. Despite being relatively infrequent, striatal interneurons constitute a variety of morphologically and neurochemically defined subtypes. Among these are the large aspiny neurons, which utilize acetylcholine as a transmitter (Bolam et al., 1984; Kawaguchi and Kubota, 1993) (see chapter: The Cholinergic Interneuron of the Striatum), and medium-sized aspiny neurons (Bishop et al., 1982; DiFiglia et al., 1976), which use GABA as a transmitter (Kita, 1993) (see chapter: GABAergic Interneurons of the Striatum). The latter class of interneurons may be further subdivided on the basis of different peptides and neurochemicals that they contain (Kita, 1993; Kubota and Kawaguchi, 1993; Kubota et al., 1993). These cell types are reviewed in the following sections.

A Medium Spiny Projection Neurons

MSNs (see chapter: The Striatal Skeleton: Medium Spiny Projection Neurons and Their Lateral Connections) take their name from their morphological appearance (Bishop et al., 1982; Chang et al., 1982; DiFiglia et al., 1976; Wilson and Groves, 1980), with a cell body of approximately 12–20 μm in diameter, from which radiate 7–10 moderately branched dendrites that are densely laden with spines. The dendrites of an individual neuron extend over an area of approximately 400 μm in diameter. These neurons also feature a local axon collateral that remains within the striatum, typically distributed over an area roughly equal in size as, but not necessarily overlapping with, the dendrites of the parent neuron (Bishop et al., 1982; Kawaguchi et al., 1990); in some cases local axon collaterals may extend over 1 mm from the parent neuron (Kawaguchi et al., 1990).

The main axon of MSNs projects out of the striatum to the GPe, GPi, and SNr (Kawaguchi et al., 1990). Two major subpopulations of MSNs, of approximately equal numbers, may be defined on the basis of their projection targets (Beckstead and Cruz, 1986; Gerfen and Young, 1988; Kawaguchi et al., 1990; Loopuijt and van der Kooy, 1985). One subset provides an axon projection to the GPe. The other subset provides a (minor) axon collateral to the GPe, and additional collaterals to the GPi and/or the SN. These latter neurons constitute the above mentioned striatal direct pathway, as they provide direct inputs to the output neurons of the basal ganglia, the GABAergic neurons of the GPi and SNr (see Fig. 1.1). The former neurons constitute the indirect striatal projection pathway, as they are connected indirectly, via the GPe and STN, with the output neurons of the basal ganglia.

MSNs all contain glutamic acid decarboxylase (GAD), the synthetic enzyme for the neurotransmitter GABA (Kita and Kitai, 1988). In addition, most of the neurons projecting to the GPe alone contain the neuropeptide enkephalin, whereas most of those projecting to the GPi and SN contain the neuropeptides substance P and dynorphin (Beckstead and Kersey, 1985; Gerfen and Young, 1988; Haber and Watson, 1983) (see also later).

B Synaptic Inputs to Medium Spiny Neurons

MSNs receive inputs from the cortex, thalamus, and amygdala, which make asymmetric synapses on dendritic spines, and to a lesser degree, dendritic shafts (Fig. 1.3). These are the major excitatory inputs to these neurons. In addition, a number of afferents from outside the striatum and from within the striatum provide inputs that function to modify the responsiveness of MSNs to excitatory input. These include dopamine afferents from the SN, inhibitory GABA (and neuropeptide) inputs from axon collaterals of other MSNs, inhibitory inputs from GABA (and peptide)-containing striatal interneurons, and inputs from cholinergic striatal interneurons (Fig. 1.3).

Figure 1.3 Canonical basal ganglia microcircuits. (A) Corticostriatal and direct/indirect pathway canonical circuits. Layer 5 cortical pyramidal neurons provide excitatory glutamatergic inputs to the spines of striatal D1- and D2-receptor-expressing medium spiny projection neurons (D1-MSNs and D2-MSNs). D1-MSNs give rise to direct pathway projections to the output nuclei of the basal ganglia (GPi/SNr), whereas D2-MSNs give rise to indirect pathway projections to basal ganglia output nuclei. Dopamine input through the nigrostriatal pathway is directed to the spine necks of D1- and D2-MSNs to modulate corticostriatal inputs. (B). Feedforward, feedback, and intrinsic striatal circuits. One feedforward circuit involves FS, parvalbumin (PV)/GABAergic interneurons that provide perisomatic synapses on both D1- and D2-MSNs. These PV neurons receive excitatory inputs from layer 5 corticostriatal neurons and are inhibited by the GPe. Intralaminar thalamic nuclei provide inputs to D1- and D2-MSNs, and contribute to a feedforward circuit involving thalamostriatal inputs to cholinergic (ChAT) interneurons that provide input to both D1- and D2-MSNs. Cholinergic neuron activity is also affected by dopamine inputs. Feedback striatal microcircuits involve interconnections between local axonal collaterals of D1- and D2-MSNs that make synaptic contact with other MSNs. Source: From Gerfen, C.R., Surmeier, D.J., 2011. Modulation of striatal projection systems by dopamine. Annu. Rev. Neurosci. 34, 441–466 (Gerfen and Surmeier, 2011).

Corticostriatal afferents make synaptic contact primarily with the expanded head of dendritic spines on MSNs (Bouyer et al., 1984; Hattori et al., 1979; Kemp and Powell, 1970; Somogyi et al., 1981). According to a quantitative study in rats (Xu et al., 1989), of all cortical synapses in the striatum, about 90% are formed with dendritic spines, and about 5% with dendritic shafts. The remaining 5% are on somata. Consistent with their excitatory nature, corticostriatal synapses are almost exclusively asymmetric and contain small rounded vesicles. Although cortical innervation of the striatum is relatively dense, as discussed earlier, input from any individual corticostriatal axon to an individual striatal MSN is very sparse (Cowan and Wilson, 1994).

Thalamic afferents from the intralaminar nuclei, including the parafascicular/centromedian complex (see chapter: The Thalamostriatal Systems in Normal and Disease States), provide inputs to the striatum that are similar to cortical afferents in the number of synapses formed (Lacey et al., 2005; Raju et al., 2008) and in that they form asymmetric synaptic contacts and have strong excitatory effects (Dubé et al., 1988; Xu et al., 1989). There are two independent thalamostriatal projections of the intralaminar nuclear complex, one originating from the parafascicular/centromedian nuclei and a separate one from rostral parts of the complex including the central lateral and paracentral nuclei. The latter intralaminar projection, like the cortical input, makes its asymmetrical synaptic contacts preferentially with the spines of MSNs, whereas projections arising from the parafascicular/centromedian nuclei form synapses with dendritic shafts including those of cholinergic interneurons and corticostriatal fibers (Lacey et al., 2007; Lapper and Bolam, 1992; Xu et al., 1989). Input from other thalamic nuclei forms synapses exclusively with dendritic spines (Raju et al., 2008; Xu et al., 1989).

Inputs from midbrain dopamine neurons (Fig. 1.3) make synaptic contacts with MSNs; these have been identified at the ultrastructural level with immunohistochemical localization of either dopamine (Voorn et al., 1986) or the dopamine synthesizing enzyme tyrosine hydroxylase (Arluison et al., 1984; Bouyer et al., 1984; Freund et al., 1984). Most of these afferents make symmetric synapses and contain large round and pleiomorphic vesicles. Of 280 synapses examined by Freund et al. (1984), 59% made synaptic contacts with dendritic spines. Unlike the axospinous synapses formed by cortical or thalamic inputs, these symmetrical synapses were usually not made on the head of the spine but on the neck, and these inputs shared the dendritic spine with another bouton forming an asymmetrical synapse (probably from the cerebral cortex or thalamus). Synapses were made onto dendritic shafts in 35%, and with somata in 6% of the cases. It should be noted, however, that dopaminergic synapses formed on spines is not a targeted phenomenon, as all striatal structures of a similar size have equal probability of being in contact with a dopaminergic axon (Moss and Bolam, 2008).

As mentioned earlier, MSNs have local axon collaterals within the striatum and these make symmetric synaptic contact with other MSNs (Wilson and Groves, 1980) (see chapter: The Striatal Skeleton: Medium Spiny Projection Neurons and Their Lateral Connections). Ultrastructural analysis of either intracellularly labeled axons (Wilson and Groves, 1980) or axons labeled with immunohistochemical localization of GAD (Bolam et al., 1985) or substance P (Bolam and Izzo, 1988) show similar synaptic relationships. Most MSN collaterals contact either the interspine shafts or necks of spines of other MSNs. These contacts are distributed somewhat closer to the cell body and proximal dendrite parts than are the dopamine contacts.

Striatal interneurons also provide important inputs to MSNs. These interneurons are discussed in more details in the following sections (and in specific chapters of this volume) and are listed here briefly. For example, boutons immunoreactive for choline acetyltransferase (ChAT), indicating input from cholinergic interneurons (see chapter: The Cholinergic Interneuron of the Striatum), make synaptic contacts with striatal MSNs as well as other striatal cells (Izzo and Bolam, 1988). These cholinergic synapses are symmetric and make contact with the cell somata (20%), dendritic shafts (45%), and with dendritic spines (34%). As with the other symmetrical synapses on dendritic spines, they share the spine with an asymmetrical synapse, usually placed more distally on the spine and resembling afferents from the cerebral cortex and thalamus.

In addition to the GABAergic MSNs, GABAergic interneurons are present within the striatum (see chapter: GABAergic Interneurons of the Striatum). GABAergic interneurons were first positively identified by loading with radioactive GABA (Bolam et al., 1983), and were later recognized as a subset of neurons staining more intensely with immunocytochemistry for GAD or GABA (eg, Bolam et al., 1985). More recently, a subpopulation has been shown to be positive for the calcium-binding protein parvalbumin (Cowan et al., 1990; Gerfen et al., 1985; Kita et al., 1990). These make numerous symmetrical synapses with the somata and dendrites of MSNs, as well as other interneurons. More than any other identified source of input, the synapses from the parvalbumin/GABA interneuron preferentially innervate the somata of MSNs (Kita et al., 1990). Another type of aspiny striatal interneurons is identified by its immunocytochemical labeling for somatostatin, neuropeptide Y, and NADPH diaphorase. These cells have also been shown to be distinguishable from parvalbumin/GABA interneurons on the basis of morphological and physiological criteria (Kawaguchi, 1993). Somatostatin-positive synapses are formed mainly on shafts of dendrites and dendritic spines of MSNs (Takagi et al., 1983).

In addition to the dopamine input from the SN, at least two other downstream nuclei of the basal ganglia send axons back to the striatum. One of these is the GPe, which provides GABAergic input to the striatum (Beckstead, 1983; Bevan et al., 1998; Kita and Kitai, 1994; Mallet et al., 2012; Staines et al. 1981) (see chapter: Organization of the Globus Pallidus). About a quarter to a third of those GPe neurons that innervate caudal basal ganglia targets also project to the striatum and their principal targets are parvalbumin-positive and NOS-positive GABA interneurons (Bevan et al., 1998; Mallet et al., 2012; Staines and Fibiger, 1984). An additional population of GPe neurons exclusively innervate the striatum, targeting both interneurons and MSNs and account for the most prominent extrinsic source of GABA in the striatum (Mallet et al., 2012). In addition, the STN also provides an input to the striatum. This input is relatively sparse as compared to the density of projections of this nucleus to SN and GP (Kita and Kitai, 1987). STN input to the striatum appears to provide asymmetric input to MSNs.

While dopamine afferents to the striatum provide the dominant input from the midbrain and brainstem, at least two other forebrain projection systems provide further inputs. These include the serotonergic afferents from the dorsal raphe and the noradrenergic afferents from the locus coeruleus. Added to the list of sources of inputs to the striatum, not covered in depth by this review, but also important for the functional integrity of the basal ganglia, are amygdala and hippocampus. Inputs from these structures are addressed in chapters Organization of Prefrontal–Striatal Connections, Gating of Cortical Input Through the Striatum, and Integrative Networks Across Basal Ganglia Circuits.

C Striatal Interneurons

Striatal neurons that exclusively give rise to axons that remain within the striatum make up 15% or less of the striatal neuron population (Bishop et al., 1982; Chang et al., 1982; DiFiglia et al., 1976; Kemp and Powell, 1971) (see chapter: Cell Types in the Different Nuclei of the Basal Ganglia). This class of neurons presents a variety of morphologically and neurochemically distinct subtypes. Two major subtypes have been identified (Fig. 1.4). One is the large aspiny neuron, which utilizes acetylcholine as a neurotransmitter (Bolam et al., 1984; Kawaguchi, 1992, 1993; Wilson et al., 1990). The other is the medium-sized aspiny GABAergic interneuron, of which there are several varieties (Kawaguchi et al., 1995; Kita, 1993).