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Cortico-Subcortical Dynamicsin Parkinson’s Disease

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Kuei-Yuan TsengEditor

Cortico-SubcorticalDynamics in Parkinson’sDisease

Editor

Kuei-Yuan TsengDepartment of Cellular and MolecularPharmacology

Rosalind Franklin University ofMedicineand Science

The Chicago Medical SchoolNorth Chicago, IL 60064, [email protected]

ISBN 978-1-60327-251-3 e-ISBN 978-1-60327-252-0DOI 10.1007/978-1-60327-252-0

Library of Congress Control Number: 2008942516

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Contents

Part I Cortico-Subcortical Circuits and Parkinson’s Disease

1 Leading Toward a Unified Cortico-basal Ganglia

Functional Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Shannon R. Blume and Kuei Y. Tseng

2 Modeling Parkinson’s Disease: 50 Years Later . . . . . . . . . . . . . . . . . 23Gloria E. Meredith and Kuei Y. Tseng

Part II Physiological Studies of the Cortico-subcortical Dynamics

and Parkinson’s Disease

3 Phasic Dopaminergic Signaling: Implications for Parkinson’s

Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37Stefan G. Sandberg and Paul E.M. Phillips

4 Striatal Dendritic Adaptations in Parkinson’s Disease Models . . . . . 55Michelle Day and D. James Surmeier

5 Diversity of Up-State Voltage Transitions During Different

Network States. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73Nicolas Vautrelle, Luis Carrillo-Reid, and Jose Bargas

6 The Corticostriatal Pathway in Parkinson’s Disease . . . . . . . . . . . . . 87Nigel S. Bamford and Carlos Cepeda

7 Cholinergic Interneuron and Parkinsonism. . . . . . . . . . . . . . . . . . . . . 105Dario Cuomo, Paola Platania, Giuseppina Martella, Graziella Madeo,Giuseppe Sciamanna, Annalisa Tassone and Antonio Pisani

8 Basal Ganglia Network Synchronization in Animal Models

of Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117Judith R. Walters and Debra A. Bergstrom

v

9 Converging into a Unified Model of Parkinson’s Disease

Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143Camila L. Zold, Mariano Belluscio, Fernando Kasanetz,Pablo E. Pomata, Luis A. Riquelme, Francois Gonon,and Mario Gustavo Murer

10 The Corticostriatal Transmission in Parkinsonian Animals:

In Vivo Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157Berangere Ballion, Nicolas Mallet, Catherine Le Moine,Mario Gustavo Murer, and Francois Gonon

11 Striatal Nitric Oxide–cGMP Signaling in an Animal

Model of Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171Anthony R. West, Stephen Sammut, and Marjorie A. Ariano

12 Dopamine–Endocannabinoid Interactions in Parkinson’s

Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185Sarah McCallum and Joseph F. Cheer

13 Glutamate Plasticity in an Animal Model of Parkinson’s

Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207Charles K. Meshul

Part III Computational Analyses of the Cortico-Subcortical Dynamics

and Parkinson’s Disease

14 Neuromodulation and Neurodynamics of Striatal Inhibitory

Networks: Implications for Parkinson’s Disease . . . . . . . . . . . . . . . . 233Tomomi Shindou, Gordon W. Arbuthnott, and Jeffery R. Wickens

15 Dopaminergic Modulation of Corticostriatal Interactions

and Implications for Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . 245John A. Wolf and Jason T. Moyer

Part IV Neurobiology and Pathophysiology of Parkinson’s Disease

16 Pathogenesis of Oxidative Stress and the Destructive Cycle

in the Substantia Nigra in Parkinson’s Disease . . . . . . . . . . . . . . . . . 261Emilio Fernandez-Espejo

17 Regulation of G-Protein-Coupled Receptor (GPCR) Trafficking

in the Striatum in Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . 273Marie-Laure Martin-Negrier, Celine Guigoni, Bertrand Bloch,and Erwan Bezard

vi Contents

18 Atypical Parkinsonism in the French West Indies: The Plant Toxin

Annonacin as a Potential Etiological Factor . . . . . . . . . . . . . . . . . . .Annie Lannuzel and Patrick Pierre Michel

19 Cognitive Deficits in Parkinson’s Disease. . . . . . . . . . . . . . . . . . . . . .Eliana Roldan Gerschcovich and Kuei Y. Tseng

Part V Pharmacological and Non-Pharmacological Treatments

in Parkinson’s Disease

20 Dopamine Replacement Therapy in Parkinson’s Disease:

Past, Present and Future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .M.A. Cenci and P. Odin

21 Molecular, Cellular and Electrophysiological Changes Triggered

by High-Frequency Stimulation of the Subthalamic Nucleus

in Animal Models of Parkinson’s Disease. . . . . . . . . . . . . . . . . . . . . .Paolo Gubellini and Pascal Salin

22 Surgical Strategies for Parkinson’s Disease Based on Animal

Model Data: GPi and STN Inactivation on Various Aspectsof Behavior (Motor, Cognitive and Motivational Processes) . . . . . . .Christelle Baunez

23 Antidromic Cortical Activity as the Source of Therapeutic

Actions of Deep Brain Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . .Gordon W. Arbuthnott, Cyril Dejean, and Brian Hyland

24 Cell-Based Replacement Therapies for Parkinson’s Disease . . . . . . .Emilio Fernandez-Espejo and Isabel Liste

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Contents vii

283

291

309

335

371

393

405

433

Contributors

Gordon W. Arbuthnott Brain Mechanisms for Behaviour Unit, OkinawaInstitute of Science and Technology Promotion Corporation, Initial ResearchProject, 12-22 Suzaki, Uruma, Okinawa 904-2234, Japan, [email protected]

Marjorie A. Ariano Department of Neuroscience, Rosalind FranklinUniversity ofMedicine and Science, 3333 Green Bay Road, North Chicago, IL,60064, USA

Berangere Ballion CNRS UMR 5227, Universite de Bordeaux, BordeauxF-33076, France

Nigel S. Bamford Department of Neurology, Pediatrics and Psychology,University of Washington, Seattle, [email protected]

Jose Bargas Departamento de Biofısica, Instituto de Fisiologıa Celular,Universidad Nacional Autonoma de Mexico, Mexico City, Mexico

Christelle Baunez Laboratoire de Neurobiologie de la Cognition, CNRSUMR6155, Aix-Marseille Universite, 3 Place V. Hugo, 13331 Marseille,France, [email protected]

Mariano Belluscio Laboratorio de Fisiologıa de Circuitos Neuronales,Departamento de Fisiologıa y Biofısica, Facultad de Medicina, Universidad deBuenos Aires, Ciudad de Buenos Aires C1121ABG, Argentina

Debra A. Bergstrom Neurophysiological Pharmacology Section, NationalInstitute of Neurological Disorders and Stroke, National Institutes of Health,Bethesda, MD 20892, USA

Erwan Bezard CNRS UMR 5227, 146 rue leo saignat, 33076 Bordeaux cedex,France, [email protected], [email protected]

Bertrand Bloch Universite Victor SegalenBordeaux 2, CNRS,Bordeaux Instituteof Neuroscience, UMR 5227, Bordeaux, France, [email protected]

Shannon R. Blume Department of Cellular and Molecular Pharmacology,Rosalind Franklin University of Medicine and Science, The Chicago MedicalSchool, North Chicago, IL 60064, USA

ix

Luis Carrillo-Reid Departamento de Biofısica, Instituto de Fisiologıa Celular,

Universidad Nacional Autonoma de Mexico, Mexico City, Mexico

M.A. Cenci Basal Ganglia Pathophysiology Unit, Dept. Experimental

Medical Science, Lund University, BMC F11, 221 84 Lund, Sweden,

[email protected]

Carlos Cepeda Mental Retardation Research Center, David Geffen School

of Medicine, University of California Los Angeles, Los Angeles, CA,

[email protected]

Joseph Cheer Neuropharmacology & Neuroscience (TSX-110), Albany

Medical College, 43 New Scotland Av., Albany, NY 12208, USA,

[email protected]

Dario Cuomo Department of Neuroscience, University ‘‘Tor Vergata’’, Rome,

Italy; Fondazione Santa Lucia I.R.C.C.S., Rome, Italy

Michelle Day Department of Physiology, Feinberg School of Medicine,

Northwestern University, Chicago, IL 60611, USA

Cyril Dejean Department of Anatomy and Structural Biology, University

of Otago Medical School, Great King Street, Dunedin, New Zealand

Emilio Fernandez-Espejo Department of Medical Physiology and Biophysics,

School of Medicine, University of Seville, Seville, Spain, [email protected]

Eliana Roldan Gerschcovich Department of Neurology, FLENI, Buenos Aires,

Argentina; Department of Cellular and Molecular Pharmacology, Rosalind

Franklin University of Medicine and Science, The Chicago Medical School,

North Chicago, IL 60064, USA

Francois Gonon CNRS UMR 5227, Universite de Bordeaux, Bordeaux

F-33076, France, [email protected]

Paolo Gubellini Institut de Biologie du Developpement de Marseille-Luminy

(IBDML), UMR6216 CNRS/Universite de la Mediterranee, Case 907, Parc

ScientifiquedeLuminy, 13288,Marseille cedex9,France, [email protected]

Celine Guigoni Universite Victor Segalen Bordeaux 2, CNRS, Bordeaux Institute

of Neuroscience, UMR 5227, Bordeaux, France, [email protected]

Brian Hyland Department of Physiology, University of OtagoMedical School,

Great King Street, Dunedin, New Zealand

Fernando Kasanetz Laboratorio de Fisiologıa de Circuitos Neuronales,

Departamento de Fisiologıa y Biofısica, Facultad de Medicina, Universidad de

Buenos Aires, Ciudad de Buenos Aires (C1121ABG), Argentina

Annie Lannuzel INSERM, UMR_S 679, Neurology and Experimental

Therapeutics, F-75013, Paris, France; UPMCUniv Paris 06, UMR_S 679, F-75005,

x Contributors

Paris, France;Department ofNeurology, CentreHospitalierUniversitaire, F-97159,Pointe-a-Pitre, Guadeloupe, F.W.I, [email protected]

Catherine Le Moine CNRS UMR 5227, Universite de Bordeaux, BordeauxF-33076, France

Isabel Liste Centro de Biologia Molecular Severo Ochoa, AutonomousUniversity, Madrid, Spain; Department of Medical Biochemistryand Biophysics, Karolinska Institute, Stockholm, Sweden

Graziella Madeo Department of Neuroscience, University ‘‘Tor Vergata’’,Rome, Italy; Fondazione Santa Lucia I.R.C.C.S., Rome, Italy

Nicolas Mallet CNRS UMR 5227, Universite de Bordeaux, Bordeaux,F-33076, France

Giuseppina Martella Department of Neuroscience, University ‘‘Tor Vergata’’,Rome, Italy; Fondazione Santa Lucia I.R.C.C.S., Rome, Italy

Marie-Laure Martin-Negrier Universite Victor Segalen Bordeaux 2, CNRS,Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France, [email protected]

Sarah E. McCallum Center for Neuropharmacology & Neuroscience, AlbanyMedical College, Albany, NY 12208, USA, [email protected]

Gloria E. Meredith Cellular and Molecular Pharmacology, RFUMS/TheChicago Medical School, North Chicago, IL 60064, USA,[email protected]

Charles K. Meshul Research Service, Neurocytology Lab, VA Medical Centerand Department of Behavioral Neuroscience and Pathology Oregon Health &Science University, Portland, OR, USA, [email protected]

Patrick Pierre Michel INSERM, UMR_S 679, Neurology and ExperimentalTherapeutics, F-75013, Paris, France; UPMC Univ Paris 06, UMR_S 679,F-75005 Paris, France

Jason T. Moyer University of Pennsylvania, Philadelphia, PA, USA

Mario Gustavo Murer Laboratorio de Fisiologıa de Circuitos Neuronales,Departamento de Fisiologıa y Biofısica, Facultad de Medicina, Universidadde Buenos Aires, Paraguay St. 2155, Buenos Aires CP1121, Argentina,[email protected]

P. Odin Department of Neurology, Central Hospital, D-27574 Bremerhaven,Germany

Paul E.M. Phillips Departments of Psychiatry & Behavioral Sciences, andPharmacology, University of Washington, Box 356560, Seattle, WA98195-6560, USA

Contributors xi

Antonio Pisani Department of Neuroscience, University of Rome ‘‘TorVergata’’, Via Montpellier, 1, 00133 Roma, Italy, [email protected]

Paola Platania Department of Neuroscience, University ‘‘Tor Vergata’’,Rome, Italy and Fondazione Santa Lucia I.R.C.C.S., Rome, Italy

Pablo E. Pomata Laboratorio de Fisiologıa de Circuitos Neuronales,Departamento de Fisiologıa y Biofısica, Facultad de Medicina, Universidad deBuenos Aires, Ciudad de Buenos Aires (C1121ABG), Argentina

Luis A. Riquelme Laboratorio de Fisiologıa de Circuitos Neuronales,Departamento de Fisiologıa y Biofısica, Facultad de Medicina, Universidad deBuenos Aires, Ciudad de Buenos Aires (C1121ABG), Argentina

Pascal Salin Institut de Biologie du Developpement de Marseille-Luminy(IBDML), UMR6216 CNRS/Universite de la Mediterranee, Case 907, ParcScientifique de Luminy, 13288,Marseille cedex 9, France, [email protected]

Stephen Sammut Department of Neuroscience, Rosalind FranklinUniversity ofMedicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA

Stefan G. Sandberg Departments of Psychiatry & Behavioral Sciences, andPharmacology, University of Washington, Box 356560, Seattle, WA98195-6560, USA, [email protected]

Giuseppe Sciamanna Department of Neuroscience, University ‘‘Tor Vergata’’,Rome, Italy; Fondazione Santa Lucia I.R.C.C.S., Rome, Italy

Tomomi Shindou Okinawa Institute of Science andTechnology,Okinawa, Japan

D. James Surmeier Department of Physiology, Feinberg School of Medicine,Northwestern University, 303 E. Chicago Ave, Chicago, IL 60611, USA,[email protected]

Annalisa Tassone Department of Neuroscience, University ‘‘Tor Vergata’’,Rome, Italy; Fondazione Santa Lucia I.R.C.C.S., Rome, Italy

Kuei Y. Tseng Department of Cellular & Molecular Pharmacology, RFUMS,The Chicago Medical School, North Chicago, IL 6004, USA, [email protected]

Nicolas Vautrelle Departamento de Biofısica, Instituto de Fisiologıa Celular,Universidad Nacional Autonoma de Mexico, Mexico City, Mexico,N. [email protected]

Judith R. Walters Neurophysiological Pharmacology Section, NationalInstitute of Neurological Disorders and Stroke, National Institutes of Health,Bethesda, MD 20892 USA, [email protected]

Anthony R. West Department of Neuroscience, Rosalind Franklin Universityof Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064,USA, [email protected]

xii Contributors

Jeffery R.Wickens Neurobiology ResearchUnit, Okinawa Institute of Scienceand Technology, Initial Research Project, 12-22 Suzaki, Uruma, Okinawa904-2234, Japan, [email protected]

John A. Wolf Hospital of the University of Pennsylvania, Division ofNeuropsychiatry, Rm.240 SkirkanichHall, 210 S. 33rd Street, Philadelphia, PA19104, USA, [email protected]

Camila L. Zold Laboratorio de Fisiologıa de Circuitos Neuronales,Departamento de Fisiologıa y Biofısica, Facultad de Medicina, Universidad deBuenos Aires, Ciudad de Buenos Aires, C1121ABG, Argentina

Contributors xiii

Part I

Cortico-Subcortical Circuits and Parkinson’sDisease

Chapter 1

Leading Toward a Unified Cortico-basal Ganglia

Functional Model

Shannon R. Blume and Kuei Y. Tseng

Basal Ganglia Circuitry: The Direct and Indirect Pathways

There is a large body of literature establishing the basal ganglia functional

organization of cortical afferents projecting to the striatum to two different path-

ways: the direct and indirect pathways [1–4]. Consistent throughout this organiza-

tion are the medium spiny neurons (MSNs) which account for approximately

90–95% of the cell population in the striatum [5, 6]. MSNs are GABAergic

projection neurons that are comprised by two functionally distinct groups of

neurons based on the expression of neuropeptides and dopamine (DA) receptors

[7]. More specifically, striatal neurons in the direct pathway contain substance

P and dynorphin, and preferentially express D1-class DA receptors [8–10]. On

the other hand, MSNs from the indirect pathway are enkephalin positive

neurons and preferentially express D2-class DA receptors [8–10]. Despite that

striatal neurons from the direct and indirect pathways exhibit opposite

responses toDA, asD1 andD2 receptors are coupled toGs andGi, respectively,

activation of these circuits typically result in inhibition of the basal ganglia

output nuclei: the globus pallidus internalis (GPi) and the substantia nigra

pars reticulata (SNpr) (Fig. 1.1A). For instance, striatal D1 activation will

increase MSNs firing and thereby increase the inhibition of the basal ganglia

output nuclei (GPi/SNpr), leading to disinhibition of the thalamocortical loop

[11, 12]. Similarly, D2 activation will result in disinhibition of the globus

pallidus externalis (GPe), increased inhibition of the subthalamic nucleus

(STN), which in turn reduces the excitatory tone to the output nuclei and

thalamocortical disinhibition. Thus, DA activation of MSNs in the direct and

indirect pathways leads to a synergistic outcome in the basal ganglia output

nuclei [13].

K.Y. Tseng (*)Department of Cellular andMolecular Pharmacology, Rosalind Franklin University ofMedicine and Science, The Chicago Medical School, North Chicago, IL, 60064, USAe-mail: [email protected]

K.-Y. Tseng (ed.), Cortico-Subcortical Dynamics in Parkinson’s Disease,Contemporary Neuroscience, DOI 10.1007/978-1-60327-252-0_1,� Humana Press, a part of Springer ScienceþBusiness Media, LLC 2009

3

Functional Changes in the Basal Ganglia After Dopamine Depletion

When chronic DA depletion occurs in the basal ganglia, as seen in Parkinson’s

disease (PD), synaptic transmission within the direct and indirect pathways

becomes imbalanced (Fig. 1.1B) [14, 15]. The lack of D2 tone in the indirect

pathway will increase inhibition of the GPe and lead to disinhibition in the

STN, thereby increasing the excitatory tone to the GPi/SNpr. The lack of

D1 receptor activation in the direct pathway will result in less inhibition of

the output nuclei. Thus, output nuclei hyperactivity in PD is expected as the

functional consequence of two parallel processes: (i) a reduced activity of the

inhibitory direct pathway and (ii) an increased activity of the STN. Increased

STN activity is believed to result from disinhibition of striatopallidal neurons

and the subsequent reduction in tonic inhibitory input from the GPe to the

STN [3, 16]. In conjunction, excessive activation of the output nuclei would lead

to a decrease in the excitatory thalamic output to the cortex, thereby causing

the motor deficits commonly seen in PD (Fig. 1.1B). This pathophysiological

model is supported by the fact that STN inactivation/lesion ameliorates motor

deficits in PD and experimental parkinsonism [17–21] and by compelling evi-

dence revealing compatible neurochemical and metabolic changes in animal

models of parkinsonism: (i) unilateral nigrostriatal DA lesion induced by intra-

cerebral injection of 6-hydroxydopamine (6-OHDA) in rats and (ii) DA depletion

inducedby systemic administration ofmethyl-phenyl-tetrahydropyridine (MPTP)

in non-human primates [3, 16, 22, 23].

GPe

STNSNpr/GPi

D1D2

GA

BA (–)

(–) GA

BA

ENK SP

(+) GLU

GLU (+)

GLU (+)

GABA (–)

GABA (–)

thalamus

GLU (+)

Cortex

SNpc

DA

(–) (+)

Normal State

GPe

STNSNpr/GPi

D1D2G

AB

A (–)

(–) GA

BA

ENK SP

(+) GLUGLU (+)

GLU (+)

GABA (–)

GABA (–)

thalamus

GLU (+)

Cortex

DA

SNpc

Parkinsonian StateA B

Fig. 1.1 Functional model of basal ganglia circuitry in normal (A) and parkinsonian (B) state.

White and black arrows indicate excitatory (glutamatergic) and inhibitory (GABAergic)neurotransmission, respectively. Enlarged and broken arrows in B indicate pathways thatare believed to be upregulated and downregulated after chronic dopamine depletion,respectively

4 S.R. Blume and K.Y. Tseng

Glutamate Decarboxylase

Glutamate is the precursor for the synthesis of GABA by the rate-limitingenzyme glutamate decarboxylase 67 (GAD67). Thus, GAD67 expression couldbe used to determine changes in activity of GABA-containing cells such as thosein the basal ganglia (Fig. 1.1) [24]. For example, an upregulation of GAD67

mRNA in SNpr [25, 26] and GPi [24, 25, 27] was consistently observed innon-human primates treated with MPTP when compared to saline controls.More importantly, L-DOPA treatment reversed these changes [24, 26, 27]. Onthe other hand, GAD67 expression in the GPe and striatum has shown to be lessclear. Herrero and colleagues found no significant changes in GAD67 mRNAexpression in the GPe of MPTP-treated animals, whereas Soghomonian’sgroup found a significant increase [25, 27].

Similar to what was found in animals treated withMPTP, 6-OHDA-lesionedrats also showed an increase in GAD67 expression in the basal ganglia outputnuclei [28–30]. However, GAD67 mRNA expression is also increased in thestriatum of DA-depleted rats, a finding that is fairly consistent across differentresearch groups [28–31] Again, all the changes induced by 6-OHDA werenormalized after L-DOPA treatment [28].

Overall, the main findings remain as predicted, that is, neuronal activity inthe GPi and SNpr is increased in DA-depleted animals, an effect that can berestored to near normal levels with L-DOPA treatment.

Cytochrome Oxidase

Among the diverse metabolic activities required to maintain neuronal function,the most important ion pump is the Na+/K+-ATPase, which consumes �60%of brain ATP [32, 33]. Interestingly, the energy (ATP) supply is almost com-pletely derived from the oxidative metabolism of glucose [33], whose final stageis catalyzed by the cytochrome oxidase I (CO-I). CO-I is the terminal enzyme ofthe mitochondrial electron-transport chain that provides most of the ATP usedin the brain [34] and is a useful marker of brain metabolic activity. This enzyme,also known as ‘‘complex IV’’ of the mitochondrial chain, is composed of13 subunits, 3 of which are encoded by the mitochondrial genome and 10 bythe nuclear genome [35]. Wong-Riley and co-workers have showed that amono-ocular injection of tetrodotoxin, a procedure used to inhibit neuronalactivity in the geniculate body, also induced a profound decrease in local CO-Iactivity [36]. Both CO-I protein levels and mRNA coding for the subunits ofCO-I are responsive to changes in neuronal activity allowing analyses of regio-nal, cellular and subcellular functional levels [34, 37, 38].

Metabolic measures using CO-I in DA-depleted animals supported the dataobtained with GAD67. Both CO-I histochemistry and mRNA are increased inthe GPi, STN and SNpr in non-human primates exposed to MPTP when

1 Leading Toward a Unified Cortico-basal Ganglia Functional Model 5

compared to controls [28, 39, 40]. L-DOPA treatment reverses the changesinduced byMPTP. Similarly changes in CO-I levels were observed after chronicDA depletion in rats. For instance, 6-OHDA-lesioned animals demonstratedincreased CO-I levels in GPi and SNpr [41], as well as the STN [42]. Thesechanges in CO-I expression were correlated with changes in neuronal firingpattern [22, 42]. It is also important to note the lack of consistent changes in theGPe regarding CO-I levels and GAD67 expression [27] after DA depletionsuggests that the hyperactive STN state in PD may not be exclusively mediatedby a disruption of the indirect pathway/GPe.

2-Deoxyglucose

In 1977, Sokoloff and colleagues developed an autoradiographic 2-deoxyglucose(2-DG) method for measuring glucose utilization in the various structures of thebrain in both normal and experimental conditions [43]. Compared to CO-Ihistochemistry, 2-DG reflects better neuronal activity occurring over shortertime periods lasting from seconds to minutes, rather than hours or weeks.Although the anatomical resolution of CO-I histochemistry is better than thatof 2-DG autoradiography [34, 44], changes in 2-DG uptake have been experi-mentally found to reflect mostly changes in synaptic, not cellular, activity. Forinstance, Kadekaro and collaborators found that 2-DG in the dorsal root gangliais taken up mostly by the axon terminals [45].

Numerous studies have investigated the impact of DA lesion on the func-tional anatomy of the basal ganglia circuitry [46–50]. Consistent throughout theliterature, glucose uptake is decreased in the STN and increased in theGPe afterDA depletion, yet no significant changes were found in the GPi and striatum[47–50]. Despite the differences between CO-I and 2-DG studies, the mainconclusions remain as predicted, in particular regarding changes in the indirectpathway: (i) glucose uptake is increased in the GPe resulting from the amplifiedstriatal GABAergic output due to the lack of D2 receptor activation and(ii) glucose utilization is decreased in the STN from the lack of inhibitoryinput from the GPe.

Chronic Dopamine Depletion and Basal Ganglia Oscillations

In vivo electrophysiological studies have uncovered other aspects of the basalganglia functional organization that cannot be easily conciliated with the classicmodel described above. For instance, the predicted hyperactivity of outputnuclei neurons, commonly measured as an increase of the mean firing rate,was reported by some groups [51–53], but not by others [54–62]. Interestingly,changes in firing pattern have consistently been reported in recent studies:neurons in the output nuclei tend to fire in bursts of action potentials and


show periodic oscillations in firing rate (Fig. 1.2). Unfortunately, only firing

rate, not firing pattern has been considered to drive the relationship between

the direct and the indirect pathways (Fig. 1.1). In the following section we will

(i) review evidence regarding the role of the striatum and the STN in the

regulation of oscillatory activity in the basal ganglia and (ii) summarize recent

data on how chronic DA lesion of the nigrostriatal pathway impacts the

cortico-basal ganglia dynamics. We will conclude with an integrated/unified

functional cortico-basal ganglia-thalamocortical model by taking into account

the temporal domain of neuronal oscillations from single cell to the system

level.

Chronic Dopamine Depletion and Firing Pattern Shiftin the Basal Ganglia

Basal ganglia output neurons in normal and control rats typically display

regular firing patterns ranging from 15 to 40 Hz when recorded in vivo under

general anesthesia [13, 54, 56, 57, 60, 63–69]. After chronic DA depletion (i.e.,

6-OHDA rats), 40–50% of SNpr neurons fire bursts of action potentials and

display low frequency oscillatory (LFO) activity (�1 Hz) [57, 64, 66–70]

(Fig. 1.2). STN lesion significantly decreased burst firing in the SNpr of

6-OHDA-lesioned rats, suggesting that the STN could mediate the emergence

0 0.3

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.005

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rela

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A 24.4 Hz

0.98 Hz

50mV

2 s

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50mV

0.5 s

non-LFO unit

B

Fig. 1.2 Substantia nigra pars (SNpr) reticulata single-unit recordings in control and 6-OHDA-

lesioned rats. Neurons in the SNpr can be classified into two main categories based on theautocorrelograms (middle panel) and the power spectra (right panel) of the interspike intervals.(A) The majority of cells recorded from control animals exhibit tonic/regular firing patterns(non-LFO) and display dominant peak within 20–30 Hz. (B) After chronic dopamine deple-tion, �40% of neurons in the SNpr show rhythmic burst firing activity (LFO) with adominant peak frequency of �1 Hz. Modified from Tseng et al [66]


of abnormal oscillatory activity after chronic DA depletion. In fact, neurons of

the GPe and STN display synchronized oscillatory burst discharge at LFO

(0.4–1.8 Hz) in mature organotypic cultures containing striatal and cortical

tissues, but lacking DA neurons [71]. Similarly, oscillatory burst discharge can

be induced by sustained membrane hyperpolarization in vitro in slices contain-

ing STN neurons [72]. The role of the STN in mediating oscillatory burst firing

in the basal ganglia is further supported from a recent work by Magill and

co-workers demonstrating that STN and GPe neurons discharge LFO bursts in

vivo in ketamine-anesthetized rats [73]. Interestingly, LFO activity within the

GPe-STN network is correlated with changes in cortical field potential, suggest-

ing that slow cortical rhythms are propagated via a cortico-STN-GP network.Recent studies indicate that chronic DA depletion enhances LFO in the STN

and output nuclei neurons. STN neurons recorded from urethane-anesthetized

6-OHDA-lesioned rats display a significantly higher number of cortically

driven LFO burst units (Fig. 1.3) [64, 69, 74, 75]. Similarly, periodic burst firing

in the SNpr of 6-OHDA-lesioned rats is correlated with slow cortical rhythms

[66, 70]. It can be speculated that slow cortical rhythms are transferred to the

SNpr via the STN in the parkinsonian state as STN lesion reduced burst firing

in the SNpr [57, 67, 68]. However, Plenz and Kitai also reported that neurons in

the GPe and STN can sustain phase-locked synchronized LFO, even in the

0.1

mV

0.5 s

non-LFO

LFO

0.5

mV

1 s

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15

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00 10 20 30 Hz

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ower

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ativ

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ower

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)

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0

%

Control(n=33)

6-OHDA(n=24)

A

Fig. 1.3 Single-unit recordings of subthalamic nucleus (STN) cells in control and 6-OHDA-

lesioned rats. (A) Cells showing burst firing activity (i.e., LFO units) were found in bothgroups though to a greater extent in animals with chronic dopamine depletion (i.e., 6-OHDA)(9/33 vs. 17/24, normal vs. 6-OHDA LFO units, respectively; p=0.0016, Fisher exact prob-ability test). Thus, non-LFO units predominated in control animals. (B) Non-LFO unitsdisplayed dominant frequency peaks within 10–30 Hz as revealed by the power spectra ofthe interspike interval. In contrast, LFO units display rhythmic burst of action potentials witha dominant peak frequency within 1 Hz


absence of cortical inputs, in organotypic cultures lacking DA neurons [71].Consequently, the possibility that both the cortex and the GPe–STN networkscontribute equally to the generation of LFO-bursting activity in the parkinso-nian basal ganglia cannot be completely ruled out, yet they are not mutuallyexclusive.

There is also evidence indicating that a disruption of striatal function couldunderlie the appearance of LFO activity in the basal ganglia after chronic DAdepletion [57, 68]. For example, stimulation of striatal D1-class DA receptorschanges the firing pattern of SNpr neurons of 6-OHDA-lesioned rats, from aLFO to a non-LFO firing mode [68]. D2 activation, however, had little impacton SNpr LFO firing [68], yet a robust effect on the mean firing rate wasobserved [68]. These findings suggest divergent roles for striatal D1 and D2receptors in themodulation of output nuclei firing pattern, an effect that may berelated to how DA receptors regulate striatal neurons function and corticos-triatal transmission [76].

Corticostriatal Function and Basal Ganglia Oscillations

As discussed above, inputs to the striatum arise from the cerebral cortex, thalamusand midbrain. At the cellular level, both DA-containing fibers and corticalglutamatergic inputs extensively converge and interact in the same striatal projec-tion cells, known as MSNs. These neurons exhibit membrane potential fluctua-tions when recorded in vivo (Fig. 1.4). Amore hyperpolarized level, also known asdown state, is interrupted by periods of sustained depolarization, the up states[77]. The onset of these events requires strong excitatory synaptic inputs drivenfrom the cerebral cortex and thalamus [77, 78] to overcome the tight hold theinwardly rectifying K+ current provides to the membrane potential during downstates. Yet there is still an ongoing debate regarding whether continuous gluta-matergic inputs are needed to sustain the depolarization [79], it becomes clear thatneuromodulators such as DA can contribute to sustain plateau depolarizationsby activating/inactivating intrinsic voltage-gated channels and by modulating thestrength of local glutamatergic excitation [80]. Thus, plateau depolarizations or upstates can be perceived as ‘‘enabling states’’, during which synchronous corticotha-lamic activity is translated into sequences of action potentials in MSNs, allowingtransmission of processed information to the output nuclei.

It has been hypothesized that chronic DA depletion may facilitate thetransmission and expression of thalamocortical oscillations in the basal gangliaas LFO burst firing [81] and that stimulation of striatal D1-class DA receptorsprevents the spreading of the rhythm [68, 82]. It remains to be determinedwhether the effect of striatal D1 stimulation on output nuclei LFO activity ismediated by the direct pathway (i.e., striatonigral projection) itself or bymodulating the GPe–STN network oscillations, two plausible mechanismsthat are not mutually exclusive.


Cortical neurons also exhibit periodic oscillations in their membrane poten-tials that are strongly correlated with the EEG oscillatory activity and local fieldpotential when recorded in vivo [83]. Only during the depolarizing phase docortical neurons fire action potentials, usually as bursts of spikes, which in turnwould allow transmission of the corticothalamic rhythms [83]. Interestingly,striatal MSN membrane potential fluctuations appear to reflect spreadingactivity of cortical field potential oscillations [81]. This conclusion is supportedby previous findings indicating that MSNs up states are driven by inputs fromthe cerebral cortex and thalamus [77, 78, 84–86]. Thus, spreading of corticalrhythms to striatal target nuclei seems to be constrained by the very low firingprobability of MSNs in healthy animals (Fig. 1.4B). In contrast, striatal MSNsrecorded from rats with chronic DA depletion displayed a more depolarizedmembrane potential (both during the down and the up state), exhibited a sig-nificant increase in the probability of firing during the up states and are moreresponsive to cortical stimulation (Fig. 1.4C). Accordingly, neurons in the GPeand SNpr display tonic regular firing during natural slow wave sleep [63, 87] and

25 mV

–77.3 mV

–92.2 mV

6-OHD A

Sham

B

C

1 s

25 mV

25 mV

0.3 scortical

stimulation

Str

*

A

40 µm

Fig. 1.4 In vivo intracellular recordings of striatal output neurons (i.e., MSN) in sham-lesioned

and 6-OHDA-lesioned rats. (A) Coronal sections immunolabeled against tyrosine hydroxylaseshow representative tissue from sham and 6-OHDA-lesioned animals. Neurobiotin stainingconfirms typical morphology of striatal MSN cells. (B andC) Striatal neurons from control and6-OHDA-lesioned animals displayed fluctuating membrane potentials, from a hyperpolarizingDOWN state to a depolarizing UP state. Compared to the sham group, striatal neurons from6-OHDA-lesioned animals display a more depolarized membrane potential, an increase inprobability of firing during the UP states. Thus, MSN in 6-OHDA animals are more responsiveto cortical stimulation as revealed by the shorter and the more depolarized membrane potentialduring the long-lasting hyperpolarizing–depolarizing phase that typically follows after themonosynaptic postsynaptic potential


anesthesia [56, 57, 88, 89]. Following chronic nigrostriatal lesions, neurons in thebasal ganglia display rhythmic burst firing, which is correlated to cortical slowwave activity [66, 70, 90, 91] (Fig. 1.2) and is strongly modulated by striatal DAreceptors [57, 68].

Altogether, these findings suggest that more excitable striatal MSNs can bedriven easily to the depolarized state and facilitate transmission of corticalrhythms to striatal target nuclei [81]. The mechanisms leading to these changesremain to be determined. Current knowledge suggests that both pre- and post-synaptic mechanisms account for the increased impact of cortical inputs onstriatal activity after chronic DA depletion [92–94].

Dopamine-Dependent Regulation of Cortically Driven Oscillatory

Activity in the Basal Ganglia and Akinesia

As described above, chronic nigrostriatal lesion increases the proportion ofbasal ganglia neurons showing rhythmic firing rate modulations coupled tocortical oscillations [67, 70, 74]. Similar coupling between cortical activity (i.e.,EEG and cortical field potential) at the STN and GPe has been reported inawake PD patients [95] and behaving rats with DA lesion [96]. Thus, it appearsthat the firing pattern of an important population of neurons in the basal gangliabecomes locked to cortical activity, an effect that may alter the coordination andselection of afferent signals required to establish specific task-directed behaviors[67, 97]. Consequently, an enhancement of this cortically dependent oscillatoryactivity could be associated to the emergence of motor deficits in PD such astremor, akinesia and rigidity [67, 97]. This is supported by the fact that inactiva-tion of the STN alleviates PD symptoms [18, 19, 98–100] and reduces theproportion of LFO units induced by chronic DA depletion in the basal ganglia[57, 68, 81].

DA receptor activation within the cortico-basal ganglia network alsoreduces the exaggerated cortically dependent oscillatory activity induced bychronic DA depletion [13, 68, 82, 96]. Therefore, it is possible that the emer-gence of cortically driven oscillatory activity in the basal ganglia occurs whenthe level of DA depletion is >70%, that is, when motor impairments in PDbecomes clinically evident. By examining the electrophysiological changes inthe output nuclei of animals with different degrees of DA cell loss, we foundthat this was the case. Cortically driven bursting activity in the basal gangliabecomes evident in animals with �70% of mesencephalic DA denervation(�75% in the SN and �55% in the ventral tegmental area [VTA]), but not inthose with �60% of DA lesion in the SNpc with an intact VTA [66] (Fig. 1.5).More importantly, animals with >95 and �70% DA cell loss exhibited similarstepping test deficits and electrophysiological changes. A similar relationshipwas also observed between the level of DA lesion and the appearance ofstepping deficits, a behavior test used to evaluate akinesia in rats [101–103].


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Fig. 1.5 Linking motor deficits, the degree of dopamine lesion and appearance of the abnormal

oscillations in the basal ganglia. (A) Stepping test deficits were not apparent in vehicle or 4 mg6-OHDA-lesioned groups, but were evident in 6 and 8 mg 6-OHDA-lesioned groups. (B) Therelationship between SN TH+ cell depletion and stepping performance (in the contralaterallimb) is demonstrated in this scatter plot. The shaded region shows the animals from the 6 and8 mg 6-OHDA-lesioned animals. (C) Double y-axis plot summarizing the relationship betweenthe mean interspike interval (ISI; left y-axis) and the proportion of LFO units (right y-axis).Different degrees of dopamine denervation can be obtained increasing doses of 6-OHDA.Animals in the 6 and 8 mg 6-OHDA-lesioned groups demonstrated a similar increase inproportion of LFO units andmean ISI, whereas animals in the 4 mg 6-OHDA-lesioned groupsdemonstrated similar proportions of LFO units and mean ISI to the vehicle group. (D & E)Scatter plots illustrate the relationship between the percentage of LFO units in relation to thelevel of dopamine denervation (i.e., number of TH+ cells in the SN) and the stepping testperformance (i.e., number of stepping adjustment). Open triangles represent animals fromvehicle and 4 mg 6-OHDA-lesioned groups. Solid triangles correspond to animals thatreceived 6 and 8 mg of 6-OHDA. (D) Animals with the greatest TH+ cell loss showed agreater proportion of LFO units. (E) Similarly, animals with deficits in stepping performanceshowed a greater proportion of LFO units. The solid lines indicate the second-order poly-nomial (D) and sigmoidal (E) (Boltzmann model) regression best fitted for all data points,respectively. Modified from Tseng et al [66]


These results indicate that the presence of cortically dependent oscillatory firingpattern in the basal ganglia after chronic DA depletion could be an importantpathophysiological feature of the parkinsonian state [66]. Thus, an appropriatelevel of DA signal is required to maintain the proper temporal coupling andtranslation of afferent activity between the thalamocortical system and thebasal ganglia nuclei.

Integration of the Motor-Limbic Circuits in the Basal Ganglia

One of the major roles of the basal ganglia is to integrate sensorimotor,associative and limbic information in the production of context-dependentbehaviors [104–107]. Traditionally, the dorsal division of the basal ganglia(dorsal striatum [ST], GP, STN and substantia nigra) is implicated in sensor-imotor control, whereas the ventral division (ventral striatum or nucleus accum-bens [NAc], ventral pallidum [VP] and ventral tegmental area) is associated tolimbic/cognitive functions. It is well known that the cerebral cortex and thebasal ganglia are functionally related via a multisynaptic loop [108]. As dis-cussed above, the information carried by the corticostriatal pathway is pro-cessed and integrated in the striatum and transmitted to the output nuclei viathe direct pathway or through the complex network interconnecting the GPeand STN, the indirect pathway. Despite the corticostriatal system, growingevidence indicates that a direct cortico-subthalamic pathway could convey simi-lar cortical information to the basal ganglia [65, 73, 87, 109–113]. Interestingly,the STN functions are not limited to motor coordination and movement con-trol. Whereas the lateral part of the STN receives projections from motorcortical areas, connections of the medial STN with the prefrontal cortex andthe limbic-associated regions of the basal ganglia [55, 114–117] emphasize thatthe STN also contributes to non-motor behavior [118, 119]. In a series of veryelegant experiments, Baunez and co-workers demonstrated that the STN playsa critical role in the regulation of impulsive actions as indicated by specificdeficits in reaction time tasks in animals with STN lesion [118–120]. Indeed, thenon-motor functions of the STN could reflect its reciprocal projections with theVP (Fig. 1.6), which receive corticolimbic information via the NAc [108, 117,121, 122]. In addition, a role of STN in spreading cortical rhythms to the basalganglia is also supported by two recent reports showing that (i) the proportionof rhythmic bursting neurons in the GPe is almost abolished after STN lesionsin 6-OHDA-lesioned rats [88] and (ii) the change in the STN activity following6-OHDA-lesions and cortical ablation is not associated with changes in GPneurons activity [74]. Taken together, it is tempting to speculate that the STN inconjunction with the dorsal and ventral striatum provides the two main path-ways through which cortical information is integrated in the basal ganglia.

In non-human primates DA depletion also shifted the firing pattern of basalganglia neurons from a non-oscillatory mode to a rhythmic burst firing [58, 59,


62, 123]. Similarly, a substantial proportion of neurons in the STN and GPe

exhibit oscillatory firing in patients with PD [124–127]. Despite that it has been

proposed that such oscillatory activity gives rise to tremor, it has been noticed in

the absence of tremor as well. Since bursting activity has been suggested to play

a specific role in synaptic plasticity and information processing [128], it seems

likely that the emergence of abnormal oscillatory activity in the basal ganglia

would result in inappropriate integration of excitatory/inhibitory inputs and

disruption of cortical information processing by promoting abnormal synchro-

nous activity within the thalamocortical network [129]. More importantly,

impairments in executive functions such as working memory and attention

deficits as well as difficulties in initiating goal-directed behaviors have been

frequently observed in PD [130, 131]. Although L-DOPA therapy in early PD

improves motor symptoms, its effects on cognitive performance are more

complex and controversial [132]. Both positive and negative effects have been

observed, suggesting that both motor and cognitive deficits in PD may or

may not share a common neuropathophysiological substrate [130, 131]. Thus,

2 s

LFO unit

0.5 s

non-LFO unit

STNGPe

GABA (–

)

GLU

(+)

GABA (–)

thalamus

DA

D2ENK (–)

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VP

D2(–)

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dorsal striatum ventral striatum

GPi/SNpr

GABA (–)

GLU (+) GLU (+) GLU (+)GLU (+)

Cortex

GLU (+) GLU (+)

GABA (–)

SNpc VTA

Fig. 1.6 An integrated functional cortico-basal ganglia–thalamocortical model that includes

neural circuits from motor and limbic structures. In the classic parkinsonian model of basalganglia circuitry (Fig. 1B) the effects of dopamine depletion is primary focus on the dorsalstriatum. However, dopamine depletion in PD takes place in both the SNpc and the VTA,changing both the dorsal and the ventral striatal circuits as well as the mesocortical regions. Inaddition, the subthalamic nucleus (STN) may play a critical role in mediating the integrationof information from sensorimotor and limbic-/cognitive-related regions of the cortex to thedorsal and ventral striata via reciprocal projection with the globus pallidus (GPe) and ventralpallidum (VP), respectively


DA-depletion-induced oscillatory activity may have a more general impact in

the genesis of the parkinsonian state that includes both motor impairments and

cognitive deficits.

Summary and Conclusions

Although the appearance of abnormal oscillatory activity observed in PD

resembles what happens in rats after 6-OHDA-induced lesions, the main fre-

quency of oscillatory activity in behaving animals (3–20 Hz) is higher than that

found in anesthetized 6-OHDA-lesioned rats (0.4–2 Hz) [67, 81]. If abnormal

spreading of cortical rhythms through the striatum and the STN underlies the

rhythmic firing pattern of output nuclei neurons in PD, the different oscillatory

activity observed in awake parkinsonian primates and anesthetized 6-OHDA-

lesioned rats may merely reflect the distinct dominant cortical frequencies

which characterize each behavioral state.In summary, DA plays a critical role in regulating the flow of cortical

information to the basal ganglia network. In PD, chronic DA depletion pro-

foundly alters the firing pattern of basal ganglia neurons and induces aberrant

signal coding of cortical information from the striatum and STN to the output

nuclei. Because neurons in the basal ganglia receive inputs from multiple

cortical and subcortical regions with different functions, and their outputs

also target cortical areas involved in cognition, the sensorimotor and cognitive

deficits observed in PD and animal models of parkinsonism could simply reflect

alterations in the integration and processing of cortical information [104].

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