Behavioural disorders induced by external globus pallidus dysfunction in primates: I. Behavioural study

DOI: 10.1093/brain/awh239 Brain Page 1 of 16

Behavioural disorders induced by externalglobus pallidus dysfunction in primatesII. Anatomical study

Chantal Francois, David Grabli, Kevin McCairn, Caroline Jan, Carine Karachi, Etienne-C. Hirsch,Jean Feger and Leon Tremblay

Correspondence to: Chantal Francois, INSERM U289,

Hopital de la Salpetriere, 47 Bd de l’Hopital, 75013,

Paris, France

E-mail: [email protected]

INSERM U289: Neurologie et Therapeutique

experimentale, Hopital de la Salpetriere, 47 Bd de

l’Hopital, 75651 Paris cedex 13, France

SummaryThe anatomical organization of the basal ganglia supports

their involvement in movement and behavioural disor-

ders. Thus dyskinesia, attention deficit with or without

hyperactivity, and stereotyped behaviour can be induced

by microinjections of bicuculline, a GABAergic antago-

nist, into different parts of the external globus pallidus

(GPe) in monkeys. The aim of the present study was todetermine the anatomo-functional circuits inside the basal

ganglia which are specifically related to each of these beha-

vioural changes. For that, axonal tracers were injected in

the same pallidal sites where abnormal behaviours have

previously been obtained by bicuculline microinjections.

The labelling was mapped in the different basal ganglia

and matched with the topography of the cortico-striato-

pallidal projections already reported in the literatureand with the distribution of calbindin immunoreactivity.

Our results first show that the pallidal sites related to

dyskinesia, attention deficit with or without hyperactivity,

and stereotyped behaviour, were respectively in motor,

associative and limbic territories, defined as weak, mod-

erate and intensive calbindin immunoreactivity. The same

relationship was observed between the distribution of the

labelling in the different basal ganglia after tracer injec-tions performed in these different pallidal sites and the

anatomo-functional territories. Thus regarding the origin

of the circuits within the striatum, tracer injections

performed in the dyskinesia site labelled neurons located

in the posterior sensorimotor putamen, those performed

in the hyperactivity and/or attention deficit labelled neu-

rons in the laterodorsal putamen and caudate nucleus,

regions corresponding to associative and anterior motor

territories, while those performed in the stereotyped beha-

viour site labelled neurons in the ventral limbic striatum.Regarding the GPe output on the basal ganglia, the

different circuits also appeared underlined by different

anatomo-functional territories, even if a partial overlap

exists. Each of these anatomical circuits systematically

involves both the internal globus pallidus (GPi) and the

substantia nigra pars reticulata (SNr) but, whereas

movement circuit is mainly related to the GPi, stereotyped

behaviour is mainly related to the SNr. Additionally,subregions of the subthalamic nucleus were also sys-

tematically involved, depending on the movement or

behavioural disorder produced. These results demon-

strate that distinct circuits involving different anatomo-

functional territories of the basal ganglia, with partial

overlap, participate in different behavioural disorders

in monkeys. It seems likely that these neuronal circuits

are involved in pathologies like Tourette’s syndrome,attention deficit/hyperactivity disorders and obsessional

compulsive troubles. This study provides the basis for

further researches with a therapeutical viewpoint.

Keywords: basal ganglia; monkeys; stereotypy; hyperactivity; attentional deficit

Abbreviations: AC = anterior commissure; ADHD = attention deficit/hyperactivity disorder; BDA = biotin dextran amine;

Cd = caudate nucleus; Cb = calbindin; GPe = external globus pallidus; GPi = internal globus pallidus; PC = posterior commissure;

SNr = substantia nigra pars reticulata; STN = subthalamic nucleus; WGA-HRP = wheat germ agglutinin conjugated to

horseradish peroxidase

Received January 26, 2004. Revised May 3, 2004. Accepted May 13, 2004

Brain # Guarantors of Brain 2004; all rights reserved

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IntroductionIt is well established that the origin and distribution of corti-

costriatal inputs allow us to subdivide the striatum into three

anatomo-functional territories. They are referred to respect-

ively as (i) sensorimotor territory processing sensorial and

motor information; (ii) associative territory processing cog-

nitive information; and (iii) limbic territory processing emo-

tional and motivational information (Alexander et al., 1986;

Parent and Hazrati, 1995b; Haber et al., 2000). These

anatomo-functional territories occupy distinct regions without

clear-cut boundaries between each of them (Parent and

Hazrati, 1995a; Haber et al., 2000). This partition in three

territories is maintained within the basal ganglia, especially in

the external globus pallidus (GPe) regarding the distribution

of the striatopallidal projections (Parent et al., 1984; Smith

and Parent, 1986; Haber et al., 1990; Saint-Cyr et al., 1990;

Hedreen and DeLong, 1991; Francois et al., 1994a). Such

anatomical organization allows us to speculate that activities

of some cortical area will affect the neuronal activity in the

corresponding striatal and pallidal territories.

Functional imaging studies (PET or functional MRI) in

humans suggest that abnormal activities in different parts

of the cortex and basal ganglia are present in various behav-

ioural disorders. It was reported that patients expressing

attention deficit/hyperactivity disorder (ADHD) have a

reduced metabolism in the prefrontal cortex and in the asso-

ciative part of the striatum (Castellanos et al., 1996; Filipek

et al., 1997; Rubia et al., 1999; Castellanos, 2001) and in the

pallidum as a unit (Aylward et al., 1996; Castellanos et al.,

1996). Tourette’s syndrome which is characterized by motor

(tics) and behavioural disorders such as obsessive-compulsive

disorder and ADHD (for a review, see Jankovic, 2001) is

marked by abnormalities in various parts of the cortex, stria-

tum and thalamus (Scarone et al., 1992; Peterson et al., 1993;

Singer et al., 1993; Hyde et al., 1995; Eidelberg et al., 1997;

Moriarty et al., 1997; Peterson, 2001). Thus in these various

behavioural disorders, the dysfunction seems limited to the

cortex and striatum, whereas the involvement of the other

components of the basal ganglia is not obviously mentioned.

Only one clinical study reported cases of obsessive-

compulsive disorder with an emphasis on the involvement

of a subcortical structure other than the striatum, since

these troubles are attributed to a bilateral lesion restricted

to the pallidum (Laplane et al., 1984, 1989).

Generally, the functional imaging approach has been, until

now, without sufficient resolution to distinguish small ana-

tomical structures or subterritories. Moreover, this approach

shows the structures where abnormal changes in activity

occur, but it does not allow us to determine which of them

is at the origin of such changes. In a complementary way, a

pharmacological approach using microinjection of a suitable

pharmacological agent in animals allows us to induce a local

disturbance of the neuronal activity within a given structure.

Then, it can be stated that a functional relationship of causality

exists between this part of the structure where a dysfunction is

induced and the expression of abnormal movements or

behavioural disorders. Indeed, we previously observed in

monkeys that microinjections of bicuculline, an antagonist

of GABAergic receptor, provoked abnormal movement

(dyskinesia) and behavioural disorders (hyperactivity, attention

deficit or stereotypy) dependent on the injection site into the

anatomo-functional part of the GPe (see Grabli et al., 2004).

The aim of the present study was to determine the ana-

tomical relationships between the origin of the inputs and the

distribution of the output pathways which are related to the

neuronal population localized in the GPe where microinjec-

tions of bicuculline have been able to induce abnormal move-

ments or behavioural disorders in monkeys. To circumvent

this question, injections of axonal tracers were performed in

different sites of the GPe where the most characteristic effects

have been obtained. This approach allowed us to determine

which anatomo-functional circuit is implicated in the different

behavioural disorders. The axonal tracers used ensured

retrograde tracing in the striatum, and thus opened the way

to correlate our results with the numerous data in the literature

concerning the corticostriatal projection and functional MRI

results in human pathology. The anterograde transport of

tracers allowed us to compare the detailed patterns of axonal

ending distribution at both the output structures of the basal

ganglia represented by the internal globus pallidus (GPi) and

the pars reticulata of the substantia nigra (SNr). We also

focused our attention on the subthalamic nucleus (STN),

another output structure of the GPe. The delineation of ana-

tomo-functional territories in the GPe, as well as in different

basal ganglia structures, has been performed according to the

distribution of calbindin (Cb) immunohistochemistry, which

was shown to be correlated with the delineation of anatomo-

functional territories in the striatopallidal complex (Francois

et al., 1994b; Karachi et al., 2002). More generally, the delin-

eation of anatomo-functional territories was compared with

afferent territories already published in the literature using a

tract-tracing method. These results have been previously

reported in an abstract form (Francois et al., 2002) and are com-

pleted by their behavioural counterparts in Grabli et al. (2004).

Materials and methodsSubjectsThree adult male African green monkeys (Cercopithecus aethiops;

H, A and B) were used in both behavioural and anatomical studies

and have been supplemented with the anatomical observations per-

formed on one macaque (Macaca mulatta MM33). They weighed

between 5 and 7 kg and were aged between 5 and 10 years, as

determined by their age at entry in captivity, dentition and hair

appearance. All studies were carried out in accordance with

European Communities Council Directive of 1986 (86/609/EEC).

The animals were kept under standard conditions (12-h light cycles,

23�C and 50% humidity).

Microinjections of bicuculline and behaviouralanalysisThe behavioural study described in Grabli et al. (2004) was con-

ducted to assess the effects of microinjection of bicuculline into the

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different functional territories of the GPe. Briefly, to perform these

microinjections and finally the injections of tracers, a stainless steel

chamber containing a perforated grid was first positioned above the

animal’s dura. For that, monkeys were first tranquillized with keta-

mine hydrochloride (10 mg/kg), then anaesthetized through intratra-

cheal intubation (fluothane 1%, nitrogen protoxide 50% and oxygen

50%). The chamber was positioned with reference to the anterior and

posterior commissures (AC and PC, respectively) visualized by ven-

triculography (Percheron et al., 1986). Since the chamber was fixed

on the skull with reference to the ventricular system of coordinates,

this device allowed us to perform all microinjections in reference to

the stereotaxic coordinates of the various parts of the GPe (for more

precise description of the experimental set-up device, see Grabli

et al., 2004).

In a first step, abnormal movements and behavioural disorders

were induced by microinjections of bicuculline in several parts of the

GPe in the two hemispheres of each monkey. Then microinjection

sites related to the most typical changes were selected for this

anatomical study.

Injections of axonal tracersInjections of axonal tracers were performed in each GPe of the three

African green monkeys studied when all behavioural studies were

achieved. They consisted of 0.1–0.2 ml of wheat germ agglutinin

conjugated to horseradish peroxidase (WGA-HRP; Sigma, St Louis,

MO, USA) 10% in 0.1 M phosphate buffered saline (PBS, 0.01 M,

pH 7.4), or of 0.5–0.8 ml of biotin dextran amine (BDA) diluted

(10%) in PBS (0.01 M, pH 7.4) injected using the same specific

device used for bicuculline micro-injection. Moreover, in order to

compensate the weakness of injection in one site (site no. 37 in

monkey H), BDA was also injected in the GPe of the experimental

case MM33 which was not involved in the behavioural studies. In

that case, the injection site was exactly at the same coordinates as

those of monkey H.

Three days (for HRP-WGA tracer) and 10 days (for BDA tracer)

after injections, the animals were deeply anaesthetized and replaced

in the stereotaxic frame as described above. Two vertical and two

horizontal metal rods (one in each hemisphere) were introduced into

the brain perpendicular and parallel, respectively, to the plane

passing through the two ventricular landmarks. These landmarks

allowed us to define two ventricular planes, transverse and horizon-

tal, in order to analyse the brains post-mortem according to the

stereotaxic landmarks. The monkeys were then perfused transcar-

dially with 400 ml of saline (0.9% at 37�C) followed by 5 l of 4%

paraformaldehyde (in 0.1 M PBS, pH 7.4 at 4�C) and 1 l of PBS with

5% sucrose. The brains were removed from the skull, rinsed in PBS

complemented with 10% sucrose for 1 day and 20% sucrose for

1 day, then frozen and cut into 50-mm-thick sections transversely

with reference to the ventricular anterior and posterior commissures

on a freezing microtome.

Histological processingOn all monkeys, Cb was revealed on regularly interspaced (one in

five) free-floating sections using a monoclonal antiserum raised

against Cb (Sigma) diluted to 1 : 1.000 for 48 h at 4�C under gentle

agitation. The primary antibodies were revealed using the ABC

method (diluted 1 : 100; Vector Laboratories, Burlingame, CA,

USA) using diaminobenzidine tetrahydrochloride (DAB; 0.05%)

as peroxidase chromogen.

For the revelation of BDA, all sections were pretreated with 1%

Triton X-100 in PBS, then incubated using avidin–biotin complex

staining (ABC, Elite, Vector Laboratories) in PBS with 1% Triton for

48 h at 4�C. Sections were treated with nickel (0.2%)-DAB (0.05%)

as peroxidase chromagen. Cell bodies could easily be visualized in

our material as biocytin occurs in trace in eukaryotic organisms

(Smith, 1992). WGA-HRP was revealed using the method previously

described by Mesulam (1978). Briefly, sections were abundantly

rinsed in 0.1 M PBS, then in acetate buffer. Preincubation was per-

formed in 0.1% nitroferricyanure (Sigma) and 0.005% 3,3-5,5 tetra-

methyl-benzidine (Sigma) solution for 15 min, and hydrogen peroxide

was added at a concentration of 0.02–0.04% for about 15 min. Sec-

tions were then counterstained with green methyl solution (0.25%).

Cartographic methodsContours of cerebral structures were traced under the microscope

with the aid of an XY plotter connected to the stage of the micro-

scope. The anteroposterior position of each section was given by the

anteriority of each section along the AC–PC axis, taking AC as

the origin of the system of axes. The dorsoventral axis was given

by the holes corresponding to the horizontal rods. The mediolateral

axis was perpendicular to the dorsoventral axis. All sections were

thus transformed into maps drawn in relation to the AC–PC system of

coordinates, and the contours of structures mapped in different mon-

keys could be directly compared. The limits of anatomo-functional

territories shown in published figures for the striatopallidal projec-

tion (Parent et al., 1984; Smith and Parent, 1986; Haber et al., 1990;

Saint-Cyr et al., 1990; Hedreen and DeLong, 1991; Hazrati and

Parent, 1992; Flaherty and Graybiel, 1994; Francois et al., 1994a)

were transferred onto the corresponding cerebral maps of our series

drawn from Cb material.

All cartographic data obtained from the left hemisphere of mon-

keys were transferred to the right hemisphere for an easier compar-

ison. The illustrations were scanned into a computer from camera

lucida drawings or charts and finished using Adobe Photoshop or

Microsoft PowerPoint software.

ResultsOverview of abnormal movement andbehavioural disorders induced by bicucullinemicroinjections into the GPeIn the three monkeys studied, microinjections of bicuculline

performed into various parts of the GPe induced three differ-

ent types of behavioural disorders. Thus injections in the

posterior and lateral part of the GPe induced abnormal move-

ment referred to as dyskinesia, those performed in the antero-

dorsal part of the GPe produced hyperactivity and/or attention

deficit, while stereotyped behaviours where obtained after

injections in the anterior and medioventral portion of the

GPe. For the present study, different sites of bicuculline

microinjections that produced the most characteristic behav-

ioural changes were chosen to perform injections of axonal

tracer. The localization of these microinjection sites is illus-

trated in Fig. 1A, and their behavioural effects induced in the

different monkeys are summarized in Table 1.

The effect obtained from site no. 3 in the right GPe of

monkey B (Fig. 1A) was leg dyskinesia without any

Abnormal behaviour and pallidal circuits Page 3 of 16


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behavioural modification (Table 1). This dyskinesia did not

modify the execution of the task. In the same monkey, site no.

21 in the left GPe (Fig. 1A) was retained as the injection of

bicuculline induced only a change in the spatial strategy in the

execution of the task, a trouble that we related to an attention

deficit. In monkey A, we have retained site no. 31 in the right

GPe, as it was associated with the production of a hyper-

activity with spatial strategy modification in the task, and

Fig. 1 Series of anteroposterior sequences of regularly interspaced transverse sections located with reference to the anterior commissuralreference point (AC) and centred on the pallidum. (A) Localization of sites of bicuculline microinjections within the GPe that produced themost characteristic behavioural changes and that were chosen to perform injections of axonal tracer. These pallidal sites elicited eitherstereotyped behaviour, or hyperactivity with attention deficit, or attention deficit alone, or abnormal movements. (B) Dark-fieldphotomicrographs of axonal tracer injections into four different cases (monkey A, left and right hemisphere, monkey B left and righthemisphere). (C) Dark-field photomicrographs of Cb-immunoreactive material. The distribution of immunoreactivity was directlycompared with the delineation of the functional territories of the striatopallidal complex (D) obtained by superimposition of data fromtracing studies in the literature (Parent et al., 1984; Smith and Parent, 1986; Haber et al., 1990; Saint-Cyr et al., 1990; Hedreen and DeLong,1991; Hazrati and Parent, 1992; Flaherty and Graybiel, 1994; Francois et al., 1994a) onto the same anteroposterior sequence of transversesections. The sensorimotor territory is represented in white, the associative territory in grey and the limbic territory in black. AC = anteriorcommissure; GPe = external globus pallidus; GPi = internal globus pallidus.



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site no. 46 in the left GPe which produced stereotypy (Table

1). Finally, in the third monkey, H, we chose to reproduce the

results obtained from monkey A, and thus selected site no. 26

right GPe which produced hyperactivity with spatial strategy

modification and site no. 37 left GPe which produced stereo-

typy (Fig. 1A and Table 1). However, in the last case (site no.

37), the injection of tracer performed was very small and

weak, and we have thus chosen to add another experimental

case (MM33) in which the axonal tracer was injected at the

same location in the GPe as in monkey H, but which was not

involved in the behavioural studies.

Relationship between the localization of theinjection sites and the pallidal territoriesAll injection sites of tracers performed in the GPe (Fig. 1B)

were compared with the distribution of Cb immunoreactivity

as seen on adjacent sections (Fig. 1C) and with the delineation

of anatomo-functional territories already reported in the lit-

erature (Fig. 1D). The Cb immunoreactivity was absent in the

posterior and lateral part of the GPe, and gradually increased

in the more anterior and medial part to reach a maximal

intensity in the most anterior and ventral parts (Fig. 1C).

The most posterior site of tracer injection where we pro-

duced abnormal movements (site no. 3) was laterally located

(AC-3.5; Fig. 1B), in a region characterized by a very weak

staining of Cb immunoreactivity (Fig. 1C), and corresponding

to the sensorimotor territory (Fig. 1D). The site in relation

with the expression of an attention deficit without hyperac-

tivity (site no. 21) was more anteriorly located in the GPe than

in the preceding case (AC-1.5; Fig. 1B). It lies in a region

characterized by a moderate staining in Cb reactivity (Fig. 1C)

and corresponding to the associative territory of the GPe at the

limit with the sensorimotor territory (Fig. 1D). The sites in

relation to the expression of an attention deficit with hyper-

activity (sites nos 26 and 31) were localized more anteriorly in

the GPe (AC-0.5; Fig. 1B) than the other site described pre-

viously. This GPe region was moderately to weakly stained

in Cb reactivity (Fig. 1C) and corresponded to the associative

territory for one site (no. 26) close to the most anterior part of

the sensorimotor territory for the other site (no. 31), the tran-

sition between both being progressive (Fig. 1C and D).

Finally, the sites chosen for tracer injection where microin-

jections elicited a stereotyped behaviour (stereotypy sites nos

37 and 46) were the most anteriorly and medially located in

the GPe (AC 0; Fig. 1B), in a region densely stained in Cb

reactivity (Fig. 1C) and which corresponded to the limbic

territory (Fig. 1D).

General labelling featuresIn all cases, retrogradely labelled cell bodies were found in the

striatum (Fig. 2A) where they were labelled in a Golgi-like

manner with filling of the whole dendritic trees (Fig. 2B and

C). Anterogradely labelled terminal axons were distributed in

the two output structures of the basal ganglia represented by

the GPi (Fig. 2D) and SNr (Fig. 2E). These labelled terminal

axons were characterized by numerous varicosities borne by

very thin, branched terminations (Fig. 2F). Intensely labelled

axons were also distributed within the STN (Fig. 2G, H and I).

The retrograde labelling observed in the STN as well as the

anterograde labelling in the striatum has not been considered

in the present study.

Retrograde and anterograde labelling relative toeach site within the GPeAfter injection of axonal tracer into site no. 3 of the GPe that

produced movement disorder, numerous retrogradely labelled

cells were distributed in the posterior and dorsal part of the

putamen (Fig. 3, grey). Anterogradely labelled terminal axons

were mainly distributed in posterior and central portions of the

GPi, whereas in the SNr, the other output of the basal ganglia,

the labelling was obviously less dense and was distributed in a

restricted anterolateral portion anteriorly and in a central part

more posteriorly. Anterogradely labelled terminals were also

largely distributed in the dorsolateral part of the STN.

After injection of axonal tracer in site no. 21 that produced

attention deficit site without hyperactivity, numerous retro-

gradely labelled cells were distributed in the striatum (Fig. 3,

black). They mainly occupied the dorsal portion of the puta-

men and of the caudate nucleus (Cd) from 4.75 anterior to AC

and 1.25 posterior to the AC. Anterogradely labelled terminal

axons were quite equally distributed in the two output struc-

tures from their anterior to their posterior extent. In the GPi,

they were observable in the lateral part anteriorly (AC-1.25)

and in its dorsal part posteriorly (AC-3.25), while in the

SNr, they were present in a ventral portion. Within the

STN, labelled terminals were mainly encountered in the

ventral portion.

When injections of tracer were performed in site no. 26

or no. 31 that produced hyperactivity and an attention deficit,

the distribution of retrograde and anterograde labelling was

obviously similar. Thus only case no. 31 in monkey A was

illustrated (Fig. 4, black). Retrogradely labelled cells were

located in the striatum occupying roughly the same antero-

posterior extent as in the preceding case (anterior ACþ 4.75

to posterior AC-0.25). However in that case, they were mainly

found in the dorsolateral part of the anterior putamen. Ante-

rogradely labelled terminal axons were distributed equally in

the two output structures of the basal ganglia, occupying their

central portion from anterior to posterior. Terminal axons also

occupied the mediodorsal portion of the anterior STN.

Finally injection of axonal tracers made in site no. 37 or no.

46 that produced stereotypy resulted in the same distribution

of labelling and only case no. 46 in monkey A was illustrated

(Fig. 4, grey). In these cases, retrogradely labelled cells were

found in the anterior part of the striatum, and more particu-

larly at the limit between the dorsal portion of the nucleus

accumbens and the ventral part of the head of the caudate

nucleus. As observed on striatal sections which were double

labelled for tracer and Cb, the labelled cells were mainly



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located in the matrix, thus outside striosomes (Fig. 2J and

K). Anterogradely labelled terminal axons were restricted to

a small anterior and medial portion of the GPi. On the

contrary, these terminals were more densely packed in the

other output structure, the SNr, where they occupied a large

part of the anteromedial portion. Labelled terminal axons

were also observed in the STN, but they were restricted to

the most anteromedial part. Contrary to the other cases,

injections of tracer within a pallidal site which induced

stereotypy also resulted in numerous labelled terminals

in the whole extent of the SN pars compacta (Figs 2L

and 4, grey).

Fig. 2 Light photomicrographs showing examples of retrograde and anterograde labelling in different basal ganglia. (A, B, C)Retrogradely labelled neurons in the putamen at different magnifications. (D) Anterograde labelled axons in the internal globus pallidusand (E) in the substantia nigra pars reticulata. (F) High magnification of anterogradely labelled varicose fibres in the internal globuspallidus. (G, H, I) Anterograde labelling in different portions of the subthalamic nucleus depending on the localization of the tracerwithin the external globus pallidus. (G) represents the pattern of distribution following injection in hyperactivity with attention deficit site(no. 31), (H) from injection in attention deficit site alone (no. 21) and (I) from injection in stereotypy site (no. 46). (J, K) Exampleof retrogradely labelled neurons in the matrix of the striatum. (L) Anterogradely labelled varicose fibres in the pars compacta of thesubstantia nigra following tracer injection in the ventral part of the GPe where microinjections elicited stereotypy. Arrows represent nigralcell bodies. Cd = caudate nucleus; GPe = external globus pallidus; GPi = internal globus pallidus; SNr = substantia nigra pars reticulata;STN = subthalamic nucleus.



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Comparison of the different neuronal networksIn order to compare these different neuronal networks under-

lying the input and output connections of the subregions of

the GPe described above, maps of the labelling distribution

obtained in different cases were transferred onto one hemi-

sphere of the monkey B (Fig. 5). Although the data were

derived from different experimental cases, they were deemed

to be comparable since all of the cerebral maps were related

Fig. 3 Distribution of labelling after injections of tracer into the sites of the external globus pallidus where microinjections elicited abnormalleg movements (Abn. mvt.) (no. 3, grey) and an attention deficit without hyperactivity (no. 21, black) in monkey B. Transverse sections areregularly interspaced from anterior to posterior and anteriorly located in reference to the anterior commissure (AC). Note that in two cases,labelled cell bodies (dots) were distributed in different parts of the putamen and of the caudate nucleus. Similarly anterogradely labelledaxons (sinuous lines) were seen in different parts of the internal globus pallidus, substantia nigra and subthalamic nucleus. The insert showsa high-power view of labelled terminal axons in the subthalamic nucleus. AC = anterior commissure; Acc = nucleus accumbens;Cd = caudate nucleus; GPe = external globus pallidus; GPi = internal globus pallidus; Pu = putamen; SNc = substantia nigra pars compacta;SNr = substantia nigra pars reticulata; STN = subthalamic nucleus.



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to the AC–PC stereotaxic coordinates system. From posterior

to anterior portions of the basal ganglia, it appeared that the

regions linked to abnormal movement circuit (yellow), were

the most caudally and laterally located in all the basal ganglia.

Moreover, the GPi appeared to be more linked to movement

disorder than the SNr. The two circuits underlying hyperac-

tivity and/or attention deficit were both more anteriorly

located. The circuit linked to the production of hyperactivity

Fig. 4 Distribution of labelling after injections of axonal tracer into the sites of the external globus pallidus where microinjections elicitedan hyperactivity associated to attention deficit (no. 31, black) and stereotypy (no. 46, grey) in monkey A. Transverse sections are regularlyinterspaced from anterior to posterior and anteriorly located in reference to the anterior commissure. Note that in two cases, labelled cellbodies (dots) were distributed in different parts of the putamen and of the caudate nucleus. Similarly anterogradely labelled axons (sinuouslines) were seen in different parts of the internal globus pallidus, substantia nigra and subthalamic nucleus. The insert shows a high-powerview of labelled terminal axons in the subthalamic nucleus. Same abbreviations as in Fig. 3.



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with attention deficit (black) tended to be more ventrally

located in the striatum and GPi than the circuit underlying

attention deficit circuit alone (green) while it occupied more

dorsal portions of the SNr and STN. However, in all structures

considered, the hyperactivity with attention deficit circuit

was partly superimposed on the attention deficit circuit

alone, as would be expected, but also on the movement dis-

order circuit, especially in the GPi (AC-2.25; Fig. 5) and in the

SNr (CA-6.25; Fig. 5). Finally, the regions linked to stereo-

typy (blue) were the most anteromedially located in all basal

ganglia with no superimposition with another circuit in any

part of the basal ganglia. Moreover, the SN as a whole (pars

Fig. 5 Comparison between the neuronal circuits which produced either abnormal movements (yellow), attention deficit alone (green),hyperactivity and attention deficit (grey) and stereotypy (blue), after tracer injections into different portions of the external globus pallidus.These circuits involve different portions of the caudate nucleus and putamen, of the internal globus pallidus, subthalamic nucleus andsubstantia nigra. Note a partial overlap between the different neuronal networks, especially in the internal globus pallidus and substantianigra. Same abbreviations as in Fig. 3.



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reticulata and compacta) appeared to be more linked to stereo-

typy than the GPi.

DiscussionBy using axonal tracer injected in restricted parts of the GPe,

where transitory behavioural disorders have previously been

produced by microinjection of bicuculline, we describe the

regions of the basal ganglia underlying these different behav-

ioural disorders. Basic principles that emerge are that (i) the

different behavioural disorders produced in monkeys are

underlined by different anatomical circuits within the basal

ganglia; (ii) these circuits involve different subregions of the

basal ganglia and appeared largely separated even if a partial

overlap exists within the output structures represented by the

GPi and SNr; (iii) each of these anatomical circuits system-

atically involves both the GPi and the SNr but not equally; (iv)

different subregions of the STN were also involved depending

on the movement or behavioural disorder produced.

Different structures of the basal gangliarelated to the GPeThe present tract-tracing study first confirms previous data

in monkeys concerning the retrograde labelling of cells in the

striatum and anterograde labelling of terminals within the

GPi, SNr and STN after tracer injection into the GPe

(Nauta and Mehler, 1966; Carpenter et al., 1968, 1981;

Hazrati et al., 1990; Shink et al., 1996). Indeed it had already

been reported that the pallidal terminals display large varico-

sities that were often closely apposed to the cell bodies and

proximal dendrites of STN, GPi and SNr (Sato et al., 2000).

The existence of preferential synaptic contacts with cell

bodies and proximal dendrites of SNr and entopeduncular

neurons in rats (the equivalent of the GPi of primates) has

been demonstrated using electron microscopy (Smith and

Bolam, 1991; Bolam and Smith, 1992). Altogether these

data suggest that all parts of the GPe project to the GPi

and SNr as well as to the STN. The present study confirms

such an organization, but also indicates that different

subregions of the GPe project to different anatomo-functional

territories of the basal ganglia. In such an organization, the

most anteromedial portion of the GPe appeared particular as it

was the only one subregion of the GPe which projects not only

to the SNr but also to the whole extent of the pars compacta.

As previously shown in monkeys, this projection appeared not

topographically organized (Haber et al., 1993).

The GPe was reported to also project to structures such

as the thalamic reticular nucleus and the pedunculopontine

nucleus, which are located outside of the basal ganglia. How-

ever, such projections are very sparse and even questioned

(Sato et al., 2000). This suggests that the different anatomo-

functional territories of the basal ganglia that were labelled in

our study are the main cerebral structures involved in the

behavioural effect produced. Our data are based on the deli-

neation of distinct anatomo-functional territories in the basal

ganglia as already done in the literature on the basis of tract-

tracing data and using the distribution of Cb immunoreactiv-

ity. Thus in the striatum and in the two pallidal segments,

but also in the SNr, the limbic territories were delineated

as regions of intense immunoreactivity, the associative terri-

tories as those of moderate Cb immunoreactivity, and the sen-

sorimotor territories as those of very weak immunoreactivity,

confirming previous data from our laboratory (Francois et al.,

1994b; Karachi et al., 2002). All these different anatomo-

functional territories of the pallidum and SNr appeared

implicated in circuits related to the expression of abnormal

movements and behavioural disorders. This is also the case

for the STN which thus appeared subdivided into different

functional subregions. This result may explain the role played

by the STN not only in motor control but also in cognitive and

motivational processes as reported in clinical and experi-

mental studies (Baunez and Robbins, 1997, 1999; Alegret

et al., 2001; Mallet et al., 2002; Funkiewiez et al., 2003).

In our study, it is not possible to determine if the extent of

the bicuculline injection site, and thus its physiological action,

can be superimposed on that of the axonal tracer injection

sites. However, injection of tracers performed within two

different sites of a given anatomo-functional territory of

the GPe where microinjections of bicuculline produced a

given behavioural effect, resulted in similar distribution of

labelling within the subregions of the basal ganglia. This thus

reinforces the result that every behavioural effect produced

is underlined by a given anatomo-functional subregion

within the basal ganglia.

Anatomical circuits underlying the movementand behavioural disordersRegions related to movement disorderThe present data first confirm that after injection of axonal

tracer into the posterior and central portion of the GPe where

microinjections produced leg dyskinesia, retrogradely

labelled cells were distributed in the posterior part of the

putamen. This striatal region is known to receive inputs

mainly from the motor, premotor and somatosensory cortex

(Kunzle, 1975; Flaherty and Graybiel, 1991; Inase et al.,

1996; Takada et al., 1998; Tokuno et al., 1999). These two

pallidal and striatal regions contain very weak Cb immuno-

reactivity, which is a characteristic feature of sensorimotor

territories (Francois et al., 1994b; Karachi et al., 2002). More-

over, we observed that the sensorimotor region of the GPe

projects to posterolateral parts of the SNr, but above all to

posterior portions of the GPi, all regions which are known to

receive inputs from the striatal sensorimotor territories

(Parent et al., 1984; Smith and Parent, 1986; Flaherty and

Graybiel, 1991, 1994; Hedreen and DeLong, 1991; Hazrati

and Parent, 1992; Francois et al., 1994a; Kaneda et al., 2002).

Electrophysiological evidence in support of the main sen-

sorimotor role of the GPi was provided by recording cells

after stimulation of motor cortical areas (Yoshida et al., 1993)



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and by retrograde transynaptic labelling of herpes virus from

motor cortical areas (Hoover and Strick, 1999). The dorso-

lateral portion of the STN where we found labelled GPe

terminations is also known to receive motor cortical

inputs (Nambu et al., 1996). It can thus be concluded that

movement disorder that can be induced by microinjection of

bicuculline in the GPe involves motor territories of all the

basal ganglia.

Regions related to hyperactivity and/or attentiondeficitThe striatal region occupied by neurons which project to the

GPe region where microinjections elicited spatial perturba-

tion in the task, suggesting attention deficit, without hyper-

activity (see Grabli et al., 2004) were located anteriorly in

dorsal portions of the putamen and of the caudate nucleus.

These striatal regions are reported to receive cortical inputs

from different areas: the associative parietal and dorsolateral

cortex (Yeterian and Pandya, 1991, 1993), the anterior part

of the motor and premotor cortex (Inase et al., 1996, 1999;

Takada et al., 1998), but above all the supplementary and

pre-supplementary motor areas (Inase et al., 1999; Kaneda

et al., 2002), the supplementary eye field (Shook et al., 1991;

Parthasarathy et al., 1992, Cui et al., 2003) and the motor

cingulate cortex (Takada et al., 2001). All these cortical areas

anterior to the primary motor cortex participate in cognitive

processes in addition to their well-known role in movement

planning and execution. In particular, the anterior part of the

premotor cortex, the dorsolateral prefrontal cortex and the

supplementary eye field which mainly project to the caudate

nucleus were reported to be specialized, among others, in

spatial attention (Corbetta et al., 1991; Corbetta and Shulman,

1998; Boussaoud, 2001).

Within the GPi, axonal fibres were located in the lateral part

anteriorly, and in its dorsal part posteriorly, while in the SNr

they were present in a ventral portion. These regions, which

appeared moderately stained on Cb immunoreactive sections,

were reported to receive striatal inputs from the most posterior

part of the associative territories, and from the most anterior

part of the sensorimotor territories (Parent et al., 1984; Smith

and Parent, 1986; Hedreen and DeLong, 1991; Hazrati and

Parent, 1992; Flaherty and Graybiel, 1994; Francois et al.,

1994a), and more specifically from striatal regions linked to

the supplementary motor area (Kaneda et al., 2002). These

regions contain neurons which are known to project via the

thalamus back to the associative prefrontal cortex as well as to

the supplementary and pre-supplementary motor cortex

(Middleton and Strick, 2000, 2002). Within the STN, axonal

fibres were confined to the anterior and ventral portion, in a

region known to receive cortical inputs mainly from the

supplementary and pre-supplementary motor areas (Takada

et al., 2001) but also, partly, from pre-supplementary and

supplementary eye field (Shook et al., 1991). Thus our results

certainly indicate that the attention deficit circuit alone is

underlined by subregions of the basal ganglia linked to the

cortical areas which play a major role in both motor planning

and attention processes.

Comparatively, hyperactivity with attention deficit circuit

involves roughly the same portions of the striatum, but the

labelling was slightly more ventrally located in the putamen

and did not reach the caudate nucleus. This striatal zone not

only receives cortical projection from the most anterior part of

the secondary motor areas such as the supplementary motor

cortex but also from the rostral cingulate motor cortex as

recently reported (Takada et al., 2001). Within the GPi,

GPe labelled axons occupied a more ventral portion, while

in the SNr they were more dorsally located than in the atten-

tion deficit circuit alone. As for the striatum, these regions,

and particularly that located in the GPi, tended to involve the

anterior part of the sensorimotor territories. The region impli-

cated in the STN was also more dorsally located than in the

preceding case and thus implicated a region which was

reported to receive inputs from the rostral cingulate motor

cortex (Takada et al., 2001). It may thus be concluded from

our results that the attention deficit with hyperactivity circuit

is underlined by subregions of the basal ganglia linked not

only to the supplementary and pre-supplementary motor areas

but also to the rostral cingulate motor cortex. These secondary

motor cortical areas are implicated not only in the execution

of the movement but also in higher-order cognitive aspects

of the movement such as motor selection or error detection

(Akkal et al., 2002; Isomura et al., 2003).

Even if it is difficult to compare attention deficit with

hyperactivity observed in monkeys with ADHD disorder

described in humans, it is interesting to note that functional

abnormalities in humans were visualized not only in prefron-

tal cortical areas (Amen et al., 1993; Amen and Carmichael,

1997; Spalletta et al., 2001) and more specifically in the

anterior cingulate cortex (Bush et al., 1999), but also in the

caudate nucleus (Castellanos et al., 1996; Filipek et al., 1997;

Rubia et al., 1999; Castellanos, 2001), in both caudate nucleus

and putamen (Vaidya et al., 1998; Teicher et al., 2000) and in

the pallidum as a unit (Aylward et al., 1996; Castellanos et al.,

1996). Our findings and these observations in humans strongly

suggest that ADHD as a whole represents a deficiency in parts

of the basal ganglia linked to associative prefrontal cortex and

to secondary motor cortical areas involved in attention pro-

cesses and motor planning.

Regions related to stereotyped behaviourThe striatal region labelled after injection of axonal tracer in

the region of the GPe where microinjections elicited a per-

sistent repetition of a single behaviour was ventromedial in

the striatum, in a region located at the limit between the dorsal

portion of the nucleus accumbens and the ventral part of the

head of the caudate nucleus. Even if neither cytoarchitectonic

nor immunohistochemical methods allows us to isolate the

nucleus accumbens from the other part of the striatum, this

striatal region is known to be the major structure that receives

limbic inputs from the orbitofrontal, anterior cingulate and



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insular cortices (Kunishio and Haber, 1994; Haber et al.,

1995; Chikama et al., 1997; Ferry et al., 2000), amygdala

and hippocampus (Russchen et al., 1985; Friedman et al.,

2002; Fudge and Haber, 2002), all regions which are

known to process emotional and motivational information.

The labelled GPe fibres originating in the site related to stereo-

typy occupied anterior and ventromedial located regions of

the GPi but above all of the SNr, regions which correspond to

limbic territories as seen on Cb-immunoreactive sections and

after comparison with a tracing study (Haber et al., 1990).

However it is clear from our results that the SNr is more linked

to limbic structures than the GPi. These regions of the output

structures of the basal ganglia are known to project to the

orbital frontal cortex via the medial part of the thalamus

(Ilinsky et al., 1985; Haber et al., 1993). In the STN,

which is free of Cb, the labelling region was also restricted

to the most rostromedial part of the nucleus, which confirms

the existence of a limbic pallidosubthalamic territory, as

recently described in our laboratory (C. Karachi, in press).

Our present anatomical evidence thus supports the early

suggestion that the pallidum could be involved in

obsessive-compulsive disorder as it was reported that

bilateral lesions in this structure can produce striking

obsessive-compulsive disorder-like behaviour (Laplane

et al., 1984, 1989).

Our data also confirm that one particular output target of

the ventral limbic GPe is represented by the dopaminergic

neurons of the SN pars compacta (Gerfen, 1992; Haber et al.,

1993; Lynd-Balta and Haber, 1994). These dopaminergic

neurons are considered to be the key for focusing attention

on significant and rewarding stimuli (Schultz, 1997). This

suggests an influence of the limbic GPe on the whole extent

of the striatum via the dopaminergic nigro-striatal projection

(Haber et al., 1993). Moreover, it was recently demonstrated

in the rat that striosomes, one of the two compartments of the

striatum which is thought to also project to the SNc (Graybiel,

1990; Gerfen, 1992), appear active when the animal performs

repetitive, stereotyped behaviours in response to dopamine

receptor agonists (Canales and Graybiel, 2000). The fact

that, in our study, neurons, labelled after injection in the

site where stereotypy was induced, were mainly found in

the matrix of the ventral striatum not in striosomes, suggests

that the output pathway of the matrix is also involved in

the production of stereotyped behaviour.

This stereotyped behaviour that was produced in our mon-

keys resembles tics and compulsive disorders described

in patients with Tourette’s syndrome or with obsessive-

compulsive disorder. Imaging studies from patients with

obsessive-compulsive disorder and with Tourette’s syndrome

reported abnormalities of volumes in the caudate nucleus

(Scarone et al., 1992; Peterson et al., 1993; Singer et al.,

1993; Hyde et al., 1995; Moriarty et al., 1997; Peterson,

2001). Abnormal neuronal activity has also been reported

at rest in the caudate nucleus but also in the ventral globus

pallidus, orbito-frontal and cingulate cortex (Eidelberg et al.,

1997; Rauch and Baxter, 1998; Saxena et al., 1998; Peterson,

2001; Rauch et al., 2001). Interestingly it was reported that

infusion of sera from patients with Tourette’s syndrome into

the ventral striatum of rats increased the rate of oral stereo-

typies (Taylor et al., 2002). Together, these data and our

present results provide strong evidence for an implication

of the limbic parts of all the basal ganglia in producing stereo-

typed behaviour.

Partial superimposition of the differentneuronal networksThere was no evidence of superimposition of the different

neuronal networks that produced abnormal behaviours and

movements within the striatum and the STN, except in limited

zones between the hyperactivity associated to attention deficit

circuit and the attention deficit circuit alone. On the other

hand, within the output structures of the basal ganglia, regions

which appeared linked to attention deficit alone overlapped

with some portions of the hyperactivity and attention deficit

circuits, as can be expected, but also with the movement

disorder circuit. This highly suggests the existence of a gra-

dient between movement, hyperactivity and attention deficit

circuits in the GPi and in the SNr. The notion that such a

gradient exists is supported by the existence of very long

dendrites especially in these two structures (Yelnik et al.,

1984, 1987), which allows convergence of information

coming from different functional striatal territories on a single

neuron. This was observed for pallidal neurons located in an

intermediate zone between the associative and the sensori-

motor territories and which respond to the stimulation of

both the caudate nucleus and the putamen (Tremblay and

Filion, 1989), and this may also be the case at the interface

between the limbic and associative territories. Such a pattern

gives the possibility of integration of functionally diverse

information, at least within the output structures of the

basal ganglia.

ConclusionOur approach allowed us to demonstrate that the different

behavioural disorders produced in monkeys by microinjec-

tions of bicuculline in different portions of the GPe are under-

lined by different anatomical circuits within the basal ganglia.

This provides strong evidence for the involvement of different

subregions of the basal ganglia (the two output structures:

GPi and SNr, and the STN) in producing abnormal movement

and behaviours. It can thus be hypothesized that different

portions of the basal ganglia organized in anatomo-functional

circuits play a role in the pathophysiology of syndromes such

as obsessive-compulsive disorder, Tourette’s syndrome or

ADHD. In such a hypothesis, these different subregions of

the basal ganglia could be considered as therapeutic targets.

Thus, high frequency stimulation, which is well known to

improve motor disorders of Parkinson’s disease when it is

centred in the sensorimotor territory of the STN (Yelnik



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et al., 2003) could also improve behavioural disorders when

other anatomo-functional subregions are targeted.

AcknowledgementsWe wish to thank Dominique Tande for expert participation

in surgical operations and immunohistochemical procedures,

and Nicholas Barton for checking the English. This work was

supported by the Institut National de la Sante et de la

Recherche Medicale (INSERM, France) and a grant from

The Tourette Syndrome Association (USA).

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Behavioural disorders induced by external globus pallidus dysfunction in primates: I. Behavioural study