Brain, Vol. 123, No. 7, 1442-1458,
July 2000
© 2000 Oxford University Press
The influence of excitotoxic basal ganglia lesions on motor performance in the common marmoset
Department of Experimental Psychology and Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, UK
Correspondence to:
A. Lisa Kendall, Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK E-mail: alk1001{at}cus.cam.ac.uk
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Abstract |
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Huntington's disease is a genetically inherited neurodegenerative disorder for which currently there is no effective treatment or cure. In order to gauge the potential therapeutic benefits of neuroprotective or restorative treatments, it is necessary to create an animal model that is associated with readily measurable and long-lasting functional impairments. The undifferentiated neostriatum and limited behavioural repertoire of rodents have led to the extension of our investigations into the common marmoset. We have used quinolinic acid to create unilateral excitotoxic lesions of the caudate nucleus or the putamen in this small non-human primate. Following rigorous investigation of each monkey on a battery of behavioural tests, we found that the unilateral putamen lesion was associated with a contralateral motor impairment that persisted for at least 9 months and withstood repeated testing. However, the unilateral caudate nucleus lesion did not appear to be associated with any detectable motor deficit. The stability and the reproducibility of the unilateral putamen lesion in the marmoset provide a suitable tool for the investigation of potential treatments for neurodegenerative disorders that attack this region of the brain.
striation; Huntington's disease; excitotoxin; primate
DARPP-32 = dopamine and adenosine-3' 5' -monophosphate-regulated phosphoprotein; GFAP = glial fibrillary acidic protein; TBS = Tris-buffered saline
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Introduction |
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The basal ganglia are a group of subcortical nuclei that are involved in the parallel processing of descending cortical information that is relayed back to the cortex via the thalamus (Alexander et al., 1986
; Alexander and Crutcher, 1990a; Wichmann and DeLong, 1996). Human and animal studies have demonstrated an involvement of the basal ganglia in motor sequencing, response selection and attentional processes (Alexander, 1994; Graybiel, 1998; Jueptner and Weiller, 1998; Lawrence et al., 1998). We owe much of our understanding of the role of the basal ganglia to the knowledge gained from various neurodegenerative disorders such as Parkinson's disease and Huntington's disease. The dopamine depletion associated with the loss of nigrostriatal neurons in Parkinson's disease produces a clinical syndrome that includes tremor, bradykinesia and impairments in gait and movement initiation (for a review, see Lang and Lozano, 1998). Similarly, striatal pathology in Huntington's disease is associated with a complex disorder where patients exhibit motor, cognitive and psychiatric disturbances (Vonsattel et al., 1985; de la Monte et al., 1988; Sharp and Ross, 1996; Harper, 1996).
Huntington's disease is a genetically inherited disorder for which currently there is no effective treatment or cure (Huntington's Disease Collaborative Research Group, 1993; Aronin et al., 1999; Reddy et al., 1999). One feature of Huntington's disease that has received much attention is that, early in the course of the disease, there is a loss of the striatal medium spiny GABAergic projection neurons (Vonsattel and DiFiglia, 1998) yet the NADPH-diaphorase/neuropeptide Y/somatostatin aspiny interneurons and the large cholinergic interneurons remain relatively preserved (Ferrante et al., 1987; Beal et al., 1988). In parallel, it was found that intra-striatal injections of the endogenous NMDA (N-methyl-D-aspartate) agonist quinolinic acid produced lesions that had a necrotic core but around that core was a transition zone where the neuropeptide Y/somatostatin and the cholinergic neurons were selectively spared (Beal et al., 1986, 1989). This, and the fact that there is a loss of putaminal NMDA receptors early in the course of the disease, led to the suggestion that the cells actually may succumb by way of an excitotoxic mechanism (Kowall et al., 1987; Young et al., 1988). Since that discovery, quinolinic acid has been used to investigate the anatomical and functional consequences of striatal lesions in both rodents and primates (for examples, see Sanberg et al., 1989; Block et al., 1993; Ferrante et al., 1993; Storey et al., 1994; Brasted et al., 1998). However, in primate studies, there has been relatively little investigation of the long-term, non-drug-induced behavioural effects of excitotoxic striatal lesions. Instead, the main aim has been to concentrate upon the development of primate models that exhibit the chorea and dyskinesia frequently seen in the early course of Huntington's disease (Hantraye et al., 1990; Kanazawa et al., 1990; Burns et al., 1995).
The present study was undertaken to provide a direct comparison of the functional and anatomical consequences of unilateral quinolinic acid lesions of the caudate nucleus or the putamen in the common marmoset. We wish to develop a striatal lesion that is associated with long-lasting and readily measurable functional deficits that can be used as a stable baseline against which to gauge the potential therapeutic benefits of neural transplantation and neuroprotective strategies. The use of unilateral lesions allows each animal to act as its own control, allows explicit comparison between the functional effects of selective caudate versus putamen lesions, and leaves one side of the brain intact to reduce the general debility associated with bilateral damage. We report on the utility of an extensive battery of motor function tests, first developed to investigate the effects of unilateral nigrostriatal lesions and middle cerebral artery occlusions in the marmoset (Annett et al., 1992a, 1994; Marshall and Ridley, 1996), to characterize the deficits associated with selective striatal lesions in the marmoset.
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Methods |
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Quinolinic acid lesions
Twelve common marmosets (Callithrix jacchus), seven males and five females, aged between 2 and 3 years were used in this study. The animals were housed in a temperature-controlled room (25 ± 2°C) that was kept on a 12 h light–12 h dark cycle. The monkeys were fed daily on specially prepared sandwiches (containing egg, high protein diet supplement and powdered primate pellets) and one piece of apple or banana, plus once weekly forage mixes. All monkeys had free access to water. All of the experimental procedures, and the animals' health and welfare, were monitored in accordance with the UK Animals (Scientific Procedures) Act 1986 and associated codes of practice.
Prior to the lesion, each monkey was pre-trained and tested on all of the behavioural measures except for apomorphine rotation (see below). The monkeys were divided into three groups of four, caudate (C15, C16, C22 and C24), putamen (P12, P14, P20 and P21) and sham, where two of the sham monkeys received sham surgery according to the caudate protocol (SC18 and SC25) and the other two according to the putamen protocol (SP17 and SP23). After pre-medication with 0.05 ml of ketamine (Vetalar®, Parke-Davis Veterinary), stereotaxic surgery was conducted under Saffan® (Pitman-Moore, UK) anaesthesia at a dose of 0.1 ml/100 g. The caudate group received 10 injections of 0.15–0.25 µl of 0.1 M quinolinic acid (Sigma), in 0.1 M phosphate buffer (pH 7.4), and the final amount of toxin injected was 200 nmol. The lesion coordinates were based on the marmoset atlas of Stephan and colleagues (Stephan et al., 1980) and are given in Table 1. The putamen group received 205 nmol quinolic acid delivered in 11 injections of 0.15–0.25 µl of 0.1 M quinolic acid (coordinates in Table 1). The sham-operated monkeys were injected with appropriate volumes of 0.1 M phosphate buffer (pH 7.4). All of the injections were conducted using a 2 µl Hamilton syringe with a 28 gauge dome-tipped needle, and the toxin or vehicle was injected at a rate of 0.1 µl per min. Any postoperative seizures were controlled using 0.05–0.2 ml injections of diazepam (Valium, Roche, 5 mg/ml), and the monkeys were kept in a darkened room until the following day when, once fully recovered, they were returned to the home cage.
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Behavioural analysis of unilateral striatal lesions in the marmoset
The staircase task
The staircase apparatus consists of a Perspex© box fitted onto the home cage door (illustrated in Fig. 1A
). A central divider prevents the animals reaching across the front of the apparatus, and a triangular segment fitted at the back of the box reduces movements to the sides, providing separate measures for the reaching ability of each hand without the need for restraint (Marshall and Ridley, 1996). The monkeys were trained to retrieve small pieces of bread soaked in glucose syrup, and one reward was placed on each step on the left and/or right staircase. The monkeys were allowed a maximum time of 300 s to clear the staircase for both bilateral and unilateral trials. This task required minimal pre-training and was conducted pre-lesion and on a monthly basis up to 10 months post-lesion. Each test session was conducted such that a bilateral trial was followed by two unilateral trials (one on each side) and this was repeated twice such that the monkey performed nine trials and had to retrieve a total of 60 rewards. All test sessions were videotaped to allow full analysis of all aspects of the monkeys' performance.
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The central staircase task
This task involved a slight modification to the apparatus used in the standard staircase task such that there was only one central opening into the front and each stair ascended up the lateral edge of the Perspex© (see Fig. 1B
). The single, central, opening means that the monkey had to perform crossover reaches such that the ipsilateral hand had to reach into the contralateral half of the monkey's body space thereby allowing a direct measurement of sensorimotor neglect to complement the motor assessment performed in the previous task. The rewards were the same and the monkey was still allowed 300 s per trial, but this time each of the six trials per session was bilateral. This task was conducted with the same frequency as the staircase task, and all test sessions were videotaped.
Tube reaching task
The next test of skilled motor function was a tube reaching task (Annett et al., 1994). This provides a more stringent assessment of individual hand-reaching ability while restricting use of the opposite hand. The opposite hand was wrapped in gauze that was then fixed in place using sticking plaster. The monkeys used their free hand to reach into a tube where sugared bread rewards were placed inside a small, 16 mm diameter, tube and the monkey was allowed a maximum of 2 min to retrieve the reward. Each monkey undertook a series of trials at different reaching distances, starting at 1 cm and increasing in 1 cm steps to a maximum of 6 cm. This task was conducted pre-lesion and at 1, 2, 3, 6 and 9 months post-lesion.
Sticky label task
This task is a sensitive measure of sensorimotor neglect as well as motor coordination and has been used extensively to assess the functional consequences of dopamine depletion in rats and marmosets (Schallert et al., 1982; Annett et al., 1992a, 1994). A cuff of adhesive postal label ~6 cm long and 2 cm wide was wrapped around each foot, the monkey was returned to the home cage and then allowed a maximum of 10 min to remove each label. The investigator observed from in front of the cage and recorded the times of contact and removal as well as the number of bites and scratches taken to remove each label. This task was performed pre-lesion and at 1, 2, 3, 6 and 9 months post-lesion.
Rotation
Although the exact mechanism which causes rotation is unknown, it has been shown that excitotoxic lesions, which destroy intrinsic striatal output neurons, induce an ipsilateral rotation bias following activation by either direct (e.g. apomorphine) or indirect (e.g. amphetamine) dopamine agonists in rats (Schwarcz et al., 1979; Dunnett et al., 1988). Three separate measures of rotational bias were used in this study, and for each assessment the monkey was placed in a specially designed observation cage (43 x 55 x 44 cm internal dimensions) that had a clear front and top to allow filming. Prior to the start of all rotation tests, each monkey was placed in the observation cage on at least six separate occasions for a total of at least 3 h for habituation to the cage, the video camera, the lighting and the room. Drug-independent rotation was measured by injecting 0.1 ml/300 g of 0.9% saline intramuscularly and then the monkey was placed in the observation cage for 60 min after the injection. The effects of dopamine imbalance were measured using two drugs and there was at least 3 days between the administration of either of the drugs. The mixed dopamine agonist apomorphine (apomorphine-HCl, Sigma) was injected at a dose of 0.5 mg/kg intramuscularly and the monkey was observed for 60 min. The indirect agonist amphetamine (D-amphetamine, Sigma) was also injected at a dose of 0.5 mg/kg intramuscularly but this time the monkey was first returned to the home cage for 30 min and then placed in the observation cage for a 30 min filming period. For all three rotational measures, the total number of 360° turns recorded on the videotape was counted and the net rotation score was calculated (ipsilateral–contralateral). Saline and amphetamine measures were conducted pre-lesion and all three rotation measures were conducted at 1, 2, 3, 6 and 9 months post-lesion. Apomorphine rotation was not measured pre-lesion as this dose is particularly high and high levels of apomorphine can be associated with distressing behaviours in the intact marmoset (Ridley et al., 1980). However, in pilot studies, it was the only dose found to result in consistent levels of ipsilateral rotation.
Anatomy of unilateral striatal lesions in the marmoset
Following completion of the behavioural assessments, the marmosets were terminally anaesthetized with a lethal dose of barbiturate (Expiral) and transcardially perfused with a pre-wash solution of 0.1 M phosphate buffer followed by 4% paraformaldehyde which was prepared in 0.1 M phosphate buffer at pH 7.3. After fixation, the brains were removed and then post-fixed in paraformaldehyde for 24 h. The brains were cryopreserved in a 25% sucrose solution until they sank, and then were sectioned on a freezing microtome at a thickness of 60 µm. One in six sections were stained using a Nissl stain (1% cresyl fast violet) for the assessment of cell viability and general morphology. A second series of sections (1 : 6) were stained using a modified thiocholine silver precipitation method (Koelle, 1955) to visualize the activity of acetylcholinesterase (AChE; for protocol see Fricker et al., 1997a). Immunohistochemical staining was conducted on free-floating sections. The sections (1 : 12 series) were quenched with 10% hydrogen peroxide/10% methanol in distilled water, washed three times in Tris-buffered saline (TBS), pH 7.4, and then placed in TBS, containing 3% normal goat serum/0.2% Triton-X 100, for 1 h before three further washes in TBS. Antibodies were diluted in TBS containing 1% normal goat serum/0.2% Triton-X 100.
Sections were then incubated for 60 h at 4°C in primary antibodies to dopamine- and adenosine-3':5'-monophosphate-regulated phosphoprotein (DARPP-32, 1 : 20 000, a kind gift from Drs P. Greengard and H. Hemmings), tyrosine hydroxylase (1 : 3000, Institute Jacques Boy, France) and glial fibrillary acidic protein (GFAP, 1 : 2000, DAKO). This was followed by three further washes with TBS and incubation in either goat anti-mouse or goat anti-rabbit biotinylated secondary antibodies (DAKO, UK) for 2 h. After further washing in TBS, the sections were incubated in streptavidin–biotin complex (Vectastain ABC kit, Vector Laboratories, Burlingame, Calif., USA) in TBS for 1.5 h. Sections were washed in TBS followed by Tris non-saline buffer, pH 7.4, and then developed in a 1 : 20 diaminobenzidine solution (Sigma) with 0.002% hydrogen peroxide. Sections were mounted on gelatin-coated slides, dehydrated in alcohols, cleared in xylene and coverslipped using DPX mountant.
The areas of remaining tissue on the lesioned side and the areas of intact caudate nucleus and putamen on the non-lesioned side were measured on DARPP-32-stained sections using a Seescan image analysis system (Seescan Image Analysis, Cambridge). A line was traced around the outer edge of the caudate or the putamen using 1 : 6 sections from the most rostral extent of each region to the post-commissural level of 7.5 as defined on the atlas of Stephan and colleagues (Stephan et al., 1980). A threshold function was used to standardize the signal obtained from the DARPP-32-positive areas. The area (in mm2) was then used to estimate caudate or putamen volume as the sum of cross-sectional areas multiplied by the distance interval between measured sections.
Statistical analyses
Full analysis was conducted using two or three factor analyses of variance with the three groups as the between-subject factor and the test session time points and ipsilateral versus contralateral as within-subject factors. All analyses were performed using Genstat 5 software. Where appropriate, post hoc analyses were performed by Newman–Keuls (and associated t-tests) to correct for multiple comparisons.
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Results |
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Behaviour
In the immediate post-lesion phase, the putamen-lesioned monkeys exhibited contralateral limb dystonia which persisted for 24–48 h after the surgery. After that time, none of the lesioned monkeys exhibited any noticeable limb weakness and all monkeys maintained a constant, healthy body weight. There was no evidence of spontaneous dyskinesias as reported in lesion studies with larger primates (Brownell et al., 1994
; Storey et al., 1994; Burns et al., 1995). One of the sham-lesioned monkeys (caudate protocol) had to be killed at 8 months post-surgery because of an unrelated illness and, consequently, there are behavioural data for only three sham monkeys for months 8–10. The most marked motor impairments detected on each behavioural task were in the putamen-lesioned group. In contrast, the caudate-lesioned monkeys appeared to exhibit little or no sensorimotor deficits. The deficits shown by the putamen-lesioned monkeys were immediately apparent on the first post-lesion assessment at 1 month and, despite some minor practice effects, particularly on the staircases, the deficits were relatively stable up to 9 and 10 months post-lesion. The putamen-lesioned monkeys did not exhibit any noticeable spontaneous motor deficits apart from occasional fitting that sometimes was triggered by handling or excitement about testing.
The staircase task
On the staircase task, the putamen-lesioned monkeys exhibited significant difficulties in using their contralateral hand and arm to pick up and remove the small rewards from the contralateral side. As shown in Fig. 2A, the latency to clear the contralateral side was significantly increased in comparison with the ipsilateral side and also in comparison with the other two groups [tests x sides x groups interaction F(20,87) = 2.15, P < 0.01]. There was no significant difference between the groups for the latency to clear the ipsilateral side, which contrasts with the paw-reaching task used in rats where striatal lesions are associated with significant reaching impairments on both sides (Fricker et al., 1997b). Detailed analysis of the videotapes revealed a number of interesting features about each of the lesion groups' performances. The putamen lesion was associated with a significant clumsiness such that the contralateral hand grabbed repeatedly to try and pick up the reward and frequently dropped the reward before finally removing it from the staircase (referred to as `reaches'). The reach numbers are shown in Fig. 2B, and the putamen-lesioned group made, on average, more than twice the number of reaches of the caudate and sham groups when clearing the contralateral side [sides x groups interaction F(2,9) = 10.60, P < 0.01]. The practice effect exhibited by each group on this task was most noticeable on a measurement, referred to as fast clears, where the reward was removed in 1 s or less after contact. Figure 2C shows the fast clears for all three groups, and as each monkey's performance improved the number increased, except for the contralateral side measurements of the putamen-lesioned group, which remained significantly low at <2 per trial [tests x groups interaction F(4,8) = 7.17, P < 0.01]. It is interesting to note that even with this more detailed analysis of the performance of each monkey, no impairments were detected in any of the measurements for the caudate nucleus-lesioned monkeys.
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The central staircase task
A similar pattern of impairments was detected on the central staircase but, because the putamen-lesioned monkeys used their ipsilateral hands to clear many of the lower pieces on the `wrong' side, the latencies to clear the ipsilateral side (where normally the contralateral hand would be used) were much faster than expected [Fig. 3A
; sides x groups interaction, F(2,9) = 4.63, P < 0.05]. The clumsiness was still very much in evidence on this task, and the number of reaches taken by the contralateral hand was significantly greater than those taken by the ipsilateral hand and each hand of the other two groups [data not shown; tests x sides x groups, F(8,35) = 2.80, P < 0.05]. Similarly the lower number of fast clears supported the dominance of the motor impairment exhibited by the contralateral hand in the putamen-lesioned group [Fig. 3B; tests x sides x groups interaction, F(8,35) = 2.40, P < 0.05]. The value of this task is that the monkey must use its ipsilateral hand in the contralateral body space such that any sensory neglect would affect performance on the contralateral side. If the deficit is predominantly motor, it would be expected that the time taken to clear rewards by the contralateral hand would be greater than that taken by the ipsilateral hand, regardless of the fact that the monkey is working in ipsilateral body space, and Fig. 3A shows that this was indeed the case. One way in which neglect might be detected is in the latency to contact each side for the first time, such that a monkey exhibiting neglect would contact the ipsilateral side first even though it was using its contralateral hand; however, analysis of this first contact also did not reveal any evidence of neglect in any of the groups [data not shown; tests x sides x groups, F(8,35) = 1.29, NS]. Both of the staircases clearly demonstrated that the putamen lesion is associated with a significant motor impairment with no evidence to suggest any overt sensory neglect.
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Tube reaching task
The tube reaching task further confirmed the existence of a significant motor impairment after a unilateral putamen lesion but not after a caudate lesion. Figure 4
shows the maximum distance reached by the contralateral hand. The distance reached by the putamen group was 3 cm or less, which was in contrast to the maximum 6 cm reached by the other two groups [tests x groups interaction, F(10,44) = 8.65, P < 0.001].
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Sticky label task
In the sticky label task (Fig. 5
), there werex no overall differences between the three groups or between the time taken to contact or remove the ipsilateral or the contralateral label in the putamen group [contact data: tests x sides x groups, F(10,44) = 1.00, NS]. This test has been used previously to demonstrate sensory neglect in both rats and marmosets (Schallert et al., 1982; Annett et al., 1992), and the lack of difference between the two sides in the putamen group supports the data in the staircase tasks suggesting that this lesion produces little overt sensory neglect.
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Rotation
The rotation measurements were extremely variable for all three groups, and only the apomorphine-induced rotation yielded a consistent post-lesion effect. Figure 6A
shows the rotation measured for 60 min after a saline injection and, despite some contralateral rotation evident in the caudate-lesioned group, there was no overall significant difference between the groups, nor was there a significant effect of the lesion [tests x groups interaction, F(10,44) = 0.7, NS]. Figure 6B shows that the contralateral bias exhibited by the caudate-lesioned monkeys was also evident after the administration of amphetamine and, as the direction was maintained post-lesion with some increase in the overall number of turns, this effect was significant [tests x groups, F(10,38) = 2.36, P < 0.05]. However, closer inspection of individual monkey performances showed that this contralateral bias in both saline and amphetamine rotation was due to the extremely large number of turns exhibited by only one monkey in this group. The putamen lesion was not associated with any significant degree of rotation after either saline or amphetamine administration.
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Apomorphine administration produced a profound ipsilateral bias in the putamen lesion (Fig. 7
) as well as a smaller bias in both the caudate and the sham group. There was a significant difference between the three groups, as the number of turns exhibited by the putamen-lesioned monkeys exceeded 200 in comparison with <50 turns seen in the other two groups [groups, F(2,9) = 10.84, P < 0.01]. The small number of turns exhibited by the sham and caudate groups is probably related to the non-specific effects of apomorphine on the overall activity of the monkeys (Ridley et al., 1980), but it is interesting that this cancelled the contralateral bias seen previously in the caudate group. There was no overall tests by groups interaction [F(4,8) = 0.42, NS], suggesting that the apomorphine tests were performed far enough apart to avoid the conditioning and sensitization effects seen in other studies (Annett et al., 1992).
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In previous striatal lesion studies with large primates, the same dose of apomorphine has been used to elicit dyskinesias (Burns et al., 1995
). Although there were no overt dyskinesias seen in the present study, the putamen-lesioned monkeys did exhibit marked contralateral arm and hand dystonia as well as some oro-facial dyskinesias during the acute drug phase. Neither the sham nor the caudate monkeys exhibited any detectable dystonia, but there were occasional repetitive behaviour patterns, such as licking the front panel of the cage, which were probably related to the high dose used in this study. At the end of the study, lower doses of apomorphine were used (0.05 and 0.1 mg/kg, 10 months post-lesion); in the caudate monkeys, the contralateral bias evident in the saline and amphetamine measurements returned and there were no stereotypies. The lower doses did still produce ipsilateral rotation in the putamen-lesioned monkeys but to a much lower degree (0.05 mg/kg mean net score = 15.67 ± 6.89; 0.1 mg/kg mean net score = 44.00 ± 29.36). In summary the behavioural analysis of the effects of unilateral caudate nucleus lesions demonstrated that there were no significant motor impairments nor was there any evidence of sensory neglect, but there was a slight tendency to rotate in a contralateral direction. The functional consequences of a unilateral putamen lesion were extremely marked and persisted for the entire post-lesion assessment period. The monkeys exhibited a significant impairment in the complex sequencing of motor actions with the contralateral arm and hand as well as a marked degree of ipsilateral rotation in response to apomorphine, but there was no evidence of sensory neglect.
Histology
In the sham-lesioned monkeys, the needle tracks were detectable in those sections that were stained with Nissl and GFAP, but there was no overt cell loss (see Fig. 8A and D). Levels of immunoreactivity for DARPP-32 and tyrosine hydroxylase were not altered in any of the sham-operated brains (Fig. 8, top row). There was, however, limited damage to the superficial layers of the overlying cortical region that may have been related to subdural scar tissue at the cortical surface associated with multiple needle penetrations.
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The caudate lesions generally spared the most anterior portion of the head and tail segments, but the body of the caudate was significantly reduced, with a corresponding collapse of the nearby brain regions and ventricular enlargement. The significant loss of tissue from the caudate region meant that the most appropriate lesion assessment procedure was to calculate the volume of remaining tissue rather than to count the actual numbers of neurons. Lesion assessments were performed on DARPP-32-stained sections (see Figs 8G and 9
), and the ratios of lesion/intact caudate, and putamen, are shown in Table 2. As can be seen in Fig. 9, all four of the monkeys in this group had comparable lesions that were located in the medial portion of the body of the caudate nucleus. The lateral part of the caudate nucleus was spared, particularly in monkeys C16 and C24. There was some additional atrophy in the medial globus pallidus mostly related to the loss of efferent striato-pallidal fibres. There was a reduction in tyrosine hydroxylase immunoreactivity that mirrored the loss of DARPP-32 and, although the brains were perfused at 12 months post-lesion, the lesioned hemispheres were still intensely gliotic (see Fig. 8, middle row).
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All four of the putamen-lesioned monkeys had very extensive lesions that encompassed all except the most rostral and the most caudal portions of the putamen region (see Figs 8 and 10
). As with the caudate lesions, the loss of tissue was so complete that the surrounding structures collapsed into the vacated space and there was considerable ventricular enlargement. In accordance with the significant loss of tissue, there were reductions in DARPP-32 and tyrosine hydroxylase immunoreactivity and in AChE staining (see Fig. 8, bottom row). The reductions in caudate and putamen volumes in all three groups were compared and there was a significant volume x groups interaction [F(2,8) = 80.76, P < 0.001] related to the loss of DARPP-32 immunoreactivity in the respective areas for the caudate-lesioned and the putamen-lesioned groups. Post hoc analyses confirmed that were was no significant reduction in DARPP-32 staining in the caudate nucleus of the putamen-lesioned monkeys and there was no significant loss of DARPP-32 staining in the putamen of caudate-lesioned monkeys. As shown in Fig. 10, the putamen lesions were highly reproducible. Additional atrophy was seen in the dorsal regions of both segments of the globus pallidus in all four monkeys, which may, in part, be related to loss of efferent fibres. The GFAP-stained sections indicated an intense gliotic reaction around the lesioned area and particularly in the overlying cortex (see Fig. 8L).
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Correlation of the post-mortem anatomy with behavioural data.
The DARPP-32 ratios of lesion/intact caudate and putamen for all 12 monkeys were correlated with behavioural scores that had been calculated for each test. The behavioural scores were calculated using means of all of the post-lesion data for each test, and then either the ratio of contralateral/ipsilateral (as for staircase latencies) or the difference between contralateral and ipsilateral (as for net rotation scores) was calculated. The correlations were performed using Pearson's r, and a summary of the results is shown in Table 3
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The ratio of lesioned over intact caudate volume did not correlate with any of the behavioural measurements, which is consistent with the lack of functional deficit seen in caudate-lesioned monkeys on all of the tests used in this study. However, there were significant correlations between the putamen ratios and all of the behavioural measurements except for saline and amphetamine rotation and the sticky label task, where no deficits had been seen in the lesioned group. Two of the most significant correlations, between putamen ratios and latency to clear the staircase and apomorphine rotation, are illustrated in Fig. 11
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In summary, in the common marmoset, excitotoxic lesions of either the caudate nucleus or the putamen are highly reproducible, with a significant loss of neurons and DARPP-32 and tyrosine hydroxylase immunoreactivity in both cases. The putamen lesions are largely complete and also impinge on the neighbouring globus pallidus. The significant correlations between putamen ratios and the behavioural scores may be related to this additional damage.
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Discussion |
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Functional consequences of basal ganglia lesions
We have shown that it is possible to create relatively focal lesions of either the caudate nucleus or the putamen in the common marmoset using multiple small injections of quinolinic acid. In addition, we demonstrate that putamen lesions are associated with a range of contralateral motor impairments that appear to remain stable over repeated assessments and over a long period of time. However, the caudate nucleus lesion was not associated with any detectable motor impairment.
In the marmoset, the loss of between 69 and 89% of the putamen (assessed by DARPP-32 staining, see Table 2) was associated with significant skilled motor deficits exhibited during the reaching and retrieval of rewards by the contralateral arm. Such deficits are consistent with rodent studies where impairments in skilled forelimb use have been shown following excitotoxic striatal lesions (Whishaw et al., 1986; Fricker et al., 1996, 1997b), particularly when those lesions target the sensorimotor area in the dorsolateral striatum (Fricker et al., 1996). The extent of the reaching impairments seen in the putamen-lesioned monkeys was similar to that found in unilateral 6-hydroxydopamine-lesioned monkeys where reaching into tubes was also significantly impaired (Annett et al., 1994). Annett and colleagues have also found that reaching for rewards on the staircase task is impaired after dopamine depletion but, rather than speed and accuracy, it is the order of reward removal which is most noticeably affected (Annett et al., 1992b). The dopamine-depleted monkeys exhibit a marked contralateral neglect such that on the staircase task ipsilateral rewards are removed first and on the sticky label task the ipsilateral label is always contacted before the contralateral label (Annett et al., 1992a). In this study, the destruction of intrinsic striatal neurons does not appear to be associated with contralateral neglect since there is no obvious bias on the sticky label task nor is there a tendency to prefer the ipsilateral body space in the central staircase task. In tasks employed to differentiate the sensory and motor elements of behavioural responses, it has been shown that rats with unilateral striatal lesions, or unilateral dopamine depletion, are not impaired in detecting contralateral stimuli but rather in making motor responses to the contralateral side (Carli et al., 1989; Brown and Robbins, 1989a, b; Brasted et al., 1999). It has also been suggested that the contralateral neglect seen in unilateral 6-hydroxydopamine-lesioned marmosets is related more to problems with initiating motor responses, confounded by a profound spontaneous rotation, than to sensory detection on the contralateral side (Annett et al., 1992). The tests employed in this study cannot prove the lack of a sensory element to the impairments seen in the putamen-lesioned monkeys, but the lack of neglect phenomena and the extent of the motor problems suggest that most, if not all, of the deficits are motor in origin.
Drug-induced rotation following administration of direct or indirect dopamine agonists is a measure that is commonly used in the analysis of basal ganglia lesions (Ungerstedt and Arbuthnott, 1970; Schwarcz et al., 1979; Pycock, 1980; Dunnett et al., 1988). We found that unilateral putamen lesions were associated with an ipsilateral rotation following apomorphine administration, but there was no consistent response following the administration of amphetamine. This contrasts with the consistent ipsilateral rotation to amphetamine and contralateral rotation to apomorphine seen in marmosets after nigrostriatal bundle lesions (Annett et al., 1992). In fact, a similar discrepancy is seen in rats, in which nigrostriatal lesions also yield consistent ipsilateral rotation under amphetamine and contralateral rotation under apomorphine (Ungerstedt, 1971a, b), whereas excitotoxic lesions of the striatum sometimes induce ipsilateral rotation in response to both drugs (Schwarcz et al., 1979; Dunnett et al., 1988) and sometimes produce opposite turning or contralateral responses in particular to apomorphine (Norman et al., 1992). Attempts to resolve this conflict in rats have suggested that, whereas the rate and direction of turning in animals with nigrostriatal lesions are related to the extent of denervation and development of postsynaptic dopamine receptor supersensitivity (Ungerstedt, 1971a; Hefti et al., 1980), the direction of turning in rats with neostriatal lesions is more related to the topography of the lesion. In particular, the most consistent contralateral rotation is obtained with lateral striatal lesions, whereas ipsilateral turning is associated more often with anterior and medial lesions (Norman et al., 1992; Fricker et al., 1996). Surprisingly, animals with relatively large lesions may show little overall rotation, which is most plausibly attributed to invasion of areas influencing both ipsilateral and contralateral turning bias. Thus, in the present study, and in contrast to marmosets with nigrostriatal lesions, it is the putamen site, equivalent to lateral neostriatum in rats, that produces rotation after excitotoxic lesion in marmosets and this is more consistent for apomorphine than amphetamine. Nevertheless, although the phenomenon of rotation may provide a simple quantitative measure of dysfunction, the cellular mechanisms underlying such rotation remain ambiguous.
Comparison with previous primate striatal lesion studies
It is difficult to make comparisons with previous striatal lesion studies in primates since the majority have lesioned both the caudate and the putamen in an effort to match the neuropathological damage of Huntington's disease (Hantraye et al., 1990; DeLong, 1990; Ferrante et al., 1993; Brouillet and Hantraye, 1995). The main aim of primate investigations in the past has been to elicit chorea and dyskinesias similar to those seen in Huntington's disease patients. The administration of dopamine agonists such as L-dopa or apomorphine to monkeys that have received kainic acid, ibotenic acid or quinolinic acid lesions of the caudate–putamen leads to the onset of a range of dyskinetic and dystonic posturing (Hantraye et al., 1990; Kanazawa et al., 1990; Brownell et al., 1994; Storey et al., 1994; Burns et al., 1995). Spontaneous dyskinesias are only seen in the immediate post-lesion phase following excitotoxic lesions and only if the lesion includes the putamen region (Brownell et al., 1994; Burns et al., 1995). If the lesion encompassed >60% of the caudate–putamen or if a ventral striatal lesion was added to the existing caudate–putamen lesion, then drug-induced dyskinesias were not seen (Hantraye et al., 1990; Kanazawa et al., 1990). This requirement for some remaining portion of the striatum implies that it is a combination of the consequence of removing part of the caudate–putamen and the action of the remaining portion that is involved in the initiation of dyskinesias. Although we did not witness a true dyskinetic profile in our putamen-lesioned monkeys, we did see elements of dystonia and some oro-facial movements during the acute drug phase following the administration of apomorphine. It is possible that the dose of apomorphine used in this study was too low since the same dose in ibotenic acid-lesioned baboons did not produce hyperkinesia or dyskinesia and most primate studies have used a dose of 1 or 2 mg/kg (Hantraye et al., 1990; Brownell et al., 1994; Storey et al., 1994). We chose the lower dose because marmosets are extremely sensitive to the action of apomorphine and, in pilot studies, we found that higher doses produced movements more akin to stereotypies (Ridley et al., 1980). It is of interest that the administration of apomorphine in kainic acid-lesioned macaque monkeys did not elicit dyskinesias, whereas L-dopa and met-amphetamine administration did produce responses (Kanazawa et al., 1990). Alternatively, it may be that the extent of the putamen lesion was simply too great for the true appearance of dyskinesias, which is consistent with a previous study where, in rhesus monkeys, the same dose of apomorphine produced dyskinesias following a posterior putamen lesion but the subsequent addition of an anterior putamen lesion abolished the response to apomorphine (Burns et al., 1995). Since it was not the main aim of the study to create another model of drug-induced dyskinesias, the use of a low dose of apomorphine that elicited a consistent ipsilateral rotation seems justified.
Functional significance of the difference between the caudate and the putamen lesioned monkeys
Anatomical tracing studies have demonstrated that motor, premotor and somatosensory cortical areas send corticostriatal projections primarily to the putamen region in primates, whereas the head and body of the caudate nucleus mostly receive efferent input from associational cortical areas such as prefrontal and cingulate cortex (Kemp and Powell, 1970; Kunzle, 1975, 1977, 1978; Selemon and Goldman-Rakic, 1985; Takada et al., 1998). This separation of corticostriatal projections is by no means complete but forms the basis of theories of basal ganglia function that rely upon the parallel processing of information along functionally segregated cortico-basal ganglia–thalamic loops (Alexander and Crutcher, 1990a; Alexander et al., 1990). Physiological studies further confirm the complex regional topography noted in anatomical studies such that there is a clear distinction between sensorimotor responses found in the putamen and the more complex behavioural responses seen in caudate nucleus neurons. Microstimulation of neurons in the putamen can elicit movement of specific body parts depending on the area that is stimulated, but that response is abolished after a focal injection of ibotenic acid (Alexander and DeLong, 1985). In addition, passive movement of limbs is nearly always associated with neuronal responses in the putamen and those neurons may display a sensitivity for the direction and/or preparation of movement (Alexander and DeLong, 1985; Crutcher and Alexander, 1990; Alexander and Crutcher, 1990b). The motor circuit, described by Alexander and colleagues, combines input from primary motor cortex with that from supplementary and premotor cortex along with somatosensory cortex to the putamen, which in turn sends topographic projections to both segments of the globus pallidus and the substantia nigra reticulata. Projections from the globus pallidus and substantia nigra to the thalamus maintain the topography, and the projections from the thalamus to premotor and motor cortex complete the loop. It seems reasonable to assume that removal of a critical component of the motor circuit, namely the putamen, will disrupt motor performance. The disruption seen in this study appears to be related more to the execution of motor acts rather than to initiation, although more specific tests may be able to tease out the exact nature of the motor problems.
The caudate nucleus is not considered to be part of the motor loop, rather, contemporary evidence suggests that the caudate nucleus is implicated more in cognitive processes such as attention and response selection in specific environmental contexts that are assigned to the two prefrontal cortico-striatal loops (Alexander et al., 1990). Following excitotoxic lesions of the caudate nucleus, we did not observe any significant motor impairment and, since the lesions were unilateral, no cognitive tasks were performed.
Application of unilateral putamen lesions in the common marmoset
The primary aim of our study was to develop a lesion model in the common marmoset that can be used for evaluating transplantation strategies for striatal repair. The criterion for such a model is that it is associated with a range of quantifiable motor impairments and that it is stable over repeated testing and over a long period of time. A unilateral quinolinic acid lesion of the putamen region in the marmoset meets these requirements and can therefore be applied in the study of potential restorative and neuroprotective strategies for diseases, such as Huntington's, that attack the striatum. In particular, following extensive studies in rodents, we have required a primate model to evaluate the effects of transplantation in the differentiated basal ganglia (with separate caudate and putamen nuclei) which also applies in man. The marmoset is ideally suited for such investigations because of its small size, ease of handling, relatively low cost and the fact that it breeds readily in captivity, which is essential for the supply of foetal material in neural transplantation studies.
In this study, we did not seek to replicate the pathology or the symptoms of Huntington's disease but rather to develop a consistently reproducible lesion with motor impairments which have been used to validate our battery of behavioural tests. As an application of this unilateral putamen lesion model in the marmoset, we recently have demonstrated partial amelioration of the motor deficits following implantation of foetal striatal tissue allografts (Kendall et al., 1998).
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The authors would like to thank Drs H. Hemmings and P. Greengard for the generous donation of the DARPP-32 antibody. In addition, thanks are due to Ms H. Cox for technical assistance in the preparation of the histological material. This work was supported by an MRC programme grant.
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Received November 26, 1999. Revised February 9, 2000. Accepted February 10, 2000.
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