Brain Advance Access originally published online on December 4, 2006
Brain 2007 130(1):265-275; doi:10.1093/brain/awl337
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Metabolic activity of cerebellar and basal ganglia-thalamic neurons is reduced in parkinsonism
1 INSERM, UMR679, Neurology and Experimental Therapeutics Paris, France 2 Pierre and Marie Curie University-Paris, Faculty of Medicine Paris, France 3 Salpetriere Hospital Paris, France 4 Experimental Neurology and Neurosurgery, Department of Human Anatomy and Psychobiology, School of Medicine, University of Murcia Campus de Espinardo, Murcia, Spain
Correspondence to: C. François, INSERM UMR679, Hôpital de la Salpetrière, 47 Bd de l'Hôpital, 75013 Paris, France Email: cfrancoi{at}ccr.jussieu.fr
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We have examined whether degeneration of nigrostriatal dopaminergic neurons causes dysfunction of both the basal ganglia-thalamic and cerebello-thalamic pathways. Changes in the activity of thalamic neurons receiving input from the basal ganglia or the cerebellum were examined in two models of Parkinson's disease, 6-hydroxydopamine (6-OHDA)-lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. Metabolic activity of the neurons was evaluated at the cellular level by quantitative in situ hybridization, using the expression of messenger RNA for subunit I of cytochrome oxidase (COI), encoded by the mitochondrial genome, as the marker. COI mRNA expression decreased significantly in thalamocortical neurons receiving input from the substantia nigra (–50.6%) or the cerebellum (–45%) in 6-OHDA-lesioned rats compared with controls. The decrease was observed in all thalamic neurons whether or not they were retrogradely labelled with a tracer injected into the motor cortex. Similarly, COI mRNA expression decreased in projection neurons and interneurons of the thalamus receiving input from the substantia nigra (–39 and –38%, respectively), the internal pallidum (–20 and –42.4%, respectively) and the cerebellum (–36.2 and –50%, respectively) of MPTP-treated monkeys compared with controls. These decreases in COI mRNA levels show that nigrostriatal denervation results in a decrease in the metabolic activity of thalamic neurons in the territories innervated by the substantia nigra, pallidum and cerebellum, which in turn is indicative of a decrease in their neuronal activity. The decrease did not concern the entire thalamus, however, since metabolic activity was unchanged in two thalamic nuclei considered to be limbic structures, the laterodorsal nucleus in 6-OHDA-lesioned rats and the anterior nucleus in MPTP-treated monkeys. Hypoactivity of both the basal ganglia-thalamic and cerebellar-thalamic pathways might therefore be implicated in the development of parkinsonian symptoms.
Key Words: Parkinson's disease; thalamus; metabolic activity; cytochrome oxidase; non-human primates
Abbreviations: COI, subunit I of cytochrome oxidase; DAT, dopamine transporter; GAD, glutamic acid decarboxylase; 6-OHDA, 6-hydroxydopamine; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; TH, tyrosine hydroxylase; WGA-HRP, wheat germ agglutinin conjugated to horseradish peroxidase
Received June 26, 2006. Revised October 3, 2006. Accepted November 6, 2006.
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In patients with Parkinson's disease, degeneration of dopaminergic neurons results in motor dysfunctions such as akinesia, rigidity and tremor. The cascade of changes induced by dopaminergic denervation of the striatum results in a net increase in the activity of the inhibitory neurons in the basal ganglia that innervate the thalamus. A decrease in the activity of the thalamic neurons receiving input from the basal ganglia, referred to as the basal ganglia territory of the thalamus, is thus expected in Parkinson's disease. Indeed, an increase in 2-deoxyglucose uptake, reflecting metabolic changes in fibres afferent to the studied structure, and a reduction in metabolic activity measured by positron emission tomography were reported in the thalamus as a whole, and more specifically in the basal ganglia territory after dopaminergic denervation in monkeys (Crossman et al., 1987
; Palombo et al., 1988; Schwartzman et al., 1988; Mitchell et al., 1989; Gnanalingham et al., 1995; Brownell et al., 2003). The activity of thalamic neurons receiving input from the cerebellum, referred to as the cerebellar territory of the thalamus, was also modified following dopaminergic denervation. Indeed, in parkinsonian patients, cerebellar–thalamic neurons fire in rhythmic bursts during pathological tremor, a symptom that can successfully be treated by lesion or deep-brain stimulation of the cerebellar territory (Benabid et al., 1991). However, only one paper has reported clear metabolic changes in the cerebellar territory of the thalamus in parkinsonian primates, as estimated by 2-deoxyglucose uptake (Palombo et al., 1988).
At the cellular level, a significant decrease in neuronal firing was detected by electrophysiological measurements in both the basal ganglia and cerebellar territories in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cats (Schneider and Rothblat, 1996) but not in MPTP-treated monkeys (Pessiglione et al., 2005). Neuronal firing was also abnormal in the basal ganglia territory of parkinsonian patients (Molnar et al., 2005). In this case, however, levodopa treatment might have influenced the firing rate.
The aim of this study was to examine whether dopaminergic denervation induces a reduction in the metabolic activity of intrinsic neurons in both the basal ganglia and cerebellar territories of the thalamus. We have addressed this question at the cellular level by quantifying the messenger RNA coding for subunit I of cytochrome oxidase (COI) encoded by the mitochondrial genome as a marker for neuronal activity. Because thalamic neurons project to the striatum as well as the cortex, as reported for parafascicular neurons (Feger and Crossman, 1984), these populations were analysed separately by retrograde thalamocortical tracing. Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of dopaminergic neurons in the substantia nigra were used for this analysis. We also studied MPTP-treated aged monkeys, because they more closely reflect patients with Parkinson's disease, and because the nigral, pallidal and cerebellar-thalamic territories are well segregated in primates (Ilinsky et al., 1985; Ilinsky and Kultas-Ilinsky, 1987; Percheron et al., 1996).
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Animals
All experiments were carried out in accordance with the recommendations contained in the European Community Council Directives of 1986. The animals were housed under conditions of constant temperature and humidity on a 12 h light/dark cycle with access ad libitum to food and water. Twenty adult male Sprague–Dawley rats weighing 250–300 mg (CERJ, Le Genest St Isle, France) and eight monkeys (Macaca arctoïdes) were used. The macaques were about 30 years old when sacrificed, as determined by their age when captured, their dentition and the appearance of their hair. They weighed between 16 and 23 kg and had never been used for any type of experiment or undergone surgery.
6-0HDA lesions in rats
Surgical procedures were performed under general anaesthesia with ketamine (50 mg/kg, Imalgène 500; Merial, Lyon, France) and xylazine (10 mg/kg, Rompun 2%; Bayer, Leverkusen, Germany) administered intramuscularly. Thirty minutes before 6-OHDA intranigral injection, all the rats were pre-treated with 25 mg/kg of desipramine hydrochloride (Sigma, St Louis, MO) and 50 mg/kg of pargyline (Sigma) (intraperitoneal) to protect noradrenergic neurons and inhibit monoamine oxidase, respectively. A stainless steel cannula connected by a catheter to a microsyringe (10 µl airtight; Hamilton), was placed in the substantia nigra pars compacta of one hemisphere under stereotaxic guidance, 5.5 mm posterior to the bregma, 1.8 mm lateral to the midline and 7.7 mm below the dura (Paxinos and Watson, 1998). Ten rats then received 2 µl of 6-OHDA (4 µg/µl in a 0.01% of ascorbic acid solution; Sigma) over a 5 min period. Another 10 animals received the same volume of vehicle (0.01% of ascorbic acid solution).
MPTP treatment in monkeys
Dopamine denervation was induced in four monkeys by repeated injections of MPTP, as published (Elsworth et al., 1987), except that the injections were separated by longer time intervals due to the increased susceptibility of aged animals to MPTP (Ovadia et al., 1995). Briefly, MPTP was injected intramuscularly (0.4 mg/kg, in NaCl 0.9%) under anaesthesia (ketamine, 5 mg/kg) every 3–5 days until a stable parkinsonian state was reached. The animals were examined every 2 days and their clinical state was rated as described (Luquin et al., 1993). After four or five injections (1.6–2 mg/kg cumulative dose), all four monkeys had a severe parkinsonian syndrome (clinical scores, 12–16 on a total of 21), which consisted of persistent akinesia, rigidity, postural instability, and intermittent episodes of action and resting tremor. The other four monkeys were used as controls. Two weeks after the last MPTP injection, the monkeys received a lethal overdose of anaesthesia and were perfused intracardially with NaCl 0.9%. The brain was removed, and the hemispheres were separated and cut into blocks that were rapidly frozen in powdered dry ice. Serial 20 µm transverse sections were then cut on a cryostat, mounted on gelatin-coated slides and stored at –80°C.
Retrograde labelling of thalamocortical cell bodies in rats
One week after lesion of the substantia nigra, thalamocortical cell bodies were labelled by retrograde transport of wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) (Sigma). The tracer was injected stereotaxically, as described previously (Orieux et al., 2000), into the secondary motor cortex, which receives a major input from the nigral thalamic territory (Mitchell and Cauller, 2001). Briefly, WGA-HRP (10% in 0.1 M PBS) was injected (0.4 µl/min) 4 mm posterior to the bregma, 2 mm lateral to the midline and 1 mm below the dura (Paxinos and Watson, 1998). Three days later, the animals were killed by a lethal intraperitoneal injection of 6% sodium pentobarbital (4 ml/kg), and perfused through the heart with a heparin/0.9% NaCl solution (10 U/ml) at 37°C. Brains were removed and frozen in cold isopentane (–40°C). Frontal sections (20 µm thick) were cut on a cryostat, mounted on gelatin double-coated slides, and stored at –80°C.
To verify the cortical injection site and visualize the retrogradely labelled neurons in the thalamus, WGA-HRP was revealed on regularly spaced sections (420 µm) for each experimental case as described previously (Orieux et al., 2000). All of these sections were then counterstained with 0.25% methyl green solution. At the selected levels, adjacent sections were used for in situ hybridization in the thalamus. Before in situ hybridization, WGA-HRP label was first revealed. The sections were then coverslipped with non-permanent medium and structures of interest containing the labelled neurons were defined by computer-assisted image analysis (Mercator, Explora Nova, La Rochelle, France). The coverslips were then removed in buffer, and the sections were dried in absolute alcohol and stored overnight at 4°C.
Assessment of nigral and striatal depletion
Immunocytochemical labelling of tyrosine hydroxylase (TH) was performed in the substantia nigra of 6-OHDA-lesioned rats and in the substantia nigra and striatum of MPTP-treated monkeys and their controls. Unfixed slide-mounted frozen sections containing the substantia nigra and, in monkeys, the caudate nucleus and putamen were taken at comparable anatomical levels. Tissue was post-fixed for 1.5 h in 3% paraformaldehyde. Endogenous peroxidase activity was inhibited (3% hydrogen peroxide) and non-specific antibody binding was prevented by preincubation at room temperature in a PBS solution containing 33% normal horse serum. The sections were then incubated at 4°C for 48 h with mouse anti-TH (1 : 5000 in PBS 0.1 M, 4°C, 48 h) (Immunostar, Hudson, WI), followed by biotinylated horse anti-mouse IgG (Vectashield, Vector Laboratories, Burlingame, CA) (1 : 250 in PBS 0.1 M). After washing, sections were incubated for 1 h with an avidin–biotin–peroxidase complex (ABC standard kit; Vector) (1 : 125 in PBS). Bound peroxidase was visualized by incubation in a Tris-buffered solution containing 0.06% hydrogen peroxide and 0.05% 3-3'-diaminobenzidine tetrahydrochloride (DAB, Sigma) as chromogen. All sections were coverslipped with Eukitt (O. Kindler, Freiburg, Germany).
Immuno-autoradiography of the dopamine transporter (DAT) in the striatum of rats was performed as described previously (Naudon et al., 1996). Six regularly spaced (480 µm) frozen sections along the anteroposterior extent of the striatum were selected at comparable anatomical levels in each rat, air-dried, pre-treated with 1% BSA in 0.1 M PBS, incubated for 24 h with a polyclonal antibody against the DAT (provided by B. Giros, INSERM, Paris-Créteil, France) diluted 1 : 4000 in 0.1 M PBS, rinsed, then incubated for 2 h with an [35S]-labelled anti-rabbit immunoglobulin at a concentration of 1/100 (initial concentration: 20 µg/ml; specific activity: 700 Ci/mmol) (Amersham Biosciences; Arlington Heights, IL). After air drying, the sections were exposed to X-ray film (Hyperfilm ß-Max; Kodak) for 26 h at room temperature in light-proof boxes. Dopaminergic lesions were quantified by measuring the optical density on the autoradiograms, as described previously (Blanchard et al., 1995).
In situ hybridization
In situ hybridization was performed with [35S]-labelled COI cRNA probes as described previously (Vila et al., 1997). The monkey probe corresponded to nt 5999–6925 of the human mitochondrial genome (EMBO databank, reference MIHSCG). The rat probe corresponded to nt 5308–6218 of the rodent mitochondrial genome (EMBO databank, reference MIRNXX). Both were subcloned in the pGEM-T Vector (Promega, Madison, WI). Sense and antisense probes were transcribed from 1 µg of plasmid as described by Fontaine et al. (1988).
Sections at the level of the basal ganglia and cerebellar territories of the thalamus were rinsed in PBS 0.1 M, acetylated with 0.25% acetic anhydride in 0.1 mM ethanolamine, followed by 0.1 M Tris/glycine treatment for 30 min and dehydrated through graded ethanol solutions. For monkey sections only, this first stage was preceded by a mild fixation in a 3% paraformaldehyde for 15 min. The sections were then incubated for 3.5 h at 50°C in a humid chamber in hybridization solution containing either the antisense or the sense [35S]-labelled cRNA probe (2.5 x 106 c.p.m.). After hybridization, the sections were washed at 50°C in 50% formamide/2x SCC, incubated for 30 min at 37°C with RNase A (100 µg/ml in 2x SCC) to digest unhybridized probe, rinsed again at 50°C in 50% formamide/2x SCC, and then washed overnight at room temperature. After a final rinse in 2x SCC, the sections were dehydrated in graded ethanol solutions containing 300 mM ammonium acetate, delipidated in xylene, dehydrated in ethanol 100 and air-dried. The sections were dipped in NTB emulsion (Kodak, Integra Biosciences), diluted 1 : 1, air-dried and stored at 4°C in light-proof boxes for 1–2 weeks. Autoradiograms were generated by exposing the slides to X-ray films (Hyperfilm ß-Max, Kodak) for 1 day to 2 weeks at 4°C. Exposed slides were developed in Kodak D-19 for 4 min at 15°C and counterstained with haematoxylin 0.1% to localize cell nuclei.
Although there are scarcely any interneurons in the rat thalamus, 20–25% of neurons in the monkey thalamus are GABAergic interneurons (Jones, 1985; Sherman, 2004). These neurons were, therefore, identified for separate analysis by immunohistochemistry with an antibody against glutamic acid decarboxylase (GAD). After in situ hybridization, the sections were post-fixed for 1 h in 3% paraformaldehyde solution, washed and incubated with rabbit anti-GAD (Chemicon, Temecula, CA) (1 : 1500 in PBS, 4°C, 72 h). This was followed by an incubation with biotinylated goat anti-rabbit IgG (1 : 250, 30 min) (Vector Laboratories) then the ABC complex (1 : 125 in PBS). The bound peroxidase was visualized by incubation in a Tris-buffered solution containing 0.06% hydrogen peroxide and 0.05% DAB (Sigma). All sections were air-dried and dipped in NTB emulsion (Kodak), exposed and revealed as described above. All sections were counterstained with haematoxylin 0.1% to localize cell nuclei. All experiments were performed on duplicate sections.
Data analysis
There is general consensus that the nigrothalamic projections to the lateral mass of the thalamus are confined, in rats, to the ventromedial nucleus (Faull and Mehler, 1978; Beckstead et al., 1979; Bentivoglio et al., 1979; Gerfen et al., 1982; Kha et al., 2001), while the cerebellum mainly innervates the ventrolateral nucleus (Aumann et al., 1996). However, the cerebellum also projects to the caudal part of the ventromedial nucleus; 50% of the neurons responding to stimulation of the substantia nigra pars reticulata also respond to stimulation of the cerebellum (Chevalier and Deniau, 1982; Deniau et al., 1992). Therefore, to avoid confusion due to overlapping innervations, quantification was performed only in the anterior part of the ventromedial and ventrolateral nucleus (level bregma –2.3 mm according to the atlas of Paxinos and Watson, 1998). The entopeduncular nucleus (the rat homologue of the medial pallidal segment) has also been reported to project to the ventromedial and ventrolateral nucleus (Deniau et al., 1992; Finkelstein et al., 1996; Kha et al., 2000). Since it is not yet known whether its afferent territory is distinct from the nigrothalamic and cerebello-thalamic territories, this structure was not studied. Maps of WGA-HRP-stained neurons in the thalamus were computer-generated to identify the retrogradely labelled neurons on sections after in situ hybridization, since the procedure washes out the labelling.
Thalamic nuclei in monkeys were identified by acetylcholinesterase histochemistry, as described (Graybiel and Ragsdale, 1978), on two anterior (nigral and pallidal territories) and posterior (cerebellar territory) sections adjacent to those used for in situ hybridization. The thalamic nuclei were delineated according to the nomenclature of Olszewski (1952). The limits of the nigral, pallidal and cerebellar territories on COI mRNA stained sections were then determined from maps generated in a previous study in our laboratory (Percheron et al., 1996). The nigral territory corresponds mainly to the magnocellular portion of the ventral anterior nucleus, the pallidal territory to the ventral lateral nucleus, pars oralis and the cerebellar territory to the ventroposterolateral nucleus pars oralis.
To determine whether the entire thalamus is altered in parkinsonism, a quantitative analysis was also performed in the laterodorsal nucleus of the thalamus in rats and in the anterior nucleus of the thalamus in monkeys, two nuclei that do not receive basal ganglia and cerebellar inputs. These nuclei, which are visible on sections containing the basal ganglia and cerebellar territories of the thalamus, are considered to be limbic thalamic nuclei because of their connections with various cortical and subcortical limbic areas (Armstrong, 1990).
COI mRNA levels were quantified on only one section in rats because nigral and cerebellar territories are located at the same level of the thalamus, and on two different sections in monkeys because the anteroposterior levels of the basal ganglia (nigral and pallidal) and cerebellar territories are different.
Quantification was performed in all neurons (WGA-HRP-positive and WGA-HRP-negative cell bodies in rats, GAD-positive and GAD-negative cell bodies in monkeys) present in circles randomly distributed by computer-assisted analysis (Mercator) within the defined limits of the thalamic nuclei. The number of circles distributed per structure, 30 circles for rats and 60 circles for monkeys, was previously determined to ensure that the structures were well covered. Thus a minimum of 15 neurons per structure in rats and of 35 neurons per structure in monkeys were analysed. The number of silver grains over the neuronal cell bodies was evaluated under polarized light by comparing the optical density to a standard curve of a defined number of silver grains. Grain density (number of silver grains per surface area of the neuron) was then calculated. Non-specific labelling was estimated with sense probes. The mean density of silver grains overlying the retrogradely labelled neurons was calculated for each experimental animal. Statistical analysis was performed using the non-parametric Mann–Whitney test. 6-OHDA-lesioned rats were compared with sham-lesioned rats, MPTP-treated monkeys with control animals. The null hypothesis was rejected for an 
risk of 0.05.
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Loss of dopaminergic neurons in 6-OHDA-lesioned rats and MPTP-treated monkeys
We first determined whether 6-OHDA injections in the substantia nigra of adult rats and intramuscular MPTP injections in aged monkeys induce a loss of dopaminergic neurons in the substantia nigra pars compacta. Immunohistochemical labelling of TH confirmed that there was a dramatic loss of dopaminergic neurons in 6-OHDA-lesioned rats (Fig. 1A') and MPTP-treated monkeys (Fig. 1B') compared with controls (Fig. 1A and B). Loss of TH-positive neurons was most severe in the lateral part of the substantia nigra; the ventral tegmental area was much less affected.
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The loss of dopaminergic innervation in the striatum was evaluated by immuno-autoradiographic labelling of the DAT in the 6-OHDA-lesioned rats and by optical density measurements of TH immunolabelling in the MPTP-treated monkeys. One 6-OHDA-lesioned rat was excluded because the degree of neuronal loss was visibly insufficient and because the optical density of dopaminergic fibres in the striatum did not differ from the optical density in the striatum of sham-lesioned rats. DAT labelling decreased 70% (P < 0.001) in the striatum ipsilateral to the lesion in the 6-OHDA-lesioned rats (n = 8) compared with sham-lesioned controls (n = 10) (Fig. 2A, A'). Striatal labelling was similar on the operated and the contralateral side of the sham-lesioned animals. The optical density of TH labelling in the caudate nucleus and putamen of MPTP-treated monkeys (n = 4) decreased by 70 and 73%, respectively, compared with control monkeys (n = 4) (P < 0.001) (Fig. 2B, B').
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COI mRNA expression decreases in neurons of the basal ganglia and cerebellar territories of the thalamus in 6-OHDA-lesioned rats
To identify the thalamic neurons that project to the motor cortex in the experimental rats, the retrograde tracer WGA-HRP was injected into the secondary motor cortex of 6-OHDA-lesioned and sham-lesioned rats. In all but one rat, WGA-HRP was injected in the centre of the secondary motor cortex and diffused into the primary motor cortex but not into the cingulate cortex, as illustrated in Fig. 3A. Numerous retrogradely labelled cell bodies were observed in the thalamus (Fig. 3B). As shown by the computer-generated map in Fig. 3C, labelled neurons were found mainly in the ventromedial nucleus, known as the nigral territory, but also in the ventrolateral nucleus known as the cerebellar territory.
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In situ hybridization to quantify COI mRNA expression in the thalamic neurons was performed after the WGA-HRP-labelled neurons were mapped, as illustrated in Fig. 3D–F. Clusters of silver grains were seen over neurons in the sections hybridized with the antisense cRNA probe (Figs 3F and 4) but not with the sense COI cRNA probe (data not shown). Examination of haematoxylin-counterstained sections showed that COI mRNA was concentrated mainly in the neuronal cell bodies, with a signal well above the background level. Much weaker labelling was detected outside the neuronal cell bodies due to the presence of mitochondria in the neuropil. As illustrated in Fig. 4, COI mRNA expression decreased in thalamic neurons in 6-OHDA-lesioned rats compared with controls. The decrease was quantified in both WGA-HRP-positive neurons and WGA-HRP-negative neurons, which may include both interneurons and projection neurons (Table 1). The decrease in COI mRNA levels in WGA-HRP-positive neurons was 50.6% (P = 0.004) in the nigral territory and 45% (P = 0.024) in the cerebellar territory (Table 1). In WGA-HRP-negative neurons, the decrease was 33% in the nigral territory (P = 0.037) and 32% (P = 0.027) in the cerebellar territory (Table 1). The loss of dopaminergic neurons in the substantia nigra pars compacta in 6-OHDA-lesioned rats therefore induces a decrease in the metabolic activity of virtually all neurons in the cerebellar as well as in the nigral territory. All thalamic regions were not affected, however, since no change in COI mRNA expression was observed in the laterodorsal nucleus of 6-OHDA-lesioned rats compared with controls (P = 0.18) (Table 1).
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COI mRNA expression decreases in neurons of the basal ganglia and cerebellar territories of the thalamus in MPTP-treated monkeys
COI mRNA expression was also quantified in MPTP-treated monkeys in neurons located in the nigral, pallidal and cerebellar territories delineated on adjacent sections by acetylcholinesterase histochemistry (Fig. 5A and B). Clusters of silver grains were seen over both GAD-positive interneurons and GAD-negative projection neurons when in situ hybridization was performed with the antisense probe (Fig. 5C), but not with the sense probe (data not shown). As observed in rats, silver grains were concentrated mainly over neuronal cell bodies but were also found, although at a lower density, outside of the neuronal cell bodies due to the presence of mitochondria in the neuropil. COI mRNA expression in GAD-negative neurons decreased 39% (P < 0.0001) in the nigral territory, 20% (P = 0.009) in the pallidal territory and 36.2% (P < 0.0001) in the cerebellar territory of MPTP-intoxicated monkeys compared with controls (Fig. 6 and Table 2). COI mRNA expression in GAD-positive interneurons decreased 38% (P = 0.002) in the nigral territory, 42.4% (P = 0.0001) in the pallidal territory and 50% (P = 0.001) in the cerebellar territory (Table 2). Dopamine depletion in MPTP-treated monkeys therefore reduces the metabolic activity of both projection neurons and interneurons in the nigral, pallidal and cerebellar territories. This result cannot be attributed to inadequate histological processing, since metabolic hyperactivity was detected in the internal segment of the pallidum of MPTP-treated monkeys compared with controls (data not shown), as reported previously (Vila et al, 1997
). Moreover, no change in COI mRNA expression was observed in the anterior nucleus of MPTP-treated monkeys compared with controls (P = 0.27) (Table 2).
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This study provides evidence that the metabolic activity of neurons located in the lateral mass of the thalamus decreases after dopaminergic denervation in two animal models of Parkinson's disease. In addition to the effect observed in the basal ganglia territory, which confirms the prediction that hyperactivity of basal ganglia output structures results in a reduction in thalamic activity, a decrease was also observed in the cerebellar territory indicating that the cerebello-thalamic system might also be hypoactive in patients with Parkinson's disease.
Significance of COI mRNA expression
The use of the mRNA of subunit 1 of the mitochondrial enzyme COI as a metabolic marker of neuronal activity is now well established (for review, see Wong-Riley, 1989; Hirsch et al., 2000). Indeed, the activity of this enzyme is regulated by changes in the synaptic firing pattern (Hevner et al., 1992) and is responsive to alterations in neuronal activity (Wong-Riley et al., 1978; Vila et al., 1996). Although it remains to be determined whether COI mRNA expression is modified by the firing pattern, this marker has been used to study the functioning of the basal ganglia in the parkinsonian state (Vila et al., 1997; Vila et al., 2000). In addition, the major advantage of this metabolic marker is that the analysis can be performed at the cellular level (Hevner and Wong-Riley, 1991) and, in this study, at the level of neuronal populations identified previously either by retrograde tracing or by immunohistochemistry. As suggested by previous studies combining both in situ hybridization and retrograde tracing (Orieux et al., 2002), we cannot exclude the possibility that the transport of the axonal tracer WGA-HRP influences neuronal metabolic activity. For this reason, we did not compare COI mRNA levels in retrogradely labelled neurons and non-retrogradely labelled neurons.
Autoradiography of 2-deoxyglucose uptake has also been used to study energy metabolism in the brain. However, the expression of COI mRNA: (i) reflects the need for oxidative metabolism during a longer period of neuronal activity than 2-deoxyglucose uptake; (ii) is related to functional activity of intrinsic neurons rather than to the activity of terminals of afferent neurons; (iii) can be analysed at the cellular level. Thus, COI mRNA expression can be considered to be a good index of steady-state long-term functional activity at the cellular level in specific areas of the brain.
Reduced activity of basal ganglia and cerebellar-thalamic neurons after dopaminergic denervation
A reduction in the metabolic activity of the thalamus as a whole has been reported in MPTP-treated monkeys, and more specifically in the basal ganglia territory (Crossman et al., 1987; Schwartzman et al., 1988; Mitchell et al., 1989; Gnanalingham et al., 1995). In this study, using COI mRNA expression as a metabolic marker, we observed the expected reduction in the metabolic activity of neurons in the basal ganglia territory, but also detected a reduction in the cerebellar territory, and this in two different animal models of Parkinson's disease. Our metabolic findings are in good agreement with electrophysiological studies revealing a decrease in the firing rate in both the basal ganglia and the cerebellar territories in MPTP-treated cats (Schneider and Rothblat, 1996). In parkinsonian patients compared with patients with pain, a decrease in the firing rate associated with a modification in the firing pattern has also been reported, but only in the basal ganglia territory (Molnar et al., 2005). Furthermore, in an electrophysiological study of MPTP-treated monkeys, no significant decrease in the firing of thalamic neurons was detected (Pessiglione et al., 2005). However, the two studies were not directly comparable. In our metabolic study, all thalamic neurons were taken into account. In the electrophysiological study, however, the population of tremor neurons, which represents about 15% of all neurons in the pallidal and cerebellar territories, was not examined. Tremorosynchronous neurons, which increase their firing rate during tremor (Guehl et al., 2003), decrease their firing rate when tremor stops (compare data from Guehl et al., 2003 and Pessiglione et al., 2005). If these neurons had been taken into account in the electrophysiological study, a decrease in the overall electrophysiological activity of the thalamic neurons would probably have been observed.
The observation that the metabolic activity of thalamic neurons is reduced not only in the basal ganglia territory but also in the cerebellar territory suggests that the entire thalamus might be reduced in the parkinsonian state. This does not seem to be the case, however, since metabolic activity was unchanged in two thalamic nuclei considered to be limbic structures, the laterodorsal nucleus of 6-OHDA-lesioned rats and the anterior nucleus of MPTP-treated monkeys. This does not exclude possible neuronal hypoactivity in other thalamic nuclei, however.
Origin of the hypoactivity of the thalamic neuron
Hyperactivity in the basal ganglia after dopaminergic denervation may explain the hypoactivity of its thalamic target, as suggested by the classical model of basal ganglia circuitry (Albin et al., 1989). In this study, thalamic activity was reduced in both projection and local circuit neurons, indicating that basal ganglia afferents influence both neuronal populations, in agreement with ultrastructural observations (Kultas-Ilinsky and Ilinsky, 1990). Why neuronal hypoactivity was observed in the cerebellar territory is less obvious, since no clear change in cerebellar activity has been reported after dopamine denervation, except during tremor. An analysis of the metabolic activity of the cerebellar neurons that project to the thalamus is needed to resolve this issue.
Changes in the activity of the basal ganglia and cerebellar output pathways are probably not the sole cause of thalamus hypoactivity in the parkinsonian state, however. The cortex, which also projects to the thalamus, is impaired in parkinsonian syndromes and might contribute to the decrease in thalamic activity. Modulatory dopaminergic, serotoninergic, noradrenergic and cholinergic systems might also influence thalamic activity. Most of these afferent neurons have excitatory effects on thalamocortical neurons (for review see Steriade et al., 1997), which if decreased by dopaminergic denervation might also reduce thalamic activity, as reported for the dopaminergic system in MPTP-treated monkeys (Freeman et al., 2001; Sanchez-Gonzalez et al., 2005). Furthermore, the ascending reticular system that innervates the thalamus, which is known to be involved in the regulation of arousal and the sleep–wake cycle, might also be altered, since sleep abnormalities are observed in parkinsonian syndromes (Lees et al., 1988). Finally, the thalamic reticular nucleus that receives input from the external segment of the pallidum (Hazrati and Parent, 1991), exerts lateral inhibition on the thalamus (Pinault and Deschenes, 1998). An alteration of this pathway after dopaminergic denervation might also contribute to the change in COI expression in the thalamus. This is not consistent with the recent finding that parafascicular thalamic neurons, which also receive reticular input, are hyperactive (Aymerich et al., 2006). Therefore, although many systems might contribute to underactivity in the thalamus in parkinsonian syndromes, there appears to be some selectivity.
How hypoactive thalamic neurons may affect their targets
Thalamic neurons located in the lateral mass were reported to project not only to the cortex but also, to a lesser degree, to the striatum (Gimenez-Amaya et al., 1995; McFarland and Haber, 2000). However, it remains to be determined whether the thalamostriatal projections are collaterals of thalamocortical axons, as suggested for the thalamic parafascicular neurons (Deschenes et al., 1996), or whether they arise from separate neuronal populations. We have shown here that metabolic activity in the thalamus of 6-OHDA-lesioned rats was reduced in all neurons that we examined, whether they project to the cortex or not. Since metabolic activity was also reduced in all thalamic neurons in MPTP-treated macaques, we conclude that output pathways of both the basal ganglia and cerebellar territories are hypoactive. This conclusion is reinforced by the fact that we distinguished the projection neurons from the GAD-positive inhibitory interneurons that represent 20–25% of the total neuronal population in the primate thalamus (Jones, 1985; Sherman, 2004).
The decrease in the metabolic activity of the excitatory thalamocortical pathway seen in our study suggests that the cortical target areas might be hypoactive in parkinsonian syndromes. This is compatible with reports of a decrease in the expression of COI (Orieux et al., 2002) and immediate-early genes (Steiner and Kitai, 2000) in several cortical areas, including the motor cortex, of 6-OHDA-lesioned rats, although an increase in metabolic activity was found in the motor cortex of 6-OHDA lesioned rats by functional magnetic resonance imaging (Pelled et al., 2002). Our results are also compatible with the hypometabolism observed in the premotor cortex of MPTP-treated monkeys using positron emission tomography (Brownell et al., 2003). Our results support therefore the hypothesis that dopamine depletion impairs the activity of thalamic neurons, and in consequence affects functioning of their cortical target neurons. But as already suggested for motor cortical neurons of MPTP-treated monkeys (Goldberg et al., 2002), it is possible that abnormal firing patterns and synchronization rather than reduced firing rates might underlie the parkinsonian state.
The reduced metabolic activity of all thalamic neurons after dopaminergic denervation in our study suggests that the thalamostriatal pathway also becomes hypoactive. Interestingly, it was reported that neurons in the intralaminar thalamic nuclei project preferentially to the striatal neurons that are at the origin of the direct pathway in the basal ganglia circuitry (Sidibe and Smith, 1996). We might speculate that if the hypoactive neurons we observed in the lateral mass of the thalamus project similarly, the hypoactivity of the direct pathway after dopaminergic denervation of the striatum (Albin et al., 1989; DeLong, 1990) would be reinforced.
Therapeutic considerations
The observation that dopaminergic denervation reduces neuronal activity in the thalamus is also important in terms of clinical outcome, and it would be interesting to determine whether levodopa therapy restores thalamic activity in both rats and monkeys. Furthermore, the thalamus is a well-known target for the surgical treatment of Parkinson's disease. The cerebellar–thalamic territory that contains numerous neurons with tremor-frequency activity is usually targeted to relieve tremor (Narabayashi and Ohye, 1983). Electrophysiological recordings in the thalamus of MPTP-treated monkeys showed that when the animals enter into a period of tremor, the mean firing rate of neurons in the pallidal and cerebellar territories increases (Guehl et al., 2003). Lesions and deep-brain stimulation of the cerebellar-thalamic territory might therefore have a beneficial effect on tremor because they suppress abnormal signals to the cortex from these tremorosynchronous neurons. The pallidal territory is also a possible target, since lesions in the sensorimotor portion of the internal pallidum have been associated with a striking improvement in drug-induced involuntary movements, bradykinesia, tremor and rigidity (Lozano and Lang, 1998). Lesions in the pallidal territory have been reported to relieve parkinsonian rigidity (Narabayashi and Ohye, 1974) and, above all, to successfully treat levodopa-induced dyskinesias in humans (Ohye, 2001) and MPTP-treated monkeys (Page et al., 1993). Deep-brain stimulation of the subthalamic nucleus is now used to alleviate all parkinsonian symptoms. Our results suggest that activation of the cerebello-thalamic pathway might be effective against non-parkinsonian tremor, whereas disinhibition of the thalamic neurons, which are repressed by overactive basal ganglia neurons, might alleviate all parkinsonian symptoms including tremor and levodopa-induced dyskinesia.
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Acknowledgements |
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This work was funded by the Institut National de la Santé et de la Recherche Médicale and the Spanish Ministry of Science SAF2002-11675-E.
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