Biomedical subjects

Jean Féger

Publications and source records attributed to Jean Féger.

15 recordsLinked to original sources

PubMed2006

Parafascicular nucleus projection to the extrastriatal basal ganglia in monkeys.

We have analyzed the parafascicular thalamic projection to extrastriatal structures of the basal ganglia using anterograde and retrograde tracing in monkeys. We identified (1) retrogradely labeled neurons in the parafascicular nucleus projecting to the anteromedial, limbic part of the external and internal pallidum, the substantia nigra and the subthalamic nucleus, (2) labeled terminals scattered in all these structures after anterograde tracer injection into the medial part of the parafascicular nucleus and (3) individual parafascicular terminals that arborized rather poorly in a large portion of each basal ganglia structure. Our study provides evidence that the parafascicular nucleus, and especially its medial part, can relay emotional and motivational information back to all basal ganglia components in primates.

Animals↗

PubMed2005

The cerebellum communicates with the basal ganglia.

The cerebral cortex is interconnected with two major subcortical structures: the basal ganglia and the cerebellum. How and where cerebellar circuits interact with basal ganglia circuits has been a longstanding question. Using transneuronal transport of rabies virus in macaques, we found that a disynaptic pathway links an output stage of cerebellar processing, the dentate nucleus, with an input stage of basal ganglia processing, the striatum.

Animals↗

PubMed2005

The mitochondrial complex I inhibitor rotenone triggers a cerebral tauopathy.

Reduced activity of the mitochondrial respiratory chain--particularly complex I--may be implicated in the etiology of both Parkinson's disease and progressive supranuclear palsy, although these neurodegenerative diseases differ substantially as to their distinctive pattern of neuronal cell loss and the predominance of cerebral alpha-synuclein or tau protein pathology. To determine experimentally whether chronic generalized complex I inhibition has an effect on the distribution of alpha-synuclein or tau, we infused rats systemically with the plant-derived isoflavonoid rotenone. Rotenone-treated rats with a pronounced metabolic impairment had reduced locomotor activity, dystonic limb posture and postural instability. They lost neurons in the substantia nigra and in the striatum. Spherical deposits of alpha-synuclein were observed in a few cells, but cells with abnormal cytoplasmic accumulations of tau immunoreactivity were significantly more numerous in the striatum of severely lesioned rats. Abnormally high levels of tau immunoreactivity were found in the cytoplasm of neurons, oligodendrocytes and astrocytes. Ultrastructurally, tau-immunoreactive material consisted of straight 15-nm filaments decorated by antibodies against phosphorylated tau. Many tau+ cell bodies also stained positive for thioflavin S, nitrotyrosine and ubiquitin. Some cells with abnormal tau immunoreactivity contained activated caspase 3. Our data suggest that chronic respiratory chain dysfunction might trigger a form of neurodegeneration in which accumulation of hyperphosphorylated tau protein predominates over deposits of alpha-synuclein.

Amyloid beta-Peptides↗

PubMed2005

Thalamic neuronal activity in dopamine-depleted primates: evidence for a loss of functional segregation within basal ganglia circuits.

Different analyses of neuronal activity in primate models of Parkinson's disease (PD) have resulted in two different views on the effects of dopamine depletion. The first is based on the higher firing rate and bursty firing pattern, and assumes that dopamine depletion results in a hyperactivity of basal ganglia (BG) output structures. The second is based on the less-specific responses to passive joint manipulation and the excessive correlations between neuronal discharges, and assumes that dopamine depletion results in a loss of functional segregation in cortico-BG circuits. The aim of the present study was to test out the predictions of these two different views on thalamic neuronal activity. Three male vervet monkeys (Cercopithecus aethiops) were progressively intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Neuronal activities were characterized using standard analyses (firing rates and patterns, receptive fields, and cross-correlations) and compared between the normal, asymptomatic (before the stabilization of motor symptoms), and parkinsonian (with persistent akinesia and rigidity) stages of MPTP intoxication. The pallidonigral thalamus (receiving projections from the BG) was characterized in both the asymptomatic and parkinsonian states by (1) an unchanged firing rate and pattern and (2) a proliferation of nonspecific neurons and correlated pairs. In contrast, the cerebellar thalamus (receiving projections from the cerebellum), was characterized by no change (asymptomatic state) or minor changes (symptomatic state). Thus the major dysfunction after dopamine depletion appeared to be the loss of functional segregation within cortico-BG circuits, which could also be at the heart of parkinsonian pathophysiology.

Action Potentials↗

PubMed2004

Persistent increase in olfactory type G-protein alpha subunit levels may underlie D1 receptor functional hypersensitivity in Parkinson disease.

Although L-dopa remains the most effective treatment of Parkinson disease, its long-term administration is hampered by the appearance of dyskinesia. Hypersensitivity of dopamine D1 receptors in the striatum has been suggested to contribute to the genesis of these delayed adverse effects. However, D1 receptor amounts are unchanged in Parkinson disease, suggesting alterations of downstream effectors. In rodents, striatal D1 receptors activate adenylyl cyclase through olfactory type G-protein alpha subunit (Galphaolf) and G-protein gamma 7 subunit (Ggamma7). We found that Galphaolf was enriched in human basal ganglia and was markedly diminished in the putamen of patients with Huntington disease, in relation with the degeneration of medium spiny neurons. In contrast, in the putamen of patients with Parkinson disease, Galphaolf and Ggamma7 levels were both significantly increased. In the rat, the degeneration of dopamine neurons augmented Galphaolf levels in the striatal neurons, specifically at the plasma membrane, an effect accounting for the increase of D1 response on cAMP production in dopamine-depleted striatum. In lesioned rats, Galphaolf levels were normalized by a 3 week treatment with l-dopa or a D1 agonist but not with aD2-D3 agonist, supporting a Galphaolf regulation by D1 receptor usage. In contrast, the increases of Galphaolf levels in patients were not affected by the duration of l-dopa treatment but correlated with duration of disease. In conclusion, our results revealed in the parkinsonian putamen a prolonged elevation of Galphaolf levels that may lead to a persistent D1 receptor hypersensitivity and contribute to the genesis of long-term complications of L-dopa.

Aged↗

PubMed2004

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

The current model of basal ganglia organization postulates the existence of a functional partitioning into sensorimotor, associative and limbic territories, implicated in motor, cognitive and emotional aspects of behaviour, respectively. This organization was proposed initially on the basis of the cortico-striatal projections and was extended to the various structures of the basal ganglia. While there is a considerable body of experimental evidence in support of an involvement of the basal ganglia sensorimotor territory in basic control of movements, evidence for the functional relevance of the non-motor territories has had to be based on a growing number of clinical observations due to the paucity of relevant animal studies. Previous studies in monkeys have, however, shown that a reversible and focal dysfunction induced by microinjections of bicuculline in the sensorimotor territory of the external globus pallidus (GPe) can generate abnormal movements. We therefore hypothesized that the same approach applied to the associative and limbic territories of the GPe would induce behavioural disorders rather than abnormal movements. To address this hypothesis, we performed microinjections of bicuculline, using the same concentration in each of the sensorimotor, associative and limbic territories of the GPe, as defined by striato-pallidal projections. Spontaneous behaviour and performance of a simple food-retrieving task during the effects of these microinjections were compared with data obtained in control conditions in the same monkeys. We found that bicuculline microinjections induced stereotypy when performed in the limbic part of the GPe, and attention deficit and/or hyperactivity when performed in the associative part. No movement disorders were observed during these behavioural disturbances. As previously described, abnormal movements were observed when bicuculline was injected into the sensorimotor territory of the GPe. The relationship between the localization of microinjection sites and the type of behavioural effect was similar for the three monkeys. Control microinjections of bicuculline into surrounding structures (striatum and internal globus pallidus) and saline injections into the GPe failed to induce any observable effect. These results support the hypotheses of functional diversity and territorial specificity in the GPe, in agreement with the parallel circuits organizational model of the basal ganglia. Furthermore, the behavioural effects shared similar features with symptoms observed in Tourette's syndrome, attention deficit/hyperactivity and compulsive disorders. Thus, our study provides experimental evidence for the involvement of the associative and limbic parts of the basal ganglia in these pathologies. These results may provide the basis for a primate model of these disorders.

Animals↗

PubMed2004

Behavioural disorders induced by external globus pallidus dysfunction in primates II. Anatomical study.

The anatomical organization of the basal ganglia supports their involvement in movement and behavioural disorders. Thus dyskinesia, attention deficit with or without hyperactivity, and stereotyped behaviour can be induced by microinjections of bicuculline, a GABAergic antagonist, into different parts of the external globus pallidus (GPe) in monkeys. The aim of the present study was to determine the anatomo-functional circuits inside the basal ganglia which are specifically related to each of these behavioural 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 literature and 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, moderate and intensive calbindin immunoreactivity. The same relationship was observed between the distribution of the labelling in the different basal ganglia after tracer injections 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 neurons in the laterodorsal putamen and caudate nucleus, regions corresponding to associative and anterior motor territories, while those performed in the stereotyped behaviour 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 systematically involved, depending on the movement or behavioural disorder produced. These results demonstrate 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.

Animals↗

PubMed2004

Annonacin, a lipophilic inhibitor of mitochondrial complex I, induces nigral and striatal neurodegeneration in rats: possible relevance for atypical parkinsonism in Guadeloupe.

In Guadeloupe, epidemiological data have linked atypical parkinsonism with fruit and herbal teas from plants of the Annonaceae family, particularly Annona muricata. These plants contain a class of powerful, lipophilic complex I inhibitors, the annonaceous acetogenins. To determine the neurotoxic potential of these substances, we administered annonacin, the major acetogenin of A. muricata, to rats intravenously with Azlet osmotic minipumps (3.8 and 7.6 mg per kg per day for 28 days). Annonacin inhibited complex I in brain homogenates in a concentration-dependent manner, and, when administered systemically, entered the brain parenchyma, where it was detected by matrix-associated laser desorption ionization-time of flight mass spectrometry, and decreased brain ATP levels by 44%. In the absence of evident systemic toxicity, we observed neuropathological abnormalities in the basal ganglia and brainstem nuclei. Stereological cell counts showed significant loss of dopaminergic neurones in the substantia nigra (-31.7%), and cholinergic (-37.9%) and dopamine and cyclic AMP-regulated phosphoprotein (DARPP-32)-immunoreactive GABAergic neurones (-39.3%) in the striatum, accompanied by a significant increase in the number of astrocytes (35.4%) and microglial cells (73.4%). The distribution of the lesions was similar to that in patients with atypical parkinsonism. These data are compatible with the theory that annonaceous acetogenins, such as annonacin, might be implicated in the aetiology of Guadeloupean parkinsonism and support the hypothesis that some forms of parkinsonism might be induced by environmental toxins.

Adenosine Triphosphate↗

PubMed2004

Disruption of self-organized actions in monkeys with progressive MPTP-induced parkinsonism. I. Effects of task complexity.

Parkinson's disease (PD) is characterized by motor symptoms, usually accompanied by cognitive deficits. The question addressed in this study is whether complexity of routine actions can exacerbate parkinsonian disorders that are often considered to be motor symptoms. To examine this question, we trained four vervet monkeys (Cercopithecus aethiops) to perform three multiple-choice retrieval tasks. In order of ascending complexity, rewards were freely available (task 1), covered with transparent sliding plaques (task 2), and covered with opaque sliding plaques cued by symbols (task 3). Thus, from task 1 to task 2 we added a motor difficulty--the recall of context-adapted movement; and from task 2 to task 3 we added a cognitive difficulty: the recall of symbol-reward associations. The more complex the task, the longer it took to learn, but after extensive training the performance was stable in all tasks, with similar retrieval durations. The monkeys then received systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injections (0.3-0.4 mg/kg) every 4-7 days, until the first motor symptoms appeared. In the course of MPTP intoxication, the behavioural performance declined while the motor symptoms were absent or mild--the retrieval duration increased, and non-initiated choices and hesitations between choices became frequent. Interestingly, this decline was in proportion to task complexity, and was particularly pronounced with the cognitive difficulty. Furthermore, freezing appeared only with the cognitive difficulty. We therefore suggest that everyday cognitive difficulties may exacerbate hypokinesia (lack of initiation, abnormal slowness) and executive disorders (hesitations, freezing) in the early stages of human PD.

Animals↗

PubMed2004

Disruption of self-organized actions in monkeys with progressive MPTP-induced parkinsonism: II. Effects of reward preference.

The motor and cognitive symptoms of Parkinson's disease (PD) are well documented, but little is known about the functionality of motivational processes mediated by the limbic circuits of basal ganglia. The aim of this study was to test the ability of motivational processes to direct and to urge behaviour, in four vervet monkeys (Cercopithecus aethiops) progressively intoxicated with systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injections (0.3-0.4 mg/kg every 4-7 days). In the food preference task, the monkeys had to retrieve two types of directly visible food, simultaneously available in the wells of a reward board. At all stages of MPTP-induced parkinsonism, the monkeys continued to take their favourite food first. In the symbol discrimination task, the wells were covered with sliding plaques cued by symbols indicating the absence or presence of a reward, and the different types of food were blocked in separate sessions. Monkeys with mild or moderate parkinsonism made fewer attempts and took longer to retrieve non-preferred compared with preferred rewards. These results indicate that motivational processes are still able to direct (food preference task) and to urge (symbol discrimination task) behaviour in MPTP-lesioned monkeys. Such a functional preservation may be related to the relatively spared dopaminergic innervation of the limbic circuits that we found in our monkeys, in agreement with the literature on humans. Furthermore, the frequency of executive disorders (such as hesitations and freezing) appeared to be much lower with the preferred rewards. Thus, the preserved motivational processes may help to overcome executive dysfunction in the early stages of human PD.

Animals↗

PubMed2003

Chronic systemic complex I inhibition induces a hypokinetic multisystem degeneration in rats.

In Parkinson's disease, nigral dopaminergic neurones degenerate, whereas post-synaptic striatal target neurones are spared. In some atypical parkinsonian syndromes, both nigral and striatal neurones degenerate. Reduced activity of complex I of the mitochondrial respiratory chain has been implicated in both conditions, but it remains unclear if this affects the whole organism or only the degenerating brain structures. We therefore investigated the differential vulnerability of various brain structures to generalized complex I inhibition. Male Lewis rats infused with rotenone, a lipophilic complex I inhibitor [2.5 mg/kg/day intraveneously (i.v.) for 28 days], were compared with vehicle-infused controls. They showed reduced locomotor activity and loss of striatal dopaminergic fibres (54%), nigral dopaminergic neurones (28.5%), striatal serotoninergic fibres (34%), striatal DARPP-32-positive projection neurones (26.5%), striatal cholinergic interneurones (22.1%), cholinergic neurones in the pedunculopontine tegmental nucleus (23.7%) and noradrenergic neurones in the locus ceruleus (26.4%). Silver impregnation revealed pronounced degeneration in basal ganglia and brain stem nuclei, whereas the hippocampus, cerebellum and cerebral cortex were less affected. These data suggest that a generalized mitochondrial failure may be implicated in atypical parkinsonian syndromes but do not support the hypothesis that a generalized complex I inhibition results in the rather selective nigral lesion observed in Parkinson's disease.

Animals↗

PubMed2003

Impairment of context-adapted movement selection in a primate model of presymptomatic Parkinson's disease.

The MPTP model allows the presymptomatic stage of parkinsonism to be studied in primates and hence specific behavioural manifestations of moderate nigrostriatal denervation to be identified. On the basis of the physiological literature, we hypothesized that depletion of striatal dopamine could impair the selection of context-relevant habits. To examine this hypothesis, we trained three African green monkeys to perform a simple reach-and-grasp task, including three contexts differing only in terms of the presence and position of transparent obstacles. At the end of training, the analysis of reaching trajectories showed that intact monkeys had built a repertoire of movements, from which they could select the appropriate one depending on the context. In the course of MPTP intoxication (0.3-0.4 mg/kg every 4-5 days) and before parkinsonian motor symptoms appeared, the reaction time (RT), movement time (MT) and variability of reaching trajectories increased in all monkeys. Frequently, the initial direction was not adapted to the context, and consequently the movement was either corrected online or restarted under visual assistance. These non-adapted trajectories appeared to be the main reason for the increase in both RT (because of difficulty in selecting) and MT (because of the need to make corrections). These observations indicate that moderate MPTP-induced dopamine depletion results in a deficit in the selection of context-adapted movement, which is compensated by corrections using either proprioceptive or visual feedback. Similar behavioural disorders might therefore occur in the presymptomatic stage of human Parkinson's disease.

Animals↗

PubMed2002

Behavioral consequences of bicuculline injection in the subthalamic nucleus and the zona incerta in rat.

The subthalamic nucleus (STN) plays a crucial role in basal ganglia functions and has been shown to be hyperactive in parkinsonian syndromes. The zona incerta (ZI), located dorsally to the STN, is also reported to be overactive after nigrostriatal denervation. In this study, we examined the behavioral consequences of an increased activity of the STN or the ZI in awake, freely moving rats. Unilateral microinjections of a GABA(A) receptor antagonist (bicuculline; 25, 50, and 100 microg/microl) were performed in the STN or in the ZI of rats, and locomotor activity, spontaneous behaviors, and the occurrence of abnormal movements were quantified. Microinjection of bicuculline (50 and 100 microg/microl) into the STN did not modify spontaneous locomotor activity, whereas it induced an increase in locomotion when injected into the ZI. Furthermore, when injected into the STN or ZI, these same doses of bicuculline produced changes in spontaneous behaviors (sniffing and grooming decreased whereas chewing and rearing increased) and the appearance of abnormal movements directed contralaterally to the injection side. Application of a lower dose of bicuculline (25 ng/microl) in the STN or ZI did not modify behavior. This study suggests that the subthalamic region including the ZI, and not the STN per se, might be involved in the induction of abnormal movements. In addition, these data suggest that the hyperactivity of neurons in this region may have different consequences in the normal state and in the pathological state.

Animals↗

PubMed2002

Consequences of dopaminergic denervation on the metabolic activity of the cortical neurons projecting to the subthalamic nucleus in the rat.

Parkinsonian symptoms are currently thought to be related to hyperactivity of the subthalamic nucleus (STN). Because the STN is known to receive many inputs including glutamatergic cortical afferent fibers, we sought to determine whether the activity of this pathway is altered after dopaminergic denervation to estimate its contribution to the impairment of STN activity. A precise mapping of the origin of the corticosubthalamic projection was first performed using retrograde and anterograde tracing methods. Cortical neurons projecting to the STN were found to originate in layer V of the motor, anterior cingulate, and dorsal insular cortices, and the most anterior tip of the frontal lobe, leading to different functional corticosubthalamic inputs. The metabolic activity of the neurons projecting to the STN, first identified by retrograde tracing, was then evaluated by in situ hybridization of the first subunit of cytochrome oxidase (COI), a marker of metabolic activity, in unilateral 6-hydroxydopamine-lesioned rats. Measurements of COI mRNA expression showed a 38 and 41.5% decrease after dopaminergic denervation in the neurons projecting to the STN located in the motor and dorsal insular areas, respectively, whereas neuronal activity was mildly changed in neurons of the anterior cingulate cortex. The modified activity of STN neurons in parkinsonism may thus result in part from complex interactions between glutamatergic hyperactive fibers originating in the thalamus and the pedunculopontine nucleus and hypoactive fibers originating in the cerebral cortex.

Animals↗

PubMed1991

The Effects of Activation or Inhibition of the Subthalamic Nucleus on the Metabolic and Electrophysiological Activities Within the Pallidal Complex and Substantia Nigra in the Rat.

The changes in local cerebral glucose utilization (LCGU) and neuronal unit activities in the subthalamic nucleus and its major target structures (the pars reticulata of the substantia nigra, the globus pallidus and the entopeduncular nucleus) following microinjection of a GABAergic antagonist (bicuculline methiodide, 0.08 nmol) or agonist (muscimol, 0.2 nmol) into the subthalamic nucleus were determined. The metabolic effect was assessed by measuring LCGU by quantitative [14C]-2-deoxyglucose autoradiography in ketamine-anaesthetized rats. Bicuculline methiodide induced increased LCGU in the ipsilateral globus pallidus, the entopeduncular nucleus and the substantia nigra pars reticulata. In contrast, muscimol decreased LCGU in these structures. The neuronal activities in the subthalamic nucleus and related structures increased following injection of bicuculline and decreased after injection of muscimol. The changes in LCGU within the structures directly related to the subthalamic nucleus were correlated with the changes in the unit activity either in the subthalamic nucleus and/or its projection structures. However, the amplitude of the relative changes in neuronal unit activity were greater than the changes in LCGU. Nevertheless, the results emphasize the functional role of the subthalamic nucleus as an activating structure within the basal ganglia.

Journal Article↗