A estimulação cerebral profunda do núcleo subtalâmico (NST) é um tratamento bem estabelecido para os sintomas refratários à medicação em paciente com doença de Parkinson avançada. Além do procedimento de implante, a programação dos eletrodos é uma etapa fundamental para atingir os resultados desejados. A primeira etapa da programação é estabelecer os limiares para efeitos adversos. Contudo, a correlação entre a localização do eletrodo e o limiar para efeitos adversos associados à estimulacao das estruturas adjacentes ainda não é bem estabelecida. Características neuroanatômicas e a localização dos eletrodos foram identificadas utilizando-se um programa de planejamento de cirurgia estereotáxica, enquanto os parâmetros de estimulação e os efeitos adversos foram obtidos dos prontuários médicos. As correlações entre estas variáveis foram testadas através de análises univariadas e análises multivariadas. Estimulação monopolar produziu efeitos adversos capsulares (EA-C) em 208 dos 316 contatos (65,8%) e efeitos adversos não-capsulares (EA-NC) em 223 dos 316 contatos (70,6%). A ocorrência de EA-C esteve associada com o número do contato (p = 0,009) e com a coordenada \"Z\" (p = 0,03), enquanto o limiar de voltagem para EA-C esteve correlacionado com o ângulo da cápsula interna (p = 0,035). A ocorrência de EA-NC esteve associada com o número do contato (p = 0,005), \"X\" (p = 0,03), \"Y\" (p = 0,004) e com a distância para o núcleo rubro (p = 0,001 e p = 0,003). Houve correlação entre o limiar de voltagem para EA-NC e o ângulo da cápsula interna (p = 0,006), o ângulo coronal do eletrodo (p = 0,02), \"X\" (p = 0,001), \"Y\" (p < 0,001), \"Z\" (p < 0,001) e com as distâncias para a cápsula interna (p = 0,02) e para o núcleo rubro (p = 0,004 e p < 0,001). EA-C estiveram associados com os contatos mais distais do eletrodo e com localização mais profunda, bem como com maior angulação da cápsula interna. EA-NC estiveram associados com os contatos mais distais do eletrodo, localizados mais medial, posterior e inferiormente e mais próximos do núcleo rubro. Ademais, houve associação entre EA-NC e eletrodos implantados com maior ângulo coronal, bem como com maior angulação da cápsula interna. Estes achados poderão ser úteis no desenvolvimento de novas estratégias para o planejamento do implante de eletrodos de estimulação cerebral profunda. / Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established treatment for medically refractory motor symptoms of patients with advanced Parkinson\'s disease. Programming of the device is as relevant to patient outcome as accurate implantation of the electrodes. The first step of DBS programming is to identify the thresholds to side effects. However, the relationship between lead location and the threshold to adverse effects is not fully understood. Anatomical measurements and electrode location were evaluated on a stereotactic surgical planning software, whereas stimulation parameters and side effects were obtained from medical records. Correlations among these variables were tested using univariate and multivariable analyses. Monopolar stimulation elicited capsular side effects (CSEs) in 208 of 316 contacts (65.8%) and noncapsular side effects (NCSEs) in 223 of 316 contacts (70.6%). The occurrence of CSEs was correlated with contact number (p = 0,009) and with the \"Z\" coordinate (p = 0,03), whereas voltage threshold to CSEs exhibited correlation with the internal capsule angle (p = 0,035). The occurrence of NCSEs was correlated with contact number (p = 0,005), \"X\" (p = 0,03), \"Y\" (p = 0,004), and the distance to the red nucleus (p = 0,001 and p = 0,003). There was correlation between voltage threshold to NCSEs and the internal capsule angle (p = 0,006), electrode\'s coronal angle (p = 0,02), \"X\" (p = 0,001), \"Y\" (p < 0,001), \"Z\" (p < 0,001), and the distances to the internal capsule (p = 0,02) and to the red nucleus (p = 0,004 and p < 0,001). CSEs were associated with more distally contacts, with deeper localization, as well as with greater internal capsule angles. NCSEs were associated with more distally contacts, with localization more medial, posterior and inferior, and closer to the red nucleus. Moreover, there was a correlation between NCSEs and electrodes implanted with greater coronal angles, as well as with greater internal capsule angles. These findings can be useful to inform novel targeting strategies for deep brain stimulation lead implantation.

Introdução: A disfunção da marcha é um dos maiores comprometimentos funcionais do paciente com a doença de Parkinson (DP). A estimulação cerebral profunda do núcleo subtalâmico tem mostrado melhora da marcha e equilíbrio. Esse efeito pode ser mantido e potencializado por programas de reabilitação motora específicos, como o treino em esteira sem e com suporte de peso corporal. No entanto, faltam estudos desses treinos em pacientes com a DP em uso desta estimulação. Objetivo: Comparar parâmetros cinemáticos lineares e angulares da marcha de pacientes com a DP em uso de estimulação cerebral profunda bilateral do núcleo subtalâmico, antes e após dois treinamentos: esteira sem e com suporte de peso corporal, associados à cinesioterapia convencional. Métodos: 12 pacientes (60,9 ± 10,6 anos; 20 ± 7 anos de doença e 20 ± 4 meses de tempo de cirurgia) completaram ambos os treinos em estudo cruzado fixo. Os pacientes passaram por 8 semanas de treino de marcha em esteira sem suporte de peso corporal e programa de cinesioterapia convencional, seguidas por 6 semanas de período sem intervenção. Posteriormente, realizaram 8 semanas de treino de marcha em esteira com suporte de peso corporal e o mesmo programa de cinesioterapia regular. As intervenções tiveram frequência de duas vezes por semana e duração de 90 minutos por sessão. A análise cinemática da marcha envolveu oito câmeras infravermelhas que detectaram 19 marcadores reflexivos nos membros inferiores dos pacientes. A análise estatística utilizou o teste Wilcoxon e foi adotado valor de p <= 0,05 como estatisticamente significante. Resultados: Ambos os treinos não mostraram diferenças significativas nos parâmetros lineares. Após o treino com suporte, observou-se aumento significativo dos seguintes parâmetros angulares: amplitude de movimento da pelve (inclinação, obliquidade e rotação); amplitude de movimento do quadril (abduçãoadução e rotação); % da fase de balanço que corresponde à flexão máxima do joelho e amplitude de movimento da progressão do pé. Conclusão: O treino em esteira com suporte de peso corporal mostrou capacidade de promover mudanças em parâmetros cinemáticos angulares da marcha. As implicações do treino em suspensão podem ter sido somadas aos efeitos neurofisiológicos da estimulação cerebral profunda e então desencadeado a melhora da mobilidade dos membros inferiores durante a marcha / Introduction: Gait disturbance is one of the hallmark features of Parkinson\'s disease (PD). Subthalamic nucleus deep brain stimulation (DBS) has shown improvements in gait and balance, and this effect can be maintained and enhanced by specific motor rehabilitation programs, such treadmill training without and with body weight support. However, at present there is a paucity of research on these combined interventions in PD with of this stimulation. Objective: To compare training-induced changes in gait linear and angular kinematic parameters among patients with PD who have used bilateral subthalamic nucleus DBS, and a combined intervention of conventional physical therapy with either treadmill training with body weight support or without support. Methods: 12 patients (age: 60.9 ± 10.6 years; disease duration: 20 ± 7 years; and time since DBS surgery: 20 ± 4 months) completed both training protocols in a fixed cross-over design. All patients received 8 weeks of treadmill training without body weight support in conjunction with conventional physical therapy, followed by a 6 weeks wash out period of no training. Thereafter, all patients received 8 weeks of body weight support treadmill training, in conjunction with the same conventional physical therapy. Both interventions had a frequency of two times per week, and duration of 90 minutes per session. Gait kinematic analysis involved eight infrared cameras that detected 19 reflective spherical markers attached to the limb lower of patients. Statistical analysis used the Wilcoxon and was adopted the value of p <= 0,05 as statistically significant. Results: Both the training no showed significant differences in linear parameters. After the body weight support training, observed there was a significant increase in following angular parameters: pelvis\' range of motion (tilt, obliquity, rotation); hip\'s range of motion (abduction-adduction and rotation); % Knee maximal flexion on Swing phase and foot progression\' range of motion. Conclusion: Treadmill training with body weight support showed an ability to promote changes in gait angular kinematic parameters. The implications of this training may have been added to the neurophysiological effects of DBS and then triggered the improved of mobility of lower limbs during gait

INTRODUÇÃO: Os efeitos da levodopa (LD) e da estimulação cerebral profunda (ECP) de núcleo subtalâmico (STN) sobre o equilíbrio e sintomas axiais são até o momento controversos. OBJETIVOS: Avaliar quantitativamente os efeitos da ECP de STN e da LD sobre o equilíbrio estático em pacientes com DP operados, em comparação com a LD em pacientes não operados. MÉTODOS: Trinta e um pacientes submetidos a ECP de STN entre 3 meses e 1 ano e meio antes da avaliação e 26 controles portadores de DP não operados, estágios Hoehn e Yahr 2 a 4 foram avaliados usando UPDRS para avaliação clínica e plataforma de força para avaliar oscilações posturais. O primeiro grupo foi avaliado com ECP e sem medicação, com ECP e com medicação e sem ECP e sem medicação. O segundo grupo foi avaliado com e sem medicação. Cada paciente foi avaliado com os olhos abertos e fechados. O deslocamento do centro de pressão anteroposterior, laterolateral, a área, velocidade e deslocamento total linear foram medidos pela plataforma de força. Os dados paramétricos foram comparados usando o teste t de Student e os dados não-paramétricos foram comparados pelo teste de Kruskal-Wallis. A avaliação clínica consistiu na parte 3 da escala UPDRS e na escala Hoehn e Yahr. Nível de significância estatística considerada foi p=0,05. RESULTADOS: Os pacientes não operados oscilaram mais quando sob efeito da levodopa do que sem medicação. No grupo operado, a maior oscilação é no grupo com ECP desligada e sem medicação. Tende a reduzir sob efeito da ECP apresenta redução significativa sob efeito simultâneo de ECP e levodopa. CONCLUSÃO: A associação da ECP de NST com medicação tem impacto positivo sobre o controle postural. O efeito da ECP de NST reverte o efeito negativo da levodopa sobre as oscilações observadas em pacientes não operados / INTRODUCTION: The effects of bilateral subthalamic (STN) DBS and medication on balance and on axial symptoms in PD have been so far inconsistent. OBJECTIVE: To assess quantitatively the effects of DBS on static balance in PD. METHODS: Thirty-one patients submitted to STN DBS over 3 months before and 26 non-operated controls with PD on Hoehn & Yahr stage \"on\" 2 to 4 were evaluated using UPDRS and a force plate to measure sway. The first group was evaluated on-DBS/off-medication, on-DBS/on-medication and off-DBS/off-medication. The second group was evaluated on and off medication. Each group was assessed with eyes open and then closed. Antero-posterior, laterolateral postural displacements of the center of pressure (COP), as well as 95% sway area, path length and speed of oscillation were analyzed and compared using t-Student test for parametrical data and Kruskal-Wallis test for non-parametrical data. Level of significance was set to p < 0.05. Clinical assessment consisted of UPDRS part 3 and Hoehn & Yahr scores for each of the conditions. RESULTS: Control patients tended to oscillate more in the on medication condition than off medication. DBS patients tended to oscillate more in the off-DBS/off medication condition, with a tendency to decrease the sway when on DBS/off medication with additional decrease when on DBS/on medication. CONCLUSION: Association of bilateral STN DBS and medication positively influences postural control in PD and surgery reverses the tendency of medication to increase body sway in non-operated patients

The Basal Ganglia consist of a number of different nuclei that form a diverse circuitry of GABAergic, dopaminergic and glutamatergic neurons. This complex network is further organized in subcircuits that govern limbic and motor functions in humans and other vertebrates. Due to the interconnection of the individual structures, dysfunction in one area or cell population can affect the entire network, leading to synaptic and molecular alterations in the circuitry as a whole. The studies in this doctoral thesis aimed at characterizing restricted subpopulations of neurons in the Basal Ganglia circuitry and their importance in the wider function of the network. To this end, we identified subpopulations of neurons in the subthalamic nucleus (STN), substantia nigra (SN) and ventral tegmental area (VTA), characterized their molecular profile and investigated their physiological role in the circuitry. Within the mouse STN, reduction of glutamatergic neurotransmission in a subpopulation expressing Paired-like homeodomain transcription factor 2 (Pitx2) led to structural alterations in the nucleus as well as biochemical alterations of the dopaminergic system in the Nucleus accumbens (NAc) and changes in reward-related behavior. In the ventral midbrain, we identified and characterized novel marker genes selective to the VTA or SN. Of these, transient receptor potential cation channel subfamily V member 1 (TrpV1) marks a population of mainly glutamatergic neurons in the VTA which project to the NAc, while gastrin releasing peptide (Grp) is expressed in a population of dopaminergic neurons neuroprotected in Parkinson's disease. Furthermore, we discovered that disruption of glutamatergic co-release of dopaminergic neurons expressing dopamine transporter (DAT), diminishes fast EPSCs and glutamate release but does not affect the acquisition of reward-related behavioral tasks. To selectively quantify glutamate release from specific subpopulations, we devised a technique combining glutamate-amperometry and optogenetics. This was used to measure glutamate released from Pitx2-expressing synaptic terminals in the Globus pallidus as well as DAT- or TrpV1-expressing terminals in the NAc. In summary, this doctoral thesis has furthered understanding of the function and importance of specific subpopulations within the Basal Ganglia circuitry and provides a novel means to investigate glutamate in the intact rodent brain within clearly defined, restricted cell populations.

Les ganglions de la base forment un ensemble de structures sous-corticales connues pour leur implication dans les processus sensori-moteurs, cognitifs et motivationnels. L’objectif de ce travail était d’approfondir le rôle des neurones du noyau subthalamique (NST), des neurones de projections et interneurones cholinergiques du striatum et des neurones du globus pallidus externe (GPe) dans la mise en place et l’exécution d’un comportement dans différents contextes motivationnels. Nous nous sommes intéressés à l’influence de l’effort et de la récompense sur l’activité de ces neurones grâce à une approche comportementale associée à des enregistrements extracellulaires unitaires chez le singe éveillé. L’influence de ces facteurs a été appréhendée dans une tâche visuo-motrice dans laquelle différents niveaux d’effort et de récompense étaient imposés à l’animal. Nos résultats comportementaux ont montré une prise en compte de la valeur des stimuli par les animaux. Les résultats électrophysiologiques obtenus montrent une implication de chacune des populations étudiées dans le traitement des informations relatives à l’effort et à la récompense. Ils suggèrent un rôle des neurones du NST, du striatum et du GPe respectivement dans la mise en place, l’exécution et l’évaluation de l’action sur la base de la valeur subjective de la récompense. Nos résultats apportent des informations nouvelles sur les substrats neurophysiologiques qui sous-tendent les processus motivationnels dans la circuiterie des ganglions de la base. / The basal ganglia form a set of subcortical structures known to be involved in sensorimotor, cognitive and motivational processes. The aim of this work was to study the role of the subthalamic nucleus (STN) neurons, the cholinergic interneurons and the projection neurons of the striatum and the neurons of the external part of the globus pallidus (GPe) in the establishment and the execution of a behavior under different motivational contexts. We examined the influence of effort and reward on the activity of these neurons with a behavioral approach combined with extracellular recordings in awake monkeys. The influence of these factors has been investigated in a visuo-motor task in which different levels of effort and reward were imposed on the animal. Our behavioral results showed a consideration of the value of the visual stimuli by the animals. Electrophysiological results showed an implication of each of the neuronal populations studied in the encoding of force and reward related information. These data suggest a role of STN, striatum and GPe in the establishment, the execution and the update of the benefit of the action based on subjective reward value. Our results bring out new features on the neurophysiological substrates underlying motivational processes in basal ganglia circuitry.

La stimulation à haute fréquence (SHF) du noyau subthalamique (NST) joue un rôle essentiel chez les patients Parkinsoniens dans l'amélioration des troubles moteurs pour lesquels la dopa-thérapie n'est plus satisfaisante. Tout comme l'administration à long terme de L-DOPA, la SHF du NST, peut aussi, selon l'intensité de stimulation, évoquer des mouvements dyskinétiques. Ces dyskinésies sont considérées comme un phénomène d'apprentissage moteur pathologique, secondaire à une altération de la transmission glutamatergique et sont sous-tendues par des modifications durables d'expression génique, notamment dans le striatum. L'objectif de ce travail de thèse est d'étudier et de comparer les mécanismes moléculaires des dyskinésies induites par la L-DOPA à celles induites par la SHF, en se focalisant plus particulièrement sur la sous unité NR2B des récepteurs NMDA. Dans un premier temps, nous avons montré par immunohistochimie que la sous unité NR2B est hyperphosphorylée dans le NST et l'EP suite à l'induction de dyskinésie par la SHF du NST chez l'animal sain. Ces résultats ont été confirmés par la suite dans un modèle animal de la maladie de Parkinson, le rat 6-OHDA. La comparaison de ces modifications avec celles observées chez le rat 6-OHDA rendus dyskinétique par un traitement chronique à la L-DOPA nous permet de suggérer que l'induction des dyskinésies est associée à une hyperphosphorylation de NR2B au sein d'une voie subthalamo-entopédonculaire alors qu'une activation de NR2B dans le striatum semble être impliquée dans l'expression des dyskinésies. Enfin, nos résultats mettent également en évidence une implication différentielle des deux structures de sorties des ganglions de la base dans les processus akinétiques et dyskinésiogènes. / High frequency stimulation of the subthalamic nucleus (STN-HFS) alleviates parkinsonian motor symptoms and indirectly improves dyskinesia by decreasing L-DOPA requirement. However, inappropriate stimulation can also trigger dyskinetic movements Dyskinesia are thought to be a pathological learning process due to an overactive glutamate transmission within the basal ganglia. Moreover, several molecular changes seem to be involved in this process. The aim of the present study is to compare the molecular mechanisms of dyskinesia induced by L-DOPA and by STN-HFS, by focusing more particularly on the NR2B-containing NMDA receptor. We show by immunohistochemistry that NR2B subunit is hyperphosphorylated within the STN and the EP during a dyskinesiogenic STN-HFS in normal rats. Similar results are obtained from 6-OHDA rats, a model of Parkinson disease. Comparison of these results with those observed in 6-OHDA dyskinetic rats chronically treated with L-DOPA suggest that dyskinesia induction is associated with an hyperphosphorylation of NR2B within a subthalamo-entopeduncular network while activation of NR2B within the striatum seem to be involved in the expression of dyskinesia. A different implication of the two output of the basal ganglia in akinetic and dyskinesiogenic process is also demonstrated. STAR Date de soutenance : 8 juillet 2011 Thèse sur travaux: non

Les ganglions de la base (GB) forment un réseau de structures sous-corticales impliquées dans la motricité volontaire, mais aussi dans des aspects plus cognitifs et motivationnels du comportement moteur. La dopamine est un neuromodulateur essentiel au bon fonctionnement de ce réseau. La synapse cortico-sous-thalamique (cortico-NST) est une synapse glutamatergique (excitatrice) transmettant les informations corticales au noyau sous-thalamique (NST), ce qui forme la première partie d’une des trois voies des GB : la voie hyperdirecte. La voie cortico-NST est impliquée dans des tâches de type « go-no-go » (arrêt d’un acte moteur débuté) et dans les effets bénéfiques de la stimulation cérébrale profonde du NST sur les symptômes de la maladie de Parkinson. Cependant, les propriétés des synapses cortico-NST ne sont pas connues. Ce manque d’informations provient, en partie, de l’anatomie particulière de cette voie, qui rend l’étude in vitro de la synapse cortico-NST difficile. L’utilisation de l’optogénétique nous a permis de contourner ce problème. En associant cette technique à l’électrophysiologie sur tranches de cerveaux de rongeur, nous avons mis en évidence un effet inhibiteur des récepteurs dopaminergiques D5 sur la transmission cortico-NST. Nous montrons également que les propriétés de plasticité à court terme de cette synapse lui permettent de réduire l’influence des messages corticaux à haute fréquence sur le NST. Les résultats obtenus au cours de cette thèse montrent que l’optogénétique est un bon moyen d’étudier la synapse cortico-NST in vitro et contribuent à améliorer la compréhension des propriétés de la cette synapse. / Basal ganglia (BG) are a group of subcortical nuclei involved in action selection and in cognitive and motivational aspects of motor behavior. Dopamine is essential for proper functioning of BG. The cortico-subthalamic (cortico-STN) synapse is a glutamatergic (excitatory) synapse involved in signal transmission from cortex to subthalamic nucleus (STN). The cortico-STN synapse is the first synapse in the hyperdirect pathway, one of the three pathways of BG. Even if the cortico-STN pathway is involved in “go-no-go” tasks (stopping of an already started motor act) and in the beneficial effects of the high frequency stimulation of the STN on Parkinsonian symptoms, properties of the cortico-STN synapse are not well described. The lack of data is due, at least in part, to the specific anatomy of the cortico-STN pathway which does not allow the use of standard methods in vitro. The use of optogenetics allowed us to circumvent this issue. By coupling this approach with electrophysiology on brain slices in rodents, we show that dopaminergic D5 receptors stimulation reduces glutamatergic transmission at cortico-STN synapses. We also show that short-term plasticity properties of this synapse reduce the influence of high frequency cortical inputs on the STN. Our findings indicate that optogenetics enables studying the cortico-STN synapse in vitro and contributes to improving our knowledge of the properties of the synapse.

No description available.

Summery The underlying mechanisms of weight gain and other affective and cognitive changes after initiation of deep brain stimulation in Parkinson's disease are still unclear. Considering the functional organization within the subthalamic nucleus (STN); limbic, associative and sensorimotor regions residing in the medial, central and later STN respectively, we hypothesized that weight gain may be related to medial localization of stimulation, while motor improvement may be related to lateral localization of stimulation within the STN (study 1). We further hypothesized that stimulation close to the limbic and associative part of the STN may be associated with negative impact on limbic system leading to enhanced anxiety and changes in the hypothalamic- pituitary- adrenal axis (HPA)(study 2). Therefore, the primary aims our study were to assess changes in body weight (study 1) and the hypothalamic- pituitary- adrenal axis (HPA) (study 2) in relation to the position of the active stimulating contact within the nucleus. ...

Au-delà des symptômes moteurs classiques de la maladie de Parkinson, d’autres troubles neuropsychiatriques, émotionnels ou cognitifs sont fréquemment observés chez le patient parkinsonien. L’apathie, définie comme une importante diminution des comportements motivés dirigés vers un but, est l’un des troubles neuropsychiatriques le plus souvent rapporté en clinique. Si ce symptôme est relativement bien maitrisé par les traitements dopaminergiques, l’application de la stimulation haute fréquence du noyau subthalamique (SHF-NST), traitement neurochirurgical de référence, entraîne sa résurgence chez environ 50 % des patients stimulés. De nombreuses données suggèrent que cette résurgence est liée à la diminution du traitement dopaminergique, permise grâce aux effets spectaculaires de la SHF-NST sur les symptômes moteurs. Au contraire, d’autres études proposent un rôle délétère direct de la SHF-NST sur les comportements motivés. Malheureusement, chez le patient, il n’est pas possible de dissocier l’effet des différents traitements. Ainsi, afin de comprendre les bases neurobiologiques de l’apathie dans la maladie de parkinson, notre laboratoire a récemment développé un modèle animal chez le rat, basé sur des approches de lésions sélectives, partielles et bilatérales des neurones dopaminergiques du mésencéphale, reproduisant un déficit motivationnel pouvant s’apparenter à l’apathie parkinsonienne.L’objectif de ce travail doctoral a été d’étudier l’effet de la SHF-NST sur les comportements motivés chez le rat sain et dans ce modèle animal, et d’en comprendre les mécanismes neurobiologiques. Pour cela, nous avons utilisé un nouveau système de stimulation portatif chez le rat, permettant d’appliquer une SHF-NST chronique et ininterrompue chez l’animal libre de ses mouvements. Dans un premier temps, nous avons évalué l’effet motivationnel de la SHF-NST chez le rat sain et parkinsonien à l’aide de tests de référence. Nous avons ainsi pu montrer que la SHF-NST induisait un déficit motivationnel sévère chez le rat sain, ou exacerbait le déficit présent chez le rat lésé. Dans un deuxième temps, compte tenu de l’efficacité chez le patient des agonistes des récepteurs dopaminergiques D2 et D3 (RD2 et RD3) sur l’apathie pré ou post opératoire, nous avons voulu corriger ce trouble induit par la SHF-NST avec un tel traitement. Cette étude pharmacologique nous a amené à montrer que le pramipexole, un agoniste D2 D3, permet de traiter complétement le déficit induit par la SHF-NST. Enfin, compte tenu de ces résultats pharmacologiques, nous avons voulu vérifier si les effets délétères de la SHF-NST ou thérapeutiques du pramipexole, étaient sous-tendus par une modification d’expression des récepteurs D2 et D3. Pour cela nous avons utilisé une nouvelle technique d’hybridation in situ pour quantifier les transcrits D2 et D3. Si la SHF-NST ne semble pas impacter l’expression de ces récepteurs, l’effet thérapeutique du pramipexole pourrait être sous tendu par une baisse d’expression du RD3 au sein du noyau accumbens.Les données obtenues au cours de ce travail doctoral suggèrent donc fortement que la SHF-NST pourrait en elle-même induire de l’apathie post opératoire. De plus, malgré l’apport thérapeutique de l’activation des RD2 et RD3 sur ce symptôme, son origine serait sous tendue par un autre mécanisme qui reste à être élucider. / Apart from the classical motor symptoms of Parkinson’s disease, neuropsychiatric, emotional or cognitive impairments are also commonly observed in parkinsonian patients. Apathy, defined as a decrease in goal directed motivated behaviours, is one of the most frequently reported neuropsychiatric symptom in PD. This impairment is relatively well alleviated by dopaminergic treatment, but subthalamic nucleus high frequency stimulation (STN-HFS), the gold standard neurosurgical treatment, leads to the resurgence of this symptom in 50% of patients. Clinical evidence suggests that this is due to the reduction of the dopaminergic treatment, made possible by the great effect of STN-HFS on motor symptoms. However, some studies propose a direct deleterious action of STN-HFS on motivated behaviors. Unfortunately, it is impossible to dissociate the effect of the different treatments in patients. Thus, in order to better understand the neurobiological basis of apathy in Parkinson’s disease, our laboratory recently developed a rodent model, based on selective, partial and bilateral lesion of mesencephalic dopaminergic neurons, reproducing a motivational deficit reminiscent of parkinsonian apathy.The aim of this thesis project is to assess the effect of STN-HFS on motivated behaviours in normal and parkinsonian rats, and to unravel the essential mechanisms. We have used a new micro-stimulation system, allowing chronic STN-HFS in freely moving animals. First, we evaluated the motivational effect of STN-HFS in healthy and lesioned rats, using appropriate behavioural tests. We showed that STN-HFS induces a motivational impairment in healthy rats, and exacerbates the deficit observed in parkinsonian rats. Then, considering their therapeutic effect on apathy before or after STN-HFS in patients, we used D2 and D3 dopaminergic receptor agonists to try to manage this deficit in rats. It was thus demonstrated that pramipexole, a D2 D3 agonist, completely alleviated this STN-HFS induced deficit. This result prompted to assess whether the deleterious effect of STN-HFS, or the beneficial effect of pramipexole, depended on modulation of D2 and D3 expression. We therefore applied a new in situ hybridization technique to quantify D2 and D3 mRNAs. We found that STN-HFS alone did not modify their expressions, but the therapeutic effect of pramipexole could be liked to down-regulation of D3 receptors within the nucleus accumbens.Our data strongly suggest that STN-HFS itself may induce post-operative apathy. Moreover, despite the beneficial effect of D2 and D3 agonist on this symptom, its origin could depend on other mechanisms that will need to be deciphered.