Regulation of Motor Function in Parkinson's Disease

描述（由申请人提供）：帕金森病的运动障碍是由多巴胺去神经支配引起的基底神经节的一系列功能改变引起的。这些功能改变背后的机制尚不完全清楚。此外，长期左旋多巴治疗通常与致残性运动并发症有关，如运动波动和运动障碍，其病理生理学也尚不清楚。该项目的长期目标是阐明帕金森病异常运动行为的病理生理机制，以期开发新的特异性治疗工具。因此，本研究的目的是：首先，定位特定基底神经节回路的功能改变；-第二，确定与神经元功能改变相关的谷氨酸调节；-最后，在上述数据的基础上，探索新的治疗方法，以特定区域的方式与谷氨酸神经传递相互作用。具体而言，该项目包括三个目标：1。通过单细胞记录研究正常和不同组帕金森猴（mptp治疗的灵长类动物）的单个基底节区神经元活动，这些动物表现出不同的运动行为，取决于治疗条件（即帕金森状态，其正常化和药物引起的运动障碍）。2. 通过比较不同动物组间谷氨酸受体的结合，研究基底神经节区谷氨酸受体对不同运动状态的敏感性。3. 目的：研究限制性基底神经节区谷氨酸能阻滞对神经元活动和运动行为的影响。研究设计包括从单个和多个神经元活动的单单元记录，受体的放射自显影结合，到对运动异常与人类疾病非常相似的帕金森猴子进行脑内给药的技术。本项目为帕金森病运动功能异常的综合研究提供了一种新的途径。因此，它将在很大程度上有助于有选择地针对特定运动条件的新治疗的基本原理。

DESCRIPTION (provided by applicant): Motor disturbances of Parkinson's disease are caused by a series of functional alterations in the basal ganglia that derive from dopamine denervation. The mechanisms underlying those functional alterations are not completely understood yet. Moreover, long-term levodopa therapy is usually associated with disabling motor complications, such as motor fluctuations and dyskinesias, whose pathophysiology also remains obscure. The long-term objective of this project is to elucidate the pathophysiologic mechanisms of abnormal motor behaviors in Parkinson's disease in view of developing new and specific therapeutic tools. Thus, this study is aimed: -firstly, to localize functional alterations in specific basal ganglia circuits; -secondly, to determine the glutamate regulation associated to an altered neuronal function; -finally, and based on the foregoing data, to explore new therapeutic approaches by interacting with the glutamatergic neurotransmission in a region-specific manner. Specifically this project comprises three aims: 1. To study the neuronal activity of individual basal ganglia regions by single cell recording in normal and various groups of parkinsonian monkeys (MPTP-treated primates) that exhibit different motor behaviors depending on treatment conditions (i.e.: parkinsonian state, its normalization, and drug-induced dyskinesias). 2. To study the glutamate receptor sensitivity in basal ganglia regions in relation to different motor conditions by comparing the binding of receptors across animal groups. 3. To study the glutamatergic blockade in restricted basal ganglia regions by determining its effects on neuronal activity and motor behavior. The research design includes techniques ranging from single- and multiple single- unit recording of neuronal activity, autoradiographic binding of receptors, to intracerebral administration of drugs in parkinsonian monkeys whose motor abnormalities closely resemble the human disease. This project proposes a novel approach to a comprehensive study of the abnormal motor function in Parkinson's disease. Thus, it will largely contribute to the rationale for new treatments that selectively target particular motor conditions.