Pathophysiology of Dystonia and Parkinsonism

描述（由申请人提供）：在北美，帕金森病（PD）影响近100万人，肌张力障碍影响多达50万人。一般认为，PD的运动表现是由于黑质纹状体多巴胺神经元的变性导致纹状体多巴胺耗竭。肌张力障碍的原因更多。最近的证据表明，肌张力障碍（产生扭曲姿势的不自主肌肉收缩）也可能与纹状体多巴胺神经传递的不足有关。在猴子中，已经表明，由颈动脉内注射MPTP诱导的单侧纹状体多巴胺耗竭导致双相障碍，即短暂性肌张力障碍，随后是稳定的帕金森综合征。肌张力障碍和帕金森综合征与纹状体多巴胺缺乏程度相当，这引起了人们对这些疾病的基本病理生理学的质疑。本项目的目的是研究帕金森综合征和肌张力障碍的病理生理学通过记录苍白球神经元的活动之前和之后的管理MPTP在猴子训练执行达到的任务。定量行为方法和PET成像将用于测量肌张力障碍、帕金森综合征和多巴胺耗竭的严重程度。在MPTP前、MPTP后的短暂张力障碍期和慢性帕金森病期记录猴苍白球内段（GPi）和外段（GPe）单个神经元的活动。具体目标是：1）确定静息苍白球放电率、模式和同步化与肌张力障碍和帕金森综合征的关系; 2）确定伴随肌张力障碍和帕金森综合征的运动相关神经元活动的特定变化;第三章以确定壳核感觉运动区是否存在躯体位置选择性的丧失以及苍白球中躯体位置选择性的丧失是否是由于异常信号在壳核中加工这些目标将测试与肌张力障碍和帕金森症相关的基底神经节功能障碍的特定假设。这项研究的结果将促进我们对帕金森综合征和肌张力障碍的病理生理学的理解，这是啮齿动物模型或人类受试者研究所不可能实现的。更好地了解病理生理学可能会导致新的治疗方法或改善目前可用的治疗方法的应用。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) affects nearly one million people and dystonia affects up to 500,000 people in North America. It is generally accepted that the motor manifestations of PD are due to degeneration of nigrostriatal dopamine neurons with resulting striatal dopamine depletion. The causes of dystonia are more numerous. Recent evidence has indicated that dystonia (involuntary muscle contractions that produce twisting postures) can also be associated with deficiencies in striatal dopamine neurotransmission. In monkeys, it has been shown that unilateral striatal dopamine depletion induced by intracarotid injection of MPTP causes a biphasic disorder with transient dystonia followed by stable parkinsonism. The association of both dystonia and parkinsonism with equivalent degrees of striatal dopamine deficiency raises questions about the fundamental pathophysiology of these conditions. The purpose of this project is to investigate the pathophysiology of parkinsonism and dystonia by recording the activity of globus pallidus neurons before and after the administration of MPTP in monkeys trained to perform a reaching task. Quantitative behavioral methods and PET imaging will be used to measure the severity of dystonia, parkinsonism, and dopamine depletion. The activity of single neurons in globus pallidus internal segment (GPi) and external segment (GPe) will be recording in monkeys before MPTP and in the transient dystonic phase and chronic parkinsonian phase after MPTP. The specific aims are: 1) to determine to determine the relationship of resting pallidal discharge rates, patterns, and synchronization to dystonia and parkinsonism; 2) to determine specific changes in movement-related neuronal activity that accompany dystonia and parkinsonism; 3) to determine whether there is loss of somatotopic selectivity in the sensorimotor region of putamen and whether the loss of somatotopic selectivity in globus pallidus is due to abnormal signal processing in the putamen. These aims will test specific hypotheses of basal ganglia dysfunction related to dystonia and parkinsonism. The results from this study will advance our understanding of the pathophysiology of parkinsonism and dystonia in ways not possible from studies in rodent models or in human subjects. Better understanding of the pathophysiology may lead to new therapies or improved application of currently available therapies.