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。人们普遍认为帕金森病的运动表现是由于黑质纹状体多巴胺神经元变性导致纹状体多巴胺耗竭。肌张力障碍的原因很多。最近的证据表明，肌张力障碍（产生扭曲姿势的不随意肌收缩）也可能与纹状体多巴胺神经传递不足有关。在猴子中，研究表明颈动脉内注射MPTP诱导的单侧纹状体多巴胺耗竭会导致短暂性肌张力障碍的双相障碍，随后出现稳定的帕金森病。肌张力障碍和帕金森氏症与同等程度纹状体多巴胺缺乏的关联提出了这些疾病的基本病理生理学问题。本项目的目的是通过记录猴子在接受MPTP训练后的白球神经元活动，来研究帕金森病和肌张力障碍的病理生理学。定量行为方法和PET成像将用于测量肌张力障碍、帕金森病和多巴胺耗竭的严重程度。在MPTP前和MPTP后的短暂性肌张力障碍期和慢性帕金森期，记录猴子苍白球内段和外段单个神经元的活动。具体目的是：1)确定静息苍白质放电率、模式和同步与肌张力障碍和帕金森病的关系；2)确定伴随肌张力障碍和帕金森病的运动相关神经元活动的具体变化；3)确定壳核感觉运动区是否存在体位选择性的丧失，白球体位选择性的丧失是否由于壳核信号处理异常所致。这些目的将测试与肌张力障碍和帕金森病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病和肌张力障碍的病理生理学的理解，这是在啮齿动物模型或人类实验中无法实现的。对病理生理学的更好理解可能会导致新的治疗方法或改进现有治疗方法的应用。

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.