REGULATION OF MOTOR FUNCTION IN PARKINSON'S DISEASE

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本研究旨在探讨帕金森氏症行为异常的病理生理机制，以期开发新的治疗手段。 我们的目标是表征基底神经节功能的改变所示的区域神经元活动的变化。 在报告期内，我们分析了苍白球（GPe）外段单细胞记录的大部分电生理数据。在“关闭”状态下，放电率显著降低（平均放电率为32 Hz），GPe活性的显著降低表明间接纹状体输出通路由于多巴胺去神经支配而产生显著的抑制性输入。 多巴胺刺激增加了所有三组中大多数神经元的放电率，根据其放电模式（暂停，非暂停和爆发）进行分类。 我们发现运动障碍（不自主运动）与多巴胺反应开始时发生的速率变化的反转有关。 在50%的神经元中发现了这种双向反应。 其余一半的神经元继续增加或减少放电频率在运动障碍表现出单向反应。 因此，运动障碍在GPe单位中表现为神经元活动的显著差异;单向变化导致大多数单位的频率更高，而双向变化导致返回基线频率。这些研究结果有助于PD异常运动行为的病理生理学的关键信息，例如，我们的研究结果与纹状体活动的不平衡可能减少多巴胺反应中直接或间接纹状体输出通路的参与的概念相矛盾。 更好地了解异常行为的机制可能有助于开发新的和更具体的治疗方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project elucidates the pathophysiologic mechanisms of abnormal behaviors in Parkinson's disease (PD) in view of developing new therapeutic tools. Our goal has been to characterize basal ganglia functional alterations as shown by changes of regional neuronal activity. During the reporting period, we analyzed most electrophysiology data of single cell recording from the external segment of the globus pallidus (GPe). Firing rates were profoundly decreased in the 'off' state (rates averaged 32 Hz), and the substantial decrease of GPe activity indicates a marked inhibitory input from the indirect striatal output pathway as a result of profound dopamine denervation. Dopamine stimulation increased firing rates in the majority of neurons in all three groups as classified according to their firing pattern (pausers, non-pausers, and bursters). We found that dyskinesias (involuntary movements) are associated with inversion of the rate changes that had occurred at the onset of the dopamine response. Such bidirectional response was found in 50% of total neurons. The remaining half of neurons continued to increase or decrease the firing frequency during dyskinesias exhibiting unidirectional responses. Thus, dyskinesias are expressed with marked differences of neuronal activity across GPe units; unidirectional changes lead to much higher frequencies in most units while bidirectional changes result in a return to the baseline frequency. These findings contribute critical information to the pathophysiology of abnormal motor behaviors in PD; for instance our results contradict the notion that an imbalance of striatal activity may reduce the participation of the direct or indirect striatal output pathways in dopamine responses. A better understanding of the mechanisms underlying abnormal behaviors may help develop new and more specific therapies.