REGULATION OF MOTOR FUNCTION IN PARKINSON'S DISEASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本项目的目的是阐明帕金森病异常行为的病理生理机制，以期开发新的治疗手段。因此，本研究的目的是：1-确定基底神经节功能改变的特征，2-确定与神经元功能改变相关的谷氨酸能调节，以及3-通过与谷氨酸能神经传递的相互作用来探索新的治疗方法。这个项目在最后一段时间里取得了很大的进展。我们以前的发现表明，运动障碍是由推翻纹状体神经元上的多巴胺作用的机制产生的。然而，这些比率变化与运动障碍发生的具体关系仍然不确定。今年，我们在低剂量左旋多巴的实验中记录了纹状体神经元的活动。当不存在运动障碍时，纹状体神经元的放电率没有显示出‘ON’状态下的倒置变化。这些结果证实了我们的新发现，即纹状体神经元中多巴胺诱导的速率变化与运动障碍有机械联系。关于神经元的活动模式，我们发现帕金森病残疾的逆转以爆发减少和爆发构象变化为特征。大多数“突发性”神经元在帕金森病逆转的转变过程中也增加了频率，这意味着多巴胺介导了这些神经元的兴奋机制，从而涉及到直接的输出途径。从到目前为止的模式分析结果，我们可以得出结论，帕金森病运动症状与纹状体神经元亚群中的爆发式放电有关。今年进行的药物测试表明，离子通道阻滞剂似乎对最初的局部注射非常有效。

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. The objective of this project is to elucidate the pathophysiologic mechanisms of abnormal behaviors in Parkinson's disease with the goal of developing new therapeutic tools. Thus, this study aims: 1-to characterize basal ganglia functional alterations, 2-to determine the glutamatergic regulation associated with an altered neuronal function, and 3-to explore new therapeutic approaches by interacting with the glutamatergic neurotransmission. This project has made great progress during the last period. Our previous findings suggested that dyskinesias are produced by mechanisms that overturn dopamine action on striatal neurons. However, the specific relationship of those rate changes to the occurrence of dyskinesias remained uncertain. This year, we recorded the activity of striatal neurons in experiments of lower doses of levodopa. Firing rates of striatal neurons did not show inversion of changes during the 'on' state when dyskinesias were not present. These results proved our novel findings of inversion of dopamine-induced rate changes in striatal neurons that is mechanistically associated with dyskinesias. Regarding the pattern of neuronal activity, we found that reversal of parkinsonian disability was characterized by a reduction of bursting and changes in burst conformation. Most 'bursty' neurons also increased their frequency during the transition to reversal of parkinsonism implying that dopamine mediates excitatory mechanisms in these neurons, thereby involving the direct output pathway. From results of pattern analysis so far, we can conclude that parkinsonian motor symptoms are associated with burst discharges in a subpopulation of striatal neurons. Drug tests performed this year indicate that ion channel blockers appear to be highly effective for initial local injections.