Cerebello-Basal Ganglia Interactions

描述(由申请人提供)：肌张力障碍包括一组不同的运动障碍，通常以肌肉长时间收缩为特征。最常见的牙痛是特发性的。尽管如此，有几个基因与肌张力障碍有关。非特发性肌张力障碍最常见的原因是基底节受损。然而，最近积累的证据支持这样的观点，即在某些情况下，小脑功能障碍也可能导致(甚至煽动)肌张力障碍。我们的工作假设是，异常的小脑活动会动态改变基底节的生理功能，从而导致肌张力障碍。在啮齿动物和灵长类动物中，已经描述了一种通过丘脑中央外侧核从小脑到基底节的直接双突触连接的解剖学基础。在这项提议中，我们希望测试一种假设，即在健康的个体中，这种双突触连接允许小脑和基底节之间的快速交流。进一步，我们将检验这样一种假设，即这种双突触通路提供了主要通道，通过该通道，异常的小脑活动迫使基底节神经元发生不规律的爆发式放电，从而导致肌张力障碍。这一提议的成功完成将促进我们对小脑和基底节之间相互作用的本质的理解，以促进运动协调。此外，它还可能提供关于小脑活动异常如何引发肌张力障碍的详细机制洞察力。

DESCRIPTION (provided by applicant): Dystonias comprise a diverse group of movement disorders that are often characterized by prolonged contraction of muscles. The most common dystonias are idiopathic. Nonetheless, several genes have been implicated in dystonia. The most prevalent cause of nonidiopathic dystonia is damage to the basal ganglia. Recently, however, evidence has amassed in support of the notion that in some cases cerebellar dysfunction may also contribute to (or even instigate) dystonia. Our working hypothesis is that aberrant cerebellar activity dynamically alters the physiologic function of the basal ganglia thus resulting in dystonia. An anatomical substrate for a direct disynaptic connection from the cerebellum to the basal ganglia via the centrolateral nucleus of the thalamus has been described both in rodents and primates. In this proposal we wish to test the hypothesis that in healthy individuals this disynaptic connection allows for rapid communication between the cerebellum and the basal ganglia. Further, we will test the hypothesis that this disynaptic pathway provides the primary conduit through which aberrant cerebellar activity forces erratic burst firing in the basal ganglia neurons thereby causing dystonia. Successful completion of this proposal will advance our understanding of the nature of interactions between the cerebellum and basal ganglia for motor coordination. Additionally, it may also provide a detailed mechanistic insight as to how aberrant cerebellar activity instigates dystonia.