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，其特征通常是肌肉收缩延长。最常见的肌张力障碍是特发性的。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神经节损伤。然而，最近有越来越多的证据支持这一观点，即在某些情况下，小脑功能障碍也可能导致（甚至诱发）肌张力障碍。我们的工作假设是异常的小脑活动动态地改变了基底神经节的生理功能，从而导致肌张力障碍。在啮齿类和灵长类动物中，都曾描述过从小脑经丘脑中央外侧核到基底神经节的直接双突触连接的解剖学基础。在这个建议中，我们希望测试的假设，在健康的人，这种双突触连接允许小脑和基底神经节之间的快速通信。此外，我们将测试这一假设，即双突触通路提供了主要的管道，通过异常的小脑活动的力量不稳定的突发发射在基底神经节神经元，从而导致肌张力障碍。成功地完成这一建议将促进我们的理解之间的相互作用的性质小脑和基底神经节的运动协调。此外，它也可以提供一个详细的机制，了解异常小脑活动如何煽动肌张力障碍。 公共卫生相关性：肌张力障碍是第三常见的运动障碍，其特征是肌肉收缩时间延长。肌张力障碍最常见的原因是基底神经节受损。然而，最近的证据表明，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。在这里，我们将测试的工作假设，导致肌张力障碍，异常小脑活动动态地改变了基底神经节神经元的生理功能，通过一个双突触通路路由通过丘脑。成功地完成这一建议将推进我们的理解小脑和基底神经节之间的相互作用的性质，运动协调，并可能提供一个详细的机制的见解，异常小脑活动如何煽动肌张力障碍。这一信息将是非常宝贵的设计合理的治疗干预小脑引起的肌张力障碍的治疗。

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. PUBLIC HEALTH RELEVANCE: Dystonias are the third most common movement disorder and are characterized by prolonged contraction of muscles. The most prevalent cause of dystonia is damage to the basal ganglia. Recent evidence, however, suggests that in some cases cerebellar dysfunction may also contribute to (or even instigate) dystonia. Here we will test the working hypothesis that, to cause dystonia, aberrant cerebellar activity dynamically alters the physiologic function of the basal ganglia neurons via a disynaptic pathway routed through the thalamus. Successful completion of this proposal will advance our understanding of the nature of interactions between the cerebellum and basal ganglia for motor coordination and may provide a detailed mechanistic insight as to how aberrant cerebellar activity instigates dystonia. This information would be invaluable for designing rational therapeutic interventions for the treatment of cerebellar-induced dystonia.