Cerebello-Basal Ganglia Interactions

小脑-基底神经节相互作用

• 批准号: 8881345
• 负责人: Kamran Khodakhah
• 金额: $ 16.17万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2015-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8881345
• 关键词: Basal Ganglia; Cell Nucleus; Cells; Cerebellar Diseases; Cerebellum; Communication; Corpus striatum structure; Dystonia; Dystonia 12; Fire - disasters; Functional disorder; Genes; Individual; Modeling; Motor; Movement Disorders; Mus; Muscle Contraction; Na(+)-K(+)-Exchanging ATPase; Nature; Neurons; Output; Parkinson Disease; Pathologic; Pathway interactions; Physiological; Primates; Protein Isoforms; Rodent; Testing; Thalamic structure; Therapeutic Intervention; Tremor; Work; design; in vivo; insight; loss of function mutation; mouse model

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.

描述（由申请人提供）：肌张力障碍包括多种运动障碍，通常以肌肉长时间收缩为特征。最常见的肌张力障碍是特发性的。尽管如此，仍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，最近越来越多的证据支持这样一种观点，即在某些情况下，小脑功能障碍也可能导致（甚至引发）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。在啮齿类动物和灵长类动物中，已经描述了小脑与基底神经节之间通过丘脑中央外侧核的直接非突触连接的解剖学基础。在这个提议中，我们希望测试这样一个假设，即在健康个体中，这种失突触连接允许小脑和基底神经节之间的快速交流。此外，我们将验证这种失突触通路提供了主要通道的假设，通过该通道，异常的小脑活动迫使基底神经节神经元不稳定的突发放电，从而导致肌张力障碍。这一建议的成功完成将推进我们对小脑和基底神经节之间运动协调相互作用本质的理解。此外，它也可能提供一个详细的机制，如何异常的小脑活动引发肌张力障碍。