The role of cerebellar Golgi interneurons in the adaptive timing of movements

描述（由申请人提供）：小脑如何实现运动学习在很大程度上仍然是一个谜。特别是，它校准运动时间的机制仍有待阐明。尽管大多数关于学习的研究都集中在神经信号通路强度的变化上，但我的工作是研究神经信号的动态。长期以来的理论表明，高尔基细胞是一类抑制性中间神经元，在控制小脑神经信号处理的动力学中起着关键作用，从而决定了习得运动的时间。为了验证这一假设，我将利用最近的几项技术进步：1)记录体内高尔基体细胞，我一直在监测运动学习前后的活动，以确定高尔基体细胞活动的变化是否可以解释运动时间的变化，2)转基因小鼠，其中高尔基体细胞可以可逆地失活，我将用它来研究从回路中去除高尔基体细胞的后果，并检查行为水平的影响。旧的理论和新的工具为我提供了一个独特的机会来研究小脑回路中特定细胞类型对运动学习功能的贡献。从本质上讲，我的工作将提供关于大脑如何编码和存储时间信息的见解。运动学习障碍是最常见的健康问题之一，包括小脑细胞瘤、脊髓小脑共济失调、小脑发育不全、小脑发育不全、自闭症等。我相信，对正常神经网络如何运作，特别是小脑如何编码运动学习的理解，将为运动学习障碍患者开发合理的治疗方法提供基础。

DESCRIPTION (provided by applicant): How the cerebellum implements motor learning is still largely a mystery. Particularly, the mechanism by which it calibrates the timing of movements remains to be elucidated. Whereas most studies of learning have focused on changes in the strength of neural signaling pathways, my work examines the dynamics of neural signaling. Longstanding theories suggest that Golgi cells, a class of inhibitory interneurons, play a critical role in controlling the dynamics of neural signal processing in the cerebellum, thus determining the timing of learned movements. To test this hypothesis, I will take advantage of several recent technical advances: 1) recording of Golgi cells in vivo, which I have been conducting to monitor activity before and after motor learning, to determine whether changes in Golgi cell activity account for changes in movement timing, and 2) transgenic mice in which the Golgi cells can be reversibly inactivated, which I will use to study the consequences of removing Golgi cells from the circuit, and examined the impact at behavioral levels. The old theories and new tools provide me a unique opportunity to investigate the contribution of a particular cell type in the cerebellar circuit to its function in motor learning. In essence, my work will provide insight on how the brain encodes and stores timing information. Motor learning disorders are one of the most common health problems including cerebellar astocytomas, spinocerebellar ataxia, cerebellar hypoplasia, cerebellar agenesis, autism, and others. My belief is that a good understanding of how normal neural networks function and how, in particular, the cerebellum encodes motor learning will provide the basis for developing rational therapeutic treatments for people suffering from motor learning disorders.