Context- and phase-dependent gating of cerebellar output

项目摘要 小脑对于产生熟练的动作是必不可少的，比如伸手，而这个结构的功能障碍 会导致破坏性运动障碍然而，小脑的输出如何影响指挥大脑的结构， 熟练的运动输出仍不清楚。小脑靶向红核（RN），脑干前运动核 控制四肢运动的神经系统我实验室以前的研究表明， 小脑（IN）间置核的光遗传学激活导致小脑（IN）的运动学扰动。 小鼠的前肢进行伸展运动12。引人注目的是，观察到的扰动的性质是 依赖于上下文，但与相位无关，例如，静止时没有运动， 在爪的伸出和返回中均发生运动。这些发现让我假设， 小脑输出的下游解释差异取决于上下文和阶段，RN是一个 介导小脑输出的不同效应的部位。为了验证这一假设，我将记录神经活动， RN在到达的不同阶段和静止时，同时光遗传地激活IN。这将使我能够 检查IN激活是否对上下文和阶段之间的RN活动有差异影响。另外，我将 记录IN激活期间前肢肌肉的活动，以确定对肌肉激活的影响 取决于上下文和阶段。我期望发现RN活动和EMG幅度都会降低 在休息期间，不同的阶段，观察到的变化将有助于解释观察到的 上下文相关性和相位不变性。我还将确定小脑红核的必要性程度 通过RN中兴奋性和抑制性设计受体的表达介导这些效应的回路， 当与IN刺激光遗传学配对时，应该揭示IN之间的输入输出关系， RN，以及由于小脑红核运动通路而影响的运动学。

Project Summary The cerebellum is essential for producing skilled movements, like reaching, and dysfunction of this structure causes disruptive motor disorders. However, how cerebellar output influences the structures that command skilled motor output remains unclear. Cerebellum targets the red nucleus (RN), a brainstem pre-motor nucleus that is known to command movements of the limbs. Previous research in my lab has shown that modest optogenetic activation of the interposed nucleus of the cerebellum (IN) results in a kinematic perturbation of the forelimb in mice performing reaching movements12. Strikingly, the properties of the observed perturbation are context-dependent, but phase-independent, e.g. there is no movement at rest, and the same change in movement occurs both in outreach and return of the paw. These findings lead me to hypothesize that cerebellar output is interpreted differentially downstream depending on context and phase, and that RN is a site that mediates differential effects of cerebella output. To test this hypothesis, I will record neural activity in RN during differing phases of reach and at rest while activating IN optogenetically. This will allow me to examine if IN activation differential effect on RN activity between contexts and phases. Additionally, I will record the activity of muscles of the forelimb during IN activation to determine if the effect on muscle activation is dependent on context and phase. I expect to find that both RN activity and EMG amplitude will be reduced during rest, different between phases, and that the observed changes will aid in explaining the observed context-dependence and phase-invariance. I will also establish the degree of necessity of the cerebellorubral circuit in mediating these effects through the expression of excitatory and inhibitory designer receptors in RN, that, when paired with IN stimulation optogenetically, should reveal the input output relationship between IN, RN, and the effected kinematics due to the cerebellorubral motor pathway.