Circuit mechanisms underlying cerebellar movement control and motor learning

描述（由申请人提供）：有效的协调要求运动系统预测适当的运动。为了做出这些预测，小脑整合了感觉运动信息和运动错误，并通过错误驱动的学习过程，建立了运动的前馈模型。几十年的小脑研究已经阐明了一个高度刻板的电路，确定了特定电路元件的作用，并提出了可能解释联想学习的细胞机制。然而，一些基本问题仍未得到解答。在小脑依赖的运动学习形式中，小脑回路中的什么地方发生了变化？在细胞和电路层面上，运动错误是如何驱动这些变化的？最后，回路变化是如何改变小脑依赖行为的？以下具体目标将在项目中解决。在具体目标1中，我们将测试由光遗传刺激直接或间接引起的PN放电暂停触发快速、高度刻板运动的假设。使用高速摄像和运动跟踪，我们将测量运动轨迹和速度，以响应各种小脑神经元的激活或抑制。我们还将对清醒小鼠的小脑神经元进行电生理记录，以检查操纵PN兴奋性对电路的影响。在具体目标2中，我们将测试联想运动学习是否可以通过将感觉刺激与光遗传学诱导的PN放电减少或增加配对来驱动。在具体目标3中，我们将使用体内电生理学来探索小脑回路中关键部位的学习神经机制，并确定错误信号如何促进这种学习。这些相互关联的目的利用一种新的行为准备，应用光遗传学，电生理学和行为学方法来唤醒小鼠，以回答有关小脑生理学的基本问题。总之，拟议的实验旨在解决在小脑领域争论了几十年的问题。我们期望我们的结果将大大提高对小脑基本生理学的理解，并解决一些长期存在的关于小脑依赖学习的谜团。此外，这些发现可能为遗传性和散发性共济失调和肌张力障碍引起的小脑功能障碍提供概念性见解。

DESCRIPTION (provided by applicant): Effective coordination requires that the motor system predict proper movements. To make these predictions, the cerebellum integrates sensorimotor information and motor errors and, through a process of error-driven learning, builds up feed-forward models of movement. Decades of cerebellar research have clarified a highly stereotyped circuit, identified roles for particular circuit elements, and suggested cellular mechanisms that might account for associative learning. However, fundamental questions remain unanswered. Where within the cerebellar circuit do changes occur during cerebellum-dependent forms of motor learning? How, at a cellular and circuit level, do motor errors drive these changes? And finally, how do circuit changes alter cerebellum-dependent behavior? The following specific aims will be addressed in the project. In Specific Aim 1, we will test the hypothesis that pauses in PN firing, evoked directly or indirectly by optogenetic stimuli, trigger rapid, highly stereotyped movements. Using high speed videography and motion tracking we will measure movement trajectories and speeds in response to activation or inhibition in various cerebellar neurons. We will also make electrophysiological recordings from cerebellar neurons in awake mice to examine the effects of manipulating PN excitability on the circuit. In Specific Aim 2 we will test whether associative motor learning can be driven by pairing sensory stimuli with optogenetically- elicited reductions or increases in PN firing. In Specific Aim 3 we will use n vivo electrophysiology to explore neural mechanisms of learning at key sites in the cerebellar circuit and to determine how error signals contribute to this learning. These interrelated aims make use of a novel behavioral preparation applying optogenetic, electrophysiological, and behavioral methods to awake mice in order to answer fundamental questions about cerebellar physiology. Together, the proposed experiments are designed to resolve issues that have been debated for decades within the cerebellar field. We expect that our results will yield a much improved understanding of basic cerebellar physiology and resolve some long-standing mysteries regarding cerebellum-dependent learning. In addition, these findings are likely to provide conceptual insights into cerebellar dysfunction caused by inherited and sporadic forms of ataxia and dystonia.