Cerebellar contributions to movement explored with patterned optical manipulation

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。浦肯野神经元的特定活动模式如何影响运动？在运动图中由神经化学定义的分区的功能分支是什么？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？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

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, build 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. How do particular activity patterns in Purkinje neurons influence movement? What are the functional ramifications of the neurochemically-defined divisions in the motor map? Where within the cerebellar circuit do changes occur during cerebellum-dependent forms of motor learning? 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 interrogate the organization of the motor map in the simplex lobe of the mouse cerebellum using optogenetic stimuli. Preliminary data show that Purkinje neuron inhibition triggers 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 with patterned illumination. 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 vivo electrophysiology will be used to determine how error signals contribute to this learning. In Specific Aim 3 we will test the hypothesis that manipulation of PN firing alters a prediction signa giving rise to feed-forward error signals. These interrelated aims make use of a novel behavioral preparation applying sophisticated optical patterning, 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.