Cerebellar contributions to movement explored with patterned optical manipulation

描述(由申请人提供)：有效的协调需要运动系统预测正确的动作。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起运动的前馈模型。几十年的小脑研究澄清了一个高度刻板的回路，确定了特定回路元素的作用，并提出了可能解释联想学习的细胞机制。然而，根本问题仍然没有得到回答。浦肯野神经元的特定活动模式如何影响运动？运动图中神经化学定义的分区的功能分支是什么？在小脑依赖形式的运动学习过程中，小脑回路的哪个部位会发生变化？最后，电路变化是如何改变小脑依赖行为的？该项目将实现以下具体目标。在具体目标1中，我们将 使用光遗传学刺激来询问小鼠小脑单纯叶的运动地图的组织。初步数据显示，浦肯野神经元抑制会触发快速、高度刻板印象的运动。利用高速摄像和运动跟踪技术，我们将测量不同小脑神经元在图案照明下的运动轨迹和运动速度。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。在特定目标2中，我们将测试联想运动学习是否可以通过配对来驱动 感官刺激与光基因引起的PN放电减少或增加。在体内，电生理学将被用来确定错误信号如何有助于这种学习。在特定的目标3中，我们将检验这样的假设，即对PN激发的操纵改变了导致前馈误差信号的预测信号。这些相互关联的目标利用一种新的行为准备，应用复杂的光学模式、光遗传学、电生理和行为方法来唤醒小鼠，以回答关于小脑生理学的基本问题。总之，拟议的实验旨在解决小脑领域内争论了数十年的问题。我们希望我们的结果将大大提高对基本小脑生理学的理解，并解开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引起的小脑功能障碍提供概念性的见解。

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, 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.