Circuit mechanisms underlying cerebellar movement control and motor learning

小脑运动控制和运动学习的回路机制

• 批准号: 8870481
• 负责人: Thomas S Otis
• 金额: $ 37.7万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8870481
• 关键词: Accounting; Address; Algorithms; Ataxia; Behavior; Behavioral; Blinking; Cerebellar Diseases; Cerebellum; Conditioned Stimulus; Data; Disease; Dystonia; Electrophysiology (science); Elements; Equilibrium; Extinction (Psychology); Eye Movements; Feedback; Forelimb; Head; Health; Hereditary Disease; Hindlimb; Inherited; Lead; Learning; Light; Location; Maps; Measures; Mediating; Methods; Modeling; Motion; Motor; Movement; Mus; Nature; Neurons; Optics; Pathology; Physiologic pulse; Physiology; Preparation; Process; Research; Role; Savings; Signal Transduction; Site; Speed; Stereotyping; Stimulus; Stroke; System; Testing; Time; Toxin; Training; auditory stimulus; awake; classical conditioning; conditioning; design; feeding; improved; in vivo; innovation; insight; kinematics; motor control; motor learning; neuromechanism; neurophysiology; novel; optogenetics; orofacial; research study; response; sensory stimulus; tumor

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.

描述（由申请人提供）：有效的协调需要运动系统预测正确的运动。为了做出这些预测，小脑整合了感觉运动信息和运动误差，并通过误差驱动的学习过程，建立了运动的前馈模型。数十年的小脑研究已经阐明了高度刻板的回路，确定了特定回路元件的作用，并提出了可能解释联想学习的细胞机制。然而，基本问题仍未得到解答。在小脑依赖形式的运动学习过程中，小脑回路内的哪些地方发生变化？在细胞和电路层面，运动错误如何驱动这些变化？最后，电路变化如何改变小脑依赖性行为？ 该项目将实现以下具体目标。在具体目标 1 中，我们将测试这样的假设：由光遗传学刺激直接或间接引起的 PN 发射暂停会触发快速、高度刻板的运动。使用高速摄像和运动跟踪，我们将测量响应各种小脑神经元激活或抑制的运动轨迹和速度。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，我们将测试是否可以通过将感觉刺激与光遗传学引起的 PN 放电减少或增加配对来驱动联想运动学习。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关键部位的学习神经机制，并确定误差信号如何促进这种学习。 这些相互关联的目标利用一种新颖的行为准备，应用光遗传学、电生理学和行为方法来唤醒小鼠，以回答有关小脑生理学的基本问题。总之，所提出的实验旨在解决小脑领域数十年来争论的问题。我们期望我们的结果将大大提高对基本小脑生理学的理解，并解决有关小脑依赖性学习的一些长期存在的谜团。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。