Cerebellar contributions to movement explored with patterned optical manipulation

通过图案化光学操纵探索小脑对运动的贡献

• 批准号: 8843686
• 负责人: Thomas S Otis
• 金额: $ 32.99万
• 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: 2014-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8843686
• 关键词: Accounting; Address; Algorithms; Architecture; Ataxia; Behavior; Behavioral; Beryllium; Cerebellar Diseases; Cerebellar cortex structure; Cerebellum; Complement; Conditioned Stimulus; Data; Disease; Electrophysiology (science); Elements; Equilibrium; Extinction (Psychology); Eye Movements; Fiber; Head; Hereditary Disease; Inherited; Knowledge; Lead; Learning; Lighting; Lobe; Lobule; Location; Maps; Measures; Memory; Methods; Modeling; Motion; Motor; Motor Neurons; Movement; Mus; Nature; Neurons; Optical Methods; Optics; Pathology; Pattern; Physiology; Preparation; Process; Property; Research; Role; Savings; Signal Transduction; Site; Speed; Stereotyping; Stimulus; Stroke; System; Testing; Time; Toxin; Training; auditory stimulus; awake; base; classical conditioning; conditioning; design; feeding; improved; in vivo; innovation; insight; kinematics; motor control; motor learning; neurophysiology; novel; optogenetics; public health relevance; research study; response; sensory stimulus; spatiotemporal; 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, 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.

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澄清了一个高度定型的回路，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，一些根本性的问题仍然没有答案。浦肯野神经元的特定活动模式如何影响运动？在运动地图中，神经化学定义的分区的功能分支是什么？在依赖小脑的运动学习过程中，小脑回路中的哪个部位发生了变化？最后，回路的改变如何改变小脑依赖行为？ 该项目将处理以下具体目标。具体目标1： 使用光遗传学刺激询问小鼠小脑的单叶中的运动图的组织。初步数据表明，浦肯野神经元抑制触发快速，高度刻板的运动。使用高速摄像和运动跟踪，我们将测量运动轨迹和速度响应激活或抑制在各种小脑神经元与图案照明。我们还将从清醒小鼠的小脑神经元进行电生理记录，以检查操纵PN兴奋性对回路的影响。在具体目标2中，我们将测试联想运动学习是否可以通过配对来驱动 感觉刺激与光遗传学引起的减少或增加的PN放电。体内电生理学将用于确定误差信号如何有助于这种学习。在具体目标3中，我们将检验这样一个假设，即对PN发射的操纵改变了一个预测信号，从而产生前馈误差信号。 这些相互关联的目标利用一种新的行为准备，应用复杂的光学图案，光遗传学，电生理学和行为方法唤醒小鼠，以回答有关小脑生理学的基本问题。这些实验旨在解决小脑领域数十年来一直争论不休的问题。我们希望我们的研究结果将产生一个更好的理解基本小脑生理学和解决一些长期存在的谜团小脑依赖性学习。此外，这些发现很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。