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

基本信息

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
项目类别：
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

项目摘要

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。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后果是什么？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？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，我们将使用光遗传学刺激询问小鼠小脑单叶运动图的组织。初步数据显示，浦肯野神经元抑制会引发快速、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，以响应具有图案照明的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光遗传学引起的 PN 放电减少或增加的感觉刺激。体内电生理学将用于确定误差信号如何促进这种学习。在特定目标 3 中，我们将测试以下假设：操纵 PN 发射会改变预测信号，从而产生前馈误差信号。这些相互关联的目标利用一种新颖的行为准备，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引起的小脑功能障碍提供概念性见解。