Defining the contributions of cerebello-spinal projection neurons to dexterous movement

定义小脑脊髓投射神经元对灵巧运动的贡献

• 批准号: 10607501
• 负责人: Oren Fairlee Wilcox
• 金额: $ 4.02万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-04 至 2026-01-03
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607501
• 关键词: Acceleration; Address; Affect; Anatomy; Ataxia; Attention; Behavior; Behavioral; Biological Assay; Brain; Brain Stem; Cerebellar Diseases; Cerebellar Nuclei; Cerebellum; Clinical Data; Data; Data Analyses; Diagnosis; Electrodes; Electromyography; Ensure; Environment; Error Sources; Forelimb; Goals; Head; Impairment; Implant; Individual; Joints; Knowledge; Laboratories; Lesion; Limb structure; Linear Models; Location; Mediating; Molecular Genetics; Motor; Motor output; Movement; Mus; Muscle; Muscle Contraction; Neurons; Optics; Output; Pathology; Pathway interactions; Pattern; Performance; Pharmacology Study; Play; Population; Positioning Attribute; Process; Research; Role; Signal Transduction; Silicon; Source; Speed; Spinal; Spinal Cord; Structure; System; Thalamic structure; Training; Vertebral column; Water; Work; defined contribution; design; deviant; grasp; improved; insight; kinematics; limb movement; motor impairment; neural; neural circuit; novel; optogenetics; prevent; recruit; response; skills; success; transmission process

PROJECT SUMMARY The cerebellum is a brain structure long known to be essential for coordinating the contraction of muscle groups across joints to enable smooth and precise limb movement. Output pathways in the cerebellar nuclei are thought to continuously generate rapid corrective signals that ensure precision during skilled movements through a process termed online correction. Up until now it has been difficult to identify and characterize the specific neural circuits that could implement this rapid refinement due to the lack of selective access to cerebellar output pathways. Recent work has shown that a subset of cerebellar output neurons project directly to the spinal cord (cerebello-spinal), providing a possible pathway for rapid and direct adjustments of the limb. However, little is known about the precise influence direct cerebello-spinal (CbSp) projections have on motor output and the timescale on which activity in these circuits may act to ensure the accuracy of dexterous behaviors. No research has explicitly investigated whether direct projections from the cerebellum to the spinal cord mediate rapid, online corrections. The overarching goal of this proposal is to define how output from the cerebellum enables skilled movements, focusing specifically on the functional role of CbSp projections and their influence on forelimb movements. The central hypotheses are: 1) CbSp projection neurons convey online corrective commands that refine forelimb movement; and 2) this refinement is achieved through activity patterns that encode predictions about limb kinematics or muscle activity. Employing a skilled water reaching assay, CbSp projections will be optogenetically silenced during performance of behavioral tasks designed to introduce sources of movement error, such as changing reach target location. Kinematic and electromyography (EMG) analyses of performance will uncover the precise corrective role of CbSp neurons in forelimb movements. Next, multielectrode silicon probes will be used to record from CbSp neurons during performance of the same water reaching tasks. Single unit activity analyses and generalized linear models trained on kinematic and neural activity data will reveal whether CpSp activity predicts corrective movements and encodes specific features such as muscle recruitment, limb velocity, acceleration, or trajectory. Moreover, analysis of data from both Aims will determine whether CbSp neurons mediate corrective signals to the forelimb during dexterous movements. This work will provide valuable insight into the neural basis of dexterous movement by expanding knowledge of how the cerebellum facilitates the speed and precision of forelimb behaviors. This research will help lay the groundwork for improved diagnosis and treatment of cerebellar pathologies.

项目摘要 小脑是一种脑结构，众所周知，对于协调肌肉群的收缩至关重要 跨关节以使肢体流畅而精确。人们认为小脑核中的输出途径 连续生成快速纠正信号，以确保在熟练运动过程中通过 过程称为在线校正。到目前为止，很难识别和表征特定的神经 由于缺乏选择性访问小脑输出，可以实现这种快速改进的电路 途径。最近的工作表明，小脑输出神经元的一部分直接投影到脊髓 （小脑脊柱），为快速和直接调整肢体提供了可能的途径。但是，几乎没有 关于直接影响小脑螺旋（CBSP）投影对电动机输出和 这些电路中哪种活动的时间表可以确保灵巧行为的准确性。没有研究 已经明确调查了从小脑到脊髓的直接预测是否会迅速，在线上 更正。该提案的总体目标是定义小脑输出如何启用熟练 运动，专门针对CBSP投影的功能作用及其对前肢的影响 动作。中心假设是：1）CBSP投影神经元传达在线校正命令 精炼前肢运动； 2）通过编码预测的活动模式实现了这种改进 关于肢体运动或肌肉活动。使用熟练的水到达测定法，CBSP预测将是 在旨在引入移动源的行为任务执行过程中，光遗传学上沉默了 错误，例如更改到达目标位置。运动性和肌电图（EMG）性能分析 将发现CBSP神经元在前肢运动中的精确纠正作用。接下来，多电极硅 在执行相同的水到达任务期间，探针将用于记录CBSP神经元的记录。单身的 在运动学和神经活动数据训练的单位活动分析和广义线性模型将揭示 CPSP活动是否预测矫正运动并编码特定特征，例如肌肉募集， 肢体速度，加速度或轨迹。此外，对两个目标数据的分析将决定CBSP是否 神经元在灵巧运动过程中介导矫正信号。这项工作将提供有价值的 通过扩大对小脑如何促进的知识，深入了解灵巧运动的神经基础 前肢行为的速度和精度。这项研究将有助于改善诊断的基础 和小脑病理的治疗。