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.

项目概要 小脑是一种大脑结构，长期以来被认为对于协调肌肉群的收缩至关重要 跨关节以实现平滑和精确的肢体运动。小脑核的输出途径被认为 不断生成快速校正信号，通过 过程称为在线校正。到目前为止，识别和表征特定的神经元还很困难。 由于缺乏对小脑输出的选择性访问，可以实现这种快速改进的电路 途径。最近的研究表明，小脑输出神经元的一个子集直接投射到脊髓 （小脑脊髓），为肢体的快速和直接调整提供了可能的途径。然而，很少的是 了解直接小脑脊髓 (CbSp) 预测对运动输出的精确影响以及 这些电路中的活动可以发挥作用的时间尺度，以确保灵巧行为的准确性。没有研究 明确研究了从小脑到脊髓的直接投射是否介导快速、在线 更正。该提案的总体目标是定义小脑的输出如何使熟练的 运动，特别关注 CbSp 投射的功能作用及其对前肢的影响 动作。中心假设是：1）CbSp 投射神经元传达在线纠正命令， 完善前肢运动； 2）这种细化是通过对预测进行编码的活动模式来实现的 关于肢体运动学或肌肉活动。采用熟练的水到达测定，CbSp 预测将是 在执行旨在引入运动源的行为任务期间光遗传学沉默 错误，例如更改到达目标位置。性能的运动学和肌电图 (EMG) 分析 将揭示 CbSp 神经元在前肢运动中的精确纠正作用。接下来，多电极硅 探针将用于在执行相同的水到达任务期间从 CbSp 神经元进行记录。单身的 单位活动分析和基于运动学和神经活动数据训练的广义线性模型将揭示 CpSp 活动是否预测纠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，对这两个目标的数据进行分析将确定 CbSp 是否 在灵巧运动过程中，神经元向前肢传递纠正信号。这项工作将提供有价值的 通过扩展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确度。这项研究将有助于为改进诊断奠定基础 和小脑病理的治疗。