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

项目摘要 小脑是一种大脑结构，长期以来被认为是协调肌肉群收缩的关键 以实现平滑和精确的肢体运动。小脑核的输出通路被认为 连续产生快速的校正信号，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细胞， 由于缺乏对小脑输出的选择性访问， 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， 已知直接小脑脊髓（CbSp）投射对运动输出的精确影响， 这些回路中的活动可能起作用以确保灵巧行为的准确性的时间尺度。没有研究 已经明确研究了从小脑到脊髓的直接投射是否介导了快速的，在线的 更正。这项提议的首要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校正命令， 优化前肢运动; 2）这种优化是通过编码预测的活动模式实现的 关于肢体运动学或肌肉活动。采用熟练的水达到测定，CbSp预测将是 在执行旨在引入运动源的行为任务期间， 错误，如更改到达目标位置。运动学和肌电图（EMG）分析性能 将揭示CbSp神经元在前肢运动中的精确矫正作用。接下来，多电极硅 探针将用于在相同的水到达任务的执行期间从CbSp神经元记录。单个 单位活动分析和运动学和神经活动数据训练的广义线性模型将揭示 CpSp活性是否预测了矫正运动并编码了特定的特征，如肌肉募集， 肢体速度加速度或轨迹此外，对来自两个目标的数据的分析将确定CbSp是否 神经元在灵巧运动期间将校正信号传递到前肢。这项工作将提供宝贵的 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善诊断奠定基础 和治疗小脑病变。

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.