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Functional dissection of cerebellar output circuits that orchestrate limb motor control

协调肢体运动控制的小脑输出电路的功能剖析

基本信息

批准号：
10524627
负责人：
EIMAN AZIM
金额：
$ 226.44万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-19 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10524627
关键词：
Affect Anatomy Anterior Ataxia Attenuated Behavior Biological Assay Cell Nucleus Cerebellar Diseases Cerebellar Nuclei Cerebellum Cerebral cortex Cervical spinal cord structure Data Deceleration Diagnosis Disease Dissection Electromyography Electrophysiology (science)Ensure Extensor Felis catus Flexor Forelimb Functional disorder Genetic Goals Hand Head Human Impairment In Situ Hybridization Injury Interneurons Lead Life Limb structure Linear Models Logic Mediating Molecular Monkeys Motor Motor Neurons Motor output Movement Movement Disorders Mus Muscle Nervous System control Neurons Neurophysiology - biologic function Optics Output Pathway interactions Phase Play Population Positioning Attribute Process Rabies Resolution Role Route Sensory Signal Transduction Spinal Spinal Cord System Testing Thalamic structure Viral Water Work arm movement base combinatorial defined contribution experimental study flexibility improved in vivo insight kinematics limb movement motor behavior motor control motor deficit motor impairment neural circuit optogenetics prevent recruit relating to nervous system repaired sensory feedback tool transcriptome sequencing

项目摘要

Project Summary The cerebellum is essential for coordinating motor behavior through rapid adjustments of ongoing movements. To refine movement, the cerebellum processes motor and sensory information, and transmits output that ultimately modulates motor neuron activity to ensure successful execution. The path through which the cerebellum can influence limb movement is through output circuits in the cerebellar nuclei (CN). Yet little is known about how CN circuits are organized and whether discrete pathways are dedicated to specific motor functions for limb control. The recent identification of a molecularly distinct subset of CN neurons that project to the cerebral cortex via the thalamus and can affect forelimb movement begins to reveal a broader neural subtype logic to cerebellar output. Further exploration indicates that there are also CN neurons that directly innervate the cervical spinal cord. These descending projections could provide a more direct route for influencing motor output, but the specific roles they have in movement execution and refinement remain poorly understood. Based on preliminary evidence, the major hypothesis of this proposal is that anatomically and molecularly distinct subsets of CN neurons have discrete contributions to forelimb motor control. Specifically, cerebellar-spinal circuits play a critical role in rapid online correction, and their functional output is needed to prevent forelimb ataxia. Three Aims will explore how spinal-projecting CN circuits differ from the more heavily studied CN circuits that project to the thalamus. Aim 1 defines specific subtypes of neurons within the cerebellar nuclei by delineating their input and output connectivity and molecular identities. The distinctions in efferent and afferent connectivity of spinal- and thalamus-projecting CN neurons will be defined using combinatorial genetic and viral circuit tracing tools in mice. In addition, molecular distinctions between these two classes of cerebellar output neurons will be identified using single nuclei RNA-sequencing and multiplexed in situ hybridization. Aim 2 sets out to establish the functional connectivity between these distinct CN subpopulations and forelimb muscles and examines how spinal- and thalamus-projecting cerebellar output pathways influence goal-directed forelimb movements. Selective optogenetic perturbation, electromyographic (EMG) recording, and high-resolution kinematic analysis will be used to determine how spinal- and thalamus-projecting CN neurons differentially affect muscle activity and online refinement of behavior. Aim 3 explores how the activity of discrete CN output pathways correlates with forelimb online correction and endpoint precision. This goal will be accomplished by recording from spinal- and thalamus- projecting CN populations and forelimb muscles during dexterous reaching behaviors, and by applying generalized linear models to determine if neural activity predicts EMG and kinematic movement features. By defining the organization of two major cerebellar output pathways and identifying the ways in which they influence dexterous movements, this work will provide insight into how diverse circuits differentially participate in motor control, and clarify how injury and disease of cerebellar circuits can lead to motor impairments in humans.

项目摘要通过对正在进行的动作进行快速调整，小脑对于协调运动行为是必不可少的。为了精炼运动，小脑处理运动和感觉信息，并将最终调节运动神经元的活动，以确保成功执行。这条路就是小脑通过小脑核团(CN)的输出回路影响肢体运动。然而，人们对此知之甚少关于CN电路是如何组织的，以及离散通路是否专用于特定的运动功能用于肢体控制。最近发现的投射到大脑的一个分子上不同的CN神经元亚群皮质通过丘脑和能影响前肢的运动开始揭示更广泛的神经亚型逻辑小脑输出量。进一步的研究表明，也有直接支配颈部的CN神经元。脊髓。这些下降的预测可以提供一条更直接的途径来影响电机产量，但他们在动作、执行和提炼中扮演的具体角色仍然知之甚少。基于初步的证据，这一建议的主要假设是在解剖学和分子上不同的CN亚群神经元对前肢运动控制有离散的贡献。具体地说，小脑-脊髓回路起着关键的作用在快速在线矫正中发挥作用，其功能输出是预防前肢共济失调所必需的。三个目标将探索脊髓投射的CN回路与投射到丘脑。目标1通过描绘小脑核内神经元的输入和分布来定义它们的特定亚型输出连接性和分子同一性。脊髓的传出和传入连接的区别-和投射丘脑的CN神经元将使用组合遗传和病毒回路追踪工具在小鼠身上进行定义。此外，这两类小脑输出神经元之间的分子差异将通过单核RNA测序和多重原位杂交。目标2着手建立功能这些不同的CN亚群和前肢肌肉之间的连接性，并检查了脊髓和丘脑-投射小脑的输出通路影响目标导向的前肢运动。有选择性的光遗传扰动、肌电(EMG)记录和高分辨率运动学分析用于确定脊髓和丘脑投射的CN神经元如何不同地影响肌肉活动和在线行为的精致。目标3探索离散的CN输出通路的活动如何与前肢相关在线修正和终点精度。这一目标将通过从脊髓和丘脑进行记录来实现在灵巧的伸展行为中投射CN群体和前肢肌肉，并通过应用通用线性模型，以确定神经活动是否预测肌电和运动学运动特征。通过定义两条主要小脑输出通路的组织，并确定它们影响的方式灵巧的运动，这项工作将提供洞察不同的电路如何不同地参与运动控制，并阐明小脑回路的损伤和疾病如何导致人类的运动障碍。