Characterization of spinal circuits underlying motor synergy function

运动协同功能背后的脊髓回路的表征

• 批准号: 10687832
• 负责人: SAMUEL L. PFAFF
• 金额: $ 61.31万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687832
• 关键词: 3-Dimensional; Ablation; Address; Adopted; Afferent Neurons; Amphibia; Architecture; Atlases; Biological Assay; Cells; Complex; Computer Systems; Development; Elements; Embryo; Embryonic Development; Feedback; Foundations; Freedom; Genetic; Goals; Grant; Heterogeneity; Hindlimb; Histologic; Individual; Interneurons; Joints; Knock-out; Knockout Mice; Label; Laboratories; Life; Link; Lumbar spinal cord structure; Maps; Mediating; Methods; Molecular; Motor; Motor Activity; Movement; Muscle; Muscle Contraction; Neural Pathways; Neurons; Neurophysiology - biologic function; Nodal; Output; Pathway interactions; Pattern; Physical therapy; Physiological; Population; Positioning Attribute; Primates; Property; Proprioceptor; Recovery; Reflex action; Research; Research Personnel; Rodent; Role; Sensory; Shapes; Signal Transduction; Specificity; Spinal; Spinal Cord; Spinal cord injury; Spinal cord injury patients; Spine pain; Stains; Stream; Synapses; System; Testing; Time; Touch sensation; Vertebral column; Viral; cell type; conditional knockout; design; experience; experimental study; improved; insight; laboratory experiment; molecular marker; molecular subtypes; motor behavior; motor control; motor learning; mouse genetics; neural; neural circuit; neuron development; neuronal patterning; neuroregulation; optogenetics; postnatal; programs; sensory feedback; synergism; transcription factor

Abstract: The CNS performs extremely complex computations with remarkable efficiency. This is exemplified by the ability to seamlessly execute motor behaviors that necessitate the coordination of multiple muscle groups controlling joints with many degrees of freedom. It is thought that one strategy to simplify motor computations is to adopt a circuit organization that links combinations of motor pools into functional units called “synergies” or “primitives”. Thus, the circuit elements that underlie motor synergies are thought to represent the basic building blocks for orchestrating the neural control of routine motor behaviors. Elegant stimulation and recording experiments from labs working with amphibians, rodents, and primates have found evidence for motor synergy circuits within the spinal cord. The major questions addressed in this grant are: (a) what is the underlying cellular and connectivity organization of lumbar spinal motor synergy circuits, (b) what neuronal subtypes comprise these circuits, and (c) what intrinsic and extrinsic factors shape the formation of these circuits? The laboratory has used trans-synaptic neuronal tracing, optogenetics, and molecular screens to identify a heterogenous (Satb1+, Satb2+, Tcfap2b+, Tcf4+) population of interconnected excitatory and inhibitory pre- motor interneurons within lamina V of the lumbar spinal cord. Based on their properties these lamina V cells are generically referred to as motor synergy encoders (MSE). The hypothesize is that the MSE cell network comprises a major computational node for motor control within the spinal cord. These cells receive inputs from the cortex and sensory neurons such as those that relay proprioceptive information. Thus, MSE neurons are well positioned to mediate coordinated muscle activation patterns arising from command centers for volitional movement as well as reflex pathways activated by sensory feedback locally within the spinal cord. The aims of this grant are designed to unravel the wiring and cellular constituents within motor synergy circuits, and to examine how these circuits form during embryonic development and early postnatal life. Aim 1 will create a cellular atlas and connectivity map of MSE neurons. This will define whether the molecular heterogeneity of MSE neurons corresponds to separate motor pool circuit-modules or physiologically-different classes of neurons used for controlling all motor pools. Aim 2 will define the pattern of propriospinal feedback from muscles onto MSE neurons. Here the goal is to establish whether the MSE circuit is based on simple labeled line pathways or has a more complex input-output relationship. Aim 3 will use transcription factor knockouts to determine whether hardwired intrinsic genetic programs establish the MSE circuitry. Aim 4 will test whether the functional MSE network arises from activity dependent feedback from proprioceptive sensory neurons. Taken together, these aims will provide a detailed molecular-cellular understanding of a critical node within the local spinal system for computing and coordinating motor activation patterns. These findings may help target motor circuits using genetics and/or neural activity to facilitate recovery from spinal cord injury.

抽象的： 中枢神经系统以显着的效率执行极其复杂的计算。这是由 能够无缝执行运动行为，需要多个肌肉组的协调 控制着许多自由度的关节。人们认为一种简化电机计算的策略 是采用一个将电动池组合到称为“协同效应”的功能单元的电路组织 或“原语”。那就是电机协同作用的电路元素代表基本 用于策划常规运动行为的神经控制的基础。优雅的刺激和记录 与两栖动物，啮齿动物和私人一起工作的实验室的实验发现了运动协同作用的证据 脊髓内的圆圈。本赠款中解决的主要问题是：（a）什么是基础 腰椎运动协同回路的细胞和连通性组织，（b）什么神经元亚型 包括这些电路，以及（c）哪些内在和外在因素塑造了这些电路的形成？ 该实验室使用了反射突触神经元追踪，光遗传学和分子筛选来鉴定 异源（SATB1+，SATB2+，TCFAP2B+，TCF4+）互连的兴奋和抑制性前 腰椎椎板V中的运动中间神经元。根据它们的特性这些薄片V细胞 通常称为运动协同作用编码器（MSE）。假设是MSE单元网络 包括一个主要的计算节点，用于脊髓内的运动控制。这些单元从 皮质和感觉神经元，例如传递本体感受信息的皮质和神经元。那是MSE神经元 在媒体协调的肌肉激活模式中，由指挥中心产生的肌肉激活模式 运动以及脊髓中本地的感觉反馈激活的运动和反射途径。 该赠款的目的旨在揭示电动机协同作用中的接线和蜂窝构成 圆圈，并检查在胚胎发育和产后早期生活中这些圆的形成。目标1 将创建一个MSE神经元的细胞图集和连通性图。这将定义分子是否 MSE神经元的异质性对应于单独的电机池电路模块或物理不同 用于控制所有运动池的神经元类。 AIM 2将定义前脊髓反馈的模式 从肌肉到MSE神经元。这里的目标是确定MSE电路是否基于简单 标记的线路路径或具有更复杂的输入输出关系。 AIM 3将使用转录因子 敲除确定硬有线的内在遗传程序是否建立了MSE电路。目标4意志 测试功能性MSE网络是否来自于本体感受的活动依赖性反馈 神经元。综上所述，这些目标将提供对关键节点的详细分子细胞理解 在局部脊柱系统中用于计算和协调运动激活模式。这些发现可能 使用遗传学和/或神经活动帮助靶向运动回路，以促进脊髓损伤的恢复。

项目成果

Spinal premotor interneurons controlling antagonistic muscles are spatially intermingled.

• DOI: 10.7554/elife.81976
• 发表时间: 2022-12-13
• 期刊: eLife
• 影响因子: 7.7
• 作者: Ronzano R;Skarlatou S;Barriga BK;Bannatyne BA;Bhumbra GS;Foster JD;Moore JD;Lancelin C;Pocratsky AM;Özyurt MG;Smith CC;Todd AJ;Maxwell DJ;Murray AJ;Pfaff SL;Brownstone RM;Zampieri N;Beato M
• 通讯作者: Beato M