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.

摘要： CNS以显著的效率执行极其复杂的计算。这一点的例证是， 无缝执行需要多个肌肉群协调的运动行为的能力 控制具有多个自由度的关节。人们认为简化电机计算的一种策略 是采用一种电路组织，将车辆调配场的组合连接成称为“协同作用”的功能单元， 或“原始人”。因此，作为电机协同作用基础的电路元件被认为代表了电机的基本特性。 构建模块，用于协调常规运动行为的神经控制。优雅的刺激和记录 实验室对两栖动物、啮齿动物和灵长类动物进行的实验发现了运动协同的证据 脊髓内的神经回路该补助金涉及的主要问题是：（a） 腰椎运动协同回路的细胞和连接组织，（B）什么神经元亚型 包括这些电路，和（c）什么内在和外在因素塑造这些电路的形成？ 该实验室已经使用跨突触神经元追踪，光遗传学和分子筛选来识别一种 相互关联的兴奋性和抑制性前体的异质性（Satb 1+，Satb 2+，Tcfap 2b+，Tcf 4+）群体， 腰髓V层内的运动中间神经元。根据它们的特性，这些V层细胞 一般称为电动机协同编码器（MSE）。假设MSE蜂窝网络 包括用于脊髓内的运动控制的主要计算节点。这些细胞接收来自 皮层和感觉神经元，如那些传递本体感受信息的神经元。因此，MSE神经元是 很好地定位到调解协调肌肉激活模式所产生的指挥中心的意志 运动以及由脊髓内局部的感觉反馈激活的反射通路。 这项资助的目的是为了解开运动协同作用中的布线和细胞成分 电路，并研究这些电路如何形成在胚胎发育和出生后的早期生活。要求1 将创建MSE神经元的细胞图谱和连接图。这将确定分子是否 MSE神经元的异质性对应于单独的运动池电路模块或生理上不同的 用于控制所有运动池的神经元类别。目标2将定义本体脊髓反馈的模式 从肌肉转移到MSE神经元。这里的目标是确定MSE电路是否基于简单的 标记的线路径或具有更复杂的输入-输出关系。AIM 3将使用转录因子 基因敲除，以确定是否硬连线固有的遗传程序建立MSE电路。目标4将 测试功能性MSE网络是否来自本体感觉的活动依赖性反馈 神经元综合起来，这些目标将提供一个详细的分子-细胞理解的一个关键节点 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