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: 10478289
• 负责人: SAMUEL L. PFAFF
• 金额: $ 60.94万
• 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/10478289
• 关键词: 3-Dimensional; 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; Instruction; Interneurons; Joints; Knock-out; Knockout Mice; Label; Laboratories; Lead; 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; T cell factor 4; Testing; Time; Touch sensation; Viral; Volition; base; cell type; conditional knockout; design; experience; experimental study; insight; laboratory experiment; molecular marker; molecular subtypes; motor behavior; motor control; motor learning; mouse genetics; neural circuit; neuron development; neuroregulation; optogenetics; postnatal; programs; relating to nervous system; 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以惊人的效率执行极其复杂的计算。这方面的例证是 能够无缝地执行需要多个肌肉群协调的运动行为 控制多个自由度的关节。人们认为，简化运动计算的一种策略 是采用一种电路组织，将机动池的组合连接成称为“协同效应”的功能单元 或者“原始人”。因此，作为马达协同作用基础的电路元件被认为代表了 构建用于协调日常运动行为的神经控制的积木。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的实验发现了运动协同作用的证据。 脊髓内的环路。这笔赠款涉及的主要问题是：(A)什么是根本的 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，以及(C)形成这些电路的内在和外在因素是什么？ 该实验室使用跨突触神经元追踪、光遗传学和分子筛选来识别 相互关联的兴奋性和抑制性前体的异质性(Satb1+，Satb2+，Tcfap2b+，TCF4+)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板层细胞 通常被称为运动协同编码器(MSE)。假设是MSE细胞网络 包括一个主要的计算节点，用于脊髓内的运动控制。这些单元格从 皮层和感觉神经元，如那些传递本体感觉信息的神经元。因此，MSE神经元是 能够很好地调节由意志指挥中心产生的协调肌肉激活模式 运动以及由脊髓内局部感觉反馈激活的反射路径。 这项拨款的目的是为了解开运动协同中的线路和细胞成分。 并研究这些电路在胚胎发育和出生后早期是如何形成的。目标1 将创建MSE神经元的细胞图谱和连接图。这将定义分子是否 MSE神经元的异质性对应于不同的运动池电路模块或生理上的不同 用于控制所有运动池的神经元的类别。目标2将定义本征脊髓反馈的模式 从肌肉到MSE神经元。这里的目标是确定MSE电路是否基于SIMPLE 标记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，以确定固有遗传程序是否建立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 在局部脊髓系统中计算和协调运动激活模式。这些发现可能 利用遗传学和/或神经活动帮助靶向运动回路，以促进脊髓损伤的恢复。