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.

抽象的： 中枢神经系统以惊人的效率执行极其复杂的计算。 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被认为是简化运动计算的一种策略。 是采用一种电路组织，将电机池的组合连接成称为“协同”的功能单元 或“原语”因此，构成电机协同作用的电路元件被认为代表了基本原理。 用于协调日常运动行为的神经控制的构建块。 两栖动物、啮齿动物和灵长类动物实验室的实验发现了运动协同作用的证据 此项资助解决的主要问题是：（a）潜在的问题是什么。 腰椎运动协同回路的细胞和连接组织，(b) 有哪些神经元亚型 包括这些电路，以及 (c) 哪些内在和外在因素影响了这些电路的形成？ 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（Satb1+、Satb2+、Tcfap2b+、Tcf4+）群体 腰脊髓第 V 层内的运动中间神经元 根据这些第 V 层细胞的特性。 一般称为电机协同编码器 (MSE)。 包括脊髓内运动控制的主要计算节点，这些细胞接收来自的输入。 皮层和感觉神经元，例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通路。 这笔赠款的目的旨在解开电机协同作用中的线路和细胞成分 目标 1。 将创建 MSE 神经元的细胞图谱和连接图，这将定义分子是否存在。 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的不同 用于控制所有运动池的神经元类别将定义本体脊髓反馈的模式。 从肌肉到 MSE 神经元，这里的目标是确定 MSE 电路是否基于简单的。 标记线路径或具有更复杂的输入输出关系的目标 3 将使用转录因子。 敲除以确定硬连线内在遗传程序是否会建立 MSE 电路。 测试功能性 MSE 网络是否源自本体感觉的活动依赖反馈 总而言之，这些目标将为关键节点提供详细的分子细胞理解。 这些发现可能会在局部脊柱系统中计算和协调运动激活模式。 利用遗传和/或神经活动帮助瞄准运动回路，以促进脊髓损伤的恢复。