Spinal Circuits for the Control of Dextrous Movement

控制灵巧运动的脊髓回路

• 批准号: 9815384
• 负责人: Martyn D Goulding
• 金额: $ 298.11万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9815384
• 关键词: 3-Dimensional; Address; Affect; Anatomy; Atlases; Behavior; Behavioral; Behavioral Assay; Biological Models; Brain; Cells; Cervical; Cervical spinal cord structure; Complex; Computer Simulation; Coupled; Data; Data Science; Databases; Development; Dissection; Electromyography; Electrophysiology (science); Elements; Ensure; Forelimb; Generations; Genetic; Goals; Human; Interneurons; Joints; Knowledge; Light; Limb structure; Link; Locomotion; Lumbar spinal cord structure; Maps; Modeling; Molecular; Motor; Motor Neurons; Motor Pathways; Motor output; Movement; Mus; Muscle; Neurons; Neurosciences; Online Systems; Periodicity; Physiological; Positioning Attribute; Property; Reagent; Research; Research Project Grants; Resolution; Series; Specific qualifier value; Spinal; Spinal Cord; Spinal Injuries; Standardization; Structure; Sum; Synapses; System; Testing; Upper limb movement; Viral; Visualization software; Weight; Work; base; behavioral outcome; brain research; cell type; connectome; data modeling; data visualization; dexterity; grasp; indexing; joint mobilization; molecular phenotype; molecular subtypes; motor control; multimodality; nervous system disorder; network models; neural model; predictive modeling; predictive test; programs; recruit; relating to nervous system; sensory input; spinal reflex; theories; tool; transcriptome sequencing

Project Summary: Overall Local networks within the spinal cord represent an essential computational layer for the control of limb-driven motor behaviors, integrating descending and sensory inputs to coordinate dexterous motor output. Significant advances have been made in characterizing the developmental programs that specify the core cardinal interneuron types that make up these motor networks. This knowledge has been used to develop a battery of mouse genetic reagents for spinal circuit anatomical and functional dissection. To date, these genetic tools have been primarily used to study locomotion and spinal reflexes in the lumbar spinal cord. Given the wider range of dexterous motor behaviors that are produced by cervical circuits and the increased oversight of these behaviors by descending motor pathways, the mouse cervical spinal cord provides a unique and tractable mammalian model system for understanding how coordinated movements are generated by local motor networks and how these motor behaviors are regulated by the brain. The overall goal of this U19 Team-Research BRAIN Circuit Program proposal is two-fold: 1) the generation of a scalable, high-resolution atlas of forelimb-premotor interneurons in the cervical spinal cord that describes their connectivity, molecular phenotypes, electrophysiological properties, and functional contributions to forelimb behaviors, and 2) the development of testable predictive neural models that describe the network interactions that give rise to limb control. The functional interrogation and modeling of these circuits, based on real behavioral outcomes and detailed information about the cell types that generate these behaviors, will ensure that the overall project is greater than the sum of its parts. Specifically, the research plan will address two overarching questions: 1) How do rhythmic spinal networks control non-rhythmic movements, which represent the majority of forelimb motor behaviors, and 2) How are these spinal circuits modified to control more complex joint movements to achieve forelimb dexterity? To address these questions, the Spinal Cord Circuit Team (TeamSCC) will generate: (a) a pre-motor interneuron connectome that includes information on cell positions and synaptic weightings, (b) a comprehensive index of the physiological properties and molecular identities of genetically distinct neuronal subtypes within each cardinal interneuron class, (c) a functional description of spinal circuit control of natural forelimb motor behaviors, and (d) a working model of the motor network that describes how circuit connectivity and dynamics give rise to key elements of forelimb behavior. Ultimately, these data will be used to generate a searchable web-based portal with 3D visualization tools linked to the molecular, electrophysiological, functional, and network model databases. Together, this work will lead to a deeper understanding of the organization and function of cervical circuitry, which will be of great value to groups that are grappling with the issue of how motor centers in the brain communicate with sensorimotor circuits in the spinal cord to control movement.

项目概要：总体 脊髓内的局部网络代表了控制肢体驱动的神经元的基本计算层。 运动行为，整合下行和感觉输入以协调灵巧运动输出。显著 在描述发展计划的特征方面取得了进展，这些发展计划规定了核心的基本原则， 中间神经元组成了这些运动网络。这些知识已被用于开发一系列 用于脊髓回路解剖和功能解剖的小鼠基因试剂。迄今为止，这些基因工具 主要用于研究腰椎脊髓的运动和脊髓反射。鉴于更广泛的 由颈部回路产生的灵巧运动行为以及对这些行为的监督增加 通过下行运动通路，小鼠颈脊髓提供了一个独特的和易于驾驭的哺乳动物 模型系统，用于了解局部运动网络如何产生协调运动，以及 这些运动行为是由大脑调节的。这个U19团队研究大脑回路的总体目标 计划建议是双重的：1）生成一个可扩展的，高分辨率的前肢-前运动区图谱 颈脊髓中的中间神经元，描述了它们的连接，分子表型， 电生理特性，以及对前肢行为的功能贡献，以及2） 可测试的预测神经模型，描述了引起肢体控制的网络交互。的 这些电路的功能询问和建模，基于真实的行为结果和详细的 有关生成这些行为的单元格类型的信息，将确保整个项目大于 各部分的总和具体来说，研究计划将解决两个首要问题：1）如何节奏 脊髓网络控制非节律性运动，这代表了大多数前肢运动行为， 2)这些脊髓回路是如何被修改以控制更复杂的关节运动来实现前肢灵活性的？ 为了解决这些问题，脊髓回路团队（TeamSCC）将产生：（a）前电机 包括关于细胞位置和突触权重的信息的神经元间连接体，（B）a 遗传上不同的神经元的生理特性和分子特性的综合指数 每个主要中间神经元类别内的亚型，（c）自然神经元的脊髓回路控制的功能描述， 前肢运动行为，和（d）运动网络的工作模型，描述电路连接如何 和动力学产生了前肢行为的关键要素。最终，这些数据将用于生成 可搜索的基于网络的门户网站，具有链接到分子，电生理，功能， 和网络模型数据库。总之，这项工作将使人们更深入地了解本组织， 颈部电路的功能，这将是非常有价值的群体正在努力解决的问题，如何运动 大脑中的中枢与脊髓中的感觉运动回路通信以控制运动。