Spinal Circuits for the Control of Dextrous Movement

控制灵巧运动的脊髓回路

• 批准号: 10011906
• 负责人: Martyn D Goulding
• 金额: $ 284.04万
• 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/10011906
• 关键词: 3-Dimensional; Address; Affect; Anatomy; Atlases; Behavior; Behavioral; Behavioral Assay; Biological Models; Brain; Cells; Cervical; Cervical spinal cord structure; Complex; Computer Models; Coupled; Data; Data Science Core; 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 behavior; motor control; mouse genetics; multimodality; nervous system disorder; network models; neural model; predictive modeling; predictive test; programs; recruit; relating to nervous system; sensory input; spinal reflex; theories; three-dimensional visualization; tool; transcriptome sequencing; web portal

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.

项目摘要：总体 脊髓中的本地网络代表了控制肢体驱动的基本计算层 运动行为，整合下降和感觉输入以协调灵活的电机输出。重要的 在表征指定核心枢机主教的发展程序方面取得了进步 构成这些电机网络的中间神经元类型。这些知识已被用来开发一个电池 小鼠遗传试剂用于脊髓解剖和功能解剖。迄今为止，这些遗传工具具有 主要用于研究腰脊髓中的运动和脊柱反射。考虑到更广泛的范围 由宫颈回路产生的灵巧运动行为以及对这些行为的监督的增加 通过下降的电路，小鼠宫颈脊髓提供了独特且可拖动的哺乳动物 了解如何通过本地电动机网络生成协调运动的模型系统以及如何生成 这些运动行为受大脑调节。该U19团队研究大脑巡回赛的总体目标 程序提案是两个方面：1）前期前期前期前期的可扩展，高分辨率地图集的产生 颈脊髓中的中间神经元描述了它们的连通性，分子表型， 电生理特性和对前肢行为的功能贡献，以及2） 可检验的预测性神经模型描述了导致肢体控制的网络相互作用。这 这些电路的功能性询问和建模，基于真实的行为结果并详细 有关产生这些行为的细胞类型的信息，将确保整个项目大于 其部分的总和。具体而言，研究计划将解决两个总体问题：1）有节奏 脊柱网络控制非节律运动，这代表大多数前肢运动行为，并且 2）如何修改这些脊柱回路以控制更复杂的关节运动以实现前肢敏捷性？ 为了解决这些问题，脊髓电路团队（TeamSCC）将产生：（a）预运动前 内神经元连接组包括有关细胞位置和突触权重的信息，（b）a 生理特性的综合指数和遗传上神经元的分子身份 每个基本中间神经元类中的子类型，（c）自然脊柱电路控制的功能描述 前肢运动行为，以及（d）电动机网络的工作模型，该模型描述了电路连接的方式 动态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Web的门户使用3D可视化工具链接到分子，电生理，功能， 和网络模型数据库。这项工作一起将使对组织和 宫颈回路的功能，这对于努力应对运动方式的群体将具有很大的价值 大脑中的中心与脊髓中的感觉运动电路进行沟通以控制运动。