Dissecting circuit and cellular mechanisms for limb motor control

剖析肢体运动控制的电路和细胞机制

• 批准号: 10522108
• 负责人: John Tuthill
• 金额: $ 107.19万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-17 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522108
• 关键词: Action Potentials; Address; Algorithms; Animals; Architecture; Behavior; Behavioral; Behavioral Paradigm; Biological Models; Brain; Complex; Data; Drosophila genus; Drosophila melanogaster; Electron Microscopy; Electrophysiology (science); Engineering; Equipment and supply inventories; Exhibits; Feedback; Femur; Fire - disasters; Flexor; Foundations; Genetic; Goals; Interneurons; Intervention; Investigation; Joints; Label; Lead; Learning; Leg; Limb structure; Locomotion; Measurement; Measures; Mechanics; Modeling; Motor; Motor Neurons; Motor output; Movement; Muscle; Muscle Contraction; Nervous System Physiology; Nervous system structure; Neuraxis; Neuromuscular Diseases; Neurons; Output; Pattern; Physiology; Population; Positioning Attribute; Posture; Production; Property; Proprioceptor; Reflex action; Role; Signal Transduction; Spinal; Spinal Cord; Spinal Injuries; Stimulus; Structure; Synapses; System; Testing; Translating; Update; Vertebrates; Work; base; cell type; exhaustion; flexibility; fly; in vivo; insight; limb movement; motor control; motor neuron function; neural circuit; neural model; neural patterning; neuroregulation; novel; optogenetics; presynaptic neurons; reconstruction; recruit; relating to nervous system; sensory feedback; therapy design; tibia; tool

Motor neurons connect to muscles and comprise the major output of the nervous system. Patterns of neural activity in motor neurons cause temporally precise muscle contractions, producing coordinated and flexible behavior. These patterns are shaped by the connectivity and physiology of premotor circuits in the spinal cord that synapse onto the motor neurons. Premotor circuits combine descending motor commands with sensory feedback signals to drive motor neuron activity. How premotor networks are structured to control motor output is not well understood, due in part to an incomplete inventory of spinal cell types, and to the difficulties of recording neural activity in behaving animals. To address this gap, this project aims to use Drosophila melanogaster as a model for investigating motor control and premotor neural circuits. With an accessible and numerically compact nervous system, a large and growing suite of genetic tools, and agile, limbed locomotion, Drosophila has the potential to provide insight into fundamental problems of motor control. We introduce a task in which flies learn to generate specific amounts of force to position the femur-tibia joint in different targets. The joint is controlled by twelve neurons which can be genetically labeled for targeted neural recordings. Electrophysiological recordings will reveal how the complete population of motor neurons function together to dynamically position the leg and to sustain a given force output. These data will address long-standing hypotheses about how premotor circuits recruit subsets of motor neurons and the degree to which that control is flexible. Then, a new electron-microscopy level reconstruction of central locomotor circuits will allow identification of key premotor neurons. Electrophysiological recordings of those premotor neurons during the behavioral task will reveal their contributions to processing sensory feedback and to controlling leg force. These results will provide a foundation for understanding how descending commands interact with internal models of body state to control locomotion, a critical step toward achieving the long-term goals of designing interventions for neuromuscular disorders and algorithms for controlling engineered systems.

运动神经元与肌肉相连，构成神经系统的主要输出。的图案 运动神经元的神经活动引起时间上精确的肌肉收缩，产生协调的 和灵活的行为方式。这些模式是由运动前回路的连接性和生理学塑造的 在脊髓中突触到运动神经元。预电机电路结合下降电机 带有感觉反馈信号的命令来驱动运动神经元活动。运动前网络是怎样的 控制运动输出的结构尚不清楚，部分原因是脊髓的库存不完整 细胞类型，以及记录行为动物神经活动的困难。为了弥补这一差距，这 该项目旨在使用果蝇作为研究运动控制和前运动的模型 神经回路。具有可访问且数字紧凑的神经系统，一个庞大且不断增长的套件 遗传工具和敏捷的四肢运动，果蝇有潜力提供洞察力 电机控制的基本问题。我们引入了一项任务，让苍蝇学习生成特定的 将股骨-胫骨关节定位在不同目标的力的大小。该关节由十二个控制 可以对神经元进行基因标记以进行目标神经记录。电生理记录 将揭示完整的运动神经元群体如何共同发挥作用来动态定位 腿并维持给定的力输出。这些数据将解决长期以来关于如何 前运动回路招募运动神经元的子集以及控制的灵活程度。然后， 中央运动回路的新电子显微镜水平重建将允许识别关键 前运动神经元。行为任务期间这些前运动神经元的电生理记录 将揭示他们对处理感觉反馈和控制腿部力量的贡献。这些结果 将为理解降序命令如何与内部模型交互提供基础 身体状态来控制运动，这是实现设计长期目标的关键一步 神经肌肉疾病的干预措施和控制工程系统的算法。