Generation of Motor Cortical Dynamics Controlling Skilled Locomotion

产生控制熟练运动的运动皮层动力学

• 批准号: 10732888
• 负责人: Britton Alan Sauerbrei
• 金额: $ 40.25万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732888
• 关键词: Acceleration; Aging; American; Animals; Area; Attenuated; Behavior; Behavioral; Brain; Brain region; Cell Nucleus; Cerebellum; Characteristics; Complex; Computational Technique; Data; Data Analyses; Deep Brain Stimulation; Dimensions; Disease; Elderly; Environment; Exhibits; Extensor; Failure; Flexor; Foundations; Future; Gait; Generations; Goals; Healthcare Systems; Impairment; Individual; Knee; Knowledge; Left; Lesion; Limb structure; Locomotion; Locomotor adaptation; Measurement; Measures; Mission; Modeling; Modification; Motor; Motor Cortex; Motor Skills; Movement; Movement Disorders; Mus; Muscle; Nervous System; Neurodegenerative Disorders; Neurologic Gait Disorders; Neurons; Output; Parietal; Parietal Lobe; Pattern; Phase; Population; Population Dynamics; Public Health; Pump; Purkinje Cells; Research; Signal Transduction; Source; Spinal; Surface; Techniques; Testing; Thalamic structure; Time; United States National Institutes of Health; Vertebral column; Walking; Work; brain machine interface; data-driven model; dynamic system; fall risk; falls; flexibility; improved; inhibitory neuron; injury-related death; innovation; kinematics; limb movement; motor control; neural; neural circuit; neurotransmission; optogenetics; skills; synergism; treadmill

PROJECT SUMMARY Walking over natural terrain with skill and flexibility requires the nervous system to adapt limb movements to environmental demands on each step. To drive the limbs over an obstacle without stumbling, the brain must generate commands to modulate the appropriate muscle synergies at a specific phase of the ongoing locomotor rhythm. The loss or impairment of these commands in disease can result in falls, which are common in older adults and impose a significant burden on the healthcare system. While previous studies have demonstrated that the motor cortex is critical for skilled locomotion, two key gaps currently impede progress in developing models of cortical control. First, because gait modification is controlled by coordinated patterns of activity across the motor cortical population, it is necessary to measure these population-level patterns in behaving animals, and to identify how these patterns relate to specific aspects of movement. Second, because motor cortex generates descending commands by integrating multiple sources of input from other brain regions, it is critical to determine how these inputs influence motor cortical dynamics along specific, behaviorally-relevant dimensions. Our long-term goal is to identify the dynamical principles governing the interactions across distributed neural populations, and to determine how these principles enable the adaptation of the locomotor pattern in a complex environment. The overall objective of this proposal is to determine how neural population dynamics in motor cortex are generated during skilled locomotion by identifying the impact of cerebellar and posterior parietal inputs on specific motor cortical dimensions. Our central hypothesis is that the cerebellum selectively drives step-entrained dimensions of motor cortical population activity that are synchronized with the rhythm of lower motor centers, while the posterior parietal cortex selectively drives motor commands for gait modification in obstacle-modulated dimensions. To directly test this hypothesis, we will first record from motor cortical ensembles in unrestrained mice performing skilled locomotion and use computational techniques to isolate step-entrained and obstacle-modulated dimensions of neural population activity (Aim 1). Next, we will use optogenetic perturbations to identify the effect of disrupting inputs from the cerebellum (Aim 2) and posterior parietal cortex (Aim 3) on activity in these dimensions. The proposed research is significant because the identification of how inputs to motor cortex generate its dynamics in healthy animals is expected to provide a foundation for future studies of how these dynamics degrade in neurodegenerative disease and aging, and to support the improvement of closed-loop deep brain stimulation strategies for movement disorders. The proposed research is innovative because it integrates the dynamical systems framework for the analysis and interpretation of data with the optogenetic toolkit for neural circuit perturbations, enabling a transition beyond the measurement of cortical population trajectories toward a definition of the underlying dynamical principles that generate them.

项目概要 熟练而灵活地在自然地形上行走需要神经系统适应肢体运动 每个步骤的环境要求。为了驱动四肢不被绊倒地越过障碍物，大脑必须 生成命令以在正在进行的特定阶段调节适当的肌肉协同作用 运动节律。这些命令在疾病中丧失或受损可能会导致跌倒，这很常见 老年人，给医疗保健系统带来沉重负担。虽然之前的研究已经 表明运动皮层对于熟练的运动至关重要，目前有两个关键差距阻碍了这方面的进展 开发皮质控制模型。首先，因为步态修正是由协调模式控制的 整个运动皮质群体的活动，有必要测量这些群体水平模式 行为动物，并确定这些模式如何与运动的特定方面相关。其次，因为 运动皮层通过整合来自其他大脑的多个输入源来生成下行命令 区域，确定这些输入如何影响特定的运动皮层动力学至关重要， 行为相关维度。我们的长期目标是确定管理 分布式神经群体之间的相互作用，并确定这些原则如何实现适应 复杂环境下的运动模式。该提案的总体目标是确定如何 运动皮层中的神经群体动态是在熟练的运动过程中通过识别以下因素的影响而产生的： 小脑和后顶叶对特定运动皮质维度的输入。我们的中心假设是 小脑选择性地驱动运动皮质群体活动的步进维度 与下运动中枢的节律同步，而后顶叶皮层选择性地驱动运动 在障碍物调制维度中进行步态修改的命令。为了直接检验这个假设，我们首先 来自不受约束的小鼠的运动皮质群的记录，这些小鼠执行熟练的运动和使用 分离神经群体的步骤夹带和障碍调制维度的计算技术 活动（目标 1）。接下来，我们将使用光遗传学扰动来识别干扰输入的影响 小脑（目标 2）和后顶叶皮层（目标 3）对这些维度的活动的影响。拟议的 研究意义重大，因为确定运动皮层的输入如何在健康的情况下产生其动态 动物有望为未来研究这些动态如何在体内降解提供基础。 神经退行性疾病和衰老，并支持闭环深部脑刺激的改善 运动障碍的策略。所提出的研究具有创新性，因为它整合了动力学 使用神经回路光遗传学工具包分析和解释数据的系统框架 扰动，使皮层人口轨迹测量之外的过渡成为可能 生成它们的基本动力学原理的定义。