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.

项目摘要 技巧和灵活地在自然地形上行走需要神经系统适应肢体运动， 每一步的环境要求。为了使四肢不绊倒地越过障碍物，大脑必须 产生命令，以调节适当的肌肉协同作用，在一个特定的阶段， 运动节律这些指令在疾病中的丧失或损伤可导致常见的福尔斯 在老年人中，这给医疗保健系统带来了沉重的负担。虽然先前研究已 证明了运动皮层对于熟练的运动至关重要，目前有两个关键的差距阻碍了 开发大脑皮层控制的模型首先，因为步态调整是由协调的模式控制的， 活动在整个运动皮层人口，有必要衡量这些人口水平的模式， 行为的动物，并确定这些模式如何与运动的特定方面。二是因为 运动皮层通过整合来自其他大脑的多个输入源来产生下行命令 区域，关键是要确定这些输入如何影响运动皮层动力学沿着具体， 行为相关的维度。我们的长期目标是确定支配 分布式神经群体之间的相互作用，并确定这些原则如何使适应 在复杂环境中的运动模式。本提案的总体目标是确定如何 运动皮层中的神经群体动力学是在熟练运动期间通过识别 小脑和后顶叶的输入对特定运动皮层尺寸的影响。我们的中心假设是， 小脑选择性地驱动运动皮层群体活动的步骤参与维度， 与较低的运动中枢的节奏同步，而后顶叶皮层选择性地驱动运动 用于在障碍物调制维度中进行步态修改的命令。为了验证这个假设，我们首先 来自进行熟练运动和使用的未受约束小鼠的运动皮层集合的记录 分离神经群体的步驱动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鉴定来自细胞的干扰输入的影响。 小脑（Aim 2）和后顶叶皮层（Aim 3）在这些方面的活动。拟议 研究是重要的，因为识别运动皮层的输入如何在健康的大脑中产生动力学， 动物有望为未来研究这些动力学如何降解提供基础。 神经退行性疾病和衰老，并支持闭环脑深部电刺激的改善 运动障碍的治疗策略所提出的研究是创新的，因为它集成了动态 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，使过渡超越测量皮质人口的轨迹， 产生它们的基本动力学原理的定义。