Neuronal Control of Motor State Transitions

运动状态转换的神经元控制

• 批准号: 10677946
• 负责人: Friederike Buck
• 金额: $ 4.77万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677946
• 关键词: Ablation; Address; Affect; Ataxia; Behavior; Behavioral; Behavioral Mechanisms; Brain; Caenorhabditis elegans; Characteristics; Chemotaxis; Complex; Disease; Environment; Food; Future; Gene Library; Generations; Genetic; Genetic study; Gilles de la Tourette syndrome; Health; Individual; Interneurons; Laboratories; Learning; Locomotion; Mental disorders; Modeling; Motor; Motor output; Movement; Nematoda; Neurons; Output; Parkinson Disease; Pathologic; Patients; Pattern; Phenotype; Physicians; Physiological; Probability; Production; Research; Role; Scientist; Signal Transduction; System; Testing; Time; Training; combinatorial; connectome; experimental study; flexibility; motor control; nervous system disorder; neural; neural circuit; neuropsychiatric disorder; novel; optogenetics; response; screening; tool

PROJECT SUMMARY Difficulty initiating or executing appropriate movement is characteristic of neurological disorders including Parkinson’s disease and ataxia, while the production of abnormally repetitive movements is seen in neurological and neuropsychiatric disorders such as Tourette Syndrome, OCD and ASD This research is aimed at understanding the neuronal mechanisms by which C. elegans nematodes initiate, execute and stabilize appropriate motor actions, in order to make predictions about how dysregulation of motor action patterns arise. Currently, our understanding of the mechanisms that generate appropriate motor outputs in physiological states and abnormal outputs in pathological states is incomplete. With 302 neurons with known connectivity and numerous genetic tools to target and manipulate individual neurons, the nematode Caenorhabditis elegans offers an excellent system to study the neuronal mechanisms of motor output generation. C. elegans locomotion is composed of a stable of sequence of motor actions/states: from forward locomotion to reversal with or without a turn, then a resumption of forward locomotion. Past studies have associated the C. elegans interneurons AIB, RIM, and AVA with reversals, however the exact neuronal contributions required to initialize, execute and stabilize motor states remain elusive. Based on their connectivity and previous experimental results, I hypothesize that AIB, RIM and AVA primarily initialize, stabilize and execute reversals, respectively, and that these functions will be reflected in their response to optogenetic perturbation, their required temporal windows to drive motor state changes and their response to combinatorial perturbation. In Aim 1, I will express the excitatory optogenetic channel, Chrimson, or inhibitory optogenetic channel, GtACR2, individually in single neurons to understand the state-dependent timing of single neuron activation or deactivation that drives motor state changes. In Aim 2, I will use the bidirectional optogenetic tool BIPOLEs (a Chrimson and a GtACR2 channel in tandem) to determine the precise temporal windows of activity required for reversal-associated interneurons to produce expected motor output. In Aim 3, I will combine optogenetic perturbation with chemogenetic silencing in order to understand the interactions between neurons required to generate stable, flexible motor states. Dissecting motor output changes in C. elegans may elucidate broader themes in motor pattern generation and its dysregulation. This research will take place in a highly supportive, inter-disciplinary laboratory environment. It requires the use of novel genetic tools for neural circuit perturbation and computational behavioral analysis, ideal for my training as a future physician-scientist studying the genetic and circuit mechanisms of behavior in health and disease.

项目摘要 难以启动或执行适当的运动是神经系统疾病的特征 帕金森氏病和共济失调，而绝对重复运动的产生 Tourette综合征，OCD和ASD等神经和神经精神疾病这项研究是 旨在了解秀丽隐杆线虫线虫启动，执行和执行和 稳定适当的运动动作，以预测运动动作失调的失调 出现模式。当前，我们对在 病理状态的生理状态和异常产量不完整。拥有302个神经元已知 连通性和众多靶向和操纵单个神经元的遗传工具，线虫 秀丽隐杆线虫提供了一个很好的系统来研究运动输出的神经元机制 一代。秀丽隐杆线虫运动由一系列运动动作/状态组成：从前进 在有或不转弯的情况下逆转的运动，然后恢复前进运动。过去的研究有 将秀丽隐杆线虫中间神经元AIB，轮辋和AVA与逆转相关联，但是确切的神经元 初始化，执行和稳定运动状态所需的贡献仍然难以捉摸。基于他们的 连通性和以前的实验结果，我假设AIB，RIM和AVA初始化， 分别稳定和执行逆转，这些功能将反映在其对 光遗传扰动，它们所需的临时窗户以驱动运动状态变化及其对 组合扰动。在AIM 1中，我将表达兴奋性光遗传通道，Chrimson或抑制作用 光遗传通道GTACR2，单个神经元中单独了解单个神经元的状态依赖时间 驱动运动状态变化的神经元激活或失活。在AIM 2中，我将使用双向 光遗传学工具两极（串联的Chrimson和GTACR2通道）确定精确的临时性 反向相关的中间神经元所需的活动窗口才能产生预期的电机输出。在AIM 3中，我 将将光遗传学扰动与化学遗传沉默结合在一起，以了解相互作用 在产生稳定的灵活运动状态所需的神经元之间。解剖电动机输出的变化。 秀丽隐杆线索可能会阐明运动模式产生及其功能失调的广播主题。这项研究会 发生在高度支持的跨学科实验室环境中。它需要使用新颖的遗传 神经电路扰动和计算行为分析的工具，非常适合我作为未来的培训 医师科学家研究健康和疾病行为的遗传和电路机制。