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.

项目概要 难以启动或执行适当的运动是神经系统疾病的特征，包括 帕金森病和共济失调，而异常重复运动的产生见于 神经系统和神经精神疾病，如抽动秽语综合症、强迫症和自闭症谱系障碍这项研究是 旨在了解秀丽隐杆线虫启动、执行和 稳定适当的运动动作，以便预测运动动作的失调如何 目前，我们对产生适当运动输出的机制的理解。 生理状态和病理状态下的异常输出是不完整的，已知有302个神经元。 连接性和众多遗传工具来瞄准和操纵单个神经元，线虫 秀丽隐杆线虫提供了一个优秀的系统来研究运动输出的神经机制 线虫的运动由一系列稳定的运动动作/状态组成：从前方开始。 过去的研究表明，在有或没有转弯的情况下反向运动，然后恢复向前运动。 将线虫中间神经元 AIB、RIM 和 AVA 与逆转联系起来，但确切的神经元 初始化、执行和稳定运动状态所需的贡献仍然难以捉摸。 连接性和之前的实验结果，我爬到AIB，RIM和AVA主要初始化， 分别稳定和执行逆转，并且这些功能将反映在它们对 光遗传学扰动，驱动运动状态变化所需的时间窗口及其响应 在目标 1 中，我将表达兴奋性光遗传学通道、Chrimson 或抑制性通道。 光遗传学通道 GtACR2 单独存在于单个神经元中，以了解单个神经元的状态依赖性时序 驱动运动状态变化的神经元激活或失活在目标 2 中，我将使用双向。 光遗传学工具 BIPOLE（Chrimson 和 GtACR2 通道串联）可确定精确的时间 逆转相关中间神经元产生预期运动输出所需的活动窗口。 将结合光遗传学扰动和化学遗传学沉默以了解相互作用 产生稳定、灵活的运动状态所需的神经元之间的变化。 线虫可能会阐明运动模式生成及其失调的更广泛主题。 它需要在高度支持的跨学科实验室环境中进行。 用于神经回路扰动和计算行为分析的工具，非常适合我未来的培训 研究健康和疾病行为的遗传和循环机制的医师科学家。