The role of the nigrostriatal circuit in self-timed movements

黑质纹状体回路在自主运动中的作用

• 批准号: 10687831
• 负责人: JOHN ASSAD
• 金额: $ 61.17万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687831
• 关键词: Address; Affect; Animals; Basal Ganglia; Behavior; Behavioral; Biological; Biological Clocks; Brain; Corpus striatum structure; Cues; Disparate; Dopamine; Dorsal; Equilibrium; Event; Exhibits; Future; Goals; Lead; Learning; Lesion; Measurement; Measures; Modeling; Monitor; Monkeys; Movement; Movement Disorders; Mus; Neurons; Optics; Parkinson Disease; Pathway interactions; Phase; Play; Ramp; Rattus; Reaction; Rewards; Role; Sensory; Signal Transduction; Speed; Testing; Time; Update; Variant; cell type; dopaminergic neuron; experimental study; interest; millisecond; neural; novel; optogenetics; predictive modeling; response; theories; time interval

Project abstract Study of movement disorders suggests that dopamine (DA) and the broader nigrostriatal circuit may play a specialized role in self-timed movements, for which the drive to move must be generated internally rather than in reaction to external events. However, classic experiments suggested that DA neurons (DANs) encode reward-prediction errors (RPEs) that occur too late to facilitate movements. In project 1, our collaborators present an updated temporal difference (TD) model for which, under appropriate conditions, RPE/DA signals “ramp-up” during ongoing behavior. These signals could be associated with, or facilitate, self-timed movements. We will address the hypothesis in three ways, using a self-timed movement task in mice. First, we will record from genetically defined DANs during self-timed movements, to assess the relationship between DAN activity and movement time. We already have strong preliminary evidence that DANs indeed ramp up their activity before self-timed movements, with the slope of ramping inversely related to the movement time. Second, we will test whether DA ramps are causal to self-timed movements, by optogenetically stimulating genetically defined DANs and examining the effect on the timing of self-timed movements. Third, the TD/RPE theory explains how DANs can evince ramping activity, but does not address how DA ramping affects downstream targets. We hypothesize that DANs facilitate self-timed movements by oppositely modulating striatal spiny projection neurons (SPNs) of the direct and indirect striatal pathways. To test this hypothesis, we will simultaneously monitor pairwise activity from genetically identified DANs, dSPNs or iSPNs to assess 1) the relationship of dSPN/iSPN balance and movement time, and 2) the cell types' influence on each other. These experiments will provide crucial information on the function of the key nigrostriatal circuit, grounded in a novel theory that makes testable hypotheses.

项目摘要 对运动障碍的研究表明，多巴胺（DA）和更广泛的黑质纹状体回路可能在运动障碍中起作用。 在自定时运动中的专门角色，为此，运动的驱动力必须在内部产生，而不是 以应对外部事件。然而，经典的实验表明，DA神经元（DAN）编码 奖励预测错误（RPE）发生得太晚，无法促进运动。在项目1中，我们的合作者 提出了一个更新的时间差（TD）模型，在适当的条件下，RPE/DA信号 在进行中的行为过程中“加速”。这些信号可以与自定时相关联，或者促进自定时。 动作我们将通过三种方式来解决这个假设，使用小鼠的自定时间运动任务。一是 将记录自定时运动期间基因定义的DAN，以评估 DAN活动和运动时间。我们已经有强有力的初步证据表明， 他们的活动之前，自定时运动，斜坡的斜率与运动时间呈负相关。 第二，我们将通过光遗传学刺激来测试DA斜坡是否与自定时运动有关。 基因定义的DAN和检查对自定时运动的时间的影响。第三，TD/RPE 理论解释了DAN如何表明活动增加，但没有解决DA增加如何影响 下游目标我们假设，DAN通过反向调制来促进自定时运动， 直接和间接纹状体通路的纹状体棘状投射神经元（SPN）。为了验证这个假设，我们 将同时监测来自遗传鉴定的DAN、dSPN或iSPN的成对活性，以评估1） dSPN/iSPN平衡与运动时间的关系; 2）细胞类型之间的相互影响。这些 实验将提供关键的黑质纹状体电路的功能，在一个新的接地的关键信息 提出可检验假设的理论。