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: 10226987
• 负责人: JOHN ASSAD
• 金额: $ 58.5万
• 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/10226987
• 关键词: Address; Affect; Animals; Basal Ganglia; Behavior; Behavioral; Biological; Biological Clocks; Brain; Corpus striatum structure; Cues; 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; neuron loss; novel; optogenetics; predictive modeling; relating to nervous system; 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 在自动计时移动中扮演特殊角色，其移动动力必须在内部生成，而不是 对外部事件的反应。然而，经典的实验表明，DA神经元(DAN)编码 奖赏预测错误(RPE)发生得太晚，无法促进行动。在项目1中，我们的合作者 提出了一种更新的时差(TD)模型，在适当的条件下，RPE/DA信号 在进行中的行为中“加速”。这些信号可以与自定时相关联或促进自定时 动静。我们将用三种方式来解释这一假说，使用小鼠的自我计时运动任务。首先，我们 将记录来自基因定义的Dans在自我计时运动期间，以评估两者之间的关系 DAN活动量和运动时间。我们已经有了强有力的初步证据，表明丹尼斯确实在增加 他们在自主定时运动前的活动，斜率与运动时间成反比。 其次，我们将通过光基因刺激来测试DA斜率是否与自我计时运动有关 从基因上定义DAN，并研究其对自我计时运动的影响。第三，TD/RPE 理论解释了DAN如何表现出斜坡活动，但没有解决DA斜坡如何影响 下游目标。我们假设DAN通过相反的调节来促进自我定时的运动 纹状体直接通路和间接通路的纹状体棘突投射神经元(SPN)。为了检验这一假设，我们 将同时监控来自遗传识别的DAN、dSPN或iSPN的配对活动，以评估1) DSPN/iSPN平衡与运动时间的关系；2)细胞类型的相互影响。这些 实验将提供关于黑质纹状体关键回路功能的关键信息，该回路植根于一种新的 提出可检验假设的理论。