Dopamine, Synaptic Plasticity and Striatal Ensemble Dynamics Underlying Motor Learning

项目总结/摘要 纹状体中的多巴胺信号传导对运动至关重要，但其在运动中的允许作用的机制基础 对运动动作的理解还不完全。长期以来的观点是，多巴胺促进运动， 差异调节纹状体的主要神经元，D1和D2多巴胺受体表达棘 投射神经元（SPNs）。具体来说，人们认为纹状体多巴胺会增加D1-并减少D2-SPN 兴奋性这一观点得到了以下方面的有力支持：1）多巴胺对D1-和D2-的影响的体外测量， SPN兴奋性和体内观察结果，2）消融多巴胺神经元减少D1-和增加 D2-SPN活性和3）D1-或D2-SPN的选择性活化分别促进或抑制 运动然而，最近的几项来自D1-和D2-SPN活性的体内记录的发现并不支持， 运动中D1和D2-SPN功能的简单“go/no-go”模型。具体来说，体内记录显示， D1-和D2-SPNs在空间重叠的簇中共同激活，在较高的运行时间下， 速度，并且两者都在运动偏移处降低它们的活动。因此，仍不清楚究竟是哪些方面 D1-和D2活性（例如，水平，时间或空间协调）由多巴胺信号调节，以及如何调节 这促进了运动。为了解决这些问题，我们开发了三种多光子成像技术， 同时记录1）D1-和D2-SPN活性，2）多巴胺轴突活性和D1-或D2-SPN的方法 活性，和3）即刻早期基因表达标记和体内D1-或D2-SPN活性。我们将会用这些 在多巴胺依赖性、条件性回避运动学习的训练过程中成像神经活动的工具 任务我们的初步数据表明，多巴胺是释放在学习运动在这项任务中，和D1- 而D2-SPN以不同的水平、定时和空间协调来编码这些运动。我们假设 这些变化是运动学习所必需的，是多巴胺的渐进和差异效应的结果。 在D1-和D2-SPN的特定子集中兴奋性突触连接的强度。我们将测试这个 通过整合我们的体内成像实验的结果与突触的离体测量， D1-和D2-SPN的强度。总的来说，我们的实验有可能解决我们的核心冲突。 了解多巴胺在运动控制中的作用，以及这一过程在神经和精神疾病中是如何出错的。 疾病

PROJECT SUMMARY/ABSTRACT Dopamine signaling in the striatum is critical for movement, yet the mechanistic basis for its permissive role in motor actions is incompletely understood. The longstanding view is that dopamine promotes movement by differentially modulating the striatum’s principal neurons, the D1 and D2 dopamine receptor expressing spiny projection neurons (SPNs). Specifically, striatal dopamine is thought to increase D1- and decrease D2-SPN excitability. This view has strong support from 1) ex vivo measurements of dopamine’s effects on D1- and D2- SPN excitability and the in vivo observations that 2) ablating dopamine neurons decreases D1- and increases D2-SPN activity and 3) the selective activation of D1- or D2-SPNs respectively promotes or suppresses movement. However, several recent findings from in vivo recordings of D1- and D2-SPN activity do not support a simple “go/no-go” model for D1- and D2-SPN function in movement. Specifically, in vivo recordings have shown that D1- and D2-SPNs co-activate in spatially overlapped clusters, both increase their activity at higher running speeds, and both decrease their activity at motion offset. Therefore, it remains unclear precisely which aspects of D1- and D2 activity (e.g., levels, timing, or spatial coordination) are modulated by dopamine signaling and how this promotes movement. To address these questions, we have developed three, multiphoton imaging approaches to simultaneously record 1) D1- and D2-SPN activity, 2) dopamine axon activity and D1- or D2-SPN activity, and 3) immediate early gene expression tagging and D1- or D2-SPN activity in vivo. We will use these tools to image neural activity during training in a dopamine-dependent, conditioned-avoidance motor learning task. Our preliminary data indicate that dopamine is released during learned movement in this task, and that D1- and D2-SPNs encode these movements with different levels, timing, and spatial coordination. We hypothesize that these changes are necessary for motor learning and result from dopamine’s gradual and differential effects on the strength of excitatory synaptic connections in specific subsets of D1- and D2-SPNs. We will test this hypothesis by integrating the results from our in vivo imaging experiments with ex vivo measurements of synaptic strength in D1- and D2-SPNs. Overall, our experiments have the potential to resolve a central conflict in our understanding of dopamine’s role in motor control and how this process goes awry in neurological and psychiatric disease.