Dopamine, Synaptic Plasticity and Striatal Ensemble Dynamics Underlying Motor Learning

项目摘要/摘要 纹状体中的多巴胺信号对运动至关重要，但它允许在运动中发挥作用的机制基础 人们对运动动作的理解还不完全。长期以来的观点认为，多巴胺通过 对纹状体主要神经元的差异性调节，表达棘多巴胺的D_1和D_2受体 投射神经元(SPN)。具体地说，纹状体多巴胺被认为增加了d1-SPN，减少了d2-spn 兴奋性。这一观点得到了1)多巴胺对d1和d2影响的体外测量的有力支持。 SPN兴奋性和体内观察2)消融多巴胺能神经元降低D_1和增加D_1 D2-SPN活性和3)选择性激活D1SPN或D2-SPN分别促进或抑制 有动静。然而，从体内记录的d1-和d2-SPN活性的几个最新发现并不支持 D1SPN和D2SPN在运动中的作用是一个简单的“去/不去”模型。具体地说，活体记录显示 在空间重叠的簇中，D1-和D2-SPN共同激活，两者都在较高的运行时增加了它们的活性 速度，并且两者都减少了它们在运动偏移时的活动。因此，目前还不清楚到底是哪些方面 D1和D2的活性(例如，水平、时间或空间协调)受多巴胺信号以及如何调节 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)D_1和D_2-SPN活性、2)多巴胺轴突活性和D_1或D_2-SPN的方法 3)体内即刻早期基因表达标记和D_1或D_2-SPN活性。我们将使用这些 多巴胺依赖的条件性回避运动学习中训练期间神经活动成像的工具 任务。我们的初步数据表明，在这个任务中，多巴胺是在习得性运动中释放的，而d1- D2-SPN以不同的水平、时间和空间协调对这些运动进行编码。我们假设 这些变化是运动学习所必需的，是多巴胺逐渐和不同作用的结果 关于D_1和D_2-SPN特定亚群中兴奋性突触联系的强度。我们将对此进行测试 通过将体内成像实验的结果与突触的体外测量相结合来提出假设 D1SPN和D2SPN的强度。总体而言，我们的实验有可能解决我们的 了解多巴胺在运动控制中的作用以及这一过程如何在神经学和精神病学中出错 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.