Dopamine modulation of synaptic plasticity and integration in the striatum

项目总结： 学习和执行运动技能是大脑的重要功能，涉及到 运动皮质和基底节。值得注意的是，初级运动皮质(M1)和 背外侧纹状体(DLS)是M1输出神经元的主要靶点，与运动学习密切相关。损失- 功能障碍研究，如DLS损伤或抑制棘突投射神经元(SPN)损害习得性运动 行为，并通过删除SPN上的NMDA受体来阻止SPN的可塑性阻止小鼠学习新的 运动技能。此外，在运动障碍方面，如帕金森氏症和L-多巴诱导的运动障碍， DLS或M1中神经元整体活动的中断可能与行为障碍有关。然而，直接 运动学习期间皮质纹状体突触可塑性和动力学的证据令人惊讶地缺乏。 造成这种差距的原因之一是皮质纹状体投射的广泛和汇聚的神经支配，它具有 这使得在运动学习过程中评估这个回路的功能和可塑性是一件具有挑战性的事情。多么 皮质纹状体突触的可塑性有助于运动学习和运动记忆的形成 目前仍不清楚。运动学习导致M1以及DLS和DLS中神经元活动模式的适应 他们的活动与习得的动作更紧密地联系在一起。对这些的有趣解释 神经元活动中的适应是这样的行为相关神经元可能代表了 运动记忆，形成运动记忆印记。在这里，我们假设运动学习会诱导突触 皮质纹状体运动神经元的可塑性，这对纹状体运动神经元的形成和巩固至关重要 运动记忆。在这项提案中，使用结合这种遗传工具的方法来标记和操纵马达 Engram神经元电生理学，体外和体内双光子成像，以及单细胞RNA- 测序，我们的目标是研究皮质纹状体回路在分子，细胞， 和电路级。主要目的是：1.研究大脑皮层和纹状体兴奋性突触的可塑性。 运动印记神经元。2：研究运动学习如何影响皮质纹状体的结构和功能 投射。3.探讨大鼠皮质纹状体突触可塑性的分子机制。 运动学习。拟议中的实验的成功将提供一个深入的，机械的理解 皮质纹状体环路中突触的可塑性和整合。鉴于突触可塑性的基础作用 在学习和执行运动技能和适应不良皮质和纹状体突触可塑性 运动障碍，我们的发现可能进一步有助于未来更有效地治疗这些疾病的策略 疾病，如帕金森氏症。

Project Summary: Learning and executing motor skills are crucial functions of the brain and involve the coordinated activity of the motor cortex and basal ganglia. Notably, the connections between the primary motor cortex (M1) and the dorsolateral striatum (DLS), a major target of M1 output neurons, are crucially involved in motor learning. Loss- of-function studies, such as DLS lesions or silencing spiny projection neurons (SPNs) impairs learned motor behaviors, and blocking SPN plasticity by deleting NMDA receptors on SPNs prevents mice from learning new motor skills. In addition, in movement disorders, such as Parkinson’s disease and L-DOPA-induced dyskinesia, disruption of ensemble activity of neurons in the DLS or M1 may mediate behavioral deficits. Yet, direct evidence of plasticity and dynamics of corticostriatal synapses during motor learning is surprisingly lacking. One reason for this gap is the widespread and convergent innervation of corticostriatal projections which has made it challenging to assess the function and plasticity of this circuit over the course of motor learning. How corticostriatal synaptic plasticity contributes to motor learning and the formation of motor memory in vivo remains unclear. Motor learning leads to adaptation of neuronal activity patterns in M1 as well as in DLS and their activity becomes more closely associated with learned movements. An intriguing interpretation of these adaptations in neuronal activity is that such behavior-related neurons may represent the neural correlate of motor memory, forming a motor memory engram. Here, we hypothesize that motor learning induces synaptic plasticity in the corticostriatal motor engram neurons, which is crucial for the formation and consolidation of motor memory. In this proposal, using approaches combining such genetic tools to label and manipulate motor engram neurons with electrophysiology, ex vivo and in vivo 2-photon imaging, and single-cell RNA- sequencing, we aim to investigate how corticostriatal circuit adapts during motor learning at molecular, cellular, and circuit levels. The major goals are: 1: To investigate cortical and striatal excitatory synaptic plasticity of motor engram neurons. 2: To examine how motor learning affects the structure and function of corticostriatal projections. 3. To determine the molecular mechanism underlying corticostriatal synaptic plasticity induced by motor learning. Success in the proposed experiments will provide an in-depth, mechanistic understanding of synaptic plasticity and integration in the corticostriatal circuits. Given the fundamental role of synaptic plasticity in the learning and execution of motor skills and maladaptive cortical and striatal synaptic plasticity seen in movement disorders, our findings may further contribute to future strategies to more effectively treat these diseases, such as Parkinson’s disease.