Dopamine modulation of synaptic plasticity and integration in the striatum

项目概要： 学习和执行运动技能是大脑的重要功能，涉及大脑的协调活动。 运动皮层和基底神经节。值得注意的是，初级运动皮层（M1）和 背外侧纹状体（dorsolatriatum，DLS）是M1输出神经元的主要靶区，在运动学习中起着至关重要的作用。损失- 功能研究，如DLS病变或沉默多刺投射神经元（SPN）损害学习运动 通过删除SPN上的NMDA受体来阻断SPN的可塑性，可以阻止小鼠学习新的 运动技能此外，在运动障碍中，如帕金森病和左旋多巴诱导的运动障碍， DLS或M1中神经元整体活动的破坏可能介导行为缺陷。然而，直接 在运动学习过程中皮质纹状体突触的可塑性和动力学的证据令人惊讶地缺乏。 这种差距的一个原因是皮质纹状体投射的广泛和会聚的神经支配， 这使得在运动学习过程中评估该回路的功能和可塑性变得具有挑战性。如何 皮质纹状体突触可塑性参与体内运动学习和运动记忆的形成 仍不清楚运动学习导致M1和DLS中神经元活动模式的适应， 它们的活动与习得的动作联系得更加紧密。一个有趣的解释这些 神经元活动的适应性在于，这种行为相关的神经元可能代表以下神经元相关： 运动记忆，形成运动记忆印迹。在这里，我们假设运动学习诱导突触 皮质纹状体运动印迹神经元的可塑性，这是至关重要的形成和巩固， 运动记忆在这个建议中，使用结合这些遗传工具的方法来标记和操纵运动神经元， 用电生理学、离体和体内双光子成像和单细胞RNA- 测序，我们的目的是研究如何皮质纹状体电路适应运动学习在分子，细胞， 和电路水平。本研究的主要目的是：1.研究大鼠皮层和纹状体兴奋性突触的可塑性， 运动印迹神经元2：研究运动学习如何影响皮质纹状体的结构和功能， 预测。3.目的：探讨海马CA 1区皮质纹状体突触可塑性的分子机制。 运动学习在拟议的实验中的成功将提供一个深入的，机械的理解， 皮质纹状体回路中的突触可塑性和整合。鉴于突触可塑性的基本作用 在运动技能的学习和执行以及适应不良的皮质和纹状体突触可塑性方面， 运动障碍，我们的研究结果可能进一步有助于未来的战略，更有效地治疗这些 疾病，如帕金森病。

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.