Dopamine modulation of synaptic plasticity and integration in the striatum

多巴胺对纹状体突触可塑性和整合的调节

• 批准号: 10607794
• 负责人: Jun Ding
• 金额: $ 48.85万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607794
• 关键词: Affect; Axon; Basal Ganglia; Behavior; Behavioral; Brain; Corpus striatum structure; Disease; Dopamine; Electric Stimulation; Electrophysiology (science); Funding; Future; Gene Expression; Genetic; Genetic Recombination; Glutamates; Goals; Image; Immediate-Early Genes; Impairment; L-DOPA induced dyskinesia; Label; Learning; Lesion; Mediating; Memory; Molecular; Molecular Profiling; Motor; Motor Activity; Motor Cortex; Motor Skills; Movement; Movement Disorders; Mus; N-Methyl-D-Aspartate Receptors; Neurodegenerative Disorders; Neurons; Output; Parkinson Disease; Pattern; Population; Role; Structure; Synapses; Synaptic plasticity; Thalamic structure; Vertebral column; cell type; effective therapy; experimental study; in vivo; interdisciplinary approach; loss of function; motor behavior; motor control; motor learning; nerve supply; neural correlate; novel therapeutics; prevent; promoter; single-cell RNA sequencing; success; tool; two-photon

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.

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) 和大脑皮层之间的连接。 背外侧纹状体 (DLS) 是 M1 输出神经元的主要目标，在运动学习中发挥着至关重要的作用。 功能障碍研究，例如 DLS 损伤或沉默多刺投射神经元 (SPN) 会损害习得运动 通过删除 SPN 上的 NMDA 受体来阻断 SPN 的可塑性可以防止小鼠学习新的东西 此外，在运动障碍中，例如帕金森病和左旋多巴引起的运动障碍， DLS 或 M1 神经元整体活动的破坏可能会直接导致行为缺陷。 运动学习过程中皮质纹状体突触的可塑性和动态性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且会聚的神经支配， 使得在运动学习过程中评估该电路的功能和可塑性变得具有挑战性。 皮质纹状体突触可塑性有助于运动学习和体内运动记忆的形成 目前尚不清楚运动学习会导致 M1 以及 DLS 和 DLS 神经活动模式的适应。 他们的活动与习得的动作变得更加密切相关。 神经活动的适应性在于，这种与行为相关的神经元可能代表以下行为的神经相关性： 运动记忆，形成运动记忆印迹在这里，我们认为运动学习会诱导突触。 皮质纹状体运动印迹神经元的可塑性，对于形成和巩固至关重要 在该提案中，使用结合此类遗传工具的方法来标记和操纵运动。 印迹神经元的电生理学、离体和体内 2 光子成像以及单细胞 RNA- 测序，我们的目标是研究运动学习过程中皮质纹状体回路在分子、细胞、 主要目标是： 1：研究皮质和纹状体的兴奋性突触可塑性。 运动印迹神经元 2：检查运动学习如何影响皮质纹状体的结构和功能。 3. 确定皮质纹状体突触可塑性的分子机制。 所提出的实验的成功将提供对运动学习的深入、机械的理解。 鉴于突触可塑性的基本作用，皮质纹状体回路中的突触可塑性和整合。 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中看到 运动障碍，我们的研究结果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，例如帕金森病。