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.

项目摘要： 学习和执行运动技能是大脑的关键功能，涉及到核的活动 运动皮层和基底神经节。 损失。 功能研究，例如DLS病变或沉默的棘刺影神经元（SPN）损害了学习的运动 行为，并通过删除SPN上的NMDA受体阻止SPN可塑性可防止小鼠学习新的 运动技能。 DLS神经元的整体活动的破坏可能会导致行为缺陷 令人惊讶的是缺乏在驾驶过​​程中可塑性和皮质纹状体突触动态的证据。 皮质纹状体Projech的广泛和收敛的原因之一 在运动学习过程中，评估电路的功能和塑料的功能和塑料使其具有挑战性。 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 仍然不清 他们的活动与学习的动作更加紧密相关。 神经元活性的适应是，这种与行为相关的神经元可能会抑制神经相关性 电机记忆，形成电动机记忆engram。 皮质纹状体运动ENGRAM神经元中的塑料，这对于形成和巩固至关重要 在此提案中，使用这种遗传工具来标记和操纵电动机 具有电生理学，离体和体内2光子成像的Engam神经元，以及单细胞RNA- 测序，我们旨在调查在分子，细胞，细胞上驾驶过程中的皮质纹状体电路如何适应。 和电路水平。 运动英语神经元2：检查运动学习如何影响皮质的结构和功能 预测3。 运动经验的成功将提供深入的机械理解 皮质纹状体电路中的突触塑料和整合。 在学习和执行运动技能以及适应不良的皮质和纹状性突触可塑性中 运动障碍，我们的发现可能进一步有助于未来的策略，以更有效地真正的treas虫 疾病，例如帕金森氏病。