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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结: