Dopamineergic Modulation of Synaptic Transmission in the Straitum

描述(申请人提供)：纹状体是基底节的关键组成部分，是前脑核团的集合，其功能对正确执行自愿运动至关重要。正常的纹状体活动受神经调节剂多巴胺的调节，纹状体多巴胺能输入的丧失会导致帕金森氏症所见的严重神经损伤。然而，尽管在了解多巴胺能信号对纹状体功能的贡献方面取得了许多进展，但多巴胺的确切作用机制仍然不清楚。多巴胺被认为影响纹状体神经元对突触输入的反应，突触输入以树突棘为靶点，突触后细胞膜的小~T微米突起不易用常规电生理方法研究。然而，使用光学成像的最新发展使在这种小空间尺度上研究神经元活动成为可能。这项工作的具体目标是详细了解多巴胺如何调节纹状体中的突触传递和整合。特别是，这些实验将解决两个关键问题。首先，多巴胺如何在单个突触水平上调节纹状体神经元对兴奋性突触输入的反应？第二，多巴胺如何改变神经元整合空间和时间分布的突触输入的能力？为了解决这些问题，将使用电生理学和双光子激光扫描显微镜相结合的方法来刺激和记录单个树突棘内的突触活动。更广泛地说，这项提议旨在为多巴胺能调节和正常纹状体活动之间的关系提供新的见解。通过扩大我们对纹状体递质系统之间相互作用的了解，这些研究将增强我们对纹状体在行为中的作用的理解，并有助于开发更好的帕金森氏病和其他运动障碍模型。

DESCRIPTION (provided by applicant): The striatum is a key component of the basal ganglia, a collection of forebrain nuceli whose function is critical for the proper execution of voluntary movements. Normal striatal activity is regulated by the neuromodulator dopamine, and loss of dopaminergic inputs to the striatum results in the profound neurological impairments seen in Parkinson's disease. Nevertheless, despite numerous advances in understanding the contribution of dopaminergic signaling to striatal function, the precise mechanisms of dopamine's actions remain elusive. Dopamine is thought to influence the response of striatal neurons to synaptic inputs that target dendritic spines, small ~T micron protrusions of the postsynaptic cell membrane not easily studied by conventional electrophysiological methods. However, recent developments using optical imaging have enabled the study of neuronal activity at this small spatial scale. The specific goal of this work is to obtain a detailed understanding of how dopamine regulates synaptic transmission and integration in the striatum. In particular, the experiments will address two key questions. First, how does dopamine modulate the response of striatal neurons to excitatory synaptic inputs at the level of single synapses? Second, how does dopamine alter the ability of neurons to integrate spatially and temporally distributed synaptic inputs? To address these questions, a combination of electrophysiology and 2-photon laser scanning microscopy will be used to stimulate and record synaptic activity within individual dendritic spines. More generally, this proposal aims to provide new insight into the relationship between dopaminergic modulation and normal striatal activity. By expanding our knowledge of the interactions between transmitter systems in the striatum, these studies will enhance our understanding of the role of the striatum in behavior and contribute to the development of better models of Parkinson's disease and other movement disorders.