Medium Spiny Neuron Excitability and Motivation

描述(由申请人提供)：动机异常是几种精神障碍的核心缺陷，包括精神分裂症、抑郁症和毒瘾。为了开发更有效的治疗策略来治疗这些缺陷，必须确定潜在的分子机制以及神经元功能和回路的相关变化。该项目的长期目标是了解纹状体主要神经元(称为中棘神经元(MSN))兴奋性改变与动机缺陷之间的因果关系。具体地说，该项目建议利用MSN中多巴胺D2受体上调的遗传小鼠模型，这与动机不足有关。应用的主要假设是，纹状体D2Rs密度的增加通过增加一类MSN-纹状体苍白球神经元的兴奋性而导致动机缺陷。目标1：检验D2R上调增加MSN兴奋性的假说；目标2：检验MSN兴奋性是动机行为的关键调节因子的假说。具体目标将通过将小鼠遗传学与行为和电生理研究相结合来完成。利用病毒介导的离子通道表达，MSN的兴奋性将在纹状体的纹状体-苍白球通路中选择性地改变。

DESCRIPTION (provided by applicant): Motivational abnormalities are core deficits in several mental disorders including schizophrenia, depression, and drug addiction. To develop more effective therapeutic strategies for these deficits the underlying molecular mechanisms and the relevant changes in neuronal function and circuitry have to be identified. The long-term goal of this project is to understand the causal relationship between altered excitability of striatal principal neurons called medium spiny neurons (MSN) and motivational deficits. Specifically, the project proposes to take advantage of a genetic mouse model of dopamine D2 receptor up-regulation in MSNs that is associated with a deficit in motivation. The main hypothesis of the application is that increased density of D2Rs in the striatum leads to motivational deficits by increasing the excitability of one class of MSNs, the striato-pallidal neurons. Two specific aims will address this hypothesis: Aim 1: To test the hypothesis that D2R up-regulation increases MSN excitability Aim 2: To test the hypothesis that MSN excitability is a key regulator of motivational behavior. The specific aims will be completed by combining mouse genetics with behavioral and electrophysiological studies. MSN excitability will be altered selectively in the striato-pallidal pathway of the striatum using virally mediated expression of ion channels.