Medium Spiny Neuron Excitability and Motivation

描述（由申请人提供）：动机异常是包括精神分裂症、抑郁症和药物成瘾在内的几种精神障碍的核心缺陷。为了开发针对这些缺陷的更有效的治疗策略，必须确定潜在的分子机制以及神经元功能和电路的相关变化。该项目的长期目标是了解纹状体主要神经元（称为中型棘神经元（MSN））的兴奋性改变与动机缺陷之间的因果关系。具体来说，该项目建议利用MSN中多巴胺D2受体上调的遗传小鼠模型，该模型与动机缺陷有关。本申请的主要假设是纹状体中D2 R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。两个具体的目标将解决这个假设：目标1：为了测试的假设，D2 R上调增加MSN兴奋性目标2：为了测试的假设，MSN兴奋性是一个关键的调节动机行为。具体目标将通过将小鼠遗传学与行为和电生理学研究相结合来完成。MSN兴奋性将使用离子通道的病毒介导的表达在纹状体的纹状体-苍白球通路中选择性地改变。 公共卫生相关性：动机异常是几种精神障碍的核心缺陷，但其潜在的分子机制以及神经元功能和回路的变化仍有待确定。研究纹状体神经元兴奋性的改变是否会导致动机障碍，将有助于理解动机背后的神经机制，并可能指导精神疾病新药的开发。

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. PUBLIC HEALTH RELEVANCE: Motivational abnormalities are core deficits in several mental disorders, but the underlying molecular mechanisms and the changes in neuronal function and circuitry have still to be identified. Studying whether altered excitability of striatal neurons leads to motivational impairments will help to understand the neuronal mechanisms that underlie motivation and could guide the development of new medication for psychiatric diseases.