Medium Spiny Neuron Excitability and Motivation

中等多棘神经元的兴奋性和动机

• 批准号: 8444494
• 负责人: Christoph Kellendonk
• 金额: $ 38.4万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-20 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444494
• 关键词: Acute; Address; Adult; Amygdaloid structure; Area; Back; Basal Ganglia; Behavior; Behavioral; Brain; Cell Nucleus; Chronic; Corpus striatum structure; DRD2 gene; Data; Development; Dopamine D2 Receptor; Drug Addiction; Genes; Genetic; Goals; Impairment; Individual; Ion Channel; Kir2.1 channel; Label; Measures; Medial; Mediating; Membrane Potentials; Mental Depression; Mental disorders; Messenger RNA; Molecular; Motivation; Mus; Neurons; Nucleus Accumbens; Output; Pathway interactions; Pharmaceutical Preparations; Potassium; Potassium Channel; Prefrontal Cortex; Proteins; Receptor Up-Regulation; Regulation; Relative (related person); Resistance; Schizophrenia; Slice; Testing; Therapeutic; Up-Regulation; Work; density; in vivo; motivational processes; mouse model; nerve supply; neuronal excitability; public health relevance; tool; virus genetics

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.

描述（由申请人提供）：动机异常是精神分裂症、抑郁症和毒瘾等多种精神疾病的核心缺陷。为了针对这些缺陷制定更有效的治疗策略，必须确定潜在的分子机制以及神经元功能和回路的相关变化。该项目的长期目标是了解称为中棘神经元 (MSN) 的纹状体主要神经元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，这种上调与动机缺陷相关。该应用的主要假设是纹状体中 D2R 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。两个具体目标将解决这一假设： 目标 1：检验 D2R 上调增加 MSN 兴奋性的假设 目标 2：检验 MSN 兴奋性是动机行为的关键调节因素的假设。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。使用病毒介导的离子通道表达，可以选择性地改变纹状体的纹状体-苍白球通路中的 MSN 兴奋性。