Medium Spiny Neuron Excitability and Motivation

中等多棘神经元的兴奋性和动机

基本信息

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
项目类别：
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

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

展开

项目摘要

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）：动机异常是多种精神分裂症，抑郁症和药物成瘾在内的几种精神疾病中的核心缺陷。为了制定这些缺陷的更有效的治疗策略，必须确定基本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称为中刺神经元（MSN）和动机缺陷的纹状体主神经元改变的兴奋性之间的因果关系。具体而言，该项目提议利用与动机不足有关的MSN中多巴胺D2受体上调的遗传小鼠模型。应用的主要假设是，纹状体中D2RS的密度增加通过增加一类MSN（纹状体 - 帕利德神经元的兴奋性）而导致动机缺陷。两个具体的目的将解决这一假设：目标1：测试D2R上调增加MSN兴奋性目标2：测试MSN兴奋性是动机行为的关键调节者的假设。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。使用离子通道的病毒介导的表达，将在纹状体的纹状体 - 帕利德途径中选择性地改变MSN兴奋性。