Cell Type Specific Control of Neuronal Signaling

神经元信号传导的细胞类型特异性控制

基本信息

批准号：
8322176
负责人：
Martilias Stephen Farrell
金额：
$ 2.71万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2013-05-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8322176
关键词：
ADORA2A gene Acetylcholine Adenosine Affect Animal Behavior Basal Ganglia Basal Ganglia Diseases Behavior Behavioral Behavioral Sciences Bioavailable Brain Brain region Clozapine Corpus striatum structure Coupled Couples Coupling Cyclic AMP DARPP Designer Drugs Development Disease Drug Delivery Systems Event FOS gene Family Functional disorder G Protein-Coupled Receptor Signaling G(q) Alpha G-Protein Signaling Pathway G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Genetic Hand Human G(i) Alpha Proteins Huntington Disease Investigation Knowledge Laboratories Lead Ligands MAPK3 gene Measures Mediating Mental disorders Mus National Institute of Mental Health Neurons Obsessive-Compulsive Disorder Oxides Parkinson Disease Pattern Pharmaceutical Preparations Phosphorylation Physiological Population Receptor Activation Research Rewards Scientist Signal Pathway Signal Transduction Specificity Technology Testing Therapeutic Transgenic Mice Transgenic Organisms Work addiction cell type design in vivo innovation insight neuronal circuitry neuropsychiatry promoter receptor receptor-mediated signaling response small molecule spatiotemporal tool

项目摘要

6. PROJECT SUMMARY / ABSTRACT Dysfunctional neuronal circuits are thought to be responsible for neuropsychiatric disorders, including obsessive-compulsive disorder, Parkinson¿s disease and addiction. G protein-coupled receptors (GPCRs) differentially modulate the activity of neuronal circuits by interacting with different G proteins, (e.g. G-alpha-s, G-alpha-i, and G-alpha-q-families), and these receptors are well-established drug targets. Distinct subpopulations of neurons comprising these circuits often express similar receptor subtypes, making it impossible to create drugs that selectively target receptors in specific circuits. In order to determine how receptors might modulate neuronal circuits, it is necessary to selectively activate GPCR signaling in a specific neuronal population in vivo. For the past two decades, efforts have been made to create tools to selectively manipulate GPCR signaling in distinct neuron populations - from small molecule ligands to genetic deletion - but these approaches have off-target effects. These off-target effects effectively eliminate the possibility to determine how GPCR signaling in a specific neuronal population affects circuitry function. A promising advancement to enable this specific manipulation is the development of the Designer Receptors Exclusively Activated by Designer Drug (DREADD) family of receptors. The objective of this proposal is to validate this recently created tool in vivo using a transgenic mouse expressing the G-alpha-s DREADD in a specific population of neurons in the striatum. Specific Aim 1 will validate the tool by determining whether the G-alpha-s DREADD activates canonical G-alpha-s signaling pathways by measuring cAMP accumulation, ERK1/2 phosphorylation, DARPP-32 phosphorylation, and c-Fos expression. Specific Aim 2 will validate the physiological relevance of the G-alpha-s DREADD-induced signaling by assessing its effects on animal behavior. The completion of this proposal will provide neuroscientists a powerful new tool to exclusively modulate GPCR signaling in specific neuronal populations.

6。项目摘要 /摘要功能失调的神经元电路是负责神经精神疾病的原因，包括强迫症，帕金森氏症S疾病和上瘾者（GPCR）通过与不同的蛋白质（例如G-Alpha-S，G-Alpha-I和G-Alpha-Q-families）相互作用来差异模块化神经元回路的活性，并且是良好的。药物靶标的。从小分子配体到遗传缺失的gpcr信号传导具有非目标效应。这是为此验证的是，在特定的纹状体中，在特定的神经元中，使用小鼠在体内撤回工具。，通过评估其ETS的压缩，磷酸化，darpp-32伪态和c-fos诱导的信号传导。