Pathway-specific Fyn signaling in the striatum and ethanol drinking

纹状体和乙醇饮用中的通路特异性 Fyn 信号传导

基本信息

批准号：
8795929
负责人：
DORIT RON
金额：
$ 35.55万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-25 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8795929
关键词：
AMPA Receptors Address Agonist Alcohol abuse Alcohol consumption Behavior Behavioral Binding Brain region Corpus striatum structure Coupled Cyclic AMP Cyclic AMP-Dependent Protein Kinases DRD2 gene Data Designer Drugs Development Disease Dopamine Dopamine D1 Receptor Dopamine D2 Receptor Ethanol Event Exhibits Extramural Activities Fluorescence GTP-Binding Proteins Gene Delivery Genes Genetic Genetically Engineered Mouse Goals Health Laboratories Light Maintenance Mediating Methodology Methods Modeling Molecular Mus N-Methyl-D-Aspartate Receptors Neurons Neurosciences Outcome Pathway interactions Pharmaceutical Preparations Phosphotransferases Physiological Physiological Adaptation Play Proto-Oncogene Proteins c-fyn Resolution Rewards Rodent Role Self Administration Signal Pathway Signal Transduction Synapses Synaptic Membranes System Techniques Testing Transgenic Mice United States National Institutes of Health Viral addiction alcohol response alcohol seeking behavior base cell type drinking drinking behavior in vivo innovation learned behavior motivated behavior neuroadaptation novel receptor recombinase tool

项目摘要

DESCRIPTION (provided by applicant): This proposal is aimed at studying signaling-dependent neuroadaptations that occur in response to ethanol in subpopulations of neurons within the dorsomedial striatum (DMS). The DMS plays a central role in goal- directed behaviors and addiction, and we found that voluntary and passive exposure of rodents to ethanol activates the tyrosine kinase Fyn specifically in the DMS. We further discovered that in response to ethanol, activated Fyn phosphorylates the NR2B subunit of the NMDARs (GluN2B) resulting in increased synaptic activity of NMDA and AMPA receptors (NMDAR/AMPAR). Finally, we showed that the Fyn-signaling pathway in the DMS plays a crucial role in mechanisms underlying ethanol-drinking behaviors. Neurons in the DMS express either dopamine (DA) D1 or D2 receptors (D1R, D2R) that form the direct "Go" and indirect "No-Go" pathways. Thus, DA is thought to have different and possibly opposite effects on D1R and D2R neurons. D1Rs are coupled to G protein αs (Gs), which activates cAMP/PKA signaling, whereas D2Rs are coupled to Gi, which inhibits cAMP/PKA. We found that Fyn activation depends on cAMP/PKA, and that in vivo administration of a D1R agonist but not D2R agonist activates Fyn signaling in the DMS, and specifically in D1R DMS neurons. Together, these data suggest the DA activates a signaling pathway consisting of D1R/Gs/Fyn/GluN2B/AMPAR in D1R neurons. Ethanol increases DA levels in the striatum, and we hypothesize that ethanol activates Fyn signaling specifically in D1R neurons in the DMS to facilitate neuroadaptations in the direct "Go" pathway that drive ethanol drinking behaviors. We also hypothesize that remote activation of Gs signaling in D1R DMS neurons is sufficient to produce similar Fyn-dependent cellular and behavioral neuroadaptations. These hypotheses will be tested in vivo using transgenic mice that express Cre in D1R or D2R neurons, and will utilize innovative molecular and chemico- genetic approaches to manipulate single genes (Cre-FLEX), and to remotely activate Gs signaling using the Designer Receptors Exclusively Activated by Designer Drugs (DREADD) method in specific subpopulations of neurons. Aim 1 and Aim 2 will determine whether Fyn-dependent adaptations induced by ethanol occur in D1R, but not D2R, neurons in the DMS, and whether Gs DREADD activation in DMS D1R neurons is sufficient to produce similar outcomes. Aim 3 will investigate the contribution of Fyn signaling in D1R DMS neurons to ethanol drinking behaviors, and whether Gs DREADD activation of Fyn in D1R is sufficient to produce ethanol seeking and drinking. Combining Molecular and Systems Neuroscience methodologies, we will unravel cell- type specific signaling adaptations that underlie the development and maintenance of ethanol drinking and seeking behaviors.

描述（由申请人证明）：该提案旨在研究依赖的神经适应，这些神经适用于传票中神经元的脉冲。我们发现，啮齿动物对乙醇的自愿性和被动在DMS中专门激活乙醇（NMDAR/AMPAR）。直接的“无行为”途径。抑制cAMP/PKA。 /gs/fyn2b/ampar in2r神经元。生产SES将在体内使用DRESS CRE在D1R或D2R神经元中耐受的转基因小鼠进行测试，以操纵单个基因（CRE-FLEX），并使用由设计器药物（DEREADD）方法远程激活GS信号传导神经元1和AIM 2将确定DMS中的D2R中的Fyn依赖性适应性，以及DMS D1R神经元中的GS Dreadd激活是否可以产生类似的D1R结果。 VEL细胞类型的特定特异性信号适应，使乙醇饮酒和寻求行为的发展和维持。