Small G proteins and alcohol use disorder

小G蛋白和酒精使用障碍

• 批准号: 10005105
• 负责人: DORIT RON
• 金额: $ 52.43万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005105
• 关键词: Actins; Address; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Behavior; Behavioral; Behavioral Paradigm; Biological Process; Brain region; Cell Polarity; Corpus striatum structure; Cytoskeleton; DRD2 gene; Data; Dendritic Spines; Development; Dorsal; Enzymes; F-Actin; Family; Family member; Female; Glutamates; Goals; Guanosine Triphosphate Phosphohydrolases; Heavy Drinking; LIM Domain Kinase 1; Light; Link; Maintenance; Mediating; Membrane; Modeling; Modification; Molecular; Molecular Genetics; Monomeric GTP-Binding Proteins; Morphology; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Outcome; Pathway interactions; Pharmacology; Phosphotransferases; Play; Publishing; ROCK1 gene; Reporting; Role; Signal Transduction; Signaling Molecule; Structure; Synapses; System; Testing; Trees; Vertebral column; Withdrawal; addiction; alcohol exposure; alcohol research; alcohol seeking behavior; alcohol use disorder; attenuation; base; cell growth; cofilin; drinking behavior; inhibitor/antagonist; insight; male; member; recruit; response; rho; rho GTP-Binding Proteins; small molecule; tool; trafficking

ABSTRACT This proposal is aimed at testing the contribution of the Rho GTPases Rac1 and RhoB in the dorsal striatum to the mechanisms underlying alcohol use disorder (AUD). Rac1 and RhoB play an important role in cytoskeleton rearrangement as well as in the remodeling of dendrites and spines. We recently discovered that excessive alcohol intake and withdrawal activate Rac1 and RhoB in the mouse dorsomedial striatum (DMS), and dorsolateral striatum (DLS), respectively. Based on published and preliminary data, we will test the hypothesis that alcohol activates Rac1 and RhoB, in DMS and DLS neurons, respectively, leading to cellular adaptations which in turn drive the development and/or maintenance of alcohol drinking behaviors including goal directed and habitual alcohol seeking. This hypothesis will be explored by the following aims. Aim 1 will determine the mechanism by which heavy alcohol use actives Rac1 and RhoB in the DMS and DLS. We will also determine whether the small G proteins are activated in subpopulation of striatal neurons. Aim 2 will determine the cellular consequences of Rac1 and RhoB activation in the DMS and DLS, respectively. Specifically, will examine the hypothesis that Rac1 activation by alcohol in the DMS promotes F-Actin formation and dendritic tree branching as well as spine maturation. We will also test the hypothesis that alcohol-dependent RhoB activation in the DLS leads to opposite outcomes e.g. dendritic tree shrinkage and increase in the number of immature spines. Aim 3 will address the behavioral consequences of Rac1 and RhoB activation in the DMS and DLS, and determine whether the small G proteins contribute to the development and/or maintenance of alcohol drinking behaviors. Finally, as the DMS and DLS are central regions in circuitries that drive goal directed and habitual behaviors, respectively, we will determine whether Rac1 and RhoB drive goal directed and habitual alcohol seeking. To achieve these goals, we plan to combine state of the art molecular/genetic tools with mouse alcohol drinking paradigms. If successful, data generated from the studies will: a. shed a light on the contribution of an important group of signaling molecules to AUD; b. will enable us to gain insights on how alcohol exposure produces structural modifications in the dorsal striatum; c. will potentially identify the molecular mechanisms underlying goal-directed and/or habitual alcohol seeking; d. as small molecules targeting Rho GTPases are being developed for other indications, the application has a clear translational trajectory.

抽象的 该建议旨在测试Rho GTPases Rac1和Rhob在背纹状体中的贡献 酒精使用障碍（AUD）的机制。 Rac1和RHOB在细胞骨架中起重要作用 重排以及树突和刺的重塑。我们最近发现过多 酒精摄入和戒断激活小鼠背纹状体（DMS）中的Rac1和Rhob，并且 背外侧纹状体（DLS）。根据已发布和初步数据，我们将检验假设 酒精分别在DMS和DLS神经元中激活Rac1和RhoB，导致细胞 改编又推动了饮酒行为的发展和/或维护 包括目标和习惯性酒精。 以下目标将探讨该假设。 AIM 1将确定沉重的机制 DMS和DLS中的酒精使用活性剂Rac1和Rhob。我们还将确定小G蛋白是否 在纹状体神经元亚群中激活。 AIM 2将确定Rac1和Rac1的细胞后果 DMS和DLS中的RHOB激活。具体而言，将研究Rac1激活的假设 DMS中的酒精促进了F-肌动蛋白的形成和树突状树枝以及脊柱成熟。我们 还将检验以下假设：DLS中酒精依赖性的RHOB激活导致相反的结果，例如 树突树的收缩并增加未成熟的刺的数量。 AIM 3将解决行为 DMS和DLS中Rac1和RHOB激活的后果，并确定小G蛋白是否是否 有助于饮酒行为的发展和/或维持。最后，作为DMS和DLS 是电路中的中央区域，分别推动目标的目标和习惯行为，我们将确定 Rac1和Rhob Drive目标是否指向和寻求习惯性酒精。为了实现这些目标，我们计划 将艺术分子/遗传工具与小鼠酒精饮用范式结合在一起。如果成功，数据 从研究产生的将：阐明了重要的信号分子的贡献 到aud; b。将使我们能够了解酒精暴露如何在背侧产生结构修饰 纹状体； c。将有可能识别目标定向和/或习惯性酒精的分子机制 寻求； d。由于针对Rho GTPases的小分子正在开发用于其他适应症 具有清晰的翻译轨迹。