Small G proteins and alcohol use disorder

摘要 该提议旨在测试背侧纹状体中Rho GTP酶Rac 1和RhoB对 酒精使用障碍（AUD）的潜在机制。Rac 1和RhoB在细胞骨架中起重要作用 重排以及树突和棘的重塑。我们最近发现， 酒精摄入和戒断激活小鼠背内侧纹状体（DMS）中的Rac 1和RhoB， 背外侧纹状体（DLS）。根据已发表的和初步的数据，我们将检验这一假设 酒精分别激活DMS和DLS神经元中的Rac 1和RhoB，导致细胞凋亡。 这些适应反过来又驱动了饮酒行为的发展和/或维持 包括目标导向和习惯性酒精寻求。 这一假设将通过以下目的进行探讨。目标1将决定重金属的 酒精在DMS和DLS中使用活性物质Rac 1和RhoB。我们还将确定小G蛋白是否 在纹状体神经元的亚群中被激活。目标2将确定Rac 1和Rac 2的细胞后果。 分别在DMS和DLS中的RhoB活化。具体来说，将检查Rac 1激活的假设， 通过DMS中的酒精促进F-肌动蛋白形成和树突树分支以及棘成熟。我们 还将检验DLS中酒精依赖性RhoB激活导致相反结果的假设，例如， 树突树收缩和未成熟刺的数量增加。目标3将解决行为 在DMS和DLS中Rac 1和RhoB激活的后果，并确定小G蛋白是否 有助于发展和/或维持饮酒行为。最后，作为DMS和DLS， 是分别驱动目标导向行为和习惯行为的电路的中心区域，我们将确定 Rac 1和RhoB是否驱动目标导向和习惯性酒精寻求。为了实现这些目标，我们计划 联合收割机最先进的分子/遗传工具与小鼠饮酒范例。如果成功，数据 从研究中产生的将：a.揭示了一组重要的信号分子 至AUD; B.将使我们能够深入了解酒精暴露如何在背部产生结构性改变， 纹状体; c.将有可能确定目标导向和/或习惯性酒精的分子机制 寻找; d.由于靶向Rho GTP酶的小分子正被开发用于其它适应症， 有一个清晰的平移轨迹

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.