A novel neuronal signaling pathway for ethanol behavioral responses in Drosophila

标题：果蝇酒精行为反应的一种新的神经元信号通路。 项目摘要 导致成瘾时不恰当行为的神经变化部分是由于转录因子依赖 决定大脑形式和功能的基因表达的变化。了解药物是如何 乙醇影响转录因子活性，发现受特定转录因子调控的基因将 提高我们对药物作用的理解，为潜在的治疗提供新的方法。 果蝇是识别乙醇分子和作用机制的有用模型。苍蝇 表现出模拟成瘾特征的行为，包括对酒精的敏感性、耐受性、偏好和 奖励。基因的保护和复杂的遗传学促进了快速发现的步伐。临床前 翻译研究帮助将苍蝇的基本发现与高等生物的成瘾模型联系起来。 核受体家族的转录因子是乙醇的候选靶标。我们只关注一件事 该家族的成员，NR4a1及其果蝇同系物Hr38，属于受表达调控的一类 水平，而不是配体结合。在啮齿动物中，NR4a1在急性酒精暴露后增加，并在长时间内 禁欲。在果蝇中，我们发现Hr38在以下特定脑区的表达类似地增加 急性酒精暴露。重要的是，我们提供了Hr38基因突变导致乙醇改变的证据。 行为，涉及Hr38，很可能是它在乙醇作用中调节的基因。 我们的目标是确定乙醇用来增加Hr38表达和 确定干扰通路组件的后果。公布的证据表明有两个Hr38 信号通路，包括与乙醇作用有关的分子。其中一些分子是 也被认为对社会环境的影响很重要，而社会环境反过来又可以对 人体和动物模型中的酒精摄入量。拟议研究的预期结果将是 乙醇参与的一种新的信号通路的功能描述。在未来的研究中，我们计划确定 改变神经功能的效应器通路。

Title: A novel neuronal signaling pathway for ethanol behavioral responses in Drosophila. Project Summary Neural changes that drive inappropriate behavior in addiction are due in part to transcription factor-dependent changes in expression of genes that set the form and function of the brain. Knowledge of how drugs like ethanol affect transcription factor activity and discovery of genes regulated by specific transcription factors will improve our understanding of drug action and provide new approaches to potential treatments. Drosophila is a useful model for identifying the molecules and mechanisms of action for ethanol. Flies exhibit behaviors that model features of addiction including ethanol sensitivity, tolerance, preference, and reward. Conservation of genes and sophisticated genetics facilitate a rapid pace of discovery. Preclinical translational studies have helped bridge basic findings in flies with models of addiction in higher organisms. Transcription factors of the nuclear receptor family are candidate targets for ethanol. We focus on one member of this family, NR4a1 and its fly homolog Hr38, that belongs to a class that is regulated by expression level, not ligand binding. In rodents NR4a1 is increased following acute ethanol exposure and in protracted abstinence. In flies we showed that Hr38 expression is similarly increased in specific brain regions following acute ethanol exposure. Importantly, we provide evidence that mutation of Hr38 results in altered ethanol behaviors, implicating Hr38 and likely the genes that it regulates in the actions of ethanol. Our goal is to define the signaling pathway that ethanol uses to increase Hr38 expression and determine the consequences of perturbing pathway components. Published evidence points to two Hr38 signaling pathways that include molecules implicated in the actions of ethanol. Some of these molecules are also thought to be important for the effects of social environment, which in turn can have profound effects on alcohol consumption in humans and animal models. The expected outcome of the proposed studies will be a functional description of a novel signaling pathway engaged by ethanol. In future studies we plan to identify effector pathways that alter neuronal function.