Transcriptional transformation of neuronal properties by binge-like alcohol intake in Drosophila

项目概要/摘要 我们感兴趣的是乙醇如何启动行为可塑性。酒精中毒会改变大脑， 短期生理和病理变化，包括乙醇耐受性、偏好和奖赏。这些 这些改变是乙醇长期影响的基础，包括在面对 消极后果烦躁和复发乙醇的直接分子靶点，对基因的影响 转录和对神经活动模式的影响可能以复杂的方式联合收割机结合，并且还不清楚 足以构建乙醇作用的预测模型。 暴饮暴食式的酒精摄入是后来发展为酒精使用障碍的最可靠的预测因素之一。 果蝇，像哺乳动物一样，变得不协调，最终用更高剂量的乙醇镇静。急性 酒精摄入过量会导致酒精耐受性的发展，这是最简单的行为形式之一。 可塑性我们的目标是尽可能详细地了解这种简单形式的乙醇诱导的可塑性， 为了揭示乙醇在大脑中作用的基本原理。的当前知识 公差令人惊讶地稀少，部件如何装配在一起仍然是未知的。 我们建议使用果蝇来了解乙醇耐受性是如何在大脑中编码的。主要 这项提议的目的是确定乙醇耐受性的大脑回路。第二个目标是绘制 耐受回路中的可塑性位点。果蝇在实现这些目标方面处于非常有利的地位。 最近的进展使识别和操纵果蝇中的小神经元可重复 比其他模式生物更容易和更快。此外，细胞类型特异性转录组学现在 在果蝇中效果很好，这让我们能够对耐受神经元群体对酒精的反应进行取样。 果蝇转基因技术允许在这些细胞中容易地操纵基因表达， 测试基因在耐受性发展中的功能。 我们的长期目标是确定乙醇作用的机制，这些机制对人类来说是保守的， 会导致酒精使用障碍。

Project Summary/Abstract We are interested in how ethanol initiates behavioral plasticity. Ethanol inebriation alters the brain, inducing short-term physiological and pathological changes including ethanol tolerance, preference, and reward. These alterations are a foundation for ethanol’s longer-term effects including continued drinking in the face of negative consequences, dysphoria, and relapse. Ethanol’s direct molecular targets, effects on gene transcription, and effects on patterns of neural activity likely combine in complex ways, and are not understood well enough to construct predictive models of ethanol’s action. Binge-like ethanol intake is one of the most reliable predictors of later developing alcohol use disorders. Drosophila, like mammals, become incoordinated and eventually sedated with higher ethanol doses. Acute binge-like ethanol intake causes the development of ethanol tolerance, one of the simplest forms of behavioral plasticity. Our goal is to understand this simple form of ethanol-induced plasticity in as great a detail as possible, in order to uncover fundamental principles of ethanol action in the brain. Current knowledge of tolerance is surprisingly sparse, and how the parts fit together remains unknown. We propose to use Drosophila to understand how ethanol tolerance is coded in the brain. The main goal of this proposal is to determine the brain circuitry for ethanol tolerance. The second goal is to map the sites of plasticity in the tolerance circuitry. Drosophila is exceptionally well-positioned to achieve these goals. Recent advances have made identifying and manipulating small sets of neurons reproducibly in Drosophila much easier and faster than in other model organisms. Furthermore, cell-type specific transcriptomics now works well in Drosophila, allowing us to sample how groups of tolerance neurons respond to alcohol. Drosophila transgenic technology permits easy manipulation of gene expression in these cells to accurately test gene function in tolerance development. Our long term goal is to identify mechanisms of ethanol action that are conserved to humans that may contribute to the development of alcohol use disorders.