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

项目摘要/摘要 我们感兴趣的是乙醇如何启动行为可塑性。酒精醉酒改变大脑，诱导 短期的生理和病理变化，包括酒精耐受性、偏好和奖赏。这些 改变是乙醇长期影响的基础，包括在面对 负面后果、烦躁不安和复发。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结合在一起，目前还不清楚 足以构建乙醇作用的预测模型。 暴饮暴食的酒精摄入量是未来发展成酒精使用障碍的最可靠的预测因素之一。 果蝇和哺乳动物一样，会变得不协调，最终会用更高剂量的乙醇来镇静。急性 暴饮暴食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。我们的目标是了解这种简单形式的乙醇诱导的可塑性 有可能，以揭示酒精在大脑中作用的基本原理。最新的知识 公差出奇地稀少，零件如何装配在一起仍是个未知数。 我们打算用果蝇来了解酒精耐受性是如何在大脑中编码的。主 这项提议的目标是确定酒精耐受性的大脑回路。第二个目标是绘制 公差回路中的可塑性位置。果蝇在实现这些目标方面处于异常有利的地位。 最近的进展使得在果蝇中识别和操作小神经元集是可重复的 比在其他模式生物中更容易和更快。此外，细胞类型特异性转录组学现在 在果蝇身上效果很好，让我们能够采样耐受神经元对酒精的反应。 果蝇转基因技术允许轻松操纵这些细胞中的基因表达，以准确地 检测基因在耐受性发育中的作用。 我们的长期目标是确定乙醇作用的机制，这些机制对人类是保守的，可能 促进酒精使用障碍的发展。

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.