Mechanisms of alcohol-induced plasticitey mediated by Arf6

酒精滥用障碍(AUD)是一种主要的健康危害，每年在美国影响数百万人 美国。反复饮酒可能会导致耐受性、偏好和消费量的增加。是这样的 行为变化和伴随的神经元可塑性是成瘾的基础，但许多分子 管理这些变化的机制仍有待阐明。胰岛素受体(INR)介导的信号转导 众所周知，神经元可以改变可塑性，但它对酒精诱导的行为反应的影响尚不清楚。 我们的目标是了解依赖Arf6的神经系统INR的细胞、神经和电路机制 酒精诱导的可塑性中的信号。这是基于我们发表的数据，即Arf6在INR信号转导中起中介作用 体内和在细胞培养中。首先，我们将确定Arf6介导的INR信号转导机制和 内吞作用。我们将系统、全面地测试已知的两个基因家族的作用。 调节Arf6的功能。其次，我们将确定特定影响酒精诱导的神经回路 耐受性和消费偏好，以及对酒精的天真厌恶反应。我们将测试这个角色 这些回路中Arf6调节剂在酒精诱导的行为反应中的作用。第三，我们将在体内确定 INR通路的信号如何影响不同的酒精诱导的行为变化的机制： 容忍度和消费偏好。我们建议研究的基因都是保守的 果蝇对人类的影响，这项拟议的研究将促进我们对果蝇 酒精引起的行为变化的调控机制。这又将导致标识新的 酒精滥用障碍治疗的危险因素和治疗靶点。

Alcohol abuse disorders (AUD) are a major health hazard that affects millions of people every year in the United States. Repeat alcohol exposure can lead to tolerance, increased preference and consumption. Such behavioral changes, and the accompanying neuronal plasticity, underlie addiction, yet many molecular mechanisms governing these changes remain to be elucidated. Signaling through the insulin receptor (InR) in neurons is known to modify plasticity, but its effects on alcohol-induced behavioral responses are not known. Our goal is to understand the cellular, neural, and circuit mechanisms of Arf6-dependent nervous system InR signaling in alcohol-induced plasticity. This is based on our published data that Arf6 mediates InR signaling in vivo and in cell culture. First, we will determine the mechanisms of Arf6-mediated InR signaling and endocytosis. We will systematically, and comprehensively test the role of two gene families known to directly regulate the function of Arf6. Second, we will determine neural circuits that specifically affect ethanol-induced tolerance and consumption preference, as well as the naïve aversive reactions to alcohol. We will test the role of Arf6 regulators in these circuits in alcohol-induced behavioral responses. Third, we will determine in vivo mechanisms how signaling from the InR pathway can affect distinct alcohol-induced behavioral changes: tolerance, and consumption preference. The genes we propose to investigate are all conserved from Drosophila to humans, and the proposed research will advance our molecular understanding of the mechanisms regulating alcohol-induced behavioral changes. This in turn, will result in the identification of new risk factors and therapeutic targets for the treatment of alcohol abuse disorders.