Research Supplement to Promote Diversity in Health-Related Research

描述（由申请人提供）：行为抑制解除，如冲动和攻击性增加，通常在醉酒和酗酒者中观察到。此外，特质行为去抑制与酒精成瘾和滥用密切相关，表明去抑制和酒精成瘾具有重叠的遗传或神经成分。然而，证实这一观点的神经生物学基础却知之甚少。我们发现雄性果蝇表现出雄性间求爱的去抑制，这是一种认知行为的去抑制，反复出现的乙醇处理和多巴胺神经元活动对这一现象至关重要。此外，缺乏多巴胺转运体（DAT）的果蝇在乙醇和社会压力的同时影响下表现出去抑制的运动行为。这些发现是新颖的，并提供了一个独特的系统来揭示乙醇诱导的去抑制的神经和细胞机制。通过利用果蝇中强大的遗传资源，本研究旨在阐明多巴胺介导乙醇诱导的去抑制机制。为了实现这一目标，我们将阐明多巴胺在认知和运动去抑制中的作用的神经底物和特异性受体。神经解剖学上简单、基因上易于适应的果蝇为这项任务提供了巨大的优势。大量研究表明，在果蝇和哺乳动物中，各种乙醇效应和介导这些效应的分子有着惊人的相似性。值得注意的是，在多巴胺相关疾病如注意缺陷多动障碍、精神分裂症、帕金森病和药物滥用和成瘾中也观察到行为去抑制。在拟议的研究中获得的知识将促进我们对乙醇以及其他成瘾物质，遗传和社会因素诱导的行为解除抑制的理解。

DESCRIPTION (provided by applicant): Behavioral disinhibition such as increased impulsivity and aggression is typically observed in inebriated humans and alcoholics. Moreover, trait behavioral disinhibition strong correlates with alcohol addiction and abuse, suggesting that disinhibition and alcohol addiction have overlapping genetic or neural components. However, the neurobiological basis corroborating this notion is poorly understood. We found that Drosophila males exhibit disinhibited inter-male courtship, a type of cognitive behavioral disinhibition, with recurring ethanol treatment and dopamine neuronal activity is crucial for this phenomenon. Furthermore, the flies lacking dopamine transporter (DAT) display disinhibited motor behavior under the simultaneous influence of ethanol and social stress. These findings are novel and provide a unique system to unravel the neural and cellular mechanisms underlying ethanol-induced disinhibition. By employing powerful genetic resources available in Drosophila, the proposed research is directed at elucidating the mechanisms by which dopamine mediates ethanol-induced disinhibition. To achieve the goal, we will clarify the neural substrates and specific receptors mediating dopamine's functions in cognitive and motor disinhibition. The neuroanatomically simple and genetically amenable Drosophila offers tremendous advantages for this task. Numerous studies reveal striking similarities of various ethanol effects and the molecules mediating those effects in Drosophila and mammals. Notably, behavioral disinhibition is also observed in dopamine-related disorders such as attention deficit hyperactivity disorder, schizophrenia, Parkinson's disease, and substance abuse and addiction. Knowledge obtained in the proposed research will advance our understanding of behavioral disinhibition induced not only by ethanol but also by other addictive substances, genetic and social factors. PUBLIC HEALTH RELEVANCE: Behavioral disinhibition is typically associated with inebriated humans and alcoholics; however, its underlying mechanism is poorly understood. The proposed research is aimed at elucidating the neural and cellular mechanisms underlying ethanol-induced motor and courtship disinhibition.