Drosophila Model for behavioral disinhibition

描述(申请人提供)：行为去抑制，如增加冲动和攻击性，通常在醉酒的人和酗酒者中观察到。此外，特质行为去抑制与酒精成瘾和滥用有很强的相关性，这表明去抑制和酒精成瘾有重叠的遗传或神经成分。然而，证实这一概念的神经生物学基础却鲜为人知。我们发现，雄性果蝇表现出不受抑制的雄性之间的求爱，这是一种认知行为去抑制，反复乙醇处理和多巴胺神经元活动是这种现象的关键。此外，缺乏多巴胺转运体(DAT)的果蝇在酒精和社会应激的同时影响下表现出不受抑制的运动行为。这些发现是新颖的，并提供了一个独特的系统来解开乙醇诱导的去抑制的神经和细胞机制。通过利用果蝇可用的强大遗传资源，拟议的研究旨在阐明多巴胺介导乙醇诱导的去抑制的机制。为了实现这一目标，我们将阐明神经底物和特定受体介导多巴胺在认知和运动去抑制中的功能。简单的神经解剖学和遗传顺从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，乙醇的各种效应以及调节这些效应的分子具有惊人的相似性。值得注意的是，行为去抑制也在多巴胺相关的障碍中观察到，如注意力缺陷多动障碍、精神分裂症、帕金森病以及药物滥用和成瘾。这项研究中所获得的知识将促进我们对行为去抑制的理解，不仅是由酒精引起的，也是由其他成瘾物质、遗传和社会因素引起的。 公共卫生相关性：行为去抑制通常与醉酒的人和酗酒者有关；然而，其潜在的机制尚不清楚。这项拟议的研究旨在阐明酒精诱导的运动和求爱解除抑制的神经和细胞机制。

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.