Alcohol-induced alterations in orbitofrontal cortex serotonin signaling

项目摘要 在美国，过度饮酒是导致死亡和经济负担的主要原因。的 在过量摄入的模式中，酗酒是最常见的，约占 可归因于酒精的死亡除了高死亡率，反复酗酒和酗酒的循环 戒断会导致大脑区域的持续适应，从而增加精神症状和 随后过度饮酒。这使个人患上酒精的风险更大。 依赖。这些结果可能是由5-羟色胺(5-羟色胺，5-羟色胺)调节失调所致。 起源于中缝背核(DR)的系统。尽管5-羟色胺的参与已得到很好的证实 在酒精使用障碍中，我们缺乏对神经回路和精确信号的透彻了解 这种监管失调背后的机制。在这项建议中，我将研究5-HT电路中的适应 从DR到眼眶前额叶皮质(OFC)，这是反复暴饮式饮酒的结果。我 将使用一系列融合和高度创新的体外和体内技术来实现这一点 请允许我测量酗酒引起的DR和DR中5-HT释放和信号动力学的变化 OFC。此外，我将探讨5-羟色胺信号在DR-OFC回路中促进过度 酒精摄入量。除了为我提供先进的技术培训和专业发展 这项提案将提供有关酗酒行为的基本信息。 关于5-羟色胺的神经回路和信号。最终，该提案将确定基于电路的信令 可用于酒精使用障碍的靶向治疗的机制。 好了！

Project Summary Excessive alcohol consumption is a leading cause of mortality and economic burden in the United States. Of the patterns of excessive intake, binge drinking is the most common and accounts for approximately half of the deaths attributable to alcohol. In addition to high rates of mortality, repeated cycles of binge alcohol intake and withdrawal cause persistent adaptations in brain regions that increase the risk of psychiatric symptoms and subsequent excessive alcohol consumption. This places individuals at greater risk for developing alcohol dependence. These outcomes may be driven by dysregulation in serotonin (5-hydroxytryptamine, 5-HT) systems originating in the dorsal raphe nucleus (DR). Although involvement of 5-HT has been well established in alcohol use disorder, we lack a thorough understanding of the neural circuits and precise signaling mechanisms that underlie this dysregulation. In this proposal, I will examine the adaptations in a 5-HT circuit from the DR to the orbitofrontal cortex (OFC) that result from repeated episodes of binge-like alcohol intake. I will accomplish this using a series of converging and highly innovative ex vivo and in vivo techniques that will allow me to measure binge alcohol-induced changes in 5-HT release and signaling dynamics in the DR and the OFC. Further, I will probe the causal role of 5-HT signaling in the DR-OFC circuit in promoting excessive alcohol intake. In addition to providing me with advanced technical training and professional development activities, this proposal will provide essential information concerning the actions of binge-like alcohol drinking on 5-HT neural circuitry and signaling. Ultimately, this proposal will identify a circuit-based signaling mechanism that can be used for the targeted treatment of alcohol use disorder. !