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 过量摄入的模式，酗酒是最常见的，约占一半的 酒精导致的死亡。除了高死亡率外，反复的酗酒和 戒断会导致大脑区域的持续适应，增加精神症状的风险， 随后过度饮酒。这使个人处于更大的风险发展酒精 依赖这些结果可能是由血清素（5-羟色胺，5-HT）调节异常引起的 起源于中缝背核（DR）的系统。虽然5-HT的参与已经得到了很好的证实， 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理解， 这是导致这种失调的机制。在这个建议中，我将研究5-HT电路中的适应性 从DR到眶额皮质（OFC），这是由反复发作的酗酒引起的。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目标， 让我来测量酗酒引起的5-HT释放和DR信号动力学的变化， OFC。此外，我将探讨DR-OFC回路中5-HT信号在促进过度的 酒精摄入量除了为我提供先进的技术培训和专业发展 活动，这一建议将提供有关行动的基本信息，狂欢般的饮酒 5-羟色胺神经回路和信号最终，该提案将确定基于电路的信令 该机制可用于酒精使用障碍的靶向治疗。 !

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. !