Alcohol-induced alterations in orbitofrontal cortex serotonin signaling

酒精引起的眶额皮质血清素信号改变

• 批准号: 10580093
• 负责人: Melanie M Pina
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-03 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580093
• 关键词: Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Anxiety; Automobile Driving; Award; Biosensor; Brain region; Cells; Chronic; Complement; Coupled; Darkness; Dependence; Development; Disease; Economic Burden; Electrochemistry; Electrophysiology (science); Fiber; Functional disorder; Future; Health; Heavy Drinking; Heterogeneity; In Situ Hybridization; Individual; Intake; Learning; Measures; Mental Depression; Methods; Molecular Profiling; Mus; Neurons; Organizational Models; Outcome; Pattern; Periodicity; Photometry; Procedures; Public Health; Receptor Signaling; Research; Research Personnel; Risk; Role; Scanning; Series; Serotonergic System; Serotonin; Serotonin Receptor 5-HT2A; Signal Transduction; Site; Synaptic Transmission; System; Techniques; Testing; Training; United States; Viral; Viral Vector; Work; alcohol behavior; alcohol exposure; alcohol use disorder; alcohol-related death; attributable mortality; binge drinking; biophysical analysis; designer receptors exclusively activated by designer drugs; dorsal raphe nucleus; drinking; experience; experimental study; genetic approach; hippocampal pyramidal neuron; in vivo; innovation; insight; mortality; neural circuit; neuroadaptation; neurotransmission; optogenetics; programs; psychiatric symptom; serotonin receptor; skills; targeted treatment; therapeutically effective; treatment strategy; uptake

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. !

项目概要 过量饮酒是美国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，大约占一半。 因酒精导致的死亡。除了高死亡率之外，反复的酗酒和酗酒也导致了死亡。 戒断会导致大脑区域持续适应，从而增加出现精神症状的风险 随后过量饮酒。这使个人面临更大的酗酒风险 依赖性。这些结果可能是由血清素（5-羟色胺，5-HT）失调引起的 系统起源于中缝背核（DR）。尽管 5-HT 的参与已得到充分证实 在酒精使用障碍中，我们缺乏对神经回路和精确信号传导的透彻了解 这种失调的机制。在本提案中，我将研究 5-HT 电路中的适应性 从 DR 到眶额皮质 (OFC)，这是由于反复酗酒造成的。我 将使用一系列融合且高度创新的离体和体内技术来实现这一目标 让我测量酗酒引起的 5-HT 释放变化以及 DR 和信号动态 OFC。此外，我将探讨 DR-OFC 电路中 5-HT 信号传导在促进过度行为中的因果作用。 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，该提案将提供有关酗酒行为的基本信息 5-HT 神经回路和信号传导。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。 ！