Sex specificity of corticolimbic circuit activity and anxiety-like behavior after alcohol exposure

酒精暴露后皮质边缘回路活动和焦虑样行为的性别特异性 酒精使用障碍(AUD)是一种复杂的临床症状，通常与其他精神疾病有关 像焦虑和抑郁这样的情况。尽管AUD的患病率和经历存在显著差异 在男性和女性中，很少有研究检查性别特有效应背后的神经生物学机制 酒精对大脑特定区域的影响。前额叶皮质(PRL)和中央杏仁核(CEA) 与焦虑和酒精依赖有关。我们之前的工作揭示了催乳素的性别差异 慢性酒精暴露后CEA活性和焦虑样行为。酒精有强烈的焦虑感，但 长期暴露会产生一种引起焦虑的表型，尤其是在戒断时。基础焦虑的影响 催乳素和癌胚抗原的性别特异性酒精敏感性水平以及催乳素→癌胚抗原在焦虑中的性别差异中的作用 长期饮酒后的类似行为仍不清楚，并提供了一个潜在的改善目标 对澳元的理解。临床前和新出现的临床证据表明，神经类固醇 别孕酮可能是一种通过作用于GABAA治疗AUDS的潜在治疗策略 受体介导的抑制性控制。正如我们之前的工作表明，在抑制性中，性别特异性适应 在PRL和CEA的对照中，我们还将研究别孕酮对乙醇诱导的调节失调的影响。 我们将使用集成的分子、细胞电生理和全动物成像方法来 严格检查催乳素、癌胚抗原和PR→癌胚抗原回路的性别差异以及突触中任何性别特异性的影响 慢性酒精暴露和戒断后的传导、E/I平衡和网络活动。我们还将 评估别孕酮对慢性酒精暴露后性别特异性变化的影响 AUD的潜在治疗策略。这些研究的结果将提供重要的 关于PFC和CEA回路活动的性别差异以及焦虑样行为和 揭示逆转特定回路功能障碍的药理学方法的潜在效果 在长期接触酒精之后。

Sex specificity of corticolimbic circuit activity and anxiety-like behavior after alcohol exposure Alcohol use disorder (AUD) is a complex clinical condition that is commonly associated with other psychiatric conditions like anxiety and depression. Despite significant differences in the prevalence and experience of AUD in men and women, few studies have examined the neurobiological mechanisms underlying sex-specific effects of alcohol on specific brain regions. The prelimbic prefrontal cortex (PrL) and central amygdala (CeA) have been implicated in both anxiety and alcohol dependence. Our previous work revealed sex-specific differences in PrL and CeA activity and anxiety-like behavior following chronic ethanol exposure. Alcohol is acutely anxiolytic, but prolonged exposure produces an anxiogenic phenotype, particularly in withdrawal. The impact of basal anxiety levels in sex-specific alcohol sensitivity in PrL and CeA and the role of PrL→CeA in sex differences in anxiety- like behavior following chronic alcohol exposure remains unknown and offers a potential target for improved understanding of AUD. Preclinical and emerging clinical evidence indicate that the neurosteroid allopregnanolone may be a potential therapeutic strategy for the treatment of AUDs via actions on GABAA receptor-mediated inhibitory control. As our previous work demonstrated sex-specific adaptations in inhibitory control in PrL and CeA, we will also investigate the impact of allopregnanolone on ethanol-induced dysregulation. We will employ an integrated molecular, cellular electrophysiological, and whole-animal imaging approach to rigorously examine sex differences in PrL, CeA, and Pr→CeA circuitry and any sex-specific effects in synaptic transmission, E/I balance, and network activity following chronic ethanol exposure and withdrawal. We will also assess the impact of allopregnanolone on any sex-specific changes following chronic ethanol exposure as a potential therapeutic strategy for the treatment of AUD. The results of these studies will provide important information on sex differences in the activity of PFC and CeA circuits and anxiety-like behavior and uncover the potential effects of a pharmacological approach to reverse specific circuit dysfunction following chronic ethanol exposure.