Project 4: Adolescent Social Isolation Increases Vulnerability to the Behavioral and Neurobiological Consequences of Chronic Ethanol Exposure in Male and Female Rats

项目总结 被诊断为焦虑症的人患AUD的可能性是后者的2-4倍 诊断与AUD的重叠进展和预后差得多的恢复有关。 尽管这一问题具有临床意义，但我们对其神经生物学仍缺乏充分的了解。 导致这些疾病频繁并存的底物。一个主要的障碍是 缺乏经过充分验证的动物模型，无法可靠地产生可能表明 罹患这些疾病的风险增加。为此，我们重新研究了一种常见的啮齿动物模型 早期生活压力、青少年社交隔离(ASI)和一系列研究都产生了强有力的数据 支持ASI作为焦虑症易感性模型的面孔、预测性和构造性的有效性 并利用这一模型确定了中脑边缘回路的深刻适应，这种适应可能 导致这种模式所产生的“澳元脆弱表型”，包括在 伏核内儿茶酚胺释放动力学及内源性兴奋性增加 杏仁基底外侧核。尽管这一模式前景看好，但我们的知识中仍然存在几个关键差距。首先，这是 该模型尚未在雌性大鼠身上仔细验证。我们的初步数据表明，它可能会促进 这种表型在女性中是脆弱的，但这种表型可能是性二型的。目标1中的实验将 因此，进行行为和神经生物学研究，以进一步验证ASI模型在 女性。其次，尽管ASI改变了许多与AUD风险增加相关的行为，但目前尚不清楚ASI是否 实际上增加了酒精依赖啮齿动物模型的脆弱性。AIM 2将整合ASI和一口井- 建立酒精依赖(慢性间歇性乙醇蒸气，CIE)啮齿动物模型 假设ASI增加了对CIE行为后果的敏感性。互补性 神经生物学研究将确定CIE是否会加剧ASI和 使用药理学和化学发生干预措施测试这些适应的因果作用。总而言之， 这些研究将进一步验证ASI作为易患AUD和焦虑症的模型 并可能有助于发现新的治疗策略，这些策略可能特别 对患有AUD和焦虑症的患者有效。

PROJECT SUMMARY Individuals diagnosed with anxiety disorders are 2-4 times more likely to develop AUD and this comorbid diagnosis is associated with a telescoped progression of AUD and a much worse prognosis in recovery. Despite the clinical significance of this problem, we still lack a full understanding of the neurobiological substrates responsible for the frequent co-occurrence of these disorders. One major obstacle has been the lack of well-validated animal models that reliably engender a behavioral profile that may be indicative of a heightened risk of developing these diseases. To that end, we have re-examined a common rodent model of early-life stress, adolescent social isolation (aSI) and in a series of studies, have generated strong data supporting the face, predictive and construct validity of aSI as a model of vulnerability to anxiety disorders and AUD in male rats, and have used this model to identified profound adaptations in mesolimbic circuits that may contribute to the “AUD vulnerable phenotype” engendered by this model, including enduring alterations in catecholamine release dynamics in the nucleus accumbens and increased intrinsic excitability in the basolateral amygdala. Despite the promise of this model, several key gaps in our knowledge remain. First, this model has not been carefully validated in female rats. Our preliminary data suggest that it may promote a vulnerable phenotype in females but that this phenotype may be sexually dimorphic. Experiments in Aim 1 will therefore conduct behavioral and neurobiological studies to further validate the utility of the aSI model in females. Second, although aSI alters many behaviors linked with increased risk of AUD, it is not known if aSI actually increases vulnerability in a rodent model of ethanol dependence. Aim 2 will integrate aSI and a well- established rodent model of ethanol dependence (chronic intermittent ethanol vapor, CIE) to test the hypothesis that aSI increases sensitivity to the behavioral consequences of CIE. Complementary neurobiological studies will determine if CIE exacerbates neurobiological adaptations engendered by aSI and test the causal role of these adaptations using pharmacological and chemogenetic interventions. Collectively, these studies will further validate aSI as a model of vulnerability to comorbid AUD and anxiety disorders in male and female rats and may facilitate the discovery of novel treatment strategies that may be particularly effective for individuals suffering from comorbid AUD and anxiety disorders.