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

项目 4：青少年社会孤立增加了雄性和雌性大鼠对慢性乙醇暴露的行为和神经生物学后果的脆弱性

• 批准号: 10079839
• 负责人: JEFFREY L WEINER
• 金额: $ 31.28万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10079839
• 关键词: Adolescence; Adolescent; Adult; Alcohol consumption; Amygdaloid structure; Animal Model; Anxiety Disorders; Behavior; Behavioral; Catecholamines; Chronic; Clinical; Data; Dependence; Diagnosis; Disease; Dopamine; Ethanol; Ethanol dependence; Exhibits; Extinction (Psychology); Face; Female; Female Adolescents; Fright; Individual; Intervention; Knowledge; Link; Measures; Mediating; Microinjections; Modeling; Neurobiology; Norepinephrine; Nucleus Accumbens; Pharmacology; Phenotype; Play; Population; Prognosis; Rattus; Recovery; Risk; Rodent Model; Role; Series; Sex Differences; Signal Transduction; Site; Social isolation; Testing; Time; Vulnerable Populations; Woman; alcohol comorbidity; alcohol exposure; alcohol research; alcohol risk; alcohol use disorder; anxiety-like behavior; behavioral phenotyping; clinically significant; comorbidity; depressive behavior; disorder risk; dual diagnosis; early life stress; experimental study; forest; kappa opioid receptors; male; neuroadaptation; novel; relating to nervous system; sexual dimorphism; therapy development; treatment strategy; vapor

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.

项目概要 被诊断患有焦虑症的个体患 AUD 的可能性是其他人的 2-4 倍，并且这种共病 诊断与 AUD 的伸缩进展和更差的恢复预后相关。 尽管这个问题具有临床意义，但我们仍然缺乏对神经生物学的充分了解。 导致这些疾病频繁同时发生的底物。一个主要障碍是 缺乏经过充分验证的动物模型来可靠地产生可能表明的行为特征 患这些疾病的风险增加。为此，我们重新研究了常见的啮齿动物模型 早年生活压力、青少年社会孤立（aSI）以及一系列研究已经产生了强有力的数据 支持 aSI 作为焦虑症易感性模型的表面有效性、预测有效性和构建有效性 雄性大鼠的 AUD，并使用该模型来确定中脑边缘回路的深刻适应，这可能是 有助于该模型产生的“AUD脆弱表型”，包括持久的改变 伏隔核儿茶酚胺释放动力学和增加的内在兴奋性 基底外侧杏仁核。尽管这个模型很有前景，但我们的知识仍然存在一些关键差距。首先，这个 模型尚未在雌性大鼠中得到仔细验证。我们的初步数据表明，它可能会促进 女性易受伤害的表型，但这种表型可能是两性二态性的。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，但尚不清楚 aSI 是否会增加 AUD 风险。 实际上增加了乙醇依赖啮齿动物模型的脆弱性。目标 2 将集成 aSI 和一个良好的 建立啮齿动物乙醇依赖模型（慢性间歇性乙醇蒸气，CIE）来测试 假设 aSI 增加了对 CIE 行为后果的敏感性。补充 神经生物学研究将确定 CIE 是否会加剧 aSI 和 使用药理学和化学遗传学干预措施来测试这些适应的因果作用。总的来说， 这些研究将进一步验证 aSI 作为 AUD 和焦虑症共病的脆弱性模型 雄性和雌性大鼠，可能有助于发现新的治疗策略，这些策略可能特别有效 对于患有 AUD 和焦虑症共病的个体有效。