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: 10310704
• 负责人: JEFFREY L WEINER
• 金额: $ 31.56万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-10 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310704
• 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; Persons; 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.

项目摘要 诊断出患有焦虑症的人发展AUD的可能性高2-4倍，并且这种合并症 诊断与AUD的望远镜进展和恢复进展差得多。 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全面了解 负责这些疾病的经常同时出现的底物。一个主要障碍是 缺乏验证的动物模型，这些模型可靠地产生一种行为特征，这可能表明 增加了患这些疾病的风险。为此，我们重新检查了一个常见的啮齿动物模型 早期的压力，青少年的社会隔离（ASI）和一系列研究产生了强大的数据 支持面部，预测性和构建ASI的有效性，作为焦虑症脆弱性的模型， 在雄性大鼠中的aud，并使用该模型来识别可能的中边缘圆圈的深刻适应 有助于该模型产生的“ AUD脆弱表型”，包括持久的改变 伏隔核中的儿茶酚胺释放动力学，并增加了固有的激动 副杏仁核。尽管有这种模型的承诺，但我们的知识仍然存在一些关键差距。首先，这个 在雌性大鼠中尚未仔细验证模型。我们的初步数据表明，它可能会促进 女性脆弱的表型，但这种表型可能是性二态的。 AIM 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模型的实用性 女性。其次，尽管ASI改变了许多行为与AUD风险增加有关，但尚不清楚ASI是否存在 实际上增加了乙醇依赖性啮齿动物模型中的脆弱性。 AIM 2将整合ASI和一个很好的 建立的乙醇依赖性啮齿动物模型（慢性间歇性乙醇蒸气，CIE）测试 假设ASI会增加对CIE行为后果的敏感性。补充 神经生物学研究将确定CIE是否加剧了ASI和ASI和 使用药物和化学遗传干预措施测试这些适应的因果作用。共同 这些研究将进一步验证ASI作为合并AUD和焦虑症的脆弱性模型 雄性和雌性大鼠，可能会促进发现新型治疗策略的发现 对患有合并AUD和焦虑症的人有效。