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

基本信息

项目摘要

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 被诊断患有焦虑症的人患AUD的可能性是其他人的2-4倍, 诊断与AUD的缩短进展和更差的恢复预后相关。 尽管这个问题的临床意义,我们仍然缺乏对神经生物学的充分了解, 底物负责这些疾病的频繁共同发生。一个主要障碍是 缺乏经过充分验证的动物模型,该模型可靠地产生可以指示 增加了患上这些疾病的风险。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,青少年社会孤立(aSI)和一系列研究,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面部、预测和结构效度, AUD,并使用该模型确定了中脑边缘回路的深刻适应, 有助于由该模型产生的“AUD脆弱表型”,包括 在丘脑核中的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一模式有希望,但我们的知识中仍存在几个关键空白。首先 模型尚未在雌性大鼠中仔细验证。我们的初步数据表明, 易受害的表型,但这种表型可能是性二态性。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 实际上增加了酒精依赖啮齿动物模型的脆弱性。目标2将整合aSI和良好- 建立了乙醇依赖性啮齿动物模型(慢性间歇性乙醇蒸汽,CIE),以测试 假设aSI增加了对CIE行为后果的敏感性。互补 神经生物学研究将确定CIE是否加剧aSI引起的神经生物学适应, 使用药理学和化学遗传学干预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和焦虑障碍共病易感性的模型, 这可能有助于发现新的治疗策略, 对患有AUD和焦虑症的患者有效。

项目成果

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JEFFREY L WEINER其他文献

JEFFREY L WEINER的其他文献

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{{ truncateString('JEFFREY L WEINER', 18)}}的其他基金

Administrative Core
行政核心
  • 批准号:
    10526641
  • 财政年份:
    2017
  • 资助金额:
    $ 31.56万
  • 项目类别:
Project 4: Convergent behavioral and neurobiological adaptations promoted by rodent models of vulnerability to alcohol use disorder and post-traumatic stress disorder
项目 4:易患酒精使用障碍和创伤后应激障碍的啮齿动物模型促进趋同的行为和神经生物学适应
  • 批准号:
    10526646
  • 财政年份:
    2017
  • 资助金额:
    $ 31.56万
  • 项目类别:
Wake Forest Translational Alcohol Research Center (WF-TARC)
维克森林转化酒精研究中心 (WF-TARC)
  • 批准号:
    10526640
  • 财政年份:
    2017
  • 资助金额:
    $ 31.56万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10310698
  • 财政年份:
    2017
  • 资助金额:
    $ 31.56万
  • 项目类别:
Neural Substrates of Comorbid Alcohol Use Disorder and Post-Traumatic Stress Disorder
共病酒精使用障碍和创伤后应激障碍的神经基质
  • 批准号:
    10188342
  • 财政年份:
    2017
  • 资助金额:
    $ 31.56万
  • 项目类别:
Wake Forest Translational Alcohol Research Center (WF-TARC)
维克森林转化酒精研究中心 (WF-TARC)
  • 批准号:
    10310693
  • 财政年份:
    2017
  • 资助金额:
    $ 31.56万
  • 项目类别:
Wake Forest Translational Alcohol Research Center (WF-TARC)
维克森林转化酒精研究中心 (WF-TARC)
  • 批准号:
    10079833
  • 财政年份:
    2017
  • 资助金额:
    $ 31.56万
  • 项目类别:
Neural Substrates of Comorbid Alcohol Use Disorder and Post-Traumatic Stress Disorder
共病酒精使用障碍和创伤后应激障碍的神经基质
  • 批准号:
    9486289
  • 财政年份:
    2017
  • 资助金额:
    $ 31.56万
  • 项目类别:
2016 and 2018 Alcohol and the Nervous System GRC
2016 和 2018 酒精与神经系统 GRC
  • 批准号:
    9171365
  • 财政年份:
    2015
  • 资助金额:
    $ 31.56万
  • 项目类别:
Translational Studies on Early-life Stress and Vulnerability to Alcohol Addiction
早期生活压力和酒精成瘾脆弱性的转化研究
  • 批准号:
    8730268
  • 财政年份:
    2012
  • 资助金额:
    $ 31.56万
  • 项目类别:

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