Main Research Component 1: Prenatal alcohol exposure: sex differences in effects on adolescent ethanol drinking, anxiety and associated neural circuitry

项目总结/摘要 主要研究构成部分1 孕妇饮酒仍然是一个惊人的普遍现象，尽管众所周知的 对受影响儿童的健康可能造成的后果。这是真的，即使酒精消费是 适度，导致一些人得出结论，怀孕期间没有安全的饮酒水平。一 即使是低到中等水平的产前酒精暴露（PAE）的最可重复的后果是 后代对乙醇的偏好和消费增加，这种现象在人类和动物身上都有发现。 模型临床前研究的最新证据发现了性别偏见效应的一致证据， 雄性后代表现出比雌性更大的PAE诱导的乙醇消耗和偏好增加。 甚至当PAE发生在性腺分化之前（在妊娠第12天之前， 啮齿动物），这表明非性腺性别偏置因素必须负责。该项目测试了 假设男性和女性之间的遗传差异（性染色体互补和相关的 X与Y染色体基因表达剂量的差异）中度PAE效应。这一假设将 使用四核心基因型小鼠进行测试，其中性染色体之间的正常关系 补体和性腺性别已经被打破;四个核心基因型因此包括XX女性，XY女性， XY雄性和XX雄性。我们将使用这个模型来系统地检验XY基因型， 不考虑性腺和性腺源性类固醇，与PAE诱导的升高相关 青少年酒精摄入量和焦虑样行为的增加，这些行为影响反映了 通过减少中膜含α-1的GABAA受体功能干扰抑制性突触信号传导 杏仁核的中央核进一步的研究将检验以下假设： kdm 6a-一个X染色体逃逸-有助于XX和XY个体对以下疾病的不同反应： PAE。总的来说，这些研究将确定妊娠期性别偏见反应的潜在机制， 酒精暴露，并可能揭示分子途径和神经回路，赋予这种易感性 对大脑和行为有广泛影响的常见环境侮辱。

PROJECT SUMMARY/ABSTRACT MAIN RESEARCH COMPONENT 1 Alcohol consumption by pregnant women remains a startlingly common occurrence, despite the well-known potential consequences for the health of exposed children. This is true even when alcohol consumption is moderate, leading some to conclude that there is no safe level of alcohol consumption during pregnancy. One of the most reproducible consequences of even low to moderate levels of prenatal alcohol exposure (PAE) is a heightened ethanol preference and consumption in offspring, a phenomenon found in both humans and animal models. Recent evidence from preclinical research has found consistent evidence of a sex-biased effect, with male offspring showing a greater PAE-induced increase in ethanol consumption and preference than females. This effect is observed even when PAE occurs prior to gonadal differentiation (before gestational day 12 in rodents), suggesting that a non-gonadal sex-biasing factor must be responsible. This project tests the hypothesis that genetic differences between males and females (sex chromosome complement and associated differences in expression dosage of X vs. Y chromosome genes) moderate PAE effects. This hypothesis will be tested using Four-Core genotype mice, in which the normal relationship between sex chromosome complement and gonadal sex has been broken; the four core genotypes thus include XX females, XY females, XY males and XX males. We will use this model to systematically test the prediction that XY genotype, irrespective of gonads and gonadally-derived steroids, is associated with heightened PAE-induced escalation of adolescent ethanol intake and heightened anxiety-like behaviors, and that these behavioral effects reflect disturbed inhibitory synaptic signaling via reduced alpha-1-containing GABAA receptor function in the medial central nucleus of the amygdala. Additional studies will test the hypothesis that differential expression of kdm6a - an X chromosome escapee – contributes to the differential responses of XX and XY individuals to PAE. Collectively, these studies will define the mechanisms underlying the sex-biased response to gestational alcohol exposure and may reveal molecular pathways and neural circuits that confer susceptibility to this common environmental insult with pervasive effects on brain and behavior.