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

项目摘要/摘要 主要研究内容1 孕妇饮酒仍然是一种令人震惊的常见事件，尽管众所周知 对受影响儿童的健康可能造成的后果。即使在饮酒量为 适度，导致一些人得出结论，怀孕期间饮酒没有安全水平。一 即使是低到中等水平的产前酒精暴露(PAE)最容易重现的后果之一是 后代对乙醇的偏好和消费增加，这是一种在人类和动物中都发现的现象 模特们。最近来自临床前研究的证据发现，性别偏见的影响是一致的， 雄性后代比雌性后代表现出更大的酒精消耗和偏好增加。 即使当PAE发生在性腺分化之前(在妊娠第12天之前)，也能观察到这种影响 啮齿动物)，这表明一定是非性腺性别偏见因素造成的。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 X和Y染色体基因表达剂量的差异)温和的PAE效应。这一假说将 用四核基因小鼠进行检测，其中性染色体的正常关系 补体和性腺的性别已经被打破；因此，四个核心基因型包括XX女性，XY女性， XY男性和XX男性。我们将利用这个模型来系统地检验XY基因， 与性腺和性腺衍生的类固醇无关，与PAE诱导的升高有关 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 内侧核内含α-1-GABAA受体功能降低所致的抑制性突触信号转导紊乱 杏仁核中央核。其他研究将检验这一假设，即差异表达 Kdm6a--一种X染色体逃逸基因--有助于XX和XY个体对 派。总而言之，这些研究将确定对妊娠的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电路，使其易感性 常见的环境侮辱，对大脑和行为都有普遍影响。

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.