Prenatal Alcohol and Anxiety: An Ontogenetic Role for CRF

摘要 怀孕期间饮酒和酗酒的比例高得惊人，这可能导致一系列 子代的缺陷被称为胎儿酒精谱系障碍。最常见的后果之一是 产前酒精暴露(PAE)是指焦虑障碍的出现，明显发生在儿童时期和 坚持到成年。与焦虑高度一致且高度相关的是#年酗酒盛行 患有PAE的个体。重要的是，即使在暴露于中等水平之后，这些观察也是显而易见的。 酒精--怀孕期间饮酒的一种常见模式。尽管有令人信服的流行病学数据， 中度PAE诱发焦虑的神经生物学机制还不是很清楚。这个 促肾上腺皮质激素释放因子(CRF)通过其同源受体CRF1R的作用与酒精有关 暴露诱导的成年男性焦虑和酒精偏好，它们的表达被PAE改变 焦虑相关的大脑结构。然而，CRF1R功能的发育时程及其如何 PAE在个体发育过程中是否改变功能尚不清楚。我们最近描述了一种温和的模式 在妊娠12天(G)使用单次暴露于蒸发乙醇的PAE，这是 杏仁核开始出现，导致青春期男性焦虑样行为增加 并影响成年男性的情绪处理，而对女性没有明显的影响。在此基础上， 我们假设G12 PAE通过个体发育降低CRF1R功能，从而导致双相 焦虑表型和导致急性酒精和CRF1R相互作用的改变。为了检验我们的假设， 目标1将确定中央杏仁核内CRF1R功能的发育时间进程及其 与焦虑样行为的关系。目标2将检查适度的G12 PAE对CRF1R改变的影响 杏仁中央核在发育期间和成年期的功能，因为它有助于PAE诱导 焦虑样行为的改变。最后，目标3将测试适度的G12 PAE对急性乙醇的影响。 中央杏仁核内CRF1R的相互作用以及CRF1R如何促进个体发育中的乙醇摄入。 这些创新的研究将测试围绕适度的长期影响的新颖和独特的假设。 PAE和描述焦虑样行为缺陷的特定神经机制及其与 酒精摄入量以特定年龄和性别的方式增加。

Abstract Alcohol drinking and alcohol abuse during pregnancy is surprisingly high which can lead to a spectrum of deficits in offspring termed Fetal Alcohol Spectrum Disorders. One of the most common consequences of prenatal alcohol exposure (PAE) is the emergence of anxiety disorders that are apparent in childhood and persist through adulthood. Coincident and highly associated with anxiety is the prevalence of alcohol abuse in individuals with PAE. Importantly, these observations are evident even following exposure to moderate levels of ethanol – a common pattern of alcohol consumption in pregnancy. Despite compelling epidemiological data, the neurobiological mechanisms underlying moderate PAE-induced anxiety are not well understood. The actions of corticotropin-releasing factor (CRF) through its cognate receptor, CRF1R, are involved in alcohol exposure-induced anxiety and alcohol preference in adult males, and their expression is altered by PAE in anxiety-related brain structures. However, the developmental time-course of CRF1R function and how its function is altered by PAE across ontogeny is unknown. We have recently characterized a model of moderate PAE using a single exposure to vaporized ethanol on gestational day (G) 12, a developmental epoch during which the amygdala begins to appear, that produces increased anxiety-like behaviors in adolescent male offspring and affects emotional processing in adult males, with no apparent effects in females. Based on this, we hypothesize that G12 PAE reduces CRF1R function through ontogeny, which contributes to the biphasic anxiety phenotype and results in alterations in acute alcohol and CRF1R interactions. To test our hypothesis, Aim 1 will determine the developmental time-course of CRF1R function within the central amygdala and its relation to anxiety-like behaviors. Aim 2 will examine the impact of moderate G12 PAE on alterations to CRF1R function within the central amygdala across development and into adulthood, as it contributes to PAE-induced alterations in anxiety-like behavior. Finally, Aim 3 will test the effect of moderate G12 PAE on acute ethanol- CRF1R interactions within the central amygdala and how CRF1R contribute to ethanol intake across ontogeny. These innovative studies will test novel and unique hypotheses surrounding the long-term effects of moderate PAE and describe neural mechanisms specific to deficits in anxiety-like behaviors and its association with elevated ethanol intake in an age- and sex-specific manner.