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，这可能导致一系列的 胎儿酒精谱系障碍。最常见的后果之一 产前酒精暴露（PAE）是在儿童时期出现的焦虑症， 持续到成年。与焦虑同时发生并高度相关的是， 个人PAE。重要的是，这些观察结果是明显的，即使在暴露于中等水平 酒精-怀孕期间饮酒的常见模式。尽管有令人信服的流行病学数据， 中度PAE诱导的焦虑的神经生物学机制还不清楚。的 促肾上腺皮质激素释放因子（CRF）通过其同源受体CRF 1 R的作用与酒精有关 成年男性中的焦虑和酒精偏好，以及它们的表达被PAE改变， 与焦虑有关的大脑结构然而，CRF 1 R功能的发育时间过程及其如何影响CRF 1 R的功能， PAE在个体发育过程中改变的功能尚不清楚。我们最近描述了一种温和的 在妊娠第12天（G）使用单次暴露于汽化乙醇的PAE，这是妊娠期间的发育时期。 杏仁核开始出现，这会增加青春期男性的焦虑行为 后代和影响成年男性的情绪处理，在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CRF 1 R功能，这有助于双相性 焦虑表型，并导致急性酒精和CRF 1 R相互作用的改变。为了验证我们的假设， 目的1将确定中央杏仁核内CRF 1 R功能的发育时程及其在脑内的表达。 与类似焦虑的行为有关。目的2将检查中度G12 PAE对CRF 1 R改变的影响 在发育和成年期，中央杏仁核内的功能，因为它有助于PAE诱导的 焦虑样行为的改变最后，目标3将测试中度G12 PAE对急性乙醇中毒的影响。 中央杏仁核内CRF 1 R的相互作用以及CRF 1 R如何在个体发育中促进乙醇摄入。 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神经机制及其与 酒精摄入量的增加与年龄和性别有关。

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.