Prenatal Alcohol Exposure, CRF and Adolescent Anxiety

项目总结 对孕妇的临床评估显示，约30%的女性在怀孕期间饮酒 怀孕了。因此，难怪与产前酒精暴露(PAE)相对应的疾病在 这是美国最常见的可预防疾病。焦虑症是最普遍的 由PAE引起的行为障碍早在儿童时期就可以观察到，然而 潜在的生物学贡献在很大程度上没有得到既定研究的支持。这一知识极限的差距 我们对酒精如何改变发展中的焦虑回路并随后阻止靶向的理解 PAE所致焦虑症状的治疗。利用啮齿动物模型，我们的实验室已经确定了一个范例 中度PAE显著改变中央内侧核GABA能神经传递 杏仁核(CEM)，这是一个与焦虑样行为调节相关的大脑区域。此外， 促肾上腺皮质激素释放因子(CRF)受体1(CRFR1)功能在青少年、男性CEM中被钝化 PAE后的后代。有趣的是，初步数据表明CRFR1的敏感性增加， 以及CRFR1调节的青少年GABA传递的方向切换 据报道，在成年人中。总而言之，这些数据有助于我们的总体假设，即 与成年人相比，CEM有助于酒精天真青少年的不适当压力反应，并且 增加PAE青少年的焦虑样行为。为了调查这些说法，我们将首先确定年龄 用全细胞电生理学研究青春期和成年大鼠中脑皮质CRF系统的差异， 原位杂交和行为药理学。其次，我们将评估PAE导致的适度变化 在青春期大鼠中，CRF和CRFR1表现出PAE后焦虑样行为的增加。在这个范围内 目的：PAE和对照(空气暴露)后代的比较将包括CEM神经生理学的研究， CRF和CRFR1的mRNA水平，以及CRFR1激活后的行为反应。成功完成 将提供对特定生理损伤的全面调查 潜在的PAE诱导的焦虑，并将为现有的关于变量的文献提供信息，如年龄和产前 暴露，这可能会影响CRF系统的灵敏度和功能。通过成立为 多种新颖的调查技术，并在酒精和行为方面的专家的指导下 在神经科学领域，该项目将为在以下领域提供卓越的培训体验提供框架 研究。

PROJECT SUMMARY Clinical assessments of expectant mothers have revealed that ~30% of women consume alcohol during pregnancy. It is thus unsurprising that disorders which correspond to prenatal alcohol exposure (PAE) are among the most common of preventable illnesses in the United States. Anxiety disorders are among the most prevalent behavioral impairments arising from PAE and can be observed as early as childhood, however investigations of underlying biological contributions are largely absent from established research. This gap in knowledge limits our understanding of how alcohol alters developing anxiety circuits and subsequently prevents targeted treatment of PAE-induced anxiety symptoms. Utilizing rodent models, our lab has characterized a paradigm of moderate PAE which significantly alters GABAergic neurotransmission in the medial nucleus of the central amygdala (CeM), a brain region associated with the regulation of anxiety-like behavior. Furthermore, corticotrophin-releasing factor (CRF) receptor 1 (CRFR1) function is blunted within the CeM of adolescent, male offspring following PAE. Interestingly, preliminary data suggest that there is an increased sensitivity of CRFR1, as well as a directional switch in CRFR1-regulated GABA transmission in adolescents relative to what has been reported in adults. Together, these data contribute to our overarching hypothesis that the CRF system within the CeM contributes to an inappropriate stress response in ethanol-naïve adolescents compared to adults, and increases anxiety-like behavior in PAE adolescents. To investigate these claims, we will first determine age differences in the CRF system within the CeM of adolescent and adult rats using whole cell electrophysiology, in situ hybridization and behavioral pharmacology. Secondly, we will assess moderate PAE-induced changes in CRF and CRFR1 within adolescent rats, that show increased anxiety-like behavior following PAE. Within this aim, comparisons of PAE and control (air-exposed) offspring will include investigations of CeM neurophysiology, mRNA levels for CRF and CRFR1, and behavioral response following CRFR1 activation. Successful completion of the proposed research will provide a comprehensive investigation of specific physiological impairments underlying PAE-induced anxiety, and will inform existing literature on variables, such as age and prenatal exposure, which may influence the sensitivity and function of the CRF system. Through the incorporation of multiple novel techniques for investigation, and under the guidance of experts in the alcohol and behavioral neuroscience field, this project will additionally provide the framework for a superior training experience in research.