Prenatal Alcohol Exposure, CRF and Adolescent Anxiety

项目摘要 对孕妇的临床评估显示，约30%的妇女在怀孕期间饮酒。 怀孕因此，毫不奇怪，与产前酒精暴露（PAE）相对应的疾病是其中之一。 这是美国最常见的可预防疾病。焦虑症是最常见的 PAE引起的行为障碍，早在儿童时期就可以观察到，然而， 现有的研究基本上没有潜在的生物学贡献。这种知识上的差距 我们对酒精如何改变发展中的焦虑回路，并随后阻止有针对性的 治疗PAE诱导的焦虑症状。利用啮齿动物模型，我们的实验室已经描述了一个范例， 中度PAE显著改变中枢内侧核的GABA能神经传递， 杏仁核（CeM），一个与焦虑样行为调节相关的大脑区域。此外，委员会认为， 促肾上腺皮质激素释放因子（CRF）受体1（CRFR1）功能在青少年、男性和女性的CeM内是钝化的。 生下的孩子，有趣的是，初步数据表明CRFR1的敏感性增加， 以及青少年中CRFR1调节的GABA传递的方向开关， 在成人中报告。总之，这些数据有助于我们的总体假设，即 与成人相比，CeM导致乙醇初治青少年的不适当应激反应， 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 使用全细胞电生理学在青少年和成年大鼠的CeM内CRF系统的差异， 原位杂交和行为药理学。其次，我们将评估PAE引起的中度变化， CRF和CRFR1在青春期大鼠中，显示PAE后焦虑样行为增加。在这 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 拟议的研究将提供一个全面的调查，具体的生理障碍， 潜在的PAE引起的焦虑，并将告知现有的文献变量，如年龄和产前 暴露，这可能会影响CRF系统的灵敏度和功能。通过掺入 多种新颖的调查技术，并在酒精和行为专家的指导下， 神经科学领域，该项目还将提供一个上级培训经验的框架， research.

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.