Adolescent alcohol exposure: impact on neuronal activation, steroids, and metabolomic profiles

科学抽象 酒精使用障碍是一个主要的公共卫生问题，困扰着大约1700万美国人， 从青春期的酗酒开始近年来，青少年女性的饮酒量超过了 青春期的男性。然而，性别特异性神经生物学机制的影响， 青少年酗酒还不太清楚。我们之前已经显示了行为上的性别特异性变化， 和青少年间歇性乙醇暴露（AIE）后脑蛋白质的变化。在工作中，我们 集中于性类固醇调节神经元活化，特别强调内侧前额叶皮质。 性类固醇对青春期的激素功能至关重要，并且会因早期酒精暴露而改变。 具体而言，我们研究了AIE暴露与戒断引起的长期性别特异性变化， 和雌性老鼠。如果酗酒改变了正常的青少年大脑发育， 含有性类固醇的神经元中的神经元活化可能在 青少年酗酒暴露和酒精使用障碍的易感性增加。目的 1将确定（1）神经元激活和类固醇受体的性别特异性和时间依赖性变化， AIE戒断和再次接触乙醇后的中皮质边缘脑结构。目标2将决定性别- 从AIE中退出后代谢组学和性类固醇谱的特异性和时间依赖性变化， 乙醇再暴露。目的3将确定AIE后内侧前额叶皮层（mPFC）的激活/抑制 暴露影响随后的乙醇饮用。这项工作的完成将阐明短期和长期 青少年乙醇暴露对类固醇受体神经元活动的影响 中皮质边缘区、代谢和性类固醇分布以及随后乙醇的前额调节 饮酒行为

Scientific Abstract Alcohol use disorders are a major public health concern afflicting approximately 17 million Americans, often beginning with binge drinking during adolescence. In recent years drinking in adolescent females has surpassed that of adolescent males. However, the sex-specific neurobiological mechanisms underlying the impact of adolescent binge drinking are not well understood. We have previously shown sex-specific changes in behavioral and brain protein changes following adolescent intermittent ethanol (AIE) exposure. In the proposed work, we focus on sex steroid regulation of neuronal activation with a particular emphasis on the medial prefrontal cortex. Sex steroids are critically important for pubertal hormonal function and is altered by early alcohol exposure. Specifically, we examine the long-lasting sex-specific changes induced by AIE exposure with withdrawal in male and female mice. If binge alcohol exposure changes normal adolescent brain development, alterations in neuronal activation in sex steroid containing neurons likely plays an important role in the lasting effects of adolescent binge alcohol exposure and increased susceptibility to development of an alcohol use disorder. Aim 1 will determine (1) sex-specific and time-dependent changes in neuronal activation and steroid receptors in mesocorticolimbic brain structures after withdrawal from AIE and ethanol re-exposure. Aim 2 will determine sex- specific and time-dependent changes in metabolomic and sex steroid profiles after withdrawal from AIE and ethanol re-exposure. Aim 3 will determine if activation/inhibition of medial prefrontal cortex (mPFC) after AIE exposure impacts subsequent ethanol drinking. Completion of this work will elucidate short- and long-term impacts of adolescent ethanol exposure on neuronal activity in steroid receptor containing neurons in mesocorticolimbic regions, metabolic and sex steroid profiles, and prefrontal regulation of subsequent ethanol drinking behavior.