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

青少年酒精暴露：对神经元激活、类固醇和代谢组学特征的影响

• 批准号: 10629731
• 负责人: Antoinette Michelle Maldonado-Devincci
• 金额: $ 14.19万
• 依托单位: NORTH CAROLINA AGRI & TECH ST UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629731
• 关键词: Address; Adolescence; Adolescent; Adult; Alcohol consumption; Alcohols; Allopregnanolone; American; Amygdaloid structure; Androgens; Behavior; Behavioral; Binding; Brain; Brain region; Chronic; Coupled; Dependence; Development; Enzyme-Linked Immunosorbent Assay; Estradiol; Estrogen Receptor beta; Estrogens; Ethanol; FOS gene; Female; Female Adolescents; Future; GPER gene; GTP-Binding Proteins; Genetic; Goals; Gonadal Steroid Hormones; Hippocampus; Hormonal; Hormones; Human; Immediate-Early Genes; Immunofluorescence Immunologic; Liver; Male Adolescents; Maps; Medial; Mediating; Metabolic; Mus; Neurobiology; Neurons; Neurosecretory Systems; Nuclear; Nuclear Magnetic Resonance; Nucleus Accumbens; Pattern; Play; Predisposition; Prefrontal Cortex; Progesterone; Proteins; Public Health; Regulation; Research; Risk; Rodent; Role; Sampling; Serum; Sex Differences; Steroid Receptors; Steroids; Structure; Structure of terminal stria nuclei of preoptic region; Testosterone; Time; Withdrawal; Woman; Work; addiction; adolescent alcohol exposure; adolescent binge drinking; adolescent brain development; adolescent substance use; alcohol exposure; alcohol measurement; alcohol research; alcohol use disorder; binge drinking; brain health; cell type; drinking; drinking behavior; forest; insight; male; metabolomics; negative affect; neurobiological mechanism; neurodevelopment; neuromechanism; neurosteroids; paraventricular nucleus; pre-clinical; receptor; receptor function; sex; small hairpin RNA; underage drinking

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.

《科学文摘》 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，通常 从青春期的酗酒开始。近年来，青少年女性饮酒人数已超过 青春期男性。然而，性别特有的神经生物学机制潜在的影响 青少年酗酒并没有得到很好的理解。我们之前已经显示出特定于性别的行为变化 以及青春期间歇性乙醇(AIE)暴露后大脑蛋白质的变化。在拟议的工作中，我们 重点是性激素对神经元激活的调节，特别强调内侧前额叶皮质。 性激素对青春期荷尔蒙功能至关重要，并会因早期饮酒而改变。 具体地说，我们研究了AIE暴露与戒断在男性中引起的长期性别特异性变化。 和雌性老鼠。如果酗酒改变了青少年正常的大脑发育， 性激素神经元的激活可能在性激素的持久效应中起重要作用 青少年酗酒和酒精使用障碍的易感性增加。目标 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戒断和乙醇再暴露后中脑皮质边缘结构的变化。目标2将决定性别- AIE和AIE停药后代谢和性激素谱的特异性和时间依赖性变化 酒精再次暴露。AIM 3将确定AIE后内侧前额叶皮质(MPFC)的激活/抑制 接触酒精会影响随后的酒精饮用量。这项工作的完成将阐明短期和长期 青春期酒精暴露对大鼠脑皮质类固醇受体神经元活动的影响 中脑皮质边缘区域、代谢和性激素谱，以及随后乙醇的前额叶调节 饮酒行为。