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; 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.

科学摘要 饮酒障碍是一个主要的公共卫生问题 从青春期的暴饮暴食开始。近年来，青春期女性的饮酒已经超过 青春期男性。但是，具有影响的性别特定的神经生物学机制 青春期的暴饮暴食尚不清楚。我们以前已经显示出行为特定的性别变化 青少年间歇性乙醇（AIE）暴露后的脑蛋白发生变化。在拟议的工作中，我们 专注于性类固醇对神经元激活的调节，特别强调内侧前额叶皮层。 性类固醇对青春期激素功能至关重要，并因早期酒精暴露而改变。 具体而言，我们检查了AIE暴露引起的持久性别特异性变化，而男性撤离 和雌鼠。如果暴饮暴力暴露改变了正常的青少年大脑的发育，则会改变 性类固醇中含有神经元的神经元激活可能在持久作用中起重要作用 青少年暴饮暴食，并增加了对酒精使用障碍发展的敏感性。目的 1将确定（1）（1）性特异性和时间依赖性的神经元激活和类固醇受体的变化 从AIE和乙醇再暴露退出后，中质粒脑结构。 AIM 2将决定性别 - 从AIE退出后，代谢组和性类固醇特征的特定和时间依赖性变化 重新暴露乙醇。 AIM 3将确定AIE后内侧前额叶皮层（MPFC）的激活/抑制是否激活/抑制 暴露会影响随后的乙醇饮用。这项工作的完成将阐明短期和长期 青少年乙醇暴露对含有神经元中神经元神经元活性的影响 中皮质骨区域，代谢和性类固醇特征以及随后的乙醇的前额叶调节 饮酒行为。