Studies universally find early age of drinking onset is linked to lifelong risks of alcohol problems and alcohol use disorder (AUD). Assessment of the lasting effect of drinking during adolescent development in humans is confounded by the diversity of environmental and genetic factors that affect adolescent development, including emerging personality disorders and progressive increases in drinking trajectories into adulthood. Preclinical studies using an adolescent intermittent ethanol (AIE) exposure rat model of underage binge drinking avoid the human confounds and support lifelong changes that increase risks. AIE increases adult alcohol drinking, risky decision-making, reward-seeking, and anxiety as well as reductions in executive function that all increase risks for the development of an AUD. AIE causes persistent increases in brain neuroimmune signaling high-mobility group box 1 (HMGB1), Toll-like receptor, receptor for advanced glycation end products, and innate immune genes that are also found to be increased in human AUD brain. HMGB1 is released from cells by ethanol, both free and within extracellular vesicles, that act on neurons and glia, shifting transcription and cellular phenotype. AIE-induced decreases in adult hippocampal neurogenesis and loss of basal forebrain cholinergic neurons are reviewed as examples of persistent AIE-induced pathology. Both are prevented and reversed by anti-inflammatory and epigenetic drugs. Findings suggest AIE-increased HMGB1 signaling induces the RE-1 silencing transcript blunting cholinergic gene expression, shifting neuronal phenotype. Inhibition of HMGB1 neuroimmune signaling, histone methylation enzymes, and galantamine, the cholinesterase inhibitor, both prevent and reverse AIE pathology. These findings provide new targets that may reverse AUD neuropathology as well as other brain diseases linked to neuroimmune signaling.

中文翻译：

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针对青少年饮酒中神经免疫和表观遗传信号的持续变化来治疗成年酒精使用障碍

研究普遍发现，饮酒年龄过早与终生出现酒精问题和酒精使用障碍 (AUD) 的风险有关。影响青少年发展的环境和遗传因素的多样性，包括新出现的人格障碍和成年后饮酒轨迹的逐渐增加，使对人类青少年发展期间饮酒的持久影响的评估感到困惑。使用青少年间歇性乙醇（AIE）暴露大鼠模型进行的临床前研究避免了人类的困惑，并支持增加风险的终生变化。AIE 会增加成人饮酒量、做出危险决策、寻求奖励和焦虑，以及执行功能下降，所有这些都会增加形成 AUD 的风险。AIE 会导致大脑神经免疫信号高迁移率族蛋白 1 (HMGB1)、Toll 样受体、晚期糖基化终产物受体以及先天免疫基因的持续增加，这些基因也被发现在人类 AUD 大脑中增加。HMGB1 通过乙醇从细胞中释放出来，无论是游离的还是在细胞外囊泡内，作用于神经元和神经胶质细胞，改变转录和细胞表型。AIE 诱导的成人海马神经发生减少和基底前脑胆碱能神经元丧失作为持续性 AIE 诱导病理的例子进行了回顾。抗炎药和表观遗传药物可以预防和逆转这两种情况。研究结果表明，AIE 增加的 HMGB1 信号传导会诱导 RE-1 转录本沉默，从而减弱胆碱能基因表达，从而改变神经元表型。抑制 HMGB1 神经免疫信号传导，组蛋白甲基化酶和胆碱酯酶抑制剂加兰他敏均可预防和逆转 AIE 病理。这些发现提供了可能逆转 AUD 神经病理学以及与神经免疫信号传导相关的其他脑部疾病的新靶点。