Crews Fulton T, Macht Victoria, Vetreno Ryan P
Departments of Pharmacology and Psychiatry, Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Adv Drug Alcohol Res. 2024 Mar 8;4:12094. doi: 10.3389/adar.2024.12094. eCollection 2024.
Adolescent alcohol drinking is linked to high rates of adult alcohol problems and alcohol use disorder (AUD). The Neurobiology of Alcohol Drinking in Adulthood (NADIA) consortium adolescent intermittent ethanol (AIE) models adolescent binge drinking, followed by abstinent maturation to adulthood to determine the persistent AIE changes in neurobiology and behavior. AIE increases adult alcohol drinking and preference, increases anxiety and reward seeking, and disrupts sleep and cognition, all risks for AUD. In addition, AIE induces changes in neuroimmune gene expression in neurons and glia that alter neurocircuitry and behavior. HMGB1 is a unique neuroimmune signal released from neurons and glia by ethanol that activates multiple proinflammatory receptors, including Toll-like receptors (TLRs), that spread proinflammatory gene induction. HMGB1 expression is increased by AIE in rat brain and in post-mortem human AUD brain, where it correlates with lifetime alcohol consumption. HMGB1 activation of TLR increase TLR expression. Human AUD brain and rat brain following AIE show increases in multiple TLRs. Brain regional differences in neurotransmitters and cell types impact ethanol responses and neuroimmune gene induction. Microglia are monocyte-like cells that provide trophic and synaptic functions, that ethanol proinflammatory signals sensitize or "prime" during repeated drinking cycles, impacting neurocircuitry. Neurocircuits are differently impacted dependent upon neuronal-glial signaling. Acetylcholine is an anti-inflammatory neurotransmitter. AIE increases HMGB1-TLR4 signaling in forebrain, reducing cholinergic neurons by silencing multiple cholinergic defining genes through upregulation of RE-1 silencing factor (REST), a transcription inhibitor known to regulate neuronal differentiation. HMGB1 REST induction reduces cholinergic neurons in basal forebrain and cholinergic innervation of hippocampus. Adult brain hippocampal neurogenesis is regulated by a neurogenic niche formed from multiple cells. AIE and studies find ethanol increases HMGB1-TLR4 signaling and other proinflammatory signaling as well as reducing trophic factors, NGF, and BDNF, coincident with loss of the cholinergic synapse marker vChAT. These changes in gene expression-transcriptomes result in reduced adult neurogenesis. Excitingly, HMGB1 antagonists, anti-inflammatories, and epigenetic modifiers like histone deacetylase inhibitors restore trophic the neurogenesis. These findings suggest anti-inflammatory and epigenetic drugs should be considered for AUD therapy and may provide long-lasting reversal of psychopathology.
青少年饮酒与成年后酒精问题和酒精使用障碍（AUD）的高发生率相关。成年期饮酒的神经生物学（NADIA）联盟的青少年间歇性乙醇（AIE）模型模拟青少年暴饮，随后戒酒至成年，以确定AIE在神经生物学和行为方面的持续变化。AIE会增加成年后的饮酒量和饮酒偏好，增加焦虑和寻求奖励行为，并扰乱睡眠和认知，这些都是AUD的风险因素。此外，AIE会诱导神经元和神经胶质细胞中神经免疫基因表达的变化，从而改变神经回路和行为。HMGB1是一种由乙醇从神经元和神经胶质细胞释放的独特神经免疫信号，它能激活多种促炎受体，包括Toll样受体（TLR），进而传播促炎基因诱导作用。在大鼠大脑和AUD患者的尸检大脑中，AIE会增加HMGB1的表达，且其表达与终生饮酒量相关。HMGB1对TLR的激活会增加TLR的表达。AIE后的人类AUD大脑和大鼠大脑显示多种TLR增加。神经递质和细胞类型的脑区差异会影响乙醇反应和神经免疫基因诱导。小胶质细胞是类似单核细胞的细胞，具有营养和突触功能，在反复饮酒周期中，乙醇促炎信号会使其敏感化或“致敏”，从而影响神经回路。神经回路受到不同影响取决于神经元 - 神经胶质细胞信号传导。乙酰胆碱是一种抗炎神经递质。AIE会增加前脑的HMGB1 - TLR4信号传导，通过上调RE - 1沉默因子（REST）来沉默多个胆碱能定义基因，从而减少胆碱能神经元，REST是一种已知可调节神经元分化的转录抑制剂。HMGB1诱导的REST减少了基底前脑的胆碱能神经元以及海马体的胆碱能神经支配。成体脑海马神经发生由多种细胞形成的神经发生微环境调节。AIE及相关研究发现，乙醇会增加HMGB1 - TLR4信号传导和其他促炎信号传导，同时减少营养因子、神经生长因子（NGF）和脑源性神经营养因子（BDNF），这与胆碱能突触标记物囊泡乙酰胆碱转运体（vChAT）的丧失同时发生。这些基因表达转录组的变化导致成体神经发生减少。令人兴奋的是，HMGB1拮抗剂、抗炎药和表观遗传修饰剂（如组蛋白去乙酰化酶抑制剂）可恢复营养并促进神经发生。这些发现表明，抗炎和表观遗传药物应被考虑用于AUD治疗，并且可能为精神病理学提供持久的逆转。
