Macht Victoria A, Vetreno Ryan P, Crews Fulton T
Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Front Pharmacol. 2022 Mar 2;13:849997. doi: 10.3389/fphar.2022.849997. eCollection 2022.
Alcohol (ethanol) use and misuse is a costly societal issue that can affect an individual across the lifespan. Alcohol use and misuse typically initiates during adolescence and generally continues into adulthood. Not only is alcohol the most widely abused drug by adolescents, but it is also one of the most widely abused drugs in the world. In fact, high rates of maternal drinking make developmental ethanol exposure the most preventable cause of neurological deficits in the Western world. Preclinical studies have determined that one of the most consistent effects of ethanol is its disruption of hippocampal neurogenesis. However, the severity, persistence, and reversibility of ethanol's effects on hippocampal neurogenesis are dependent on developmental stage of exposure and age at assessment. Complicating the neurodevelopmental effects of ethanol is the concurrent development and maturation of neuromodulatory systems which regulate neurogenesis, particularly the cholinergic system. Cholinergic signaling in the hippocampus directly regulates hippocampal neurogenesis through muscarinic and nicotinic receptor actions and indirectly regulates neurogenesis by providing anti-inflammatory regulatory control over the hippocampal environmental milieu. Therefore, this review aims to evaluate how shifting maturational patterns of the cholinergic system and its regulation of neuroimmune signaling impact ethanol's effects on adult neurogenesis. For example, perinatal ethanol exposure decreases basal forebrain cholinergic neuron populations, resulting in long-term developmental disruptions to the hippocampus that persist into adulthood. Exaggerated neuroimmune responses and disruptions in adult hippocampal neurogenesis are evident after environmental, developmental, and pharmacological challenges, suggesting that perinatal ethanol exposure induces neurogenic deficits in adulthood that can be unmasked under conditions that strain neural and immune function. Similarly, adolescent ethanol exposure persistently decreases basal forebrain cholinergic neuron populations, increases hippocampal neuroimmune gene expression, and decreases hippocampal neurogenesis in adulthood. The effects of neither perinatal nor adolescent ethanol are mitigated by abstinence whereas adult ethanol exposure-induced reductions in hippocampal neurogenesis are restored following abstinence, suggesting that ethanol-induced alterations in neurogenesis and reversibility are dependent upon the developmental period. Thus, the focus of this review is an examination of how ethanol exposure across critical developmental periods disrupts maturation of cholinergic and neuroinflammatory systems to differentially affect hippocampal neurogenesis in adulthood.
酒精（乙醇）的使用及滥用是一个代价高昂的社会问题，会在人的整个生命周期中对个体产生影响。酒精的使用及滥用通常始于青春期，并一般会持续到成年期。酒精不仅是青少年滥用最为广泛的药物，也是世界上滥用最为广泛的药物之一。事实上，孕期饮酒率居高不下，使得发育过程中接触乙醇成为西方世界神经功能缺损最可预防的原因。临床前研究已确定，乙醇最一致的作用之一是其对海马体神经发生的破坏。然而，乙醇对海马体神经发生的影响的严重程度、持续性和可逆性取决于接触时的发育阶段以及评估时的年龄。使乙醇的神经发育影响变得复杂的是调节神经发生的神经调节系统（尤其是胆碱能系统）的同时发育和成熟。海马体中的胆碱能信号传导通过毒蕈碱和烟碱受体作用直接调节海马体神经发生，并通过对海马体环境微环境提供抗炎调节控制间接调节神经发生。因此，本综述旨在评估胆碱能系统不断变化的成熟模式及其对神经免疫信号传导的调节如何影响乙醇对成体神经发生的作用。例如，围产期接触乙醇会减少基底前脑胆碱能神经元数量，导致海马体长期发育紊乱并持续至成年期。在环境、发育和药理学挑战后，成年海马体神经发生中明显出现过度的神经免疫反应和紊乱，这表明围产期接触乙醇会在成年期诱发神经发生缺陷，在使神经和免疫功能紧张的条件下这些缺陷会显现出来。同样，青少年接触乙醇会持续减少基底前脑胆碱能神经元数量，增加海马体神经免疫基因表达，并在成年期减少海马体神经发生。围产期和青少年期接触乙醇的影响都不会因戒酒而减轻，而成年期接触乙醇导致的海马体神经发生减少在戒酒后会恢复，这表明乙醇诱导的神经发生改变及其可逆性取决于发育时期。因此，本综述的重点是研究在关键发育时期接触乙醇如何破坏胆碱能和神经炎症系统的成熟，从而对成年期海马体神经发生产生不同影响。
