Vetreno Ryan P, Bohnsack John Peyton, Kusumo Handojo, Liu Wen, Pandey Subhash C, Crews Fulton T
Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.
Addict Biol. 2020 Mar;25(2):e12731. doi: 10.1111/adb.12731. Epub 2019 Feb 18.
Binge drinking and alcohol abuse are common during adolescence and cause lasting pathology. Preclinical rodent studies using the adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2-day on/2-day off from postnatal day [P]25 to P55) model of human adolescent binge drinking report decreased basal forebrain cholinergic (ie, ChAT+) neurons that persist into adulthood (ie, P56-P220). Recent studies link AIE-induced neuroimmune activation to cholinergic pathology, but the underlying molecular mechanisms contributing to the persistent loss of basal forebrain ChAT+ neurons are unknown. We report here that the AIE-induced loss of cholinergic neuron markers (ie, ChAT, TrkA, and p75 ), cholinergic neuron shrinkage, and increased expression of the neuroimmune marker pNF-κB p65 are restored by exercise exposure from P56 to P95 after AIE. Our data reveal that persistently reduced expression of cholinergic neuron markers following AIE is because of the loss of the cholinergic neuron phenotype most likely through an epigenetic mechanism involving DNA methylation and histone 3 lysine 9 dimethylation (H3K9me2). Adolescent intermittent ethanol caused a persistent increase in adult H3K9me2 and DNA methylation at promoter regions of Chat and H3K9me2 of Trka, which was restored by wheel running. Exercise also restored the AIE-induced reversal learning deficits on the Morris water maze. Together, these data suggest that AIE-induced adult neuroimmune signaling and cognitive deficits are linked to suppression of Chat and Trka gene expression through epigenetic mechanisms that can be restored by exercise. Exercise restoration of the persistent AIE-induced phenotypic loss of cholinergic neurons via epigenetic modifications is novel mechanism of neuroplasticity.
暴饮暴食和酒精滥用在青少年时期很常见，并会导致持久性病变。使用人类青少年暴饮暴食的青少年间歇性乙醇（AIE；5.0克/千克，腹腔注射，从出生后第[P]25天至P55天，2天给药/2天停药）模型进行的临床前啮齿动物研究报告称，基底前脑胆碱能（即ChAT+）神经元减少，这种减少会持续到成年期（即P56 - P220）。最近的研究将AIE诱导的神经免疫激活与胆碱能病变联系起来，但导致基底前脑ChAT+神经元持续丢失的潜在分子机制尚不清楚。我们在此报告，在AIE后从P56至P95进行运动暴露可恢复AIE诱导的胆碱能神经元标志物（即ChAT、TrkA和p75）丢失、胆碱能神经元萎缩以及神经免疫标志物pNF-κB p65表达增加。我们的数据表明，AIE后胆碱能神经元标志物表达持续降低是由于胆碱能神经元表型丧失，很可能是通过涉及DNA甲基化和组蛋白3赖氨酸9二甲基化（H3K9me2）的表观遗传机制。青少年间歇性乙醇导致成年期Chat启动子区域以及Trka的H3K9me2的H3K9me2和DNA甲基化持续增加，而通过轮转跑步可使其恢复。运动还恢复了AIE诱导的莫里斯水迷宫逆向学习缺陷。总之，这些数据表明，AIE诱导的成年期神经免疫信号传导和认知缺陷与通过表观遗传机制抑制Chat和Trka基因表达有关，而运动可以恢复这种抑制。通过表观遗传修饰对AIE诱导的胆碱能神经元持久性表型丧失进行运动恢复是神经可塑性的一种新机制。
