Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, 60612, USA; Jesse Brown Veterans Affairs Medical Center, Chicago, IL, 60612, USA.
Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, 60612, USA.
Neuropharmacology. 2019 Oct;157:107679. doi: 10.1016/j.neuropharm.2019.107679. Epub 2019 Jun 20.
Binge drinking during adolescence increases the risk for neuropsychiatric disorders including alcoholism in adulthood. DNA methylation in post-mitotic neurons is an important epigenetic modification that plays a crucial role in neurodevelopment. We examined the effects of intermittent ethanol exposure during adolescence on adult behavior and whether DNA methylation changes provide a plausible explanation for the lasting effects of this developmental insult. One hour after last adolescent intermittent ethanol (AIE), growth arrest and DNA damage inducible protein 45 (Gadd45a, Gadd45b, and Gadd45g) mRNA expression was increased and DNA methyltransferase (DNMT) activity and Dnmt3b expression was decreased in the amygdala as compared to adolescent intermittent saline (AIS) rats. However, AIE rats 24 h after last exposure displayed increased DNMT activity but normalized Gadd45 and Dnmt3b mRNA expression compared to AIS rats. In adulthood, rats exposed to AIE show increased Dnmt3b mRNA expression and DNMT activity, along with decreased Gadd45g mRNA expression in the amygdala. DNA methylation of neuropeptide Y (Npy) and brain-derived neurotrophic factor (Bdnf) exon IV is increased in the AIE adult amygdala compared to AIS adult rats. Treatment with the DNMT inhibitor 5-azacytidine (5-azaC) at adulthood normalizes the AIE-induced DNA hypermethylation of Npy and Bdnf exon IV with concomitant reversal of AIE-induced anxiety-like and alcohol-drinking behaviors. These results suggest that binge-like ethanol exposure during adolescence leads to dysregulation in DNA methylation mechanisms in the amygdala which may contribute to behavioral phenotypes of anxiety and alcohol use in adulthood.
青少年时期的狂饮会增加成年后患神经精神疾病的风险，包括酗酒。有丝分裂后神经元中的 DNA 甲基化是一种重要的表观遗传修饰，在神经发育中起着至关重要的作用。我们研究了青少年时期间歇性乙醇暴露对成年行为的影响，以及 DNA 甲基化变化是否为这种发育损伤的持久影响提供了合理的解释。与青少年间歇性盐水（AIS）大鼠相比，最后一次青少年间歇性乙醇（AIE）后 1 小时，杏仁核中生长停滞和 DNA 损伤诱导蛋白 45（Gadd45a、Gadd45b 和 Gadd45g）mRNA 表达增加，DNA 甲基转移酶（DNMT）活性和 Dnmt3b 表达减少。然而，与 AIS 大鼠相比，最后一次暴露后 24 小时的 AIE 大鼠显示出 DNMT 活性增加，但 Gadd45 和 Dnmt3b mRNA 表达正常化。在成年期，暴露于 AIE 的大鼠表现出 Dnmt3b mRNA 表达增加和 DNMT 活性增加，以及杏仁核中 Gadd45g mRNA 表达减少。与 AIS 成年大鼠相比，AIE 成年大鼠杏仁核中的神经肽 Y（Npy）和脑源性神经营养因子（Bdnf）外显子 IV 的 DNA 甲基化增加。在成年期用 DNA 甲基转移酶抑制剂 5-氮杂胞苷（5-azaC）处理可使 Npy 和 Bdnf 外显子 IV 的 AIE 诱导的 DNA 高甲基化正常化，同时逆转 AIE 诱导的焦虑样和饮酒行为。这些结果表明，青少年时期类似狂欢的乙醇暴露会导致杏仁核中 DNA 甲基化机制失调，这可能导致成年期焦虑和饮酒行为表型。
