BACKGROUND Experiences of abuse and neglect during childhood are major predictors of the emergence of depressive and suicidal behaviors throughout life. The underlying biological mechanisms, however, remain poorly understood. Here, we focused on the opioid system as a potential brain substrate mediating these effects. METHODS Postmortem samples from three brain structures regulating social bonds and emotions were analyzed. Groups were constituted of depressed individuals who died by suicide, with or without a history of severe child abuse, and of psychiatrically healthy control subjects. Expression of opioid peptides and receptors was measured using real-time polymerase chain reaction. DNA methylation, a major epigenetic mark, was investigated using targeted bisulfite sequencing and characterized at functional level using in vitro reporter assays. Finally, oxidative bisulfite sequencing was used to differentiate methylation and hydroxymethylation of DNA. RESULTS A history of child abuse specifically associated in the anterior insula with a downregulation of the kappa opioid receptor (Kappa), as well as decreased DNA methylation in the second intron of the Kappa gene. In vitro assays further showed that this intron functions as a genomic enhancer where glucocorticoid receptor binding regulates Kappa expression, unraveling a new mechanism mediating the well-established interactions between endogenous opioids and stress. Finally, results showed that child abuse is associated in the Kappa intron with a selective reduction in levels of DNA hydroxymethylation, likely mediating the observed downregulation of the receptor. CONCLUSIONS Altogether, our findings uncover new facets of Kappa physiology, whereby this receptor may be epigenetically regulated by stressful experiences, in particular as a function of early social life.

中文翻译：

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虐待儿童对κ阿片受体的表观遗传调控

背景 童年时期的虐待和忽视经历是一生中出现抑郁和自杀行为的主要预测因素。然而，潜在的生物学机制仍然知之甚少。在这里，我们将阿片类药物系统作为调节这些影响的潜在大脑底物。方法分析了来自三个调节社会联系和情绪的大脑结构的死后样本。小组由自杀身亡的抑郁个体组成，有或没有严重虐待儿童的历史，以及精神健康的对照受试者。使用实时聚合酶链反应测量阿片肽和受体的表达。DNA 甲基化是一种主要的表观遗传标记，使用靶向亚硫酸氢盐测序进行研究，并使用体外报告基因检测在功能水平上进行表征。最后，氧化亚硫酸氢盐测序用于区分 DNA 的甲基化和羟甲基化。结果 前脑岛的虐待儿童史与κ阿片受体 (Kappa) 的下调以及 Kappa 基因第二个内含子的 DNA 甲基化降低特别相关。体外试验进一步表明，该内含子作为基因组增强子发挥作用，其中糖皮质激素受体结合调节 Kappa 表达，揭示了介导内源性阿片类药物与压力之间已确立的相互作用的新机制。最后，结果表明，Kappa 内含子中的虐待儿童与 DNA 羟甲基化水平的选择性降低有关，这可能介导了观察到的受体下调。结论 总之，我们的发现揭示了 Kappa 生理学的新方面，