Child abuse has devastating and long-lasting consequences, considerably increasing the lifetime risk of negative mental health outcomes such as depression and suicide. Yet the neurobiological processes underlying this heightened vulnerability remain poorly understood. The authors investigated the hypothesis that epigenetic, transcriptomic, and cellular adaptations may occur in the anterior cingulate cortex as a function of child abuse.

Postmortem brain samples from human subjects (N=78) and from a rodent model of the impact of early-life environment (N=24) were analyzed. The human samples were from depressed individuals who died by suicide, with (N=27) or without (N=25) a history of severe child abuse, as well as from psychiatrically healthy control subjects (N=26). Genome-wide DNA methylation and gene expression were investigated using reduced representation bisulfite sequencing and RNA sequencing, respectively. Cell type–specific validation of differentially methylated loci was performed after fluorescence-activated cell sorting of oligodendrocyte and neuronal nuclei. Differential gene expression was validated using NanoString technology. Finally, oligodendrocytes and myelinated axons were analyzed using stereology and coherent anti-Stokes Raman scattering microscopy.

A history of child abuse was associated with cell type–specific changes in DNA methylation of oligodendrocyte genes and a global impairment of the myelin-related transcriptional program. These effects were absent in the depressed suicide completers with no history of child abuse, and they were strongly correlated with myelin gene expression changes observed in the animal model. Furthermore, a selective and significant reduction in the thickness of myelin sheaths around small-diameter axons was observed in individuals with history of child abuse.

The results suggest that child abuse, in part through epigenetic reprogramming of oligodendrocytes, may lastingly disrupt cortical myelination, a fundamental feature of cerebral connectivity.

虐待儿童具有毁灭性和长期的后果，大大增加了一生中负面的心理健康后果（如抑郁和自杀）的风险。然而，这种高度脆弱性背后的神经生物学过程仍然知之甚少。作者研究了这样的假说：表皮遗传，转录组和细胞适应可能是虐待儿童的一种功能，在扣带回前皮发生。

分析了来自人类受试者的死后大脑样本（N = 78）和来自早期环境影响的啮齿动物模型（N = 24）。人体样本来自因自杀而死亡的抑郁症患者，有（N = 27）或没有（N = 25）有严重虐待儿童的历史，以及精神健康对照组（N = 26）。分别使用简化表示的亚硫酸氢盐测序和RNA测序研究了全基因组DNA甲基化和基因表达。少突胶质细胞和神经元核的荧光激活细胞分选后，进行差异甲基化基因座的细胞类型特异性验证。使用NanoString技术验证了差异基因表达。最后，使用体视学和相干的抗斯托克斯拉曼散射显微镜分析少突胶质细胞和有髓的轴突。

虐待儿童的历史与少突胶质细胞基因DNA甲基化的细胞类型特异性变化以及髓磷脂相关转录程序的全面损害有关。在没有虐待儿童史的抑郁自杀完成者中没有这些作用，并且它们与在动物模型中观察到的髓磷脂基因表达变化密切相关。此外，在有虐待儿童史的个体中，观察到小直径轴突周围髓鞘厚度的选择性显着降低。

结果表明，虐待儿童（部分通过少突胶质细胞的表观遗传重编程）可能会持续破坏皮质髓鞘形成，这是大脑连接的基本特征。