Association of a History of Child Abuse With Impaired Myelination in the Anterior Cingulate Cortex: Convergent Epigenetic, Transcriptional, and Morphological Evidence

扣带回前部 表观遗传学 DNA甲基化 虐待儿童 生物 少突胶质细胞 髓鞘 心理学 神经科学 基因表达 医学 毒物控制 基因 遗传学 认知 中枢神经系统 伤害预防 环境卫生
作者
Pierre‐Eric Lutz,Arnaud Tanti,Alicja Gąsecka,Sarah Barnett-Burns,John J. Kim,Yi Zhou,Gang G. Chen,Marina Wakid,Meghan Shaw,Daniel Almeida,Marc-Aurèle Chay,Jennie Yang,Vanessa Larivière,Marie-Noël M’Boutchou,Léon C.L.T. van Kempen,Volodymyr Yerko,Josée Prud’homme,Maria Antonietta Davoli,Kathryn Vaillancourt,Jean‐François Théroux,Alexandre Bramoullé,Tieyuan Zhang,Michael J. Meaney,Carl Ernst,Daniel Côté,Naguib Mechawar,Gustavo Turecki
出处
期刊:American Journal of Psychiatry [American Psychiatric Association Publishing]
卷期号:174 (12): 1185-1194 被引量:170
标识
DOI:10.1176/appi.ajp.2017.16111286
摘要

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.
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