TY - JOUR
T1 - Association of a History of Child Abuse With Impaired Myelination in the Anterior Cingulate Cortex
T2 - Convergent Epigenetic, Transcriptional, and Morphological Evidence
AU - Lutz, Pierre-Eric
AU - Tanti, Arnaud
AU - Gasecka, Alicja
AU - Barnett-Burns, Sarah
AU - Kim, John J
AU - Zhou, Yi
AU - Chen, Gang G
AU - Wakid, Marina
AU - Shaw, Meghan
AU - Almeida, Daniel
AU - Chay, Marc-Aurele
AU - Yang, Jennie
AU - Larivière, Vanessa
AU - M'Boutchou, Marie-Noël
AU - van Kempen, Léon C
AU - Yerko, Volodymyr
AU - Prud'homme, Josée
AU - Davoli, Maria Antonietta
AU - Vaillancourt, Kathryn
AU - Théroux, Jean-François
AU - Bramoullé, Alexandre
AU - Zhang, Tie-Yuan
AU - Meaney, Michael J
AU - Ernst, Carl
AU - Côté, Daniel
AU - Mechawar, Naguib
AU - Turecki, Gustavo
PY - 2017/12/1
Y1 - 2017/12/1
N2 - OBJECTIVE: 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.METHOD: 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.RESULTS: 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.CONCLUSIONS: The results suggest that child abuse, in part through epigenetic reprogramming of oligodendrocytes, may lastingly disrupt cortical myelination, a fundamental feature of cerebral connectivity.
AB - OBJECTIVE: 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.METHOD: 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.RESULTS: 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.CONCLUSIONS: The results suggest that child abuse, in part through epigenetic reprogramming of oligodendrocytes, may lastingly disrupt cortical myelination, a fundamental feature of cerebral connectivity.
KW - Adult Survivors of Child Abuse
KW - Animals
KW - Axons/pathology
KW - Case-Control Studies
KW - Cell Count
KW - DNA Methylation
KW - Epigenesis, Genetic
KW - Gene Expression
KW - Gyrus Cinguli/metabolism
KW - Humans
KW - Myelin Sheath/metabolism
KW - Neurons/metabolism
KW - Oligodendroglia/metabolism
KW - Rats
KW - Transcription, Genetic
U2 - 10.1176/appi.ajp.2017.16111286
DO - 10.1176/appi.ajp.2017.16111286
M3 - Article
C2 - 28750583
SN - 0002-953X
VL - 174
SP - 1185
EP - 1194
JO - American Journal of Psychiatry
JF - American Journal of Psychiatry
IS - 12
ER -