LAUSR

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.