Prenatal maternal stress is associated with increased sensitivity to neuropathic pain and sex-specific epigenetic and transcriptomic dynamics in the prefrontal cortex

Prenatal maternal stress (PNS) is a common early-life adversity. PNS has been linked to greater vulnerability to chronic pain in the offspring. PNS results in increased hypersensitivity after Chronic Constriction Injury (CCI) of the sciatic nerve, a common rodent model for chronic neuropathic pain. These behavioral effects are accompanied by altered levels of enzymes that regulate DNA methylation in the frontal cortex. DNA methylation, the addition of a methyl group onto cytosine bases of cytosine-guanine (CpG) sites in the genome, is an epigenetic mechanism by which life experiences can reprogram gene expression. The goal of this study was to identify differentially methylated regions that might contribute to the increased pain sensitivity following nerve injury in adulthood. Prior studies indicate widespread, sex-specific transcriptomic changes and numerous differentially methylated regions (DMRs) in the frontal cortex following PNS and nerve injury. Here we performed genome wide DNA methylation and transcriptome-wide RNAseq analysis in the frontal cortex of male and female mice that underwent PNS, CCI or both. Our analysis revealed sex-dependent changes in DNA methylation and mRNA expression, including in pathways related to neuronal and brain development, axonogenesis and synaptic regulation. The effect of DNA methylation on mRNA expression was tested in a subset of target genes. These studies suggest a role for DNA methylation in embedding increased risk for chronic pain in adulthood associated with early-life adversity.