Epigenetic regulation of sex differences in susceptibility to stress

Under current diagnostics depression and stress related mood disorders have a higher occurrence in women than men. Little is known of the biological mechanisms contributing to these sex differences and how they may impact potential new therapeutics. Here we examine how DNA methylation contributes to sex specific stress vulnerability in adult animals. Mice of both sexes were exposed to variable stress and given a behavioral test battery to examine stress sensitivity. Female mice expressed depressionassociated behavior across all tests stress exposure whereas males were behaviorally resilient. Markers of pre and post-synaptic plasticity and spine morphology were examined using a combination of immunohistochemistry and cell filling. Females demonstrated circuit specific pre-synaptic alterations that may contribute to stress susceptibility in the absence of post-synaptic alterations in spine density or phenotype. Viral over-expression in combination with transgenic knockout strategies was used to manipulate DNA methyltransferase (DNMT) 3a levels in NAc and examine behavior. Transcriptional profiles were measured following DNMT3a knockout. Increasing the expression of DNMT3a site specifically in NAc shifted both males and females to a stress susceptible state following exposure to a sub-threshold variable stress. Excising DNMT3a site specifically from NAc in adulthood made female mice behaviorally resilient to variable stress. Removal of DNMT3a shifted the female transcriptome to a more male like state. Together, these studies examine an epigenetic mechanism that regulates transcriptional sex differences in reward circuitry mediating behavioral susceptibility and resilience to variable stress