Epigenetic regulation of sex differences in susceptibility to stress

Under current diagnostics depression and stress related mooddisorders have a higher occurrence in women than men. Little isknown of the biological mechanisms contributing to these sexdifferences and how they may impact potential new therapeutics.Here we examine how DNA methylation contributes to sexspecific stress vulnerability in adult animals. Mice of both sexeswere exposed to variable stress and given a behavioral test batteryto examine stress sensitivity. Female mice expressed depressionassociatedbehavior across all tests stress exposure whereas maleswere behaviorally resilient. Markers of pre and post-synapticplasticity and spine morphology were examined using acombination of immunohistochemistry and cell filling. Femalesdemonstrated circuit specific pre-synaptic alterations that maycontribute to stress susceptibility in the absence of post-synapticalterations in spine density or phenotype. Viral over-expression incombination with transgenic knockout strategies was used tomanipulate DNA methyltransferase (DNMT) 3a levels in NAc andexamine behavior. Transcriptional profiles were measured followingDNMT3a knockout. Increasing the expression of DNMT3asite specifically in NAc shifted both males and females to a stresssusceptible state following exposure to a sub-threshold variablestress. Excising DNMT3a site specifically from NAc in adulthoodmade female mice behaviorally resilient to variable stress.Removal of DNMT3a shifted the female transcriptome to amore male like state. Together, these studies examine an epigeneticmechanism that regulates transcriptional sex differences in rewardcircuitry mediating behavioral susceptibility and resilience tovariable stress