Sex-specific Patterns of the Epigenome as a Putative Mechanism in Fear-related Memory

Emotionally relevant experiences can generate long-term memories that persist over one’s life.  However, some memories may be so strongly associated with that emotional event that they can lead to post-traumatic stress disorder (PTSD) or other anxiety-related disorders. According to the American Psychological Association, women suffer from higher rates of PTSD despite the fact that males are at a higher risk of experiencing a traumatic event.  One way by which this might be mediated is through a sex-chromosome-specific epigenetic modifiers such as the histone demethylase, ubiquitously transcribed X chromosome tetratricopeptide repeat gene (Utx).  This histone demethylase acts directly on the histone modification H3K27me3, which is a repressive chromatin mark associated with DNA methylation and gene silencing.  In addition, it has been shown that Utx is an x-escapee gene, meaning females would express higher levels of Utx, which may lead to greater gene activation in response to learning. Indeed, we have observed marked increases in gene expression (i.e. Rab3a) in female mice following behavioral training, which may contribute to sex differences in memory formation. Our preliminary data demonstrate that females retain fear memory significantly more compared to males.  Based on this observation, we hypothesize that Utx knockdown in females will lead to a behavioral-phenotype similar to that of males.  Conversely, we hypothesize that by overexpressing Utx in males, we will observe a behavior comparable to that of females. We find there is no difference in the acquisition of fear memory, however, there is a significant resistance to the extinction of cued fear memories in females.  Additionally, we find evident mRNA levels for BDNF and Utx are increased in the prefrontal cortex of female mice.  In order to fully understand the functional relevance of these effects, we will package lentivirus with Utx shRNA and overexpressing constructs then stereotaxically inject into the prelimbic region of the prefrontal cortex.  We will perform the same behavioral experiments along with extraction of tissues to run qRT-PCR.  Lastly, we will perform ChIP-PCR looking at Utx occupancy of the BDNF promoter in response to behavioral training.  The outcome of these experiments will elucidate the epigenetic mechanisms involved in the acquisition and extinction of persistent fear memories in the female brain.