Whether a woman’s estrogen level is high or low could determine if she may be susceptible to developing post-traumatic stress disorder (PTSD), according to recent research. Estrogen has been found to epigenetically change gene activity in the brain and could even protect a woman from emotional numbness, flashbacks, and difficulty sleeping – all symptoms of PTSD – after a shocking or traumatic situation.
Researchers analyzed an epigenetic mark called DNA methylation, which is known to turn genes off. They used blood samples collected from nearly 300 women of the Grady Trauma Project, including those who suffered from abuse and violence and had a low income. Among this group, some women were of child-bearing age and experienced a rise and fall of estrogen levels during their normal menstrual cycles, and other women had already completed menopause and had significantly lower estrogen levels.
Associate Professor and Vice Chair of Research in the Department of Gynecology and Obstetrics at Emory University School of Medicine, Alicia Smith, PhD, said, “We knew that estrogen affects the activity of many genes throughout the genome. But if you look at the estrogen-modulated sites that are also associated with PTSD, just one pops out.”
This site is found in a gene known as HDAC4, which encodes histone deacetylase 4 and is implicated in the regulation of memory and learning. They found that DNA methylation differences of HDAC4 CpG sites were associated with PTSD diagnosis in women. Specifically, methylation of a specific CpG site in HDAC4 was “higher in PTSD cases than controls, and higher methylation of this site was associated with lower estradiol levels.”
In addition, genetic variation in HDAC4 was connected to a lower level of HDAC4 gene activity and impacted how women responded to and recovered from fear. Those with the variation reacted more fearfully on a fear-related test than those without it.
Brain imaging even showed changes in their “resting state”. Two regions of the brain linked to fear learning, known as the amygdala and the cingulate cortex, demonstrated stronger connections when active.
Furthermore, when experimenting with female mice, the HDAC4 gene in the amygdala was activated during fear learning, but only when their estrogen levels were low. These results could point to using estrogen to reduce the effects or prevent the risk of women developing PTSD following trauma. Interestingly, the researchers indicate that estrogen could even alter how a woman perceives pain.
“Together, these results support estrogenic influence of HDAC4 regulation and expression that may contribute to PTSD in women,” the researchers reported.
Further exploration into the epigenetic effects of estrogen on certain genes, especially those related to PTSD, will help progress our understanding and guide us towards potential new therapies.
Bailey Kirkpatrick
Source: Maddox, S.A., Kilaru, Shin, J., Jovanovic, T., Almli, LM., Dias, Norrholm, S.D., Fani, N., Michopoulos, V., Ding, Z., Conneely, K.N., Binder, E.B., Ressler , Smith, A.K. (2017). Estrogen-dependent association of HDAC4 with fear in female mice and women with PTSD. Molecular Psychiatry,
Reference: Woodruff Health Sciences Center. How estrogen modulates fear learning — molecular insight into PTSD. Emory University. 25 Jan 2017. Web.
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