Post-traumatic stress disorder (PTSD) is a mental health condition that may emerge after a traumatic experience, such as natural disasters, accidents, war, or violence. People with PTSD may have intrusive memories of the trauma and develop strong negative reactions, such as anxiety, toward mild stimuli.

Women are twice as likely as men to have PTSD. In fact, it is estimated that 10–12 per cent of women develop PTSD in their lives — compared to just five to six per cent of men — and the effect of PTSD tends to last longer in women. 

In a recent Nature study, a group of UTM researchers led by professor of psychology Dr. Iva B. Zovkic reported on a protein in the brain that may play a role in the sex difference of PTSD and other fear-related disorders. 

It is important to note that differential experiences of PTSD may not completely be explained by physiology — non-biological factors such as gender socialization can play a role, which this study does not address.

Fear among mice

This protein, called H2A.Z, is a histone variant implicated in the formation and retention of memories. Histones are the proteins that strands of DNA wrap around to form chromosomes. The reduction of this protein in the brain has been found to enhance fear memory in male mice. The researchers sought to discover whether the reduction or deletion of this protein affects female mice in a similar way.

In a simple fear conditioning test, male and female mice in a chamber were allowed to roam freely before they were subjected to a mild stressor and later removed from the chamber. The next day, when put back in the same chamber, all mice show a fear response, where they froze in place instead of exploring as usual. 

This freezing behaviour is measured as a proxy of their fear memory. As expected, male mice with H2A.Z deletion showed a greater fear memory than control male mice. But surprisingly, H2A.Z deletion had no influence on fear memory of female mice. This hints at the sex-specific effects of this protein on fear memory. 

To model a PTSD-triggering situation, the researchers dialed up the stressors. This time, mice received 10 mild stressors randomly spaced in an hour. The next day, mice were returned to the same chamber, and their freezing behaviour was measured as a proxy of their fear sensitization. 

No difference was found between the H2A.Z-deletion group and the control group in male mice. However, there was a significant difference between the two groups in female mice. The female mice with H2A.Z deletion exhibited reduced fear sensitization compared to the control group. This shows that the reduction of this protein has a protective effect on female mouse models of PTSD.

To understand the observed sex-specific effects of the protein, the researchers found that H2A.Z has higher binding to several genes that are associated with memory in the hippocampi of female mice. This indicates that there may be higher levels of H2A.Z in female mice and points to H2A.Z as a potential therapeutic target for alleviating PTSD-related conditions in women.

Physiological differences in human brains

These findings may be relevant to humans, in which H2A.Z is also present. H2A.Z is involved in the regulation of transcription and DNA repair, and has been similarly implicated in diverse biological processes, including memory.

Physiologically, trauma is shown to have divergent effects in male and female brains. The hypothalamus-pituitary axis, which is a central stress response system, seems to be more sensitized in female brains, while the hyperarousal system, which leads to heightened state of anxiety, appears to be more sensitized in male brains.

These sex differences in responses to stress and trauma, observed in both mice and humans, point to a potential need for sex-specific therapies in treating PTSD. Currently, there are a variety of treatments for PTSD, including cognitive behavioural therapy and pharmacotherapy. While women and men may respond differently to PTSD therapies, the current literature regarding the sex differences in therapy outcomes is largely limited and warrants further investigation.