Female brain forms fear memories through unique molecular process

Women are twice as likely as men to develop post-traumatic stress disorder (PTSD) - and new research may offer a biological clue as to why.

A Virginia Tech study found that the female brain forms fear memories using a molecular process not seen in the male brain.

The findings suggest that treatments for PTSD may need to be tailored differently for men and women, said the study's lead researcher, Timothy Jarome, an associate professor of neurobiology in the School of Animal Sciences located within the College of Agriculture and Life Sciences.

Women are more likely to have PTSD than men, but they don't report experiencing more traumatic events. This points to a neurobiological mechanism that's engaged in females during a traumatic event, and it may help explain the difference we see in PTSD."

Timothy Jarome, associate professor of neurobiology, School of Animal Sciences, Virginia Tech

Published in the journal Behavioural Brain Research, the study identifies a previously unstudied molecular tag in the brain known as K27 polyubiquitination that appears to play a key role in how the female brain stores fear memories.

Mapping fear memory

Using rats, researchers examined two regions of the brain tied to fear and memory: the hippocampus, which helps connect experiences to places, and the amygdala, which processes fear and emotion.

The team found that levels of K27 polyubiquitination rose in the hippocampus of females after a fear-learning experience, but not in males. When researchers reduced K27 ubiquitination using a gene-editing technique, they found that females had trouble holding onto the memory, while males were unaffected.

"Just because males and females can learn or remember the same experience doesn't mean how their brains get there is the same," Jarome said. "If we're developing treatments for conditions like PTSD or trying to improve memory, we may need different approaches for males and females."

In the amygdala, the team saw no significant change in K27 polyubiquitination levels after the fear-learning task.

"That was a bit surprising," Jarome said. "We would typically expect the amygdala to be where you'd see a lot of this happening because it's so important in emotion. But we saw it in a broader memory region, and it was specific to one sex."

The researchers also found that K27 polyubiquitination attaches to a protein called ACAT1 in the hippocampus during memory formation in females. ACAT1 has been linked to Alzheimer's disease, which affects the hippocampus and disrupts memory, raising the possibility that it may play a role in both memory formation and loss, Jarome said.

Students advance memory disorder research

Jarome's lab focuses on understanding the molecular mechanisms behind memory disorders, including Alzheimer's disease, dementia, and PTSD, with the goal of finding better ways to treat them. This project and its student research team were funded by a grant from the National Institute of Mental Health.

Students - both graduate and undergraduate - played a central role in the research. Former Ph.D. students Morgan Patrick and Shannon Kinkaid served as the study's lead authors, alongside a multidisciplinary team of student researchers and collaborators across Virginia Tech. 

Jarome and his team are now studying other forms of polyubiquitination - a molecular tagging system cells use to regulate proteins - to see how each may differ between males and females. There are eight known forms of this tag, and early evidence suggests at least one may be more active in males.