High estrogen levels in brain may increase women's risk of stress-related memory issues

Findings of UC Irvine-led study could lead to new ways of addressing PTSD, dementia

Orange, Calif. — Experiencing multiple acute stresses at the same time, as in natural disasters or mass shootings, can leave lasting memory scars. New research from UC Irvine suggests that levels of estrogen in the brain may play a surprising role in this vulnerability, especially for women. The study, published today in Neuron, provides insight into why women are more likely than men to develop post-traumatic stress disorder and face higher dementia risk later in life.

Led by Tallie Z. Baram, PhD, Distinguished Professor of pediatrics, anatomy & neurobiology, and neurology at the UC Irvine School of Medicine, the research found that exposure to several simultaneous stressors can lead to persistent memory problems, difficulty recalling events and heightened responses to reminders of trauma. These impairments can last for weeks or months, whereas a single stressful event does not produce the same effects.

Estrogen is widely known to support learning and memory. But this study revealed that high levels of estrogen in the hippocampus, a brain region critical for memory, can increase vulnerability to stress-related memory problems. When female mice were exposed to stressors during hormonal cycle phases when estrogen levels were high developed enduring memory loss and heightened fear of trauma reminders, while lower estrogen levels were protective. Males, who naturally produce high estrogen levels in their hippocampus, were also susceptible, though more mildly and through different estrogen receptor pathways.

High estrogen changes how genes in brain cells are “switched on” by loosening DNA structure, a state called permissive chromatin. Normally, this flexibility is advantageous because it helps with learning and adaptation. But during extreme stress, it can allow harmful, enduring changes in memory circuits.

“High estrogen is essential for learning, memory and overall brain health,” said Baram, who’s also a Donald Bren Professor and Danette Shepard Chair in Neurological Studies. “But when severe stress hits, the same mechanisms that normally help the brain adapt can backfire, locking in long-lasting memory problems.”

Memory issues are driven by different estrogen receptors in men and women – alpha in men and beta in women. Blocking the relevant receptor prevented stress-related memory problems even when estrogen levels remained elevated, highlighting potential targets for sex-specific therapies.

“A lot of what determines vulnerability is the state your brain is already in,” said co-author Elizabeth Heller, PhD, associate professor of pharmacology at the University of Pennsylvania Perelman School of Medicine. “If a traumatic event hits during a period when estrogen is already unusually high, the biology can amplify the impact in lasting ways. This study shows that a state of high estrogen in a specific brain region promotes vulnerability to stress in both male and female subjects.”

Women were found to form stress memories faster, generalize fear more readily and experience longer-lasting effects than men. Importantly, vulnerability depends on hormone levels at the time of stress, not afterward. These results help explain why traumatic events such as natural disasters, mass violence and assaults can cause long-term memory problems and why women are roughly twice as likely as men to develop PTSD.

Supported by the National Institutes of Health, the study was conducted by researchers from UC Irvine, the University of Pennsylvania Perelman School of Medicine and the University of British Columbia.