New research from the University of California, Irvine indicates that estrogen levels in the brain may influence women's risk of developing stress-related memory problems. The study, published in Neuron, explores why women are more likely than men to develop post-traumatic stress disorder (PTSD) and face a higher risk of dementia later in life.
The research team, led by Dr. Tallie Z. Baram, Distinguished Professor at UC Irvine's School of Medicine, found that exposure to multiple acute stressors can cause persistent memory issues and heightened responses to trauma reminders. These effects can last for weeks or months, whereas a single stressful event does not have the same impact.
Estrogen is commonly recognized for its role in supporting learning and memory. However, the study revealed that high levels of estrogen in the hippocampus—a region important for memory—can make individuals more vulnerable to stress-related memory problems. Female mice exposed to stress during phases with high estrogen developed lasting memory loss and increased fear responses to trauma reminders. Lower estrogen levels appeared protective against these effects. Male mice also showed susceptibility, though less severe and through different estrogen receptor pathways.
The researchers found that high estrogen alters gene expression in brain cells by loosening DNA structure, known as permissive chromatin. While this process usually supports learning and adaptation, under extreme stress it can result in harmful changes within memory circuits.
"High estrogen is essential for learning, memory and overall brain health," said Baram. "But when severe stress hits, the same mechanisms that normally help the brain adapt can backfire, locking in long-lasting memory problems."
The study identified that different types of estrogen receptors drive these effects: alpha receptors in men and beta receptors in women. Blocking these specific receptors prevented stress-related memory issues even when estrogen levels were elevated, suggesting potential avenues for sex-specific therapies.
Researchers also observed that women form stress memories more quickly, generalize fear more easily, and experience longer-lasting effects compared to men. Importantly, vulnerability depends on hormone levels at the time of experiencing stress rather than afterward. This may explain why traumatic events such as natural disasters or mass violence lead to prolonged memory problems and why women are about twice as likely as men to develop PTSD.
The study was supported by the National Institutes of Health and involved collaboration between UC Irvine, the University of Pennsylvania Perelman School of Medicine, and the University of British Columbia.
