A new study at Yale shows that high levels of estrogen may render the brain more susceptible to the detrimental effects of stress.

These findings may explain why stress-related mental illnesses including depression, phobias and post-traumatic stress disorder (PTSD) occur at least twice as often in women and decline after menopause.

Stress is known to affect the prefrontal cortex (PFC) function in the brain, which plays a role in memory and cognitive function. Many of the stress-related and anxiety disorders more prevalent in women have been shown to cause irregular PFC function. This is also true in animals, though until now sex differences in this phenomenon had not been studied.

Researchers Becca Shansky GRD ’05 and Yale School of Medicine associate neurobiology professor Amy Arnsten found that both genders of mice performed equally well while stress-free, and both made many memory errors under high stress.

However, female mice with high levels of estrogen performed much more poorly on memory tasks while under low stress, which had no effect on male mice.

Shansky said while estrogen plays an important role in accounting for this performance disparity, the specific biological basis has yet to be determined.

“So far, we don’t see any difference in these animals, between the male and female, when their estrogen levels are low, either when females are in a low-estrogen level in their cycles, or the ovaries have been removed,” she said. “It’s pretty clear [that estrogen is causing these disparities], but how that’s happening, we don’t know yet.”

Arnsten said a possible explanation is that estrogen affects cell pro cesses in the PFC to hamper its function in stressful situations.

“It looks like estrogen is promoting receptors and intracellular changes that promote the stress response and reducing receptors that normally diminish the stress response,” Arnsten said.

These findings may be important in refining the treatment of stress-related disorders in women.

“[Stress-related mental illnesses] are known to affect the prefrontal cortex, and if we can figure out what the mechanism is, maybe we can figure out a new target for antidepressants,” Shansky said. “We’re trying to identify — what drugs would effect these intracellular signaling pathways.”

This study shows that PFC dysfunction corresponds with the activation of a gene called CREB1, which encodes for a regulatory protein that controls the expression of many other genes in the brain. Previous studies have shown that mutations in CREB1 are linked to major depressive disorder (MDD), which affects 15 percent of the population and is more prevalent in women. This mutation only occurs in females, particularly young women.

“Our data indicates that the molecular signals that cause prefrontal cortex dysfunction activate CREB1, so our studies provide a link to [previous] genetic studies in humans,” Arnsten said. “It would suggest that estrogen in combination with this mutation may overamplify the processes [that cause MDD] and make a particular subset of women especially susceptible to recurrent [MDD].”