UB Study Reveals Molecular Cause of Female Stress Resilience

The study, published in Molecular Psychiatry by the Nature Publishing Group, also points toward possible therapies to help males improve their response to stress.

The research team found that female rats respond better to stress due to the enzyme aromatase, which produces estradiol—an estrogen hormone.

Levels of this enzyme were significantly higher in the prefrontal cortex of female rats when compared to male counterparts.

The protective effect was present even in females whose ovaries were removed, suggesting that brain-produced estrogen provides this stress-resistant benefit.

The researchers exposed young rats of both genders to periodic physical restraint stress for a week, producing a safe but challenging condition, such as when humans feel frustrated or under pressure, notes senior author Zhen Yan, PhD, professor of physiology and biophysics.

Females had no difficulty recalling and recognizing objects they were shown previously, whereas male rats exhibited impaired short-term memory.

An impaired ability to remember a familiar object correctly signifies a disturbance in the prefrontal cortex’s glutamate receptors.

This brain region of the prefrontal cortex controls high-level executive processes, including working memory, attention, decision-making and emotion, all of which depend on the excitatory signaling mediated by glutamate receptors.

The glutamate receptors in the prefrontal cortex stay intact in stressed females, the researchers discovered. However, a previous study by Yan’s group (published in Neuron, 2012) found a loss of these receptors when young male rats were subjected to repeated stress.

These findings also add to a growing body of evidence identifying the glutamate receptor as the molecular target of stress and the mediator of the stress response.

By manipulating the amount of estrogen produced in the brains of rats, the researchers made males respond to stress more like females and females respond more like males.

Blocking estrogen signaling in the brains of stressed females caused detrimental effects, explains Yan.

Conversely, activating estrogen signaling in males succeeded in blocking the detrimental effects of stress.

“If we could find compounds similar to estrogen that could be administered without causing hormonal side effects, they could prove to be a very effective treatment for stress-related problems in males,” she says.

Such a therapy could therefore potentially alleviate or prevent more serious conditions, including psychiatric disorders, which stress can trigger in vulnerable individuals.

The study, “Estrogen Protects against the Detrimental Effects of Repeated Stress on Glutamatergic Transmission and Cognition,” was conducted by the following researchers from the Department of Physiology and Biophysics: first author Jing Wei, PhD, postdoctoral associate, and Eunice Y. Yuen, PhD, former research assistant professor; Xiangning Li, PhD, postdoctoral associate and Ping Zhong, PhD, research scientist.

They collaborated with co-authors from Washington State University and Rockefeller University.

The research was funded by the National Institute of Mental Health, part of the National Institutes of Health.