From The Quarterly, Summer 2014

This May, Francis Collins, M.D., Ph.D., Director of the National Institutes of Health, co-authored a much-discussed commentary in the journal Nature reminding scientists of the need to test their theories on both males and females, in experiments ranging from animal models of disease to human clinical trials. More studies will now be required to include females in their study samples to be approved for funding.

For researchers who study the impact of stress on the brain, this came as a welcome message. For years, their observations have shown striking differences in the response of males and females to stress. It is well known that male rodents are more likely than females to be adversely affected by low to moderate levels of repeated, “subchronic” stress.* But why?

A major step forward in understanding the biology behind this phenomenon has been taken by a research team led by Zhen Yan, Ph.D., of the State University of New York, Buffalo (1999 and 2004 NARSAD Grantee). The team included Foundation Scientific Council member Bruce S. McEwen, Ph.D., of The Rockefeller University (also a 1998 NARSAD Distinguished Investigator Grantee) and Ilia N. Karatsoreos, Ph.D., a 2013 NARSAD Young Investigator Grantee at Washington State University, Pullman.

In the May 2014 issue of Molecular Psychiatry, the team reported a series of clear distinctions in the responses of male and female rats to a week of repeated, subchronic stress.* As expected, females showed no impairment in a memory test given at the end of the stress period, while males were clearly impaired. The test measured the function of a cognitive system centered in the brain’s prefrontal cortex (PFC),* and specifically the integrity of nerve transmission in excitatory neurons,* activated by the neurotransmitter glutamate. But when the team then blocked receptors, or docking ports, for the hormone estrogen located on the surface of PFC excitatory neurons* (or eliminated them altogether), female rodents no longer were protected against the ill-effects of repeated stress. They showed memory impairments just as stressed males did. Conversely, when a version of the female hormone was injected into stressed males, they experienced no memory impairments, just as normal stressed females had.

"The results suggest that estrogen protects against the detrimental effects of repeated stress” in glutamate-activated neurons, in tasks centered in the PFC, the scientists concluded. Important though this sex difference is, it is specific to subchronic stress. For, as the team notes, over the lifespan, women are more likely than men to experience major depression.

Both phenomena are the consequence of biological differences. Women’s lifetime vulnerability to major depression is understood to be a result of hormonal fluctuations related to the reproductive cycle and child-bearing. As for the biological difference accounting for female protections against at least some forms of stress, the new study points to hormones, but specifically to the ability of brain cells to locally synthesize estrogen—an ability confirmed in this study. It would be one of the fundamental brain differences among the sexes that Dr. McEwen has devoted much effort to studying throughout his celebrated career.