In recent years, a great deal of attention has been devoted by brain researchers to differences among the sexes in vulnerability to stress, and in turn, to the risk for disorders including anxiety and depression. As noted by the National Institute of Mental Health, major depressive disorder and anxiety disorders are more frequently diagnosed each year among American women than men.

A wide range of factors including normally occurring fluctuations in hormone levels in women, both monthly and across the life-cycle, are part of the story. But the biological mechanisms through which differences between the sexes affect their relative vulnerability to stress remains the subject of intense research.

A newly published study addresses mechanisms operating at the cellular and subcellular levels that may mediate the differences in stress vulnerability between males and females. A team led by Juan Song, Ph.D., of the University of North Carolina, Chapel Hill, studied this question in the specific context of serotonin system, which has been deeply implicated in stress response and the regulation of mood. Dr. Song is a 2013 BBRF Young Investigator. 2020 BBRF Young Investigator Ya-Dong Li, Ph.D., was also a member of the team.

Now, in a new paper published in Cell Reports, Dr. Song and colleagues demonstrate how sex-specific expression of distinct cellular receptors for serotonin in neural precursor cells in the mouse hippocampus appear to account at least in important part for the differential vulnerability to stress of male and female mice.

The mouse brain, thanks to evolution, is both structurally and functionally very closely related to the human brain and has long been used to study processes that cannot readily be studied in people. In the case of the new study, experiments were performed that included genetically “knocking out” a specific type of serotonin receptor in hippocampal neural precursor cells, something that cannot be done in people.

Dr. Song is an expert on the process called neurogenesis, or the birth of new neurons, in the adult brain. BBRF Scientific Council member and past prize winner and grantee René Hen, Ph.D., was among the pioneers who forged linkages between new nerve cell birth during adulthood and mood disorders. He and others have shown that the response to some antidepressant treatments corresponds with robust adult neurogenesis, as does vulnerability to chronic stress.

The cells that give rise to new neurons are neural stem cells (or NSCs). NSCs that are active in a portion of the hippocampus called the dentate gyrus are the source of much adult neurogenesis in mice and people.

Dr. Song’s team was interested in how, in NSCs of the hippocampus, the expression of specific subtypes of serotonin receptors differs in males and females, and how stress interacts with distinct serotonin receptor types to regulate adult neurogenesis.

There are seven classes and a total of 14 subtypes of serotonin receptors—basically, docking ports for the neurotransmitter—in cells of the hippocampus. The team focused on the serotonin 1A receptor (called H5T1A by scientists), which is the most studied serotonin receptor subtype in the context of stress response, depression, antidepressant efficacy, and regulation of adult hippocampal neurogenesis.

Past studies have shown that administering agents that stimulate or suppress the activity of serotonin 1A receptors have the effect, respectively, of increasing and decreasing the proliferation of the NSCs that give rise to new neurons. The mechanisms accounting for this remain unknown.

The team used genetic modification to effectively delete serotonin 1A receptors in hippocampal NSCs, in mice of both sexes—both at “baseline,” and after they were exposed to repeated stress. In female mice, deletion of serotonin 1A receptors reduced the pool of NSCs that are the basis for adult neurogenesis. This was accompanied by increased expression of a different serotonin receptor type, the serotonin 7 receptor. Increased serotonin 7 receptor expression in hippocampal NSCs was also observed when female mice were subjected to stress.

In contrast to females, males at baseline, i.e., not under stress, tend to express the serotonin 7 receptor in hippocampal NSCs. This might be expected to make them vulnerable when under stress—but the research found that “males appear to develop adaptive strategies” to keep signaling at serotonin 7 receptors at low levels when they are under stress. This seems to enable them to prevent their pool of NSCs from being depleted when under stress.

This basic difference in how serotonin receptor subtypes are expressed in hippocampal NSCs in males and females, and how the serotonin system responds when they are under stress, may provide “a general mechanism,” the team said, for understanding how vulnerability to stress differs between males and females.

On the basis of their experiments the researchers concluded that maintenance of serotonin 1A receptors and/or their activity in hippocampal NSCs may provide “an inhibitory tone” that is essential for maintaining the pool of NSCs that adult neurogenesis—and by implication, stress resiliency—requires.

The team notes that the type 1A and type 7 serotonin receptors are structurally and functionally dissimilar, and the nature of their relationship and interaction under conditions of stress are important to understand more fully. The current study, for its part, does indicate, they said, a sex-dependent role for the type 1A receptor in regulating the function of the hippocampus under conditions of stress. A reduction in hippocampal neural precursors and in hippocampal neurogenesis “may predispose females to enhanced responses to future stress and development of depressive behaviors.”

Pursuit of these new clues to the different responses of males and females to stress are part of the much larger effort among researchers to develop personalized treatment strategies that could, for instance, specifically respond to inherent biological differences and resulting vulnerabilities to stress among the sexes.