Why male mice tolerate stress better than females

Why male mice tolerate stress better than females

It's a well-known fact that our social and emotional behaviors—and disorders associated with these behaviors— vary between men and women. For example, autism is more prevalent among men, while anxiety-related disorders tend to be more common in females. Differences in hormone levels and brain circuitry are thought to contribute to this variation, but the specific mechanisms responsible are not well understood.

Now, scientists at Rockefeller University have identified a key molecule within this circuitry that is responsible for relieving anxiety. Intriguingly, it doesn't appear to reduce anxiety in female mice, only in males.

Researchers demonstrated that a protein called corticotropin releasing hormone binding protein (CRHBP) reduces anxiety in male mice by halting the activity of a stress-inducing hormone. Published in Cell, the results may provide insights into new therapies for anxiety-related conditions.

In this study, the researchers asked what this particular cell type does in a male brain, suspecting from previous research on oxytocin that the stress response may be affected. Using optogenetics, a technique in which these neurons were engineered to fire in response to light, they examined the mice performing several tasks to test their anxiety levels.

"If mice are anxious, they won't go out into unprotected areas," says senior author. "We found that if you activate these cells in males, they will leave the protected area more often, meaning they are less anxious. But in females, activating these cells made no difference in anxiety."

These findings suggest that different behaviors are affected in male and female mice when these neurons are activated by oxytocin: anxiety is reduced in males, while social behavior is increased in females.

Researchers next sought to identify the molecular mechanisms at play in these varied responses. Using a technique known as TRAP they looked for proteins produced by the oxytocin-sensing neurons. The CRHBP protein was among the most abundantly produced in these cells.

"Our findings led us to propose a signaling pathway in these neurons in which oxytocin stimulates production of CRHBP," says the senior author. "CRHBP then binds to a hormone called corticotropin-releasing hormone, preventing it from performing its normal job to increase stress."

The question then became, why is the anxiety-reducing effect of CRHBP dominant in males, but doesn't seem to work in females? Further experiments revealed that corticotropin-releasing hormone levels are much higher in females to begin with. One possibility is that CRHBP can't lower corticotropin-releasing hormone levels enough in females to make a difference. In males, however, it lowers the level of the stress hormone below a threshold that matters behaviorally, and effectively decreases stress and anxiety.

These results may explain how oxytocin can both promote social behaviors in females and alleviate stress and anxiety in males. And they suggest that while the brain circuits that control male and female behaviors may look exactly the same, they still function differently because they don't respond the same way to certain hormones.

"But even though our findings may provide some insight into gender differences, they are even more important for understanding what may be different between individuals," senior author says. "Emotional and social behaviors are complicated, so finding any clues to why some people are more vulnerable to anxiety than others, or why some are social while others aren't, matters. These are fundamental questions of human behavior that we don't yet understand fully."




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