Gender Differences in the Stressed-Out Brain

New neuroscience complicates gender theories which maintain that behavior is shaped by social expectations

By Signe Brewster

Press an American to explain the differences between men and women and you will get a whole gamut of answers. They might say women are more emotional. Or, they might say the only fundamental differences are reproductive organs and hormones, that everything else is a product of social expectations (i.e. nurture over nature).

Both answers are questionable. Until now there hasn’t been much neuroscience to prove it, but that’s all going to change soon. In February, the National Institutes of Health made it a requirement for grant applications to report the sex of the animals used in experiments.

Previously, most stress research had been conducted only on male mice. In response to the gender bias, a team of neuroscientists decided to conduct a study that compared the way the brains of male and female mice respond to stress. Their research, published in the Journal of Neuroscience in December, found that male and female mice both exhibit neurological signs of depression when they are stressed, but female mice show changes earlier.

The researchers identified a particular gene that is more active in female mice in response to stress. They then silenced this gene in female mice, causing them to produce the “male” pattern of genetic response that made them more resilient to stress. The researchers also overactivated the gene in males, replicating the “female” genetic response and making the males more prone to stress-induced depression. According to the introduction to the study, this same gene has been found to be overactivated in particular brain regions of depressed humans.

“The attitude has been that females were males plus estrogen,” says researcher Georgia Hodes of the Icahn School of Medicine at Mount Sinai, who led the study. “As much as males and females can do the same thing, their biology isn’t the same and we need to be cognizant of this when we come up with medical treatments.”

University of California, Irvine, neurobiology professor Larry Cahill has spent years speaking out about the differences between male and female brains, and calling for change at the basic research level.

“If there are sex influences on brain function everywhere, at all levels, and as a field we’re still pretending they’re not there, that’s bad. That’s bad in particular for women.”

– Larry Cahill

“Our history of understanding biological differences in the brains of men and women is that we haven’t tried to understand it,” Cahill says. “We haven’t tried to understand it because we overwhelmingly assumed there was nothing there to talk about it. That’s how it has been for basically the history of neuroscience.”

For decades, female subjects were mostly excluded from human clinical trials. A 1977 Food and Drug Administration guideline banned studies from including women who had the potential to become pregnant — and, as a result, develop birth defects. As scientists believed differences between men and women stopped at their reproductive differences, few questioned the omission.

The practice of relying on men for human clinical trials didn’t begin to reverse until 1988, when the U.S. government began issuing new guidelines for including women. By this time it had become clear that men and women were not the same, that they responded differently to different drugs.

“We’ve reached a critical mass of data, especially from the last 15–20 years, showing without any question anymore that there are, in fact, sex influences everywhere in brain function,” Cahill says. “We’ve already reached the main take-home message, which is…If there are sex influences on brain function everywhere, at all levels, and as a field we’re still pretending they’re not there, that’s bad. That’s bad in particular for women.”

Acknowledgement of these differences has been slow. Zolpidem, an insomnia aid commonly called Ambien, was approved in 1992. It took 20 years for manufacturers to begin making a half-dose version for women, who were found to metabolize the drug at a much slower rate, putting them at risk of impaired driving the morning after taking the pill.

“Pretty much any drug developed before the 90s was probably mostly developed on men,” Hodes says. “Ambien was a big wake up call.”

While there’s now recognition that the brain processes chemicals differently according to sex, it’s still poorly understood how these processes affect behavior. There are many steps that occur between the brain responding to a chemical and the behavior that consequently appears. Thus, merely observing that the male and female brain respond differently to stress chemicals does not necessarily explain a difference in behavior, particularly considering all the other environmental factors that shape the way a person acts. But the fact that researchers in the stress study were able to alter the behavior of male and female mice through genetic manipulation poses questions for academics who argue for the social construction of gender.

Many gender theorists maintain there’s a difference between “sex” and “gender.” Sex denotes the difference between “male” and “female” depending on biological features such as chromosomes, sex organs, and hormones. “Gender” denotes the difference between “men” and “women” depending on social factors such as behavior, dress, and role in society.

Influential feminist theorist Judith Butler holds that men and women behave differently because of what she calls “gender performativity.” She recently said in a Big Think video interview: “We act as if that being of a man or that being of a woman is actually an internal reality or something that is simply true about us, a fact about us, but actually it’s a phenomenon that is being produced all the time and reproduced all the time. So to say gender is performative is to say that nobody really is a gender from the start.”

If the distinctions between “sex” and “gender” are understood and maintained in society more broadly, then the biological differences of males and females can be medically treated while men and women are regarded as social constructions. Of course, neuroscience will complicate this easy solution if it continues to publish studies indicating that behavior, a trait associated with “gender performativity” instead of biology, can be attributed to a difference in the way the brain responds to chemicals.

Auburn University assistant professor of sociology Tal Peretz classified growing evidence of differences between the sexes as proof that the “nature vs. nurture” debate is flawed. Everyone experiences the world through his or her unique combination of gender and sex. A woman’s brain may alter itself over time due to ongoing stress experienced as a result of her gender — a biological effect based on her socially constructed role.

Myer Solis-Cohen’s 1906 book warned that improper dress can cause women’s diseases Courtesy of Wiki Commons

“I think it’s really important to understand this new research not as, ‘this is what’s nature and that’s what is nurture,’ but it’s really somewhere in the middle. We are not remotely at a place in terms of the neuroscience or in terms of understanding society to where we can say this is what’s nature and that’s what is nurture,” Peretz says. “Everything is always both.”

In the meantime, neuroscientists are pushing for recognition of biological differences, arguing that it could lead to substantial progress in women’s healthcare.

“I think we’re just starting to understand how stress may differently affect the male and female brains, which puts us ahead in places to look for target treatments,” Hodes says. “It does a disservice to women to say that they should just be treated like men. You can’t ignore half the population and say it’s not important.”

Signe Brewster is a San Francisco-based journalist who writes about emerging science, technology, and Silicon Valley. Her work has appeared in New Scientist, MIT Technology Review, and Wired.