Guess which sex behaves more erratically... at least in mice

For decades, male mice have been the default in scientific experiments that test new drugs or examine the connections of the brain. The reason? Female mice, which experience a four- to five-day cycle of fluctuating ovarian hormones, were thought to be too complicated. Accounting for the hormonal changes was viewed as too cumbersome and too expensive.

But the estrous cycle has little to do with how female mice behave, according to a new study that used machine-learning software to track the second-to-second behavior of animals exploring an open space. Male mice actually exhibited more erratic behavior than females did. The study, published in the journal Current Biology on Tuesday, challenges century-old stereotypes that kept female animals out of laboratory research — and, until the 1990s, barred women from clinical trials.

The new research is “tipping all of these assumptions about sex differences and the influence of hormones on their head,” said Rebecca Shansky, a behavioral neuroscientist at Northeastern University and a co-author of the new study.

The cost of excluding females — whether human or animal — from scientific research is high. Women are almost twice as likely as men to experience severe side effects from drugs, most of which have dosages based on the initial testing done in men. Women also may not derive the same benefits from the drugs.

Women “capable of becoming pregnant,” as the federal government put it, were largely excluded from clinical trials of drugs until 1993, when a new law required researchers funded by the National Institutes of Health to include women and minority groups. In the decades since, women have made up close to half of clinical research participants, though they still lag behind in studies of certain drugs, like those used to treat cardiovascular disease and psychiatric disorders.

But a large sex gap persisted in basic science research using lab animals, studies that pave the way to medical breakthroughs. In neuroscience, according to a review published in 2010, studies of male lab animals outnumbered female ones by a factor of five.

“That disconnect between what was in the lab and what was in the clinic was of concern,” said Dr. Janine Clayton, director of the Office of Research on Women’s Health at the N.I.H. “Lots of studies were only employing male mice, with no scientific justification.”

Male mice exhibited more unpredictable behavior than females did. Hormones in males also fluctuate, typically changing over the course of a day. And male mice that are housed together establish a dominance hierarchy, with alpha males expressing more than 10 times as much testosterone as the submissive ones. “So it could be that actually, for 100 years, we’ve had it exactly backwards — it’s really variation in male hormones that’s affecting behavior more greatly than female hormones,” Dr Sandeep Robert Datta, a neurobiologist at Harvard Medical School who is a co-author of the study said. “That’s a hypothesis, but it’s one we’re going to test.” The new report is the latest of several studies to make scientists question longstanding assumptions about the impacts of hormones in female lab animals.

Ghorayshi covers the intersection of sex, gender and science for NYT©2023

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