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How estrogen cycles change female mice’s (and possibly people’s) brains, governing sexual receptivity

A discovery about how a neural circuit located deep in the brains of female mice changes in response to estrogen could offer insight into human brains.

A discovery about a neural circuit located deep in the brains of female mice may give scientists a map to learn more about female human brains, according to a new study published in Cell and led by molecular neuroscientist Nirao Shah, MBBS, PhD.

The study pinpoints a massive cyclical change in the anatomy of a small nerve circuit deep inside the brains of female mice. It's these variations, in that single circuit, that determine the females' willingness to mate with males.

It's long been known that female mice are sexually receptive only during ovulation, which occurs every five days. But in the Cell study, Shah and his colleagues have shown why.

They found that the number of neural connections between two nearby structures in female mice's brains triples briefly at the time of ovulation, when circulating estrogen levels peak, then drops back to baseline levels as estrogen concentrations drop back to their cyclical lows.

This massive, hormone-driven waxing and waning of connectivity between the two brain structures -- absolutely essential to sexually receptive behavior in female mice, the study showed -- is also exclusive to females. The anatomical change doesn't occur in males even if they're experimentally charged up with equivalent amounts of estrogen.

"Our data suggest that the female brain is being dynamically reorganized in a dramatic fashion across the cycle," Shah told me. In a mouse, this immense rewiring-and-dismantling exercise repeats itself every five days.

Mice aren't people, of course -- and they're not pandas, either. While a mouse's ovulatory cycle is only five days long, giant pandas experience just one complete cycle a year -- a whopping 70-fold difference. Humans are intermediate, with ovulation occurring about once a month.

Also differing among mammalian species is the relationship between ovulation and sexual receptivity. In mice, ovulation drives receptivity. In rabbits, it's the opposite: Ovulation occurs only after a female has mated successfully with a male. As for us humans, it's generally accepted that ovulation and sexual receptivity -- and for that matter, behavior in general -- are independent of one another.

But Shah, whose research has revealed numerous other connections between hardwired neuroanatomic circuits and sex-differentiated behavior in mammals, pointed out that the brain structures of interest in the new study are found in a region that's similar across species.

That makes him think that hidden in the human brain could be an explanation for a range of findings related to the menstrual cycle and sex hormones in humans: For example, monthly lows of estrogen in women are accompanied by an increased incidence of migraines, seizures, dysphoria, and shortness of breath, Shah said. And there's evidence that sexual receptivity among women has a cyclical sex-hormone tie-in, too.

The origin of the nerve cells of interest -- the ventrolateral part of the ventromedial hypothalamus -- is found in humans as well as in mice. But the destination of those nerve cells in mice -- the anteroventral periventricular nucleus -- hasn't been located yet in our species. 

"It's a tiny slip of a nucleus, a mere three or four cells in diameter," said Shah, making it tough to spot via standard brain-imaging methods. Not to mention that people may not have been looking.

"Now we know exactly what's happening in mice," Shah said. "This could make it easier to figure out what's with people."

Image by geralt

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