Neurons that comprise fewer than 0.001 per cent of all brain cells may be crucial for maintaining a pregnancy

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A tiny set of neurons deep inside the brain is fundamental to viable pregnancies in mice. These neurons are also present in human female brains and could provide clues about unexplained recurrent miscarriages and IVF difficulties.  

Nirao Shah at Stanford University, California, and his colleagues discovered the neurons while looking for gene expression changes in different parts of the female mouse brain during pregnancy. They observed a small population of neurons that completely transformed.

The levels of gene expression in these neurons changed over 30-fold when mice became pregnant for the first time, converting them to a new class of neurons that functioned in a completely different way by mid-gestation. “This cell type is exclusive to pregnancy,” the researchers write.

The previously unknown set of neurons is in an area deep in the centre of the brain called the preoptic hypothalamus, which is also involved in sexual and parental behaviours. The neurons have receptors for pregnancy-related hormones like progesterone, which may be responsible for switching the neurons on after the initial fertilisation of an egg.

Once activated, these neurons appear to coordinate the implantation of the embryo in the uterus and maintain the ongoing pregnancy. When Shah’s team created female mice without this special type of neuron, the mice were able to mate and become pregnant, but their pregnancies all ended at an early stage. This was because their embryos couldn’t implant in the lining of the uterus.

“Certainly, the fact that when you get rid of these neurons, you lose these pregnancies, is really suggestive,” says Jennifer O’Chan at the Icahn School of Medicine at Mount Sinai, New York.

These neurons comprise fewer than 0.001 per cent of all brain cells, making it remarkable that their selective elimination completely blocks the ability to establish viable pregnancies, write Shah and his colleagues.

However, further research will be required to investigate how these neurons actually do this, says O’Chan. “They’ve shown that these neurons change robustly during pregnancy, but then how are they actually communicating with the uterus? Is it hormonal? Are they secreting some kind of factor? If they could identify that, I would be very convinced.”

It would also be interesting to study whether these neurons are permanently changed by pregnancy or eventually return to their original state, says O’Chan, since her own research has found that pregnancy induces long-lasting changes in the brain.

Shah’s team also analysed an existing atlas of gene expression in the human brain and found that women have the same special set of neurons in their preoptic hypothalamus, hinting these neurons may play a similar role in human pregnancies. “You can’t do these types of experiments in humans, so we have to extrapolate here, but mouse and human brains do tend to be fairly well-conserved,” says O’Chan.

Just over half of miscarriages are known to be caused by genetic errors in the embryo, but the rest can’t be explained. For example, some people undergoing IVF have multiple embryos that appear genetically healthy, but none seem to implant once they are inserted in the uterus, for reasons that are unclear. Some who conceive naturally also have recurrent early pregnancy losses for no detectable reason.   

According to Shah and his colleagues, these fertility challenges may relate to the neurons they discovered, potentially paving the way for new treatments. “We speculate that a subset of such events reflects failure of particular neural circuits to recognize, monitor, or adapt to gestation,” they write. 

“If, for example, you found that these neurons were releasing a fundamental signalling molecule that was important for implantation, you might be able to turn that into a therapeutic for people with fertility issues,” says O’Chan.