Saturday, November 27

They discover a neural circuit related to female fertility and menopause



Scientists have known for a century that females become more active just as they are about to ovulate, a behavior that evolved to increase their chances of mating when they are fertile.

Now, a team from the University of California (UC) in San Francisco has identified the neural circuitry and signaling pathway that cause sexually receptive females of many species to increase their physical activity in this critical moment of their lifes.

The work was done in mice, but the researchers hope it will be confirmed in humans, since behavior is related to a fundamental aspect of life.

The discovery also illuminates what happens at menopause when the loss of estrogen disrupts this circuit of activity.

At that point, both mouse and human females become more sedentary, gain weight, and develop metabolic disorders such as type 2 diabetes.

The discovery offers the possibility of a new type of treatment for menopause that avoids the negative effects of estrogens and energizes the neuronal circuit of female activity with genetic technology (CRISPRa).

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How the neural circuit works

How the neural circuit works When estrogen bathes the brain, it interacts with the estrogen receptor α (ERα) to activate a gene called Mc4r. This interaction produces melanocortin-4 receptors (MC4R) on the surface of estrogen-sensitive neurons in a part of the brain called the ventrolateral ventromedial hypothalamic nucleus (VMHvl), which regulates how energy is used in adult women.

The team identified two sites in the brain where ERα binds to Mc4r to regulate its activity, thus establishing a clear link between the hormone receptor and the gene.

To their surprise, the team also discovered that VMHvl neurons activated by this circuit project into a part of the hippocampus equipped with “speed cells” that control how fast the mouse moves.

These neurons also project into a region of the rhombencephalon that mediates sexual receptivity and physical activity.

Known gene

Known gene The gene at the center of this circuit, Mc4r, is well known for its role in regulating energy, appetite and weight in adult women – mutated forms of the gene cause obesity, which is particularly serious in women.

The MC4R receptor is also the target of bremelanotide, which is marketed under the brand name Vyleesi to treat a condition called hypoactive sexual desire disorder (HSDD) in premenopausal women.

To make sure the neurons were actually making the mice more active, the researchers used a chemogenetic technique called DREADD (Receptors Activated Exclusively by Designer Drugs) to make VMHvl neurons express a receptor that could only be activated by a chemical. harmless added to your water.

Weightloss

Weightloss When their VMHvl neurons were stimulated in this way, both males and females became more active and the females even lost almost 10 percent of their body weight after 24 hours of continuous administration. Inhibiting these neurons had the opposite effect, making the women more sedentary.

The same happened in female mice that lacked ovaries and had been put on a high-fat diet. A single instance of DREADD stimulation reversed the damaging metabolic effects of both estrogen depletion and diet-induced obesity. Long-term administration caused the obese mice to lose weight dramatically and improve their overall metabolic health.

The team also used CRISPRa, a technique that upregulates gene expression without changing the gene itself, to increase the activity of Mc4r.

Both males and females became more active, but the effects were stronger in the females and their bones became thicker. However, they did not lose weight, probably because they also ate more.

Importance of estrogen

Importance of estrogen The results of this study add to the debate about hormone replacement therapy for menopausal symptoms. Many doctors stopped prescribing it after an influential 2002 study found it slightly increased the risk of endometrial and breast cancer, as well as blood clots and stroke, the scientists explain.

The authors of this research consider, in light of their discovery, that this reaction should be reviewed.

“Estrogen has a profound effect on behavior and can make a difference in your well-being,” explains lead author Holly Ingraham in a release.

“Let’s at least find out what he’s doing, so maybe we can avoid it and get those positive estrogen effects in another way, through another drug, another target. Until we have that, women are just going to be stuck with, ‘You’re not going to have what makes you feel better.’ That is why I am so passionate about this research, “he concludes.

Reference

Reference Oestrogen engages brain MC4R signalling to drive physical activity in female mice. William C. Krause et al. Nature (2021). DOI:https://doi.org/10.1038/s41586-021-04010-3

Top photo: Alicia Petresc. Unplash.


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