Scientists Map Brain Circuits That Promote Fertility Women’s Activities

Figure 1: VMHvl neurons are sensitive to estrogen and maintain energy expenditure in adult female mice. Credit: DOI: 10.1038 / s41586-021-04010-3

Scientists have known for a century that female animals become more active when they are about to ovulate. This behavior has evolved to increase the likelihood of mating during childbirth.

Currently, a team at the University of California, San Francisco has identified specific neurons and signaling pathways that run around many species of sexually receptive females during this critical period. Although the work was done in mice, researchers expect it to be tolerated by humans, as behavior is associated with such basic aspects of life.

“Why do you want to get up and move?” He is a professor of molecular physiology at the University of California, San Francisco. Nature.. “Well, if you activate the circuits of these neurons, that’s probably the reason.”

This finding also reveals what happens during menopause as estrogen loss disrupts this circuit of activity and makes both mouse and human women more sedentary. Gain weight, Develop metabolic disorders such as type 2 diabetes. And it offers the possibility of treating a new kind of menopause that avoids estrogen and reactivates the circuit with CRISPRa technology.

“As we discover what estrogen does in our brains, we’ll probably discover many of its benefits,” Ingraham said. “This is just one area of ​​the brain that has powerful effects, and I would also like to know about other circuits in the brain that affect well-being and cognition.”

When estrogen soaks the brain, it interacts with the estrogen receptor α (ERα) to activate a gene called Mc4r. This produces melanocortin 4 receptors (MC4Rs) on the surface of estrogen-sensitive neurons called the ventrolateral ventromedial hypothalamic nucleus (VMHvl), which is part of the brain, and regulates the use of energy in adult women.

The research team uses techniques established in the brains of living mice by co-lead author Dr. Jessica Tolkoon, an assistant professor at the Cold Spring Harbor Laboratory in New York, to pinpoint where proteins attach to DNA. I created a map. A technique called CUT & RUN or targeted cleavage and release using nucleases identifies two sites where ERα binds to Mc4r and regulates its activity, establishing a clear link between hormone receptors and genes. Did.

Surprisingly, the team also discovered that VMHvl neurons activated by this circuit project onto parts of the hippocampus with “speed cells” that control the speed of mouse movement. Neurons also project to areas of the retencephalon that mediate sexual receptivity and physical activity.

The gene Mc4r at the heart of this circuit is well known for its role in energy, appetite, and weight regulation. Adult woman, And genetic variants cause particularly severe obesity in women.

The MC4R receptor is also the target of blemelanothide, sold under the brand name Vyleesi, to treat a condition called acquired systemic sexual desire disorder (HSDD) in premenopausal women.

To ensure that neurons are actually more active in mice, researchers use a chemical generation technique called DREADD (Designer Receptors, which is exclusively activated by Designer Drugs) that is harmless to VMHvl neurons. Water that expresses receptors that can only be activated by the addition of chemicals.

When VMHvl neurons were so stimulated, both male and female mice became more active, and after 24 hours of continuous administration, females lost nearly 10 percent of their body weight. Inhibiting these neurons had the opposite effect, making women more sedentary.

The same thing happened in female mice that had no ovaries and were fed a high-fat diet. A single instance of DREADD stimulation reversed the harmful metabolic effects of both estrogen depletion and dietary obesity. Long-term administration dramatically reduced obese mice and improved overall metabolic health.

The team also increased the activity of Mc4r using CRISPRa, a technique that upregulates gene expression without altering the gene itself. Both male and female mice became more active, but the effect was stronger in females and their bones became thicker. They didn’t lose weight, but probably because they also ate more.

“These data not only underscore the important role of Mc4r in promoting these activities, but are also exciting. NeuronBut they also suggest how gene therapy tools are adapted to target lucrative factors downstream of estrogen signaling, “says the University of California, San Francisco, Cell Molecular Drugs. Dr. William Klaus, the lead author of the Faculty of Science researcher, said.

The beneficial results are added to the discussion of hormone replacement therapy for the symptoms of menopause. Many doctors stopped prescribing after finding in an influential 2002 study that they had a slightly increased risk of endometrial and breast cancer, as well as blood clots and stroke.

But Ingraham said it was worth seeing again.

“Estrogen can have a big impact on behavior and make a difference in your well-being,” she said. “At least find out what it’s doing, and then avoid it and estrogen Another method, another drug, another target. Until that happens, women stick to “you can’t get anything that makes you feel good.” So I am very passionate about this research. ”

Studies provide new insights into menopause and weight gain

For more information:
William C. Krause et al, estrogen, is involved in MC4R signaling in the brain and promotes physical activity in female mice. Nature (2021). DOI: 10.1038 / s41586-021-04010-3

Quote: Scientists are fertile women obtained on October 14, 2021 from https: // (October 14, 2021) Maps brain circuits that promote day) activity

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Scientists Map Brain Circuits That Promote Fertility Women’s Activities

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