Scientists map the brain circuit that drives activity in fertile females


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

Now, a team from UC San Francisco has identified the specific neurons and signaling pathway that are running sexually receptive females of many species at this critical time. The work was done in mice, but researchers expect it to be confirmed in humans because the behavior is linked to such a fundamental aspect of life.

“Why do you want to get up and move? Asked Holly Ingraham, PhD, Herzstein professor of molecular physiology at UCSF and lead author of the study published in Nature. “Well, if you turn on the circuit in these neurons, maybe that’s why.”

The finding also sheds light on what happens during menopause, as loss of estrogen disrupts this circuit of activity, and human mice and females become more sedentary, gain weight, and develop metabolic disorders like type 2 diabetes. And it offers the possibility of a new type of menopause treatment that bypasses estrogen and reactivates the circuit with CRISPRa technology.

“As we find out what estrogen does in the brain, we’ll likely discover more of its benefits,” Ingraham said. “This is just one area of ​​the brain, and it has a powerful effect. We would also like to learn more about other brain circuits that affect well-being and cognition.

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

The study team created an accurate map of where proteins attach to DNA, using technology established in the brains of living mice by lead co-author Jessica Tollkuhn, PhD, assistant professor at the Cold Spring Harbor Laboratory in New York. The technique, called CUT & RUN or Cleavage Under Targets and Release Using Nuclease, identified two sites 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. Neurons also project into an area of ​​the hindbrain that mediates sexual receptivity and physical activity.

As we learn more about what estrogen does in the brain, we are likely to discover more of its benefits. It is only one area of ​​the brain and it has a powerful effect.

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

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

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

When their VMHv1 neurons were stimulated in this way, male and female mice became more active and females lost nearly 10 percent of their body weight after 24 hours of continuous administration. Inhibition of these neurons had the opposite effect, making women more sedentary.

The same thing happened in female mice that lacked ovaries and were put on a high fat diet. A single example of DREADD stimulation reversed the harmful metabolic effects of estrogen depletion and diet-induced obesity. Long-term administration caused obese mice to lose weight considerably and improve their overall metabolic health.

The team also used CRISPRa, a technique that upregulates gene expression without altering the gene itself, to increase Mc4r activity. Male and female mice became more active, but the effects were stronger in females and their bones became thicker. However, they did not lose weight, possibly because they also ate more.

“These data are exciting not only because they highlight the key role of Mc4r in these activity-promoting neurons, but also because they also suggest how gene therapy tools could be adapted to target beneficial factors downstream. of estrogen signaling, ”said lead author William Krause, PhD, a researcher in the Department of Cellular and Molecular Pharmacology at UCSF.

The beneficial results add to the debate over hormone replacement therapy for menopausal symptoms. Many doctors stopped prescribing it after an influential 2002 study found that it slightly increased the risk of endometrial and breast cancer, as well as blood clots and strokes.

But Ingraham said it was worth another look.

“Estrogen has a profound effect on behavior and can make a difference to your well-being,” she said. “Let’s at least see what it does, so maybe we can get around it and get these positive estrogen effects in another way, by another drug, another target.” Until we have that, women just say, “You’re not going to have what makes you feel better. This is why I am so passionate about this research.

Other study authors include Ruben Rodriguez, Navneet Matharu, Andreas N. Rodriguez, Adriana M. Padilla-Roger, Kenichi Toma, Candice B. Herber, Stephanie M. Correa, Xin Duan and Nadav Ahituv, all from UCSF ; and Bruno Gegenhuber, from the School of Biological Sciences at the Cold Spring Harbor Laboratory.

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