A team at UC San Francisco has identified the specific neurons and signaling pathways that make sexually receptive females of many species run or feel inclined to be active around their ovulation time. The study was published in Nature.
“As we discover what estrogen does in the brain, we’re probably going to discover more of its benefits,” lead researcher Holly Ingraham said. “This is just one area in the brain, and it has a powerful effect. We’d also like to know more about other circuits in the brain that affect well-being and cognition.” The team created a precise map of where proteins attach to DNA. The technique used, 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 the VMHvl neurons activated by this circuit project into a part of the hippocampus equipped with “speed cells” that control how fast the mouse moves. The neurons also project into a region of the hindbrain that mediates sexual receptivity and physical activity.
To be sure the neurons really were making the mice more active, the researchers used a chemogenetic technique called DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) to make the VMHvl neurons express a receptor that could only be activated by a harmless chemical added to their water. When their VMHvl neurons were stimulated that way, both male and female mice became more active, and the females lost nearly 10 percent of their body weight after 24-hours of continuous administration. Inhibiting these neurons had the opposite effect, making females more sedentary.
The same thing happened in female mice that lacked ovaries and had been put on a high-fat diet. A single instance of DREADD stimulation reversed the harmful metabolic effects of both estrogen depletion and diet-induced obesity. Long-term administration caused obese mice to slim down dramatically, and it improved 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 male and female mice became more active, but the effects were stronger in females, and their bones grew thicker. They did not lose weight, however, most likely because they also ate more.