Stanford Medicine scientists locate key brain circuit containing the seat of male libido | News Center

Stimulation of the tract containing the Substance P-secreting BNST neurons accelerated activity in the Substance P receptor-bearing neurons in the preoptic hypothalamus, ramping up activity in the latter neurons over a roughly 90-second period, faithfully followed — after a 10- to 15-minute delay — by the full sequence of male mating behavior: mounting, penetration and ejaculation.

It turns out that when Substance P binds to its receptors on those neurons in the preoptic hypothalamus, it gradually sensitizes the neurons so they become increasingly active.

Directly infusing Substance P into the vicinity greatly accelerated the ability of the male mouse to begin mating with a willing female. Direct activation of the Substance P receptor-bearing neurons in the preoptic hypothalamus even led to mating with inanimate objects.

No rest period

Virtually all male mammals experience a so-called refractory period, a stretch of time required before full sexual drive and capability is restored after ejaculation.

For the mice used in this study, the normal refractory period is five days. But directly stimulating just the Substance P receptor-containing neurons of the preoptic hypothalamus via manipulations prompted male mice that had just ejaculated to immediately reprise their sexual mating routine all the way to a second consummation in the presence of a female mouse.

“It took one second or less for them to resume sexual activity,” Shah said. “That’s a more than 400,000-fold reduction in the refractory period.”

On the other hand, Shah said, “if you silence just this set of preoptic-hypothalamus neurons, the males don’t mate, period,” although there are no other noticeable effects.

The Substance P receptor-containing neurons in the preoptic hypothalamus connect to two downstream brain centers that are known to be critical to, respectively, voluntary movement and experiencing or anticipating pleasure.

Nature is far from footloose in its conservation of such important brain circuitry from one mammalian species to the next, Shah said.

“It’s very likely there are similar sets of neurons in the human hypothalamus that regulate sexual reward, behavior and gratification,” he said. “And they’re probably quite similar to the ones we’ve observed in mice.”

Applications for treatment of sex drive

The study’s findings could lead to drugs that serve as libidinal rheostats, capable of tamping down sex circuitry in the brains of men with hyperactive sex drives, or, alternatively, boosting sex drive in men who suffer from a lack of desire.

“If these centers exist in humans — and now we know where to look — it should be possible to design small molecules that can be used to regulate these circuits,” Shah said.

“Such drugs would be quite different from today’s phosphodiesterase inhibitors,” which counter erectile dysfunction, Shah said. “Instead of generally enhancing blood flow in small vasculature throughout the body, they would directly amplify or tamp down a specific brain area that controls male sexual desire.”

Activating the male-mouse mating circuit had no direct effect on male aggressiveness, Shah said. So, a drug that increased libido in a male by this mechanism of action would be unlikely to trigger aggressive behavior.

Shah’s group is actively seeking to elucidate the equivalent circuits in females.

Researchers affiliated with the Allen Institute for Neural Dynamics and Columbia University contributed to the work.

The study was funded by the National Institutes of Health (grants R01NS049488, R01NS104565 and R01NS050835), the National Science Foundation, the Wu Tsai Neurosciences Institute, Pew Charitable Trust, the GG Gift Fund and the PD Soros Foundation.