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The Brain Circuits Behind Male Sex Drive Have Been Mapped for the First Time

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Researchers at Stanford University have identified a brain hub that controls sexual arousal in male mice. By tweaking signaling in this area, the team was able to enhance or extinguish sexual desire and even let male mice engage in sexual activity immediately after ejaculation. Researchers hope that this line of study could lead to treatments for sexual problems in human men.

The findings are published in Cell.

The principles of pleasure

“We’ve singled out a circuit in male mammals’ brains that controls sexual recognition, libido and mating behavior and pleasure,” said Dr. Nirao Shah, a professor of psychiatry and of neurobiology at Stanford and the senior author of the study.

The study meticulously explored the function and connections of this brain circuit. The researchers bred a group of male, virgin mice who were kept in isolation from female mice after they were weaned a few weeks after birth to rule out any social influences on their behavior. When these mice encountered a stranger animal and realized it was female, a brain circuit lit up. This appears to be the key location for determining mouse libido.

Once this region was activated, a series of related circuits were stimulated, including those that encouraged the mice to engage in the voluntary movements required for mating behavior and those that help anticipate and produce pleasure for the animal in response.

Forget the G-spot, it’s time for the P-spot

Shah’s previous work explored connections from the brain’s emotional center – the amygdala. His team showed that altering neurons that extended from a subregion called the bed nucleus of the stria terminalis (BNST) to another brain area – the preoptic hypothalamus – could turn male mice’s ability to recognize the sex of another mouse on and off like a light switch.

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This latest work furthered this line of study. “We wanted to know exactly which of these neurons were talking to exactly which neurons in the preoptic hypothalamus once that recognition occurred,” said Shah.

Within the BNST, Shah’s team tracked down a set of brain cells that behaved differently by secreting a protein called substance P. Looking in the preoptic hypothalamus, the team found these cells’ complement – a linked group of neurons that expressed receptors activated by substance P.

When this neuronal circuit was stimulated, a 10-to-15-minute timer appeared to start ticking. Once this time had elapsed, the mice started the full glut of mating behaviors: mounting, penetration and ejaculation. The team was able to speed this process up further by injecting substance P directly into the circuit area. If the receptors themselves were directly stimulated, the urge to mate became so strong that mice would attempt to copulate with anything around them, inanimate objects included. The stimulation appeared to be pleasurable for the mice, judging by the release of the hormone dopamine and the mice’s tendency to self-stimulate if given the option.

Cracking the refractory period

The influence of this brain circuit appears to extend beyond a simple desire for sex. Nearly all male mammals, humans very much included, have a “refractory period” built into their sexual brain hardware. After ejaculation, a waiting period ensues before full sexual drive and performance is restored.

This delay may have been the cause for an occasional frustration among enthusiastic human partners, but perhaps we should consider ourselves fortunate – mice have to wait a remarkable four days after ejaculation before their sex drive is restored.

But when substance P-sensitive neurons were stimulated in mice who had just ejaculated, barely a second’s pause was required before the mice were once again ready to do the deed. “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.” Importantly, the intervention did not affect other key mouse behaviors, like aggression.

These changes were not a one-way street, however. “If you silence just this set of preoptic-hypothalamus neurons,” Shah said, “the males don’t mate, period.” The mice were also otherwise unaffected by this libido loss.

A new motor for male sex drive?

Does this almanac of amorous rodent behavior have any uses in humans? Shah reckons that our brain circuitry could look very similar in this area. “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.”

“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. Currently used drugs for low sex drive, like Viagra, work by altering blood flow throughout the body. You can make a broken-down car move again by towing it with a repair truck, but the stricken vehicle isn’t fixed. Treatments that target the substance P brain circuit directly would be more precisely targeted, the equivalent of a new engine and a recharged car battery.

The next step for Shah’s team? A look into female libido – an area that, depressingly, remains relatively mysterious to biomedical science.

Reference: Bayless DW, Davis C ha O, Yang R, et al. A neural circuit for male sexual behavior and reward. Cell. 2023. doi:10.1016/j.cell.2023.07.021

This article is a rework of a press release issued by Stanford University. Material has been edited for length and content.