Female Mice Hot for Guys Who Cry

Attempts at mixing up love potions go back at least to Tristan and Isolde, but since the discovery of pheromones it has become increasingly clear that many animals have only to look to their armpits - and an assortment of other glands - for an irresistible concoction of their own. Pheromones are small molecules that animals release into the air, and when another animal of the same species detects them, the pheromone will cause a specific social behavior – perhaps most notably, an increase in sexual receptivity. While many people are excited by the prospect of chemicals that might improve their sex lives, pheromones make neuroscientists randy for another reason: they represent an opportunity to dissect how the brain works. As far as we can tell, the brain is a huge network of smaller circuits. This means that to do things like control movement and store memories, the brain relies on circuits of nerve cells that communicate with one another to store info or output some kind of behavior. Presumably, the behavior associated with a pheromone relies on a specific neural circuit that is activated when a pheromone is detected by an animal. So, once a pheromone is isolated, you can use it to search out the neural circuit in the brain that is responsible for the behavior; just spray the chemical into the air and watch for a change in behavior of the animal you are studying. Theoretically, experiments like this may help determine exactly how small sets of nerve cells generate behavior. This is a big deal, because although we think small circuits run the brain, we know surprisingly little about the details of how these circuits are wired up.

This summer, a Japanese group in pursuit of a circuit to call their own published a study examining the role of a potential pheromone called ESP1 in sexual behavior of female mice. ESP1 has a quirk, though: it is released in the tears of male mice. Although tears and sex may seem an unlikely pairing to us humans, previous results suggested that ESP1 might be a sex pheromone. Besides, it would be the smell of the tears, not the look of them, causing the excitement. Banking on this, the group characterized ESP1, the proteins that detect it (its receptor) and the nerve cells that use this receptor to tell whether ESP1 is present in the air. By sticking electrodes up a female mouse’s nose, they found that ESP1 sprayed in the surroundings causes electrical responses in neurons of the vomeronasal organ - long thought to be solely responsible for pheromone detection. This organ contains a number of small populations of neurons that respond very specifically to single pheromone types. The group confirmed that ESP1 was indeed responsible for the electrical activity by testing mice whose ESP1 receptors were non-functional. As expected, females without functioning receptors showed no activity in their vomeronasal organ when exposed to ESP1.

The electrical activity in the ESP1-detecting neurons is likely relayed further into the brain to control sexual behavior by activating a neural circuit. To check this, the group exposed normal females and females with non-functional ESP1 receptors to ESP1, introduced them to male mice and watched the magic unfold. Normally, female mice play hard-to-get, and rightly so: although mouse courtship begins with the suitor chasing his crush around like we all used to do in the school yard, he quickly jumps straight to 3rd base, attempting “anogenital investigation.” He then immediately tries to mount – romance has apparently been dead in the mouse world for quite some time. When the female is finally convinced by his wares she initiates lordosis, a perhaps not unfamiliar backward curvature of the spine, facilitating the entry of the penis into the vagina. Females exposed to ESP1 before males were introduced were almost 5 times more likely to initiate lordosis and allow mating than those not exposed to ESP1, while the mutant females, who had no ESP1-evoked activity in their vomeronasal organs, were no more likely than unexposed females. Although most of these experiments were done by exposing the females to purified ESP1, the researchers also compared female responses to males who had ESP1 naturally in their tears and those who didn’t. The results weren’t quite as strong as with purified ESP1, but males who had ESP1 were more successful in their quest.

Although the exact circuitry involved in the sexual behavior has yet to be studied in depth, one thing is clear: female mice are turned on by the smell of tears in their man’s eyes. I wouldn’t count on crying as a go-to pick up line though; humans do respond physiologically to pheromones, but where in the brain and how we detect them is still a mystery, and anything similar to ESP1 has yet to be found in human tears. For now we should either get the good stuff by mail or keep counting on our armpits. (Two for one: the latter is apparently good for the environment.)