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Right Now | Sexual Circuitry

When Minnie Turns Mickey

March-April 2008

If males are from Mars and females from Venus, as self-help author John Gray memorably suggested, sex hormones usually get the blame for placing them so far apart. Scientists have long believed that exposure to hormones close to birth and during puberty organize and activate neural circuits to trigger or suppress male or female behavior.

But surprising findings in the lab of Higgins professor of molecular and cellular biology Catherine Dulac, published last summer in the journal Nature, offer a profoundly new way to think about how male and female brains develop. Working with postdoctoral fellow Tali Kimchi and Jennings Xu ’08, Dulac discovered that sex-specific behaviors in mice switch on and off at the command of the vomeronasal organ (VNO), a collection of non-olfactory sensory receptors located in the nasal septa of mice and other mammals.

The VNO allows mice to sense pheromones: chemicals that animals within a species give off to communicate “who is male, who is female, who is a pup, who is a parent, who is kin, and who is a foreigner,” Dulac explains. Her lab is devoted to examining the control of instinctive behavior—particularly social actions such as aggression, maternal behavior, and courtship—within animal brains. In an effort to determine how the VNO affects behavior among female mice, Dulac and her coauthors bred “knock-out mice” lacking the TRPC2 gene, thereby deactivating the VNO.

When Dulac’s coauthor Kimchi placed these female mutants in a cage with normal male mice, “what she observed was completely astonishing,” Dulac says. “The females started to behave exactly like males.” Suspecting an error, the puzzled researchers checked the mice to ensure that they truly were female. But there was no mistake. Though female, with normal hormone levels and estrus cycles, these mice emitted ultrasonic vocalizations normally sung by males to attract mates and, like males, they mounted their cage mates and engaged in pelvic thrusting. When impregnated by male mice, these females also lacked the usual maternal behavior. They neglected their pups shortly after birth and failed to attack intruder males while nursing their young.

Dulac says the researchers wondered if the mice behaved oddly because they had grown up without a functional VNO, which altered their brain development. “In sensory biology,” she explains, “there is an important concept known as ‘critical period,’ which holds that if a sensory modality is not used during early development, it won’t function properly, even if it is restored.” She cites classic experiments conducted with kittens that were blindfolded from birth. When the masks were later removed, the kittens couldn’t see properly because their brains had never developed the appropriate neural pathways to process visual information. But when Dulac’s team tested this hypothesis by surgically removing VNOs from adult female mice that had developed normally, the surgically altered females still behaved just like males.

These VNO-free females led Dulac and her coauthors to craft a dramatically new hypothesis about brain development: female mouse brains, they propose, contain a fully functional circuit that produces male behavior, but the VNO serves as a switch to repress male behavior and activate female behavior. In fact, Dulac suspects that all mouse brains contain circuits for both male and female behavior, and pheromonal cues determine which circuit is activated. “From a developmental standpoint,” she says, “this makes a lot of sense, because male and female have essentially the same genome, and one genome helps to build one brain.” She believes this model may very well apply to other animals, including humans, but further research is needed. “Our new model has many implications,” Dulac says, “and it will be exciting to conceive experiments to see how robust [it] is.”

The mouse findings don’t apply directly to humans; for starters, we don’t have vomeronasal organs to switch between male and female circuits—just pits where the VNO used to be. Evolution failed to preserve the organ, Dulac says, because humans rely more heavily on their eyes than their noses: roughly a third of the rodent brain is dedicated to smell and pheromone detection, where nearly a third of the human brain is devoted to sight.

This fact led Dulac to theorize that visual input in humans may play the same role as pheromones do in mice. “Humans hate to consider that they have instinctive behavior,” she observes. “We see ourselves as very rational animals, completely in control of what we want to do.” Yet humans, she adds, do have a pheromone equivalent: pornography. “It elicits sexual behavior, which is exactly what happens to a mouse smelling a pheromone,” she says. “Obviously we can resist some of the stimuli; we have many layers of control for behavior. But there is something here that reminds us of the instinctive behavior in animals.”       

~Erin O ’Donnell