PAGE 5 OF 6
Tsai and her colleagues found that a protein called Par4 binds to a type of dopamine receptor and that mice with mutated Par4 demonstrate something akin to depression. Dopamine is a neurotransmitter active in the brain pathways governing mood, reward, and motivation.
In one standard test, mutant mice placed in a clear plastic container filled with water stopped swimming long before wild-type mice. “They are fully conscious, but they quickly become immobile,” says Tsai. “They don't struggle. There is a loss of motivation.”
In another experiment, hungry mutant and wild-type mice are placed in an open environment with food at the far end. Mice are averse to open spaces, so this set-up presumably creates some anxiety. Wild-type mice are quick to surmount their discomfort and find the food. But the depressed mice take a very long time to follow suit.
“The mutant animals fail to do what they need to do,” says Tsai. “They find it more difficult to overcome their anxiety and fear.” Most current medications for depression, the SSRIs (selective serotonin reuptake inhibitors) and MAOIs (monoamine oxidase inhibitors), modify synaptic levels of serotonin or norepinephrine. Tsai's experiments with depressed mice suggest that dopamine may also provide an excellent target for intervention.
Closer examination of animal neurobiology doesn't just tell us about disease—it tells us much about normal human behavior, too. “If you want to study behavioral genetics,” says HHMI investigator Catherine Dulac, a molecular biologist at Harvard University, “you need something robust so that the changes you introduce will be observable.”
Few behaviors are more robust and observable than reproduction, Dulac adds. In mice, as in many animals, certain behaviors hard-wired into the brain—mating and aggression, for example—are strongly influenced by airborne molecules, called pheromones, released by one animal and perceived by another.
Although the vomeronasal organ (VNO), the structure a mouse uses to sense pheromones, resides in the nasal cavity, researchers have long believed that the animal's pheromone-sensing apparatus is completely separate from the olfactory system, which regulates smell.
Dulac and her colleagues discovered last year that the conventional view is likely to be wrong. The researchers used a modified virus to trace the connections from the VNO and the olfactory system to neurons producing luteinizing hormone-releasing hormone (LHRH), thought to be activated by pheromones.
The neural input into the LHRH neurons did not come primarily from the VNO, as they'd expected; instead, LHRH neurons seemed to receive input from the olfactory epithelium—a sheet of cells inside the nasal cavity that are involved in smell. Mutant male mice without VNOs are able to mate, Dulac has found, but do so indiscriminately with both males and females. Mutant males without functional olfactory epithelia, however, no longer respond to sexual stimuli such as female urine.
The findings raise some interesting questions about human sexual behavior. Despite oft-cited anecdotal evidence, the fact that humans have no VNO has long argued against the possibility that their reproductive habits are influenced by pheromones. Now, it appears, a VNO may not be necessary for pheromones to work in humans.
“Mating and reproduction are animal behaviors, and humans are animals too,” says Dulac. She hears an instinctive confirmation of the evolutionary link every time she gives a talk about her work. “It's very striking to me that, even though I am showing pictures of male and female mice, there are instantly giggles in the room,” she says. “Somehow, everyone senses that this behavior raises questions about human behavior.”