In his semiautobiographical novel, Remembrance of Things Past, French author Marcel Proust recounts several episodes in which particular tastes and smells—the most famous one that of a madeleine dipped in tea—suddenly bring to life childhood memories. Catherine Dulac read all seven thick volumes of Proust's masterpiece while growing up in Montpellier, France, with her parents, two literature scholars. Little did she know then that her own research would one day shed light on how cues from the senses shape our behavior.
After completing a Ph.D. in developmental biology at the University of Paris, in 1993 Dulac joined the laboratory of neuroscientist and HHMI investigator Richard Axel at Columbia University in New York City. A couple of years earlier, Axel and then-postdoc Linda Buck (also an HHMI investigator) had identified the first odorant receptor genes; both scientists later shared a Nobel prize for that discovery. "That paper was a real ah-hah moment for me," says Dulac. "The olfactory system became a genetically and molecularly amenable system in which very specific markers can help determine and manipulate the identity of neurons."
In Axel's lab, Dulac started looking for another group of markers: pheromone receptors. Pheromones are chemicals that define social interactions in animals, discriminating, for example, between potential mates and rivals. Their receptors are expressed specifically by neurons in the vomeronasal organ (VNO), a distinct structure at the base of the nasal cavity.
Although pheromonal cues are not essential for directing social behavior in humans, understanding how pheromone signals are processed in the mouse brain would yield, Dulac reasoned, fundamental insights into brain function, regardless of species. "The overarching question is how does the brain cope with genetically encoded information, regardless of whether signals come from the nose, ears, or eyes," she says.
Dulac developed a bold new technology for generating libraries of complementary DNA in individual neurons—which contain all the genes expressed in that particular cell. Using that technology, she identified the first family of pheromone receptors. After establishing her own research group at Harvard University, she continued to identify more pheromone receptor families (which today comprise more than 300 members) and other molecules unique to VNO neurons. With these "molecular tools" in hand, she was able to probe the role of VNO in animal behavior—and the results were something no one had expected.
She discovered, for example, that pheromone receptors relay their signals through a common pathway involving the transient receptor potential C2 channel (TRPC2). Male mice lacking the gene for TRPC2 fail to display aggression toward other males and initiate sexual and courtship behaviors toward both males and females. "It was assumed that the VNO was essential for mating, but we found that it is needed for sex discrimination," says Dulac, who published that work in 2002.
Five years later, her group reported that female mice lacking TRPC2 exhibited fewer female-specific behaviors and had adopted characteristics of male sexual and courtship behaviors. These findings suggest that neuronal circuits underlying male-specific behaviors are present in the female mouse brain, but the VNO acts to repress male behaviors and activate female ones. "The concept of a 'male brain' and a 'female brain' went out the window with that study," says Dulac.
Dulac's group was used to surprises. They had searched for neuronal pathways originating from the VNO and feeding into brain neurons responsible for mating and reproduction. But they could not find any. "One day a student came into my office and told me, 'I have been trying and cannot find anything in the VNO. I think we should drop this,'" recalls Dulac. "That is when I said 'No, this is great. This is even better.'"
They eventually found that the neuronal pathways that lead to brain regions involved in mating originate from a discrete population of olfactory sensory neurons inside the nasal cavity. "The results were consistent with the conclusion that the VNO is not involved in triggering mating behavior, but rather in modulating the sex specificity of mating" says Dulac. In simple terms, the results of Dulac's studies suggested that a neuronal circuit involving olfactory neurons is responsible for mating and another, involving VNO neurons, is required for sex determination and identity. "But we know these two systems talk to each other," says Dulac. "We have defined them in broad strokes. And now we have to figure out exactly how they work."
Dulac is passionate about putting together such puzzles. "So many times we were confronted with completely unexpected results that left us perplexed," she says. "That led to an extremely interesting time trying to figure out the answer."
But she still has time to keep up with her other passions: sports, literature, and the arts. She has run seven marathons and is always eager for new hiking or biking adventures. She continues to be an avid reader and was thrilled to find out that the 2008 Nobel Prize in Literature went to one of her favorite French authors, Jean-Marie Gustave Le Clézio. "I absolutely love this author and have read many of his books. Since moving to the United States, I have tried to give the books to my friends but almost none of them are translated in English," she says. "I hope that will change."