CATHERINE DULAC'S PHENOMENAL PHEROMONE FASCINATION
August 6th, 2007
The brain’s cognitive abilities fascinate most people in neuroscience, but Catherine Dulac is drawn to the non-cerebral, genetically encoded, instinctive behaviors on which an animal’s very survival depends.
"An animal can’t reinvent the wheel each time it goes out in the world," explains Dulac, the Higgins Professor of Molecular and Cellular Biology and the new chair of the Molecular and Cellular Biology (MCB) Department. "It can’t relearn what a predator is, or how to recognize its mother." To root out how instinctive behavior is encoded in the brain, she focuses on "man’s" best model organism, the mouse. Whereas the visual cortex takes up a third of the human brain, the mouse devotes that third to the olfactory system. So Dulac has devoted her meteoric career to learning how olfaction underlies relevant murine behaviors like mating, male aggression towards rivals, and maternal devotion.
In 1995, she identified the first molecular receptors for detecting the odorless but potent pheromones that trigger such social behaviors. These airborne chemicals, along with odorants, waft into the nasal cavity. According to textbooks, odorants stimulate receptors in the main olfactory epithelium, which signals the olfactory bulb, while pheromones stimulate the vomeronasal organ (VNO), a specialized "accessory" that is defunct in more visual primates and humans, which sends signals elsewhere in the brain. Dulac is now studying how the pheromone sensing system develops and connects into neural networks in the brain regions that enable specific instinctive responses. Along the way, she’s overturned several textbook dogmas and made some provocative discoveries about pheromone detection and its effect on behavior.
From France, With Love
Growing up in the rural wine- and oyster-producing Languedoc region of southern France gave Dulac many useful skills. For instance, she is likely the fastest oyster opener in Harvard Square, and her nose really knows a good wine. Her love of the outdoors has taken her trekking and kayaking throughout South America – and running many a marathon – and also initiated her fascination with discovery. "As long as I can remember, I wanted to tackle the unknown," she recalls. "I always wanted to do research."
She attended the elite Ecole Normale Supérieure in Paris and received a Ph.D. from the University of Paris in biology and biochemistry. She entered Nicole Le Douarin’s lab in the Institut d'Embryologie du Collège de France to study developmental biology and neural crest formation. "I could have stayed there my entire life, but I wanted to try something new – for a few years."
She joined Richard Axel’s lab at Columbia University in 1993. He and his then post-doc Linda Buck (now co-Nobel Laureates) had just discovered the first olfactory receptor and were developing a completely new experimental model to study sensory function with molecular tools.
"It was an opportunity to look at the origin of these functional innate states," Dulac recalls of those exciting days. After her post-doctoral studies, she came to the MCB, and never looked back. "I loved the principle of this multi-disciplinary department where evolutionary biologists, chemists, physicists, and engineers join us in studying everything from yeast to mice on any type of topic. I greatly enjoy the scholarly atmosphere of the College. It’s irresistible. My colleagues are very approachable and helpful, and I love the ability to teach some of the most gifted students in the world."
As the new department chair, Dulac wants to nurture MCB’s evolution as a community of scientists and teachers. "We are building on our strengths – molecular and cellular biology – while reaching out to the physical and chemical sciences, and people with quantitative and engineering skills. For example, it seems that many scientists in the physics department would like to convert to Neuroscience or to Systems Biology."
After arriving at MCB, Dulac built a lab that now has 17 members. Within a year, she was named a Howard Hughes Medical Institute investigator, and continues to accumulate honors, including her 2004 election to the American Academy of Arts and Sciences. Of her 50 research papers, she’s most proud of two landmark studies, and a hot-off-the-press follow up to the first.
In a 2002 Science article, she upended the received wisdom that pheromone activation of the VNO controls mating behavior. She created mice without a functioning VNO by knocking out the Trpc2 gene, which encodes a channel that, she’d discovered, allows pheromones to stimulate the VNO. She expected the VNO-less mutant males to show utter indifference to females, but to her big surprise, the males were quite eager to mate with females. "They just tried to mate with males, too! And they didn’t display the usual aggression towards rivals," she recalls. "That was a different spin on what the VNO controlled -- not mating, but gender detection."
So what does control mating behavior, if not the VNO? According to dogma, pheromones entering the VNO stimulate neurons that release the luteinizing hormone releasing hormone (LHRH), which regulates mating behavior. But in a 2005 Cell paper, Dulac traced LHRH neurons back to their origins – and again astonished the field. She genetically modified a mouse so that its LHRH neurons activated a conditional pseudorabies virus. This virus infects neurons with a fluorescent label and jumps from one synapse to the next, backtracking through the neurons that innervate LHRH neurons, effectively painting the pathway back to its source. That source was not the VNO after all, but the main olfactory system’s epithelium.
If they aren’t stimulated by the VNO, Dulac wondered, could LHRH neurons actually mediate pheromone-driven mating behavior? To find out, she compared the behaviors of an existing strain of mice lacking a functioning olfactory epithelium and mice that lacked a functioning VNO. Only the males with nonfunctioning olfactory epithelia showed no interest in sex. Thus, contrary to dogma, the primary olfactory system actually can detect pheromones, at least those important to male mating behavior.
Don’t Forget the Ladies
"It’s a sad truth that most of the behaviors that have been studied are in males," Dulac laughs. "Maybe it’s thought to be more important, or maybe it’s easier." But Dulac and colleagues wondered about females from the strain used in the 2002 study, the ones that lack a functioning VNO and can’t discriminate gender. The results are just appearing in the August 5th issue of the journal Nature from work performed in her laboratory by Tali Kimchi, a postdoctoral fellow, in collaboration with Jennings Xu, an undergraduate student.
To the team’s bemusement, the mutant females behaved just like normal males. They excitedly investigated their companion and attempted to mount it for mating. They also exhibited other male courtship behavior, including an amorous ultrasound pitch. And they were terrible mothers. "They just wandered around instead of staying in the nest with the pups," Dulac reports. To see if this behavior arises developmentally or is programmed by the VNO, the team surgically removed the VNO from normally developing wild-type females. These females behaved exactly like the mutants.
"So we think the VNO in females has a dual role," Dulac explains. "It constantly represses male behavior and also activates maternal behavior." Ever fearless, Dulac challenges yet another assumption that, she says, the new data now clearly contradicts: instead of the male and female brains each having a distinctive circuitry that regulates sexually dimorphic behaviors, the female (and likely male) brain contains latent circuitry for both male- and female-specific behaviors. "What is different between the two sexes is the switch," she says, "and the switch is a sensory switch mediated by VNO activity, not by hormones."
A Lesson for People
Dulac understands the temptation to apply her provocative findings to humans. For instance, do we detect pheromones through our olfactory system, too? The most important lesson to Dulac, though, is how people pursue science. "The mutants without a functioning olfactory epithelium had been around for 10 years, but since no one suspected it would affect their mating behavior, no one ever looked at mating behavior. The link between the VNO and mating behavior was never questioned. But scientific discovery requires being able to see things through new eyes and not to simply accept dogma." That’s an instinct that will serve her well as the new chair of MCB.