For a creature that can’t go on Facebook or rely on clothing cues, the mouse is remarkably adept at navigating its social environment. With just a sniff of another mouse’s urine, the little rodent can tell if the other mouse is male or female, friend or foe. The chemical signals in the urine, or pheromones, even tell a mouse to delay or accelerate puberty, abort a pregnancy, start mating or opt for a fight instead. This pheromone system “is doing an amazing amount of things,” says Ron Yu, Associate Investigator at the Stowers Institute.
Immunofluorescent image from the main olfactory bulb of a transgenic mouse that has been genetically engineered to alter its neuronal connections. Axon guidance molecules are shown in red, olfactory sensory neuron axons that express the marker protein lacZ are in green and cell nuclei are shown in blue.
Image: Yu lab
So how does this process work? How can a chemical wafting through the air send a signal to the brain that triggers the appropriate behavior? That’s the fundamental question Yu has taken on—and he has made considerable progress. With a series of innovative experiments, Yu and his lab have figured out how to visualize pheromone-triggered activities in large numbers of nerve cells. And in a groundbreaking paper in Science, his team used genetically engineered mice to show that whole different sets of neurons respond depending on whether an intruder is male or female. “It’s a very interesting problem—and we’ve been fortunate enough to find some of the answers,” says Yu.
Yet ironically, Yu never set out to probe the neural circuitry of behavior. As a child growing up in China, he was enthralled by astronomy and physics. But when it came time to go to university, fate intervened. “Life is full of accidents,” Yu shrugs.
A top high school student, Yu had worked hard for a chance to get accepted into the country’s best physics department. But before he even applied for college, Tsinghua University, a top ranking university in Beijing, offered him a spot in a new biological sciences program—even waiving the usual extensive college entrance exam. “I was never interested in biology up to that point, but bypassing the grueling entrance exam seemed like a good thing,” he says.
Yu found himself with a dynamic group of elite students at Tsinghua University. “Like everybody else, I had to work hard to keep up with the rest of the class,” he recalls. Yet, he wasn’t ready to let go of his dream of studying physics. He successfully navigated the university’s academic bureaucracy and added physics classes to his already grueling schedule.
After graduating with a major in biology and minor in physics—a rare achievement among biology students—Yu decided to continue his studies in the U.S. He was accepted into graduate programs at Northwestern University in Chicago and Columbia University in New York City. Northwestern was his first choice—but again fate would have it otherwise. Northwestern wasn’t able to process the paperwork for his student visa. Columbia was.
Doing science at Columbia, where he worked with Lorna Role on the electrical properties of cells, “was fantastic,” Yu says. “Lorna was a great advisor. While I was doing a rotation in her lab, she trusted me to build an electrophysiology rig from scratch,” recalls Yu and adds that, “watching neurons in action was so gratifying. I didn’t think I would want to do anything else.” He spent long hours in front of his recording rig but still found time to compete in rollerblade races in Central Park and Brooklyn’s Prospect Park.
Immunofluorescent staining of the VNO tissue in a cross section. The red signal stains for ANO1, an ion channel that is expressed in the VNO and a candidate for mediating pheromone triggered responses. Cell nuclei are shown in blue.
Image: Yu lab
Yu didn’t take the plunge into genetics and molecular biology until his post-doctoral position in 1996. “It was sort of by accident,” he says. He thought about going to Germany to continue working on electrophysiology, but his wife was enrolled in a Ph.D. program in the U.S. Hesitant to make a quick decision, he began to work on a collaborative project between Role and the legendary Richard Axel at Columbia University. In 1991, Axel had cloned the first odorant receptors, for which he was awarded the Nobel Prize in 2004.
When Yu joined Axel’s lab, pheromone receptors—odorant receptors’ little-known cousins—had just been discovered. Yu was captivated by the challenge of figuring out how pheromones dictate behavior—and by Axel himself. “The way Richard does science, thinking about both the big picture and the technical details, opened my eyes,” he says.
Working at Columbia and then at the Stowers Institute, which he joined in 2005, Yu was able to combine molecular genetics, electrophysiology, optical imaging, and studies of animal behavior to explore the biology of behavior. The interdisciplinary approach is paying off.
One of Yu’s achievements was figuring out how a pheromone causes an electrical signal to race up to the brain. The process starts when the chemical signal reaches a receptor on a nerve cell in the so-called vomeronasal organ (VNO), which is located in a mouse’s nose. While still at Columbia, Yu and colleagues discovered that pheromone binding to the receptor opens up an ion channel in the cell’s membrane called TRPC2. That triggers the cell to release calcium, exciting the neuron and sending a wave of electricity up a chain of neurons to the brain. Knock out the TRPC2 gene and mice can’t seem to tell genders apart, and males try to mount each other. At Stowers, he identified parallel signaling pathways that operate alongside TRPC2 and are just as important.
But which neurons are responsible for which behaviors? To find out, Yu’s lab added a gene to mice that makes cells light up with a fluorescent glow when the cells release calcium. The team exposed the transgenic mice to either male or female mouse urine, which is chock full of pheromones. Then the researchers watched to see which cells began to glow. “During my Ph.D. I was able to watch one neuron’s response at a time,” Yu says, “With the new transgenic mice generated in the lab, we can watch hundreds of cells simultaneously, with each blink telling a story.”
The results, reported in Science in 2008, were striking. “It turned out that about one percent of the cells are exclusively activated by male mouse urine,” Yu says. A completely different—and larger set—of cells respond to female urine. That makes sense biologically, Yu says. Each of the hundreds of cells in the VNO seem to have unique receptors explaining, he says, the wide repertoire of mouse behavior in response to different pheromones. In addition, the greater number of responsive cells to female signals explains how the more complex physiological states of the females, such as stages of the estrous cycle, are detected and interpreted by other females and perhaps, by males.
There’s plenty more to be discovered. “We want to trace the circuit into the brain and understand how the information is processed,” Yu says. That will not only explain how chemical signals can lead to specific behaviors, but it will also help illuminate how the other senses work. And while humans have only a vestigial vomeronasal organ, Yu’s research may lead to a deeper understanding of the biology underlying our own desires and actions. But what it probably will never explain is how some people—like Yu—are able to transform life’s random events into fruitful opportunities.