Graduate Training in Neuroscience
University of Washington
Affiliate Professor, FHCRC
Humans and other mammals can detect thousands of different chemicals present in the external environment. These chemicals are perceived as odors or tastes, or they act as pheromones, stimulating specific behaviors or physiological effects in conspecifics. The discriminatory power of the olfactory system is immense. Even a slight change in the structure of an odorant can alter its perceived odor, for example, from orange to sweaty. How do mammals detect such an enormous diversity of chemicals-and how does the brain translate those chemicals into perceptions and behaviors? To explore these questions, we have used a combination of molecular, genetic, and cellular approaches to first determine the molecular bases of chemosensory detection and then examine how chemosensory stimuli are represented, or encoded, in the brain. In initial studies, we identified the odorant receptor (OR) family, a family of ~1000 different receptors that are responsible for detecting odorants in the nose. In later studies, we found three smaller chemosensory receptor families, one for pheromones, one for bitter tastes, and one for sweet tastes. In addition to providing insight into the molecular basis of olfactory and taste detection, these receptor families have provided molecular tools for exploring the neural mechanisms underlying perception. Our experiments indicate that the OR family is used in a combinatorial fashion to encode odor identities. Each OR detectsnumerous odorants, but different odorants are recognized by different combinations of ORs. Changing the concentration of an odorant, or slightly altering its structure, changes its receptor code, providing an explanation for the ability of such changes to alter a chemical's perceived odor. In other studies, we found that OR inputs are roughly organized into four zones in the nose and then reorganized into a stereotyped sensory map in the olfactory bulb of the brain. To examine odor coding at higher levels of the olfactory system, we developed a genetic method for visualizing neural circuits. Using this technique, we found a quite different sensory map in the olfactory cortex. This map is virtually identical in different individuals. The patterning of OR inputs in the brain provides insight into the ways in which chemical stimuli give rise to perceptions, emotions, and memories. We are currently developing new genetic approaches to further elucidate how chemicals are translated into perceptions and to uncover the neural circuits and cells that mediate fear and aggression, responses that can be elicited by odors and pheromones. Our lab is also interested in the mechanisms underlying aging and lifespan. We are particularly intrigued by the possibility that there is a central control of lifespan in which a subset of body cells influences aging in the body as a whole. We are taking two approaches to this question. First, we are conducting a high throughput screen for chemicals that extend lifespan in C. elegans, which will be followed by target identification and characterization. Second, we are using genetic tracers in mice to investigate the cellular and molecular mechanisms that regulate one landmark of aging, puberty.