Dr. Linda Buck

ODOR AND PHEROMONES SENSING IN MAMMALS
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 or other social cues that induce innate behaviors or physiological effects. 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. We later found four additional types of chemosensory receptors: a family of candidate pheromone receptors in the vomeronasal organ, receptors for bitter and sweet tastes on the tongue, and, most recently, a small family of receptors in the nose that may detect social cues. 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 have shown that the OR family is used in a combinatorial fashion to encode odor identities. Each OR detects numerous 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. OR inputs are again reorganized at the next higher level of the olfactory system, the olfactory cortex, but how these inputs are ultimately translated into odor perceptions is still a mystery.

Our lab is also exploring how pheromones and other social cues generate instinctive behaviors and hormonal changes. By expressing a genetic tracer we had developed in hypothalamic GnRH neurons that control reproduction, we were able to visualize other neurons with which GnRH neurons communicate and obtain evidence that these neurons receive pheromone signals not only from the vomeronasal organ, but also from the nose.

We are now using additional molecular and genetic approaches to further elucidate how chemicals are translated into perceptions and to uncover the neural circuits and specific neurons that mediate instinctive behaviors such as fear and aggression.

MECHANISMS OF AGING
Aging leads to a decline in olfactory perception and other neural functions as well as an increase in the incidence of many diseases. In an initial effort toward identifying drugs that might delay these effects, we screened 88,000 diverse small molecules for the ability to increase the lifespan of the nematode C. elegans. In addition to identifying numerous chemicals with this ability, we found a human antidepressant that can increase the animal's longevity by acting on receptors similar to those it contacts in humans. We would now like to test the chemicals we have identified in this and a related screen for their effects on models of aging in mammalian cell culture.