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NEUROBIOLOGY How the Nose Knows a Multitude of Different Odors Humans can perceive thousands of distinct odors, even though the nose has only about 1,000 odorant receptors. Until now, scientists have not been able to identify the mechanisms underlying this feat. Linda Buck, a Howard Hughes investigator, postdoctoral fellow Bettina Malnic, and their colleagues in Japan have shown how the olfactory system distinguishes so many different odorants. Their findings, which appear in the March 5 Cell, also help explain why slight alterations in an odorant or a change in its concentration can cause a dramatic shift in its perceived odor. Linda Buck (r) and graduate student Bettina Melnic have discovered how the nose discri-minates a vast number of different odorants. Buck, HMS associate professor of neurobiology, and her team used a combination of calcium imaging and single-cell RT-PCR to identify receptors in the mouse that recognize specific odorants. In response to volatile chemicals, olfactory neurons show transient increases in intracellular calcium detectable by calcium imaging. Using single-cell RT-PCR, the researchers first determined that each olfactory neuron expresses only a single odorant receptor gene. They then showed that the olfactory system uses combinations of odorant receptors to recognize different odors. They found that a single receptor can recognize multiple odorants and a single odorant can be recognized by multiple receptors, but that different odorants are recognized by distinct combinations of receptors. This combinatorial coding scheme appears to permit the nose to discriminate a vast number of different smells. Receptor Teamwork In addition, they showed that odorants nearly identical in structure are recognized by different, but often overlapping, sets of odorant receptors. Human studies have demonstrated that even a slight change in the structure of an odorant can cause a dramatic shift in its perceived odor. For example, when the hydroxyl group of octanol is replaced by a carboxyl group to make octanoic acid, its odor changes from orange and roselike to rancid and sweaty. "This explains something that has puzzled people for a very long time," Buck says. "If you change the structure of an odor molecule--even slightly--its odor can undergo a profound change." Buck's findings also explain another well known phenomenon of human perception: the perceived quality of an odorant can differ with a change in its concentration. Indole, for example, has a putrid odor when concentrated but is perceived as floral when diluted. "We call the set of receptors that recognize the odor its code," Buck says. "If you change the concentration of the odor, you can also get a change in its code." Odorants that enter the nose are detected by millions of olfactory neurons. These neurons transmit signals to the olfactory bulb of the brain, which sends signals to the primary olfactory cortex. From there, olfactory information is relayed both to higher cortical areas and to the limbic system, enabling the conscious perception of odors and their emotional and motivational effects. Detecting Pheromones In 1997, Buck and research fellow Hiroaki Matsuami identified a separate family of pheromone receptors in mice. Like odorant receptors and a family of pheromone receptors previously identified, these receptors belong to the same G-protein­coupled receptor super family. However, they have an unusual structure that suggests they may be responsible for recognizing a different class of pheromone. The finding paves the way for the identification of pheromone molecules, the subconscious odorous chemicals released by mammals that elicit mating and other innate behaviors in members of the same species. Recently, Buck and graduate student Lisa Horowitz developed a genetic method for tracing neural circuits, which opens the way to tracing odor and pheromone pathways deep in the brain. This technique should also be widely applicable to a variety of neural systems. It is expected to be particularly useful for elucidating neural circuits that involve small subsets of neurons, and for studying the development of neural connections as they occur in utero. Eventually, she and her colleagues hope to determine how signals derived from different odorant receptors are represented in the olfactory cortex and other areas of the brain and how individual components of an odor code are decoded to yield the perception of an odor. --Peta Gillyatt Back to Top