HHMI investigators Richard Axel, Columbia University, and Catherine Dulac, Harvard University, are revealing the wiring of the systems involved in smell and pheromones, respectively.

They discovered that each neuron in the nose expresses only one receptor gene. Thousands of neurons with the same receptor are scattered in the nose, but their axons all converge in a few specific glomeruli (spheroid structures) at two spots in the olfactory bulb.

How does the olfactory system distinguish among thousands of odorants, some with nearly identical structures? Buck's group discovered that odorant receptors are used combinatorially to encode odor identities. "Just as letters of the alphabet can be used in different combinations to form a multitude of different words, odorant receptors are used in different combinations to create a vast array of different odor perceptions," says Buck. In the olfactory bulb, each odorant is thus represented by a unique combination, or "map," of glomeruli at differing positions, with a similar activation profile in every individual.

This map must be conveyed in some form on to the next, more complex, levels of processing in the brain. Tracing these pathways and events is, for Axel, something most easily done in the simple nervous system of the fruit fly. With powerful imaging techniques, he can visualize individual neurons connecting the fly's antennal lobe (analogous to the olfactory bulb in mammals) to higher brain structures. In collaboration with HHMI investigator David J. Anderson and Seymour J. Benzer at the California Institute of Technology, Axel has traced the path of nerve signals that are activated when the fly detects carbon dioxide gas, a component of a "stress odorant" that traumatized flies emit to warn other flies away. The researchers found that a single type of olfactory neuron detects the CO₂ and that those neurons connect to a single glomerulus in the antennal lobe. By tracing this simple "dedicated circuit" at successively higher levels, Axel hopes ultimately to close the entire loop from input to output.

In the mouse, Buck and her colleagues have traced the pathway from single types of odorant receptors in the nose through the olfactory bulb to the olfactory cortex. This work revealed that the cortex also has a stereotyped map of odorant receptor inputs. However, while inputs from different receptors are segregated in the olfactory bulb, they are mapped onto the cortex in a partially overlapping fashion. Moreover, single cortical neurons appear to receive signals from combinations of odorant receptors, suggesting that they might integrate signals from different receptors that recognize the same odorant.

Buck's group also reported that some cortical neurons respond to a mix of two odorants, but not to either one alone. "We think that what we are seeing in the cortex may be an initial step in the reconstruction of an odor image from its deconstructed features, which are encoded by combinations of odorant receptor inputs," Buck says.

Flavors are made up of inputs from the taste buds of the tongue as well as from olfactory information stimulated by the aromas of food wafting up into the rear of the nasal cavity. Taste-bud neuronal receptors are sensitive to five basic qualities—bitter, sweet, sour, salty, and umami (glutamate or "savory"). These ancient senses likely evolved for seeking nutrients and avoiding toxins or spoiled food.

Photos: Axel, Matthew Septimus; Dulac, Matt Kalinowski

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