New research retraces connections between nose and brain

Every second our noses are bombarded with hundreds of smells, some pleasant, others not. Before we can react, however, our brains must first recognize an odor, and there are multiple steps between the nose and the brain. New research by Rockefeller’s Peter Mombaerts delves into the function and wiring of the neurons that mediate odor detection and signaling to the rest of the brain.

Scent signals. Olfactory neurons do not use a protein called OCAM to stick together, as previously thought. Instead, new research shows that whether neurons from the nose have the protein (top), or not (bottom) they still come together to form glomeruli, ball-shaped structures in the olfactory bulb of the brain.

In the nose, neurons expressing one thousand different odorant receptors are ready to receive incoming smells. Each olfactory neuron only expresses one odorant receptor, but multiple neurons can all express the same receptor. Beyond the nose, extensions of these neurons, called axons, come together in the brain’s olfactory bulb to form a structure called a glomerulus. There, the different odors are processed, and then the glomeruli send signals to higher areas of the brain.

Mombaerts and colleagues found that a protein called OCAM, long thought to be involved in the process by which axons extend to the olfactory bulb, is actually more important for the internal structure of the glomeruli. And, furthermore, even though all of the neurons that extend axons to the same glomerulus express the same odorant receptor, they don’t all respond equally to the incoming odor.

Since its discovery 20 years ago, OCAM has been thought to play a leading role in how the connections between the nose and the olfactory bulb are established. OCAM, which stands for olfactory cell adhesion molecule, is believed to interact only with other OCAM proteins, which causes it to act like glue between neurons. Mombaerts, in collaboration with Andreas Walz at Rockefeller and with Helen Treloar and Charles Greer at Yale University, removed the OCAM gene from mice by using a technique of genetic manipulation. To their surprise, the organization of the connections between the nose and the olfactory bulb seemed quite normal.

“We tested all of the standing hypotheses of OCAM’s role by generating mice missing the OCAM gene,” says Mombaerts, who published the findings in Molecular and Cellular Neuroscience. “But we found no obvious effects on the topography of the olfactory system. Even better, the mutant mice actually had a better sense of smell, in some regards. But what we did see was that structures inside the individual glomeruli were disrupted.”

The Greer Lab at Yale previously reported that glomeruli are normally separated into two compartments, one where the incoming neurons interact with specialized interneurons, and a second compartment where these interneurons interact with second-order neurons in the olfactory pathway. Greer speculated that the compartmentalization of synaptic circuits within glomeruli may help the neurons coordinate their activity. But in mice missing OCAM these two compartments were no longer defined, and the different types of connections were more mixed. Mombaerts and his colleagues theorized that while the mice may be more sensitive to odors, they may not be able to discriminate between them as well without this compartmentalization.

Meanwhile, a second paper by Mombaerts, published in Proceedings of the National Academy of Sciences, reports how the different neurons that express the same odorant receptor and project their axons to specific glomeruli respond when they detect an odor. In a collaboration with Anne Vassalli at Rockefeller, Gordon Shepherd at Yale University, and Xavier Grosmaitre and Minghong Ma at the University of Pennsylvania, Mombaerts shows that neurons expressing a receptor called MOR23 can respond to the same odor with dramatically different sensitivities.

The scientists used a technique called perforated patch-clamp recording, which is often used to record the electrical currents in nerve cells, but had not been applied to mouse olfactory neurons that express the same odorant receptor. A very small glass tube, containing an electrode, is sealed to a small patch of the neuron’s membrane, and then the membrane is ruptured just under this micropipette, giving it access to the interior of the cell. The electrode can record minute changes in electrical properties and currents within the cell, letting the scientists get direct measurements on the electrophysiological properties of olfactory neurons that all express the same odorant receptor.

The analysis showed that the threshold to respond could vary by as much as 100 times among neurons that express MOR23. Though the scientists can’t be sure what is responsible for the findings (it could be something as simple as the age of the neurons) they are encouraged that the patch clamp technique seems to be a reliable method to begin exploring how the sense of smell works in the living animal.

“We show that this approach is a powerful way to study how a peripheral input can shape the activity within an individual glomeruli,” says Mombaerts. “It will be interesting to go further and determine how the different responses are transformed into signals that are sent to other parts of the brain.”

Molecular and Cellular Neuroscience Online: March 10, 2006
Proceedings of the National Academy of Sciences 103(6): 1970-1975 (February 7, 2006)