DURHAM, N.C. -- Using a high-resolution video technique on laboratory rats, neurobiologists at Duke University Medical Center have captured the first detailed images of the living brain in the act of recognizing specific odor molecules. The scientists say their achievement will open the way to deciphering the brain's internal "language" of smell.
More broadly, say the researchers, the imaging technique can give them new insights into the machinery of learning, as they explore how training alters the odor-recognition process.
The researchers -- graduate student Benjamin Rubin and Howard Hughes Medical Institute Investigator Lawrence Katz -- reported their achievement in the July issue of Neuron. To record odor-recognition, the researchers refined an imaging technique used to visualize brain activity in other parts of the brain. They increased its resolution tenfold to detect changes in the tiny hair-thin olfactory structures, called glomeruli, in rats' brains.
They began their studies by thinning out a section of a rat's skull until they could see the olfactory bulbs -- stem-like projections in the forebrain that receive signals from the chemical receptor cells that line the nasal passages.
Rubin's and Katz's objective was to visually detect when a specific odorant triggered the activity of a specific glomerulus -- tiny basketlike structures covering the surfaces of the olfactory bulb. These glomeruli, each about the diameter of a human hair, are the basic units of olfactory reception. Previous research has shown that each of the 2,000 glomeruli in the olfactory bulbs receives impulses from nasal receptors tuned to specific odorants, relaying those signals to higher processing centers in the brain.
The scientists' detection method depended on the fact that active cells consume more oxygen, converting oxygen-carrying oxyhemoglobin to deoxyhemoglobin. Since deoxyhemoglobin absorbs red light more than the oxygenated form, the scientists could distinguish activated glomeruli by imaging the olfactory bulbs under a red light shone through the rat's skull. Activated glomeruli showed up as distinctive dark spots on the images.
To map how glomeruli responded to odors, the scientists recorded images of the olfactory bulbs as they exposed the rats to chemical odorants that smelled like bananas, caraway and spearmint, as well as the mixed-chemical smell of peanut butter.
"We found that we could visualize individual glomeruli, achieving the best resolution anyone has obtained so far," said Katz. "And most exciting, we found that we could see distinctive patterns of activated areas from different odorants."
What's more, said Katz, the researchers found that activation patterns in olfactory bulbs on one side of an animal's brain matched those on the other. Also, the patterns of activation were highly similar from animal to animal.
"Thus, this technique can serve as our guide, our Rosetta stone, for deciphering the olfactory response and even helping us to understand higher olfactory processing areas of the brain," said Katz.
For instance, Katz said, he and Rubin also reported experiments in which they varied the concentration and molecular structure of odorants and observed how the activation pattern of glomeruli changed. They found that the activation maps changed significantly as they increased the concentration of the odorant chemical amyl acetate several thousandfold. Also, the activation maps changed as they exposed the rats to a series of slightly different aromatic chemicals called aldehydes. These aldehydes differed only in the number of carbons in their chainlike structure.
"Previously, you simply couldn't compare such responses to multiple concentrations and multiple chemicals in the same animal, because the only technique available was to use tracers that could only detect response to a single odorant," said Katz. "Also, that technique required killing the animal and doing detailed analyses that took weeks."
Rubin's and Katz's experiments already have settled a critical question about the nature of olfactory processing in the brain.
"There has been considerable debate in the field about whether closely related odorants could be distinguished by spatial mapping, or whether there was some timing of neuronal firing involved. However, we have found that we could distinguish odorants just on the basis of the pattern of activated glomeruli," Katz said.
Katz believes the olfactory visualization system offers high promise in studying the machinery of the learning process.
"In rodents, the olfactory system is the sensory system of choice, and we believe we can see the early stages of learning at the olfactory bulb level. Since our system is very rapid and non-invasive, we think it offers an extraordinary pathway to studying learning."
Such learning experiments could involve imaging changes in animals' response to odorants as they are trained to associate an odorant with a reward, said Katz. Also, he said, by studying genetically altered mice with altered olfactory systems, scientists could gain important clues to the molecular basis of olfaction in particular, and sensory processing in general.
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