Timing is everything. For a mouse trying to discriminate between the scent of a tasty treat and the scent of the neighborhood cat, timing could mean life or death. In a striking discovery, Carnegie Mellon University scientists have linked the timing of inhibitory neuron activity to the generation of odor-specific patterns in the brain's olfactory bulb, the area of the brain responsible for distinguishing odors.
Their work, appearing in the Nov. 8 issue of the Journal of Neuroscience, describes for the first time a cellular mechanism linking a specific stimulus to the timing at which inhibitory neurons fire. This breakthrough lays a cellular foundation for the "temporal coding hypothesis," which proposes that odor identity is encoded by the timing of neuronal firing and not the rate at which neurons fire.
Past research has shown that specific odors trigger unique patterns of electrical activity in the brain. Generating these patterns requires reliably timed inhibition, but relatively little was known about the timing of the activity of inhibitory neurons -- until now.
"There is a clear link between which odor is being presented and the time at which inhibitory neurons fire. This timing controls which excitatory neurons are active and at which time. This modulation contributes to the generation of reliable temporal patterns of neuronal activity," said Nathan Urban, an assistant professor of biological sciences at the Mellon College of Science at Carnegie Mellon.
Populations of mitral cells, a type of excitatory neuron in the olfactory bulb, receive input from neurons in the nose that respond to a single odorant. After receiving this input, the mitral cells convey messages about odor identity to other parts of the brain. But they don't simply relay information. Their activity, and therefore which message they send, is modulated by the inhibitory activity of granule cells. In a first, Urban has shown that the timing of granule cell firing encodes odor information.
Urban's work is especially provocative given that the traditional view holds that the rate of neuronal firing is what really matters, not the time that it takes for a stimulated neuron to fire. Recognition of a stimulus like an odor relies on the orchestrated firing of neurons, both ones that excite other neurons to relay a message as well as ones that inhibit or alter how a message is relayed.
"Our results indicate that the latency period before a single granule cell fires is associated with a specific odor, thus linking the timing of inhibitory modulation of mitral cell activity to odor identity. In other words, the timing of granule cell firing conveys different messages. In this case, the messages relay which odor is present," explained Urban.
Urban monitored the subtle-yet-coordinated activity of populations of granule cells in living brain slices using calcium imaging, an optical imaging technique that has never been applied to studies of the olfactory system. Urban loaded the neurons with a fluorescent dye that emits a yellow glow. This glow decreases when the dye binds to calcium. Because the flow of calcium ions into and out of cells corresponds to their firing, Urban was able to actually watch which neurons were firing and when.
Urban stimulated mitral cells, which in turn stimulated granule cells. He found that granule cells respond by firing over a range of times, from a fraction of a millisecond to hundreds of milliseconds. But, according to Urban, the most striking observation was that specific granule cells reliably fired with the same latency when they receive input from certain populations of mitral cells. Input from one group of mitral cells (hence, one set of odor receptors) caused certain granule cells to fire with a 500-millisecond delay, for example. Input from another set of mitral cells (a different set of odor receptors) caused the same granule cells to fire with a 50-millisecond delay. Thus, he found that the timing of granule cell firing is directly related to the input the mitral cells receive -- the original odorant.
"This is the first time we have seen reliable timing of firing. It turns out that cells are better at clocking their firing than previously thought," Urban said.
"This finding is a springboard to addressing other important questions," Urban added. "For example, what are the molecular mechanisms by which granule cells time their firing? We are now exploring this question, as well as how we can observe this odor-specific timing in living animals."
The research is supported by the National Institute of Deafness and Communication Disorders.
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