illustration by VSA Partners

Wired for Smell

Circuits of excitation and inhibition help the brain interpret odors.

Curry-infused Thai food, a gas leak, a dirty cat box. Through sensory cells in the nose, the brain makes quick sense of the good and the bad in our olfactory universe.

The initial phase of the sense of smell is well understood. So-called olfactory receptors—dogs have around 1,000 types of receptors, humans have hundreds, fruit flies around 50—sit on neurons in a vertebrate’s nose or on a fly’s antenna. Each neuron carries one type of receptor, and all neurons with the same type converge at an arborlike structure called a glomerulus and pass their information to other neurons.

All glomeruli reside in the same brain region: the antennal lobe in fruit flies and the olfactory bulb in vertebrates. Different odors activate different combinations of receptors, producing a kind of olfactory code, with each olfactory receptor acting as a chemical “channel” that conveys a stream of information like a radio channel.

Less clear is exactly what happens next. How do neural networks make sense of these activation patterns, direct the information to different parts of the brain, and alter an organism’s behavior in response? “The key problem in the field has become figuring out how information is processed across these channels,” says HHMI early career scientist Rachel Wilson at Harvard University, who, along with Liqun Luo of Stanford University, has begun to figure out how the brain processes smell information and routes it to different brain regions.

Luo, an HHMI investigator, is an expert at mapping how cells course through the nervous system as an animal develops to adulthood. He also has investigated where olfactory information goes after it leaves a glomerulus. In research reported online in Nature on December 22, 2010, Luo and his team mapped the connections from glomeruli in the olfactory bulb to different areas of the mouse brain.

The group found that the amygdala, a brain region responsible for emotion, receives inputs from glomeruli predominantly in one part of the olfactory bulb. Previously, scientists found that knocking out this part of the olfactory bulb makes a mouse no longer react with fear to the smell of a predator, leading Luo to speculate that the amygdala uses odor information to control the innate fear response. By contrast, the piriform cortex, a major area for smell processing, received a broad, unorganized set of inputs from glomeruli, suggesting that it calculates an overall view of the olfactory environment.

In a related study, HHMI investigator Richard Axel of Columbia University and colleagues injected dye into specific glomeruli to trace neurons to the piriform cortex and the amygdala. Squaring with the findings from Luo’s group, the researchers found that individual glomeruli send neurons to all parts of the piriform cortex, whereas they send neurons to more defined regions of the amygdala. Those findings appeared online on March 30, 2011, in Nature.

Wilson is exploring how signals are adjusted and combined at the glomeruli. Each glomerulus is a way station where long-distance neurons meet, but the glomeruli are also connected to each other by local neurons, called interneurons. Typically, these interneurons dampen the signals sent by other neurons, so scientists have reasoned that they must be involved in synthesizing and analyzing all the information coming through the different olfactory channels. But exactly what they are doing has been mysterious. “What’s going on with the local interneurons?” wondered Wilson. “Why do you need so many?”

The two investigators tackled these questions together by matching Luo’s expertise in deciphering wiring maps with Wilson’s skill at measuring neuron activity by recording electrical impulses. In research reported in Nature Neuroscience in April 2010, they mapped interneuron patterns and activity in the fruit fly brain.

Using a fluorescence-based technique Luo developed to image small numbers of neurons (see sidebar, “Better Maps”), his lab group tracked subgroups of interneurons. Conventional wisdom held that these interneurons should connect all glomeruli into a large web, and researchers found that some groups of interneurons held this pattern, communicating among all olfactory channels. But others acted differently, connecting exclusive groups of glomeruli in private networks.

Luo’s group also found that the interneuron patterns weren’t the same from one fly to the next, suggesting variability in wiring that’s also been observed in vertebrates. Thus, Luo suggests, studies of the relatively simple fly brain might provide more direct insights into how the human brain works.

Better Maps

Navigating the nervous system requires a good map.

To complement those studies, Wilson’s team looked at how the interneuron mapping pattern related to the neural activity flowing into glomeruli. They found that the more active glomeruli tended to have more interneuron connections than their less active counterparts. That finding suggests that the ones with the most activity need more interneurons to dampen their output before sending information to other brain regions.

Wilson thinks this arrangement might provide a way for the olfactory system to monitor activity and keep it in the most useful range. By connecting all glomeruli “channels,” inhibitory interneurons can adjust overall activity so that the brain can make sense of the signals, much like a digital camera takes a light reading to make sure the subject of a photo is visible—neither too much nor too little light.

Wilson has also identified another type of interneuron that helps adjust olfactory signals. While most interneurons use chemical signals to dampen other neurons, Wilson and her colleague Emre Yaksi found that some interneurons use electrical communication to excite other neurons.

The work, published September 2010 in Neuron, showed that these special interneurons appear to have two jobs: They excite neurons in different glomeruli by linking directly to them, but they indirectly squelch the same neurons by prodding the inhibitory interneurons to push harder on the brakes. Fine-tuning the balance between these opposing forces helps keep olfactory signals in a range that’s just right, says Wilson.

The results are a glimpse at the complex way the nervous system interprets information about smells. “To understand what’s going on in higher brain regions is not just counting which receptors are active,” says Wilson, it’s also how active they are. Stay tuned for more advances as they sniff out the secrets of how we get a whiff of our world.

Scientist Profile

Harvard Medical School
Stanford University
Developmental Biology, Neuroscience
Columbia University