Scientists have further decoded how mammalian brains perceive odors and distinguish one smell from thousands of others.
In experiments in mice, NYU Grossman School of Medicine researchers have for the first time created an electrical signature that is perceived as an odor in the brain’s smell-processing center, the olfactory bulb, even though the odor does not exist.
Because the odor-simulating signal was manmade, researchers could manipulate the timing and order of related nerve signaling and identify which changes were most important to the ability of mice to accurately identify the “synthetic smell.”
“Decoding how the brain tells apart odors is complicated, in part, because unlike with other senses such as vision, we do not yet know the most important aspects of individual smells,” says study lead investigator Edmund Chong, MS, a doctoral student at NYU Langone Health. “In facial recognition, for example, the brain can recognize people based on visual cues, such as the eyes, even without seeing someone’s nose and ears,” says Chong. “But these distinguishing features, as recorded by the brain, have yet to be found for each smell.”
The current study results, published online in the journal Science on June 18, center on the olfactory bulb, which is behind the nose in animals and humans. Past studies have shown that airborne molecules linked to scents trigger receptor cells lining the nose to send electric signals to nerve-ending bundles in the bulb called glomeruli, and then to brain cells (neurons).
The timing and order of glomeruli activation is known to be unique to each smell, researchers say, with signals then transmitted to the brain’s cortex, which controls how an animal perceives, reacts to, and remembers a smell. But because scents can vary over time and mingle with others, scientists have until now struggled to precisely track a single smell signature across several types of neurons.
For the new study, the researchers designed experiments based on the availability of mice genetically engineered by another lab so that their brain cells could be activated by shining light on them—a technique called optogenetics. Next they trained the mice to recognize a signal generated by light activation of six glomeruli—known to resemble a pattern evoked by an odor—by giving them a water reward only when they perceived the correct “odor” and pushed a lever.
If mice pushed the lever after activation of a different set of glomeruli (simulation of a different odor), they received no water. Using this model, the researchers changed the timing and mix of activated glomeruli, noting how each change impacted a mouse’s perception as reflected in a behavior: the accuracy with which it acted on the synthetic odor signal to get the reward.
Specifically, researchers found that changing which of the glomeruli within each odor-defining set were activated first led to as much as a 30 percent drop in the ability of a mouse to correctly sense an odor signal and obtain water. Changes in the last glomeruli in each set came with as little as a 5 percent decrease in accurate odor sensing.
The timing of the glomeruli activations worked together “like the notes in a melody,” say the researchers, with delays or interruptions in the early “notes” degrading accuracy. Tight control in their model over when, how many, and which receptors and glomeruli were activated in the mice, enabled the team to sift through many variables and identify which odor features stood out.
“Now that we have a model for breaking down the timing and order of glomeruli activation, we can examine the minimum number and kind of receptors needed by the olfactory bulb to identify a particular smell,” says study senior investigator and neurobiologist Dmitry Rinberg, Ph.D.
Rinberg, an associate professor at NYU Langone and its Neuroscience Institute, says the human nose is known to have some 350 different kinds of odor receptors, while mice, whose sense of smell is far more specialized, have more than 1,200.
“Our results identify for the first time a code for how the brain converts sensory information into perception of something, in this case an odor,” adds Rinberg. “This puts us closer to answering the longstanding question in our field of how the brain extracts sensory information to evoke behavior.”
New research untangles the complex code the brain uses to distinguish between a vast array of smells, offering a scientific explanation for how it separates baby powder from bleach, lemon from orange, or freshly cut grass from freshly brewed coffee.
A single scent can trigger a complex chain of events in what’s known as the olfactory bulb, the brain’s control center for smell. To unravel the intricacies of that process, researchers in the U.S. and Italy turned to a technique known as optogenetics, which uses light to control neurons in the brain. In research on mice, they used light to trick the brain into thinking it smelled a particular scent, then studied brain activity to understand the role different neurons play in a mouse’s ability to recognize that scent. Their findings were published Thursday in Science.
When we encounter a certain smell, it stimulates a specific pattern of activity among tiny spheres known as glomeruli, which are found in the olfactory bulb. The odor plays across these glomeruli like a melody across piano keys: Just as a tune is made distinct by which keys are pressed and at what point in the melody, a scent is made distinct by which glomeruli are activated and in what order.
A tune remains identifiable even with some tweaks: We can still place a melody marred by a wrong note or a mistimed beat. Likewise, we can still recognize a scent altered by some change in its characteristic activity pattern. The researchers wanted to understand how the specific combination of neurons that respond to a scent — including where they’re located, and when they’re activated — might affect whether the brain registers a smell as recognizable.
To do so, the researchers harnessed optogenetics to activate genetically engineered, light-sensitive neurons. The scientists used light to stimulate a specific pattern across glomeruli in mouse brains, which gave the mice the experience of smelling a particular scent — even though that scent that did not actually exist outside of their own heads.
You can do this experiment with the music. I’ll play different music and see which notes are more important, less important,” said Dmitry “Dima” Rinberg, a neuroscientist at NYU Langone Health and a senior author of the study. “We asked not on the level of the external stimulus, but at the level of stimulating neurons.”
The scientists trained the mice to respond in a particular way to this “synthetic smell.” Then, they introduced different tweaks to that pattern — like wrong notes in the melody — and watched to see which of those changes affected whether a mouse could still “smell” the scent.
Justus Verhagen, Yale researcher who studies taste and smell and was not involved in the research, said that the new paper builds on past research into the locations of olfactory neurons and the timing of their activation by bringing the two factors together into a single, comprehensive model.
The difference in the perception seems to follow fairly linearly with the magnitude of the change in either space or time of the stimulation of the olfactory system,” he said. “That linearity is kind of surprising because, in neuroscience, we’re very used to a lot of nonlinear effects.”
The study also cemented the findings of previous research, which has shown that receptors activated earlier are more essential to scent recognition than those activated later on.
“If I messed up with the first note, you have a much higher chance to misinterpret the melody than if I messed up with the 25th note,” Rinberg explained. That makes sense from an evolutionary perspective, he added — animals out in the wild need to make instantaneous assessments of danger. It’s what’s known as the primacy effect. Rinberg added that the effect carries over even to lower-stakes settings like smelling wine, where the specific notes that might suggest where the grapes were harvested only follow after we get past the immediately overwhelming impression of alcohol.
There are no immediate therapeutic applications of the research, Rinberg said. But a better understanding of how the brain perceives scent could one day shed more light on other scientific questions that also involve smell, such as why people sometimes temporarily lose their sense of smell when sick, which has been observed in some patients with Covid-19. Verhagen said research on the logic of the olfactory system could also be of use in developing new technologies.
“In terms of medicine, there is increased interest in brain-machine interfaces. And so it is very important to understand how the brain encodes stimuli,” he said. “If we understand that coding logic, we can use that to help people who have deficits.”
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