Sense of Smell, Lost to Ills Like Parkinson’s, Appears Quite Complex

The way that cells in the nose sense scents is more complicated than previously thought, a study reports.

A better understanding of this system could be important to interpreting better how the brain processes scents, and in understanding neurological diseases, like Parkinson’s, where loss of smell is a common early symptom.

The study, “Widespread receptor-driven modulation in peripheral olfactory coding,” was published in Science.

Our sense of smell allows us to detect chemicals in the air, which our brains interpret as various scents or odors.

“The mammalian nose is arguably the best chemical sensor on the planet, able to detect and discriminate among a large and diverse repertoire of mostly small, organic molecules,” the researchers wrote.

Deep in the nose is the olfactory epithelium, which contains thousands of nerve cells, called olfactory sensory neurons (OSNs, also called olfactory receptor neurons or ORNs). Each OSN expresses one specific type of chemical receptor. Because of this, it has long been assumed that individual ‘scent molecules’ activate particular receptors. Experiments using single scents have also supported this framework.

However, scents rarely come one-by-one in the real world. Indeed, most scents are actually combinations. “Even a simple cup of coffee has [more than] 800 volatile components,” the researchers wrote.

This example suggests that, in a scent mixture, each individual scent component activates certain receptors.

Then, the individual signals are sent to the brain, where they are combined into a single scent that is perceived — this is how other senses, like vision, work. However, this has been hard to test in olfaction, in large part because technology to monitor our many different olfactory sensory neurons simultaneously hasn’t existed.

Researchers here took advantage of a recently developed technology called SCAPE (Swept Confocally Aligned Planar Excitation) microscopy. This technique “allows the responses of thousands of single neurons within the intact olfactory epithelium to be monitored in parallel during delivery of repeated odor combinations,” they wrote.

“SCAPE microscopy has been incredibly enabling for studies where large volumes need to be observed at once and in real time,” Elizabeth Hillman, PhD, a study co-author and professor at Columbia University, said in a press release. “Because the cells and tissues can be left intact and visualized at high speeds in three dimensions, we are able to explore many new questions that could not be studied previously.”

The researchers exposed mice to three scents: one described as almond, on as floral (jasmine), and one as citrus. The responses of thousands of OSNs in their noses were measured in response to each of these scents individually, or in combinations of two or three.

Some of the OSNs behaved as expected — that is, they were activated when a given component was present, and not activated otherwise. However, many OSNs had more complicated responses.

“We expected the response to a mixture of odors to look a lot like the sum of responses to the original odors,” said Stuart Firestein, PhD, a study co-author and Columbia professor. “Instead, we observed complex interactions where a second odor enhanced a neuron’s response to the first odor, or in other cases, inhibited [prevented] a neuron’s response.”

Additional experiments using other smells had similar results.

These findings suggest that the way smells are initially perceived by our sensory systems is more complex than previously thought.

Importantly, they suggest that smell may be distinct from other sensory systems — in vision, for instance, receptors are activated by certain wavelengths of light, and the brain then combines these signals into an image.

“Olfaction thus appears unusual in using stimulus-induced complex activity starting at the level of primary sensory receptors,” the researchers wrote.

Researchers speculated that this more complicated sensory system might allow for a more nuanced sense of smell. If there were truly a one-to-one relationship between scent molecules and receptors, then mathematically, there would be a hard limit to the number of different odors that could be sensed, since humans have a limited number of receptors (about 400 total).

The more nuanced system observed, characterized by activation, inhibition, and enhancement all in combination, might have evolved to expand the olfactory system’s sensitivity to different smell combinations.

Beyond improving our understanding of brain biology, these findings may be relevant to disease.

In some disorders — including Parkinson’s, Alzheimer’s, and COVID-19 — losing the sense of smell can be an early symptom. Better understanding how this sense works could help in finding ways to better detect and diagnose these diseases.