Whether hearing, seeing, tasting or touching: For most of our senses, science has a fairly precise picture of how different receptors ensure that we can perceive the world around us. An exception so far has been the sense of smell. Now, for the first time, researchers have mapped the countless nerve cells with their thousands of different receptors in the nose. The results provide fundamental knowledge that can help develop therapies for smell loss.
Our sense of smell is vital to us. It tells us whether food is spoiled and warns us if there is a fire nearby or harmful substances get into the air we breathe. It also plays an important emotional role: for example, a familiar smell can suddenly bring back beautiful or painful memories from our past. Even when it comes to tasting, the nose is at least as important as the tongue. A loss of the sense of smell means that we can no longer perceive the subtle flavor nuances of our food – a frustrating and psychologically stressful experience. If the cause was just a bad cold, the sense of smell usually returns on its own after a few days. However, some illnesses, including COVID-19, can cause a persistent loss of this sensory dimension.
Therapies that restore the ability to smell are still missing. This is partly because the sense of smell is the most complex of all our senses and many details about how it works are still unclear. “We cannot restore the sense of smell without understanding how it works at a fundamental level,” says Sandeep Datta of Harvard Medical School in Boston. For all other senses, there have long been maps that show how the receptors in the eye, ear, tongue and skin are organized and how they correspond to the corresponding regions in the brain. “The sense of smell has been the only exception so far,” says Datta. “It is the meaning for which there was no map available for the longest time.”
Surprising organizational structure
Now Datta has created such a map for the first time together with a team led by first author David Brann. To do this, the researchers examined around 5.5 million nerve cells in more than 300 mice. Using a combination of single-cell sequencing and spatial analyzes of gene activity, they analyzed which olfactory receptors were expressed where in the small rodents’ noses. “The mouse nose is now arguably the best sequenced neural tissue ever, but we needed this amount of data to understand the system,” says Datta.
Mice have around 20 million olfactory neurons with more than a thousand types of olfactory receptors. Each type of receptor is responsible for a specific scent molecule. Complex smells arise from the interaction of different molecules, each of which activates its own specialized nerve cells. Until now, science assumed that the different types of receptors were randomly distributed in the nose.
But when analyzing their data, Brann and his colleagues discovered a surprising pattern: the neurons with the same type of receptor were arranged in dense, overlapping strips from the tip of the nose to the base of the nose. “Our results bring order to a system previously thought to be disordered, fundamentally changing our understanding of how this works,” says Datta.
Basis for new treatments
The highly organized receptor map was consistent across all mice and reflected the organization of the olfactory map in the brain. As the researchers discovered, the order comes about through a gradient of the molecule retinoic acid. Depending on its concentration, this vitamin A acid regulates the gene activity of the olfactory neurons so that they express exactly the right type of receptor depending on their spatial location. If the researchers changed the retinoic acid concentration, the receptor map shifted.
In further studies, the team plans to also examine the arrangement of olfactory receptors in humans and find out to what extent the odor map discovered in mice is consistent across different species. Based on these findings, it could be possible in the future to develop new treatment methods such as stem cell therapies or brain-computer interfaces to restore a lost sense of smell. “The sense of smell has a truly profound and pervasive impact on human health, so restoring it is not only for pleasure, but also for safety and psychological well-being,” says Datta.
Source: David Brann (Harvard Medical School, Boston, Massachusetts, USA) et al., Cell, doi: 10.1016/j.cell.2026.03.051