Scientists at Harvard Medical School have created the first detailed map of smell receptors in the nose, catching up with similar achievements in sight, hearing and touch. The map reveals that smell receptors are highly organised into tight bands based on type. The findings provide foundational knowledge needed to develop better therapies for loss of smell.
The sense of smell is an integral part of everyday life, yet from a scientific perspective, “olfaction is super-mysterious,” says Sandeep (Robert) Datta, professor of neurobiology in Harvard’s Blavatnik Institute. Basic biological understanding lags behind that of vision, hearing and touch.
Mouse nose, photos courtesy of Datta Lab.
Working with mice, Datta and his team have now created the first detailed map of how the thousand-plus types of smell receptors in the nose are organised. They discovered that the neurons expressing these receptors – long thought to be random – actually have a high degree of spatial organisation. They form horizontal stripes based on receptor type from the top of the nose to the bottom.
The researchers also established that the receptor map in the nose matches smell maps in the olfactory bulb of the brain, providing clues about how information moves from the nose to the brain. While the smell map is an exciting discovery in its own right, Datta said, it also provides foundational information that could help scientists develop therapies for loss of smell, which are currently lacking.
Our understanding of olfaction has lagged behind other senses, in part because it is more complicated than the other senses. Mice, for example, have around 20 million olfactory neurons that express more than a thousand types of smell receptors, compared with only three main types of visual receptors for color vision. Each type of smell receptor detects a unique subset of odor molecules.
Datta had been studying various aspects of olfaction, including what causes loss of smell in COVID-19, and how the brain organises information about odours. As genetic techniques became more powerful, he and colleagues decided to revisit the idea of building a smell map. In their new study, the researchers combined single-cell sequencing and spatial transcriptomics techniques to examine around 5.5 million neurons in more than 300 individual mice. The first technique allowed them to identify which smell receptors were expressed by neurons in the nose, and the second let them determine the locations of those receptors. 
They discovered that the neurons are organised into tight, overlapping, horizontal stripes from the top of the nose to the bottom based on the type of smell receptor they express. This highly organised receptor map was consistent across the mice and mirrored the organisation of smell maps in the brain, just like researchers have observed in vision, hearing, and touch.
The researchers then investigated how the smell map in the nose forms and identified retinoic acid – a molecule that helps control gene activity – as a key driver. They found that a gradient of retinoic acid in the nose guided each neuron to express the correct type of smell receptor based on its spatial location. Adding or removing retinoic acid caused the receptor map to shift up or down.
A separate study led by the lab of Catherine Dulac, the Xander University Professor in the Department of Molecular and Cellular Biology at Harvard University, and published in the same issue of Cell, had consistent findings.
Now, the researchers are exploring why the receptor stripes are in this specific order. The team is also studying smell receptors in human tissue to understand to what degree the smell map is consistent across species. Such understanding will inform efforts to develop treatments – such as stem cell therapies or brain-computer interfaces – for loss of smell and its consequences, which include an increased risk of depression.
“Smell has a really profound and pervasive effect on human health,” Datta said. “Restoring it is not just for pleasure and safety but also for psychological well-being.”
The findings were published April 28 in the journal Cell.
