Summary: For over 30 years, the sense of smell has been the “black box” of neuroscience. While we have long understood the precise maps for vision, hearing, and touch, the nose was believed to be a chaotic, random landscape.
A new study has finally debunked this theory. Using massive-scale genetic sequencing, researchers discovered that the nose is actually organized into an incredibly precise series of horizontal stripes. This “smell map” mirrors the organization of the brain, providing the foundational blueprint needed to finally develop therapies for the loss of smell.
Key Facts
- The “Stripe” Discovery: Instead of receptors being scattered randomly, Harvard researchers found that the 1,000+ types of smell receptors in mice form tight, overlapping horizontal stripes from the top of the nose to the bottom.
- Hydraulic Precision: The map is driven by retinoic acid, a molecule that acts as a spatial guide. A gradient of this acid tells each neuron which receptor to express based on its exact “latitude” in the nose.
- Brain-Body Symmetry: The researchers confirmed that the spatial map in the nose corresponds directly with the “smell maps” in the olfactory bulb of the brain, much like the retina corresponds to the visual cortex.
- Data at Scale: The study is one of the most comprehensive neural mapping projects ever conducted, analyzing 5.5 million neurons across more than 300 mice using single-cell sequencing and spatial transcriptomics.
- Clinical Significance: This map is essential for developing stem cell therapies or brain-computer interfaces to treat anosmia (loss of smell), a condition linked to increased risks of depression and decreased safety.
Source: Harvard
For most of us, the sense of smell is an integral part of everyday life; it plays a critical role in providing information about our surroundings, alerting us to potential dangers, enhancing our sense of taste, and evoking emotions and memories.
Yet from a scientific perspective, “olfaction is super-mysterious,” said Sandeep (Robert) Datta, professor of neurobiology in the Blavatnik Institute at Harvard Medical School, with basic biological understanding lagging behind that of vision, hearing, and touch.
Working in 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 organized.
They discovered that unlike what scientists had long believed, the neurons expressing these receptors have a high degree of spatial organization: They form horizontal stripes based on receptor type from the top of the nose to the bottom.
“Our results bring order to a system that was previously thought to lack order, which changes conceptually how we think this works,” said Datta, senior author of the study.
Moreover, the researchers established that the receptor map in the nose matches up with 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.
“We cannot fix smell without understanding how it works on a basic level,” he said.
The findings published April 28 in Cell.
A missing map
Maps have long existed that describe how receptors in the eye, ear, and skin are organized to capture and interpret auditory, visual, and touch information — and scientists have figured how these maps correspond with those inside the brain.
However, “olfaction has been the one exception; it’s the sense that has been missing a map for the longest time,” Datta said.
This is 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.
Scientists first began identifying smell receptor types in 1991. Over the next 35 years, researchers investigated whether there was a smell map in the nose. However, they could only observe that receptors tended to be expressed in one of a handful of zones in olfactory tissue. This led to the prevailing theory that receptor expression was largely random, meaning that smell was unlike the other senses.
Datta had been studying various aspects of olfaction, including what causes loss of smell in COVID-19 and how the brain organizes information about odors. As genetic techniques became more powerful, he and colleagues decided to revisit the idea of building a smell map.
An organizational structure, unveiled
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.
“This is now arguably the most sequenced neural tissue ever, but we needed that scale of data in order to understand the system,” Datta said.
They discovered that the neurons are organized 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 organized receptor map was consistent across the mice and mirrored the organization 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.
“We show that development can achieve this feat of organizing a thousand different smell receptors into an incredibly precise map that’s consistent across animals,” Datta said.
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, that published in the same issue of Cell had consistent findings.
Much-needed knowledge
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, so restoring it is not just for pleasure and safety but also for psychological well-being,” Datta said. “Without understanding this map, we’re doomed to fail in developing new treatments.”
Authorship, funding, disclosures
Additional authors on the paper include David Brann, Tatsuya Tsukahara, Cyrus Tau, Dennis Kalloor, Rylin Lubash, Lakshanyaa Kannan, Nell Klimpert, Mihaly Kollo, Martin Escamilla-Del-Arenal, Bogdan Bintu, Andreas Schaefer, Alexander Fleischmann, and Thomas Bozza.
Funding: Funding for the research was provided by the National Institutes of Health (grants R01DC021669, R01DC021422, R01DC021965, and F31DC019017), the Yang Tan Collective at Harvard, and a National Science Foundation Graduate Research Fellowship.
Key Questions Answered:
A: Complexity. Humans have three types of color receptors, but mice have over a thousand types of smell receptors. Until recent advances in genetic sequencing, we didn’t have the “resolution” to see the subtle horizontal patterns. It looked like static until we looked at millions of cells at once.
A: Yes. The “stripes” mean that certain receptor types are physically higher or lower. This spatial organization likely helps the brain process complex odors more efficiently by categorizing them before the signal even reaches the olfactory bulb.
A: Directly. Senior author Sandeep Robert Datta previously studied how COVID-19 causes smell loss. This new map provides the “wiring diagram” researchers need to understand how to regrow olfactory neurons in the correct positions to restore a functional sense of smell.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this olfaction and brain mapping research news
Author: Katie Brace
Source: Harvard Medical School
Contact: Katie Brace – Harvard Medical School
Image: The image is credited to Datta Lab
Original Research: Closed access.
“A spatial code governs olfactory receptor choice and aligns sensory maps in the nose and brain” by David H. Brann, Tatsuya Tsukahara, Cyrus Tau, Dennis Kalloor, Rylin Lubash, Lakshanyaa Thamarai Kannan, Nell Klimpert, Mihaly Kollo, Martín Escamilla-Del-Arenal, Bogdan Bintu, Andreas Schaefer, Alexander Fleischmann, Thomas Bozza, and Sandeep Robert Datta. Cell
DOI:10.1016/j.cell.2026.03.051
Abstract
A spatial code governs olfactory receptor choice and aligns sensory maps in the nose and brain
Although topographical maps organize many peripheral sensory systems, mouse olfactory sensory neurons (OSNs) are thought to randomly choose which one of ∼1,100 possible olfactory receptors (ORs) to express, with spatial organization in the olfactory epithelium limited to a handful of broad anatomical “zones” that modestly restrict OR choice.
Here, we reveal that each OR is instead expressed at a unique mean dorsoventral position, thereby instantiating a stereotyped receptor map in the olfactory epithelium. OSN dorsoventral identities are encoded by a coherent gene expression program, which includes key transcription factors and axon guidance molecules; use of this program reflects a dorsoventral gradient in retinoic acid signaling, translates each physical location into a spatially appropriate distribution of potential OR choices, and aligns receptor maps in the nose and brain.
Spatial order in the olfactory system, therefore, arises from a continuously varying transcriptional code that precisely organizes the many discrete channels responsible for smell.
