A new study from the lab of Catherine Dulac, the Xander University Professor of Molecular and Cellular Biology at Harvard, in collaboration with Xiawei Zhuang of Harvard’s Departments of Chemistry and Physics, offers the most comprehensive molecular map to date of how smells are detected in the nose and represented in the brain. Using a powerful spatial transcriptomics method, the research team constructed high-resolution atlases showing where nearly every olfactory receptor in the mouse is expressed—and exactly where neurons carrying those receptors project in the brain.
The work, recently published in Cell (PDF) was led by Bogdan Bintu, who carried out the research as a joint graduate student in the Dulac and Zhuang labs and is now an assistant professor of Cellular and Molecular Medicine at the University of California, San Diego.
“This paper is really about the front end of smell—what happens at the level of the sensory neurons in the nose,” says Bintu. “These neurons are remarkable because there are about a thousand different types in the mouse, and each type expresses just one olfactory receptor and sends its axon to a very specific location in the brain.”
A long-standing mystery in olfaction
For decades, neuroscientists have known that olfactory sensory neurons in the main olfactory epithelium (MOE) project with astonishing precision to discrete structures called glomeruli in the olfactory bulb (OB). These projections are highly stereotyped: neurons expressing the same receptor converge on the same pair of glomeruli in every animal.
What has remained unclear is how the full repertoire of olfactory receptors—nearly 1,100 in mice—is spatially organized in the nose, how that organization is translated into a map in the brain, and how those maps relate to function.
“People had looked at a handful of receptors at a time,” Bintu explains. “But measuring a thousand receptor types across the entire tissue was technically out of reach. Without a complete map, it was impossible to see the underlying logic of the system.”
Applying MERFISH to the olfactory system
To overcome this barrier, the team turned to Multiplexed Error-Robust Fluorescent In Situ Hybridization, or MERFISH—a spatial transcriptomics technology developed by Harvard Professor of Chemistry and Chemical Biology Xiaowei Zhuang and previously applied by the Dulac lab to questions of brain organization and behavior. In this study, MERFISH was used to directly visualize the expression of nearly the entire olfactory receptor gene family within intact tissue.
Using this approach, the researchers built two detailed atlases: one capturing the spatial distribution of olfactory sensory neurons within the MOE, and another charting their three-dimensional projections into the olfactory bulb.
The results revealed striking patterns. In the nose, receptors are arranged in continuous, ring-like gradients that expand from the center of the epithelium toward the periphery, with additional organization along a perpendicular basal-to-apical axis. In the brain, these same gradients are remapped onto the dorsal-ventral and anterior-posterior axes of the olfactory bulb.
“What’s beautiful is how systematic it is,” says Bintu. “The spatial organization in the nose is preserved and transformed in a very precise way in the brain.”
Precision wiring, conserved across animals
The olfactory bulb maps turned out to be remarkably consistent across individuals. The team found that axonal targeting precision is on the order of 200–300 micrometers—roughly the width of one or two glomeruli—matching estimates from earlier functional studies.
“That level of stereotypy tells you this wiring diagram is genetically programmed,” Bintu says. “It’s not random, and it’s not learned. The brain knows exactly where these neurons are supposed to go.”
By integrating their spatial maps with existing single-cell RNA sequencing datasets, the researchers also identified candidate transcription factors, axon guidance cues, and signaling molecules that may coordinate receptor choice with precise wiring to the brain.
Linking maps to meaning
Beyond anatomy, the study connects spatial organization to function. By combining MERFISH with single-molecule detection of the activity marker Egr1, the team mapped which receptors—and which regions of the olfactory system—respond to ethologically relevant odors, including social cues and predator scents.
Distinct categories of odors activated spatially constrained domains in both the MOE and the olfactory bulb. Male and female social odors, predator odors, and pup cues each engaged different regions of the map, suggesting that biologically important smells are processed in dedicated neural territories.
“These results challenge some simple ideas about how attractive versus aversive odors are organized,” Bintu notes. “Instead, the system seems optimized to route different categories of information into specific circuits that drive very different behaviors.”
A foundation for future work—and human studies
The atlases produced in this study are intended as a community resource, providing a framework for future molecular and functional investigations of smell. As more receptors are matched to their natural ligands, researchers will be able to place those responses into a precise anatomical and genetic context.
Perhaps most intriguingly, the approach does not rely on genetically engineered animals, opening the door to studies of human tissue.
“In principle, the same technology can be applied to postmortem human samples,” says Bintu. “The olfactory bulb is often collected but understudied. Understanding whether the same organizational principles apply in humans could have implications for neurodegenerative disease, where smell is often one of the first senses affected.”
For Dulac and her colleagues, the work represents a major step toward decoding how chemical signals from the environment are transformed into structured neural representations—and, ultimately, into behavior.
“This study finally lets us see the olfactory system as a whole,” Bintu says. “Once you have the full map, you can start asking entirely new questions about how the brain interprets the world through smell.”
(PDF)
