Loss of Smell Therapies Informed by Olfactory Receptor Spatial Mapping

A new study published in Cell titled, “A spatial code governs olfactory receptor choice and aligns sensory maps in the nose and brain,” led by researchers from Harvard Medical School (HMS) has created the first detailed map of the spatial distribution of over 1,000 olfactory receptors in the epithelium. The study informs the development of therapies for loss of smell, where treatment options are limited.

The researchers examined approximately 5.5 million neurons in more than 300 individual mice using single-cell sequencing and spatial transcriptomics. Results showed that neurons are organized into tight, overlapping, horizontal stripes from the top to the bottom of the nose based on the type of smell receptor expressed. This highly organized receptor map was consistent across mouse models and mirrored the organization of smell maps in the brain. Similar maps have been observed in vision, hearing, and touch.

Notably, the olfactory map was informed by a gradient of retinoic acid in the nose, which allowed each neuron to express the correct type of smell receptor based on its spatial location.  

“Our results bring order to a system that was previously thought to lack order, which changes conceptually how we think this works,” said Sandeep (Robert) Datta, PhD, professor of neurobiology at HMS and senior author and corresponding author of the study. “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.” 

The authors also found that the receptor map in the nose matches up with smell maps in the olfactory bulb of the brain, shedding insight into how information moves from the nose to the brain. 

While sensory maps that describe how receptors in the eye, ear, and skin are organized to capture and interpret auditory, visual, and touch information, mapping olfactory receptors has been a longstanding challenge due to high receptor diversity. As an example, mice have approximately 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. 

The team is also studying smell receptors in human tissue to understand to what degree the smell map is consistent across species to inform treatments, such as stem cell therapies and loss of smell and its consequences, such as 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.” 

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