It has been found that worms have a molecular mechanism for detecting odor differences. Being able to smell could mean the difference between life and death for nematodes that live in the soil and rely on olfaction for survival. But for decades, researchers have struggled to explain how these worms can tell the difference between a thousand different aromas. The equilibration of human eyesight is aided by a conserved protein that has recently been identified by researchers at the University of Toronto. The implications of their discovery extend far beyond nematode olfaction, and may even help us better understand how our own brains work.

The study’s principal investigator was Derek van der Kooy, a professor of molecular genetics at the University of Toronto’s Temerty Faculty of Medicine and the director of the Donnelly Centre for Cellular and Biomolecular Research. One of the model organisms used in the neuroscience research at the van der Kooy lab is the worm Caenorhabditis elegans. First author and recent van der Kooy lab Ph.D. recipient Daniel Merritt exclaims, “The worms have an incredible sense of smell — it’s absolutely amazing.”

Soil, fruit, flower, and bacterial molecules are just some of the many that can be detected by these sensors. Patient urine can be tested for the presence of biomarkers of cancer and explosives, he claimed. Approximately 1300 odorant receptors were discovered in C. elegans over the past three decades, making this nematode a champion sniffer. Each of the receptors in a cockroach’s nose is tuned to pick up only one specific odor, just like in humans, but that’s about where the similarities end.

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Hundreds of sensory neurons line the inside of our noses, and each one only expresses a single receptor type. When a neuron is stimulated by an odorant, the signal is sent down the neuron’s long process, or axon, and eventually translates into the sensation of smell in the brain. Separating the axonal cables responsible for transmitting the various olfactory signals allows for discrimination between them. Only 32 olfactory neurons house all 1300 of a worm’s receptors. “Clearly, the one neuron-one smell strategy is not going to work here,” Merritt said.

Worms, despite this, can tell the difference between odors picked up by the same neuron. Pioneering research from the early 1990s showed that when exposed to two attractive odors, where one is uniformly present and the other is localized, the worms crawl towards the latter. A molecular explanation for how this behavior is controlled, however, has been elusive. Somehow the worm is able to distinguish between the upstream components despite the fact that all the information sensed by this neuron is combined into a single signal. That’s where we came to it,” said Merritt.

A former master’s student of Merritt’s named Isabel MacKay-Clackett, who is also a co-first author on the paper, hypothesized that the worms may be able to detect the intensity of the odors. It is their theory that the worms will eventually become desensitized to the ubiquitous odors and stop paying attention to them. This would allow the receptors to be activated and signal transduction to occur in response to the weakly present odors, which may be more helpful in guiding behavior.

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They also had an inkling as to the molecular basis of this phenomenon. A protein named arrestin is a well-established desensitizer of the so-called- G protein-coupled receptors (GPCRs), a large family of proteins that perceive external stimuli, to which odorant receptors belong to. Arrestins for example allow us to adjust vision in bright light by damping down signaling through the photon-sensing receptors in the retina.

When a stronger and weaker odor are sensed by the same neuron, the group speculated that arrestin might also act in worms to desensitize the receptors for the stronger odor. To test their hypothesis, they exposed the worms lacking the arrestin gene to two different attractive smells in a Petri dish. They mixed one smell into the agar medium to make it uniform and put the worms on top. The other smell was placed at one spot some distance from the worms.

The absence of arrestin rendered the worms unable to track down the source of the diminished odor. Arrestin, like squinting the human eye in bright sunlight, helps remove an overwhelming sensation, in this case ambient smell, allowing the worms to detect a localized smell and move towards it, as explained by MacKay-Clackett. However, arrestin is not needed when the smells are detected by different neurons, indicating that the worms use the same discrimination strategy as vertebrates when the smell signals travel down different axons.

The team looked at different sets of smells and neurons and found they all obeyed the same logic, said Merritt. They also used drugs to block arrestin and found that this too abolished smell discrimination. The finding is significant because it is the first evidence showing that arrestin can fine-tune multiple sensations.

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“There is no case known in biology before this where arrestin is being used to allow for discrimination of signals external to the cell,” said Merritt. Moreover, he noted that the same mechanism may be at work in other animals in which multiple GPCRs are expressed on the same cell, particularly in the brain. Our brains are bathed in neurochemicals that signal through hundreds of different GPCRs, raising a possibility that arrestin, of which there are four types in humans, could be key for information processing.

“Our work provides one piece of the puzzle of how the worms’ amazing sense of smell works, but it also informs our understanding of how GPCR signaling works more broadly within animals,” said Merritt.

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