Inhibition Is So Hot Right Now

First, whoever says scientists don't have a sense of humor don't have a sense of humor.

Image credit: This imaginary perfume bottle illustrates the role pheromones play in Drosophila courtship decisions by featuring the silhouettes of a male chasing a courted female. Naming this fictional eau de pheromone “Dew Lover” was inspired by the etymological origin of the genus Drosophila, which is based on the modern scientific Latin adaptation of the Greek words drósos (“dew”) and phílos (“loving”). Vernier et al.  show that the coupling of the perception and production of some mating pheromones is regulated by the action of a pleiotropic pheromone receptor. Credit: Digital art by Yehuda Ben-Shahar, Washington University in St. Louis

Now for the main point -- up until recently, much of our understanding of olfactory perception came from looking at receptor activity. You expose a receptor to an odor and see if it lights up, and with that you make a kind of odor map coordinating odorant molecules and receptor proteins. 

Things are different now, because instead of just looking at how receptors are stimulated by odors, we also look at how they are inhibited, because it turns out there is just as much to be learned from receptor inhibition as there is activation. And, the interplay of activate-inhibit sure sounds a lot like the ons and offs of computer processing, meaning that the nose-brain may be a lot more useful as a model for a primitive computer than we thought.

Examining the chemicals involved in insect mating

Jan 2023, phys.org

https://phys.org/news/2023-01-chemicals-involved-insect.html

Researchers reported that a single protein called Gr8a is expressed in different organs in male and female flies and appears to play an inhibitory role in mating decision-making. The findings point to one of the ways that flies could put up behavioral barriers to protect against mating with the wrong kind of partner.

"A single pleiotropic protein can function as both a receptor for pheromones in sensory neurons, as well as contribute to their production in the pheromone-producing cells (oenocytes) of males, by way of a less-understood process."

The scientists still have not pinpointed exactly how the chemoreceptor affects the way the signal is produced, but they do know that it causes quantitative and qualitative differences in pheromones. And even small changes in pheromones could be enough to keep closely related flies from finding each other attractive—and change their mate choice behaviors.

"Based on what we have observed, mutations in a single gene could provide a molecular path for a pheromonal communication system to evolve while still maintaining the functional coupling between a pheromone and its receptor," Ben-Shahar said. "Our research uncovers a potential avenue for pheromonal systems to rapidly evolve when new species arise."

Or when a species decides to rapidly evolve itself; looking at you mass population control.

via Washington University St Louis: Cassondra L. Vernier et al, A pleiotropic chemoreceptor facilitates the production and perception of mating pheromones, iScience (2022). DOI: 10.1016/j.isci.2022.105882

https://phys.org/news/2023-01-chemicals-involved-insect.html

Post Script - Pheromones Again

Pachyderm perfume: How African elephants use odor to communicate

Apr 2023, phys.org

https://phys.org/news/2023-04-pachyderm-perfume-african-elephants-odor.html

We tested the DNA, glands, urine and manure of 113 African elephants in wildlife parks in Malawi to identify family groupings," and "We found a number of chemicals were common to group members, but others that were unique to each individual, and found that smell was used to distinguish characteristics including age, health, reproductive status and family relationships between elephants.

"We observed elephants greeting each other by squealing and flapping their ears," he said.

"We believe they're pushing their pheromones towards the other elephant as a sign of recognition.

"When elephants charge each other flapping their ears, rather than making themselves look bigger, we believe they're blowing their pheromones as a warning not to mess with them."

"Some of the animals in the study were bred in captivity, and one of the tricks they'd been taught was to take a tourist's hat and smell it," he said.

"When the tourist came back hours later the elephant would be able to immediately identify who the hat belonged to."

via University of Queensland: Katharina E. M. von Dürckheim et al, A pachyderm perfume: odour encodes identity and group membership in African elephants, Scientific Reports (2022). DOI: 10.1038/s41598-022-20920-2

https://dx.doi.org/10.1038/s41598-022-20920-2

Frankenscience

This discovery provides a great example of how machine learning and optogenetics are blowing open our doors of perception.

In this case, scientists created an artificial olfactory receptor (this one derived from OR5A2). You can think of it like the ultimate musk receptor, because after matching it against 100 mammal-nose-brain gene sequences, it's the best-fit for all the animals at once.

But it doesn't really exist in any one animal; it's simply the most in-between of all of them. They call it a "consensus protein". I call it a frankenstein receptor. 

That was machine learning to the rescue, but then they called their friend optogenetics -- they further engineer this artificial protein to produce light when activated. This is a common technique these days that allows us to measure the receptor activity; it's like being able to ask an animal to tell you whether it smells something or not. Then they go back and find all the odorants that match this new frankenstein receptor -- if it lights up, it's a match.

They found no new musks actually, which suggests we know all of them already, but this could work for other odors:

Chemists propose unifying theory of musk - Engineered olfactory receptor may explain why structurally diverse molecules smell similar.

Chemical and Engineering News, Nov 2022

https://cen.acs.org/biological-chemistry/biochemistry/Chemists-propose-unifying-theory-musk/100/web/2022/11

The three receptors known to recognize musk compounds only respond to a subset of musk-scented compounds.

The researchers compared the amino acid sequences for a given odorant receptor across 112 mammal species to determine the most common amino acid at each position and made a receptor with this so-called consensus sequence.

The engineered protein differs from human OR5A2 at 25 of its 324 amino acids ... .

Using the structures of compounds that do and do not activate the receptor, the researchers developed a machine learning model and used it to screen a database of odorant structures and human perceptions. The model, Mainland says, claims to identify known musk molecules much better than prior models trained only using the database. Although they do not report any new musky compounds in the study, the authors say that the Kao Corporation has filed patents related to the work.

via Duke University and Kao Corporation, Tokyo: Proc. Natl. Acad. Sci. U.S.A. 2019, DOI: 10.1073/pnas.1804106115

http://dx.doi.org/10.1073/pnas.1804106115

And this is a pretty big deal in smell science:

First molecular images of olfaction open door to creating novel smells

Mar 2023, phys.org

https://phys.org/news/2023-03-molecular-images-olfaction-door.html

First molecular-level, 3D picture of how an odor molecule activates a human odorant receptor.

Odorant receptors are notoriously challenging, some say impossible, to make in the lab for such purposes. The Manglik and Matsunami teams looked for one that was abundant in both the body and the nose, thinking it might be easier to make artificially, and one that also could detect water-soluble odorants. They settled on a receptor called OR51E2, which is known to respond to propionate—a molecule that contributes to the pungent smell of Swiss cheese.

This molecular snapshot showed that propionate sticks tightly to OR51E2 thanks to a very specific fit between odorant and receptor. The finding jibes with one of the duties of the olfactory system as a sentinel for danger.

"This receptor is laser focused on trying to sense propionate and may have evolved to help detect when food has gone bad," said Manglik. Receptors for pleasing smells like menthol or caraway might instead interact more loosely with odorants, he speculated.

"We've dreamed of tackling this problem for years," he said. "We now have our first toehold, the first glimpse of how the molecules of smell bind to our odorant receptors. For us, this is just the beginning."

via University of California, San Francisco: Aashish Manglik, Structural basis of odorant recognition by a human odorant receptor, Nature (2023). DOI: 10.1038/s41586-023-05798-y

https://dx.doi.org/10.1038/s41586-023-05798-y

Image credit: AI Art - Iridescent Myxomycete - 2023

The Olfactory Determinants of Culture

First direct evidence that babies react to taste and smell in the womb

Oct 2022, phys.org

https://medicalxpress.com/news/2022-09-evidence-babies-react-womb.html

4D ultrasound -- Fetuses exposed to carrot showed more "laughter-face" responses while those exposed to kale showed more "cry-face" responses.

via Durham University: Flavour Sensing in Utero and Emerging Discriminative Behaviours in the Human Fetus, Psychological Science (2022). DOI: 10.1177/09567976221105460

https://dx.doi.org/10.1177/09567976221105460

Ancient humans had same sense of smell, but different sensitivities

Jan 2023, phys.org

https://phys.org/news/2023-01-ancient-humans-sensitivities.html

"We had the odorant receptor genomes from Neanderthal and Denisovan individuals and we could compare them with today's humans and determine if they resulted in a different protein."

So then they tested the responses of 30 lab-grown olfactory receptors from each hominin against a battery of smells to measure how sensitive each kind of receptor was to a particular fragrance.

The laboratory tests showed the modern and ancient human receptors were essentially detecting the same odors, but their sensitivities differed.

Denisovans -- less sensitive to floral, better at sulfur, balsamic, and honey

Neanderthals -- less responsive to green, floral and spicy scents

via Duke University: Claire A. de March et al, Genetic and functional odorant receptor variation in the Homo lineage, iScience (2022). DOI: 10.1016/j.isci.2022.105908

https://dx.doi.org/10.1016/j.isci.2022.105908

Image credit: AI Art - Photograph of a Neanderthal Nikon 85mm DSLR - 2023.jpeg

Reminder that "mummy fever" was a thing back in the 1800's and it was a big deal to break out the mummy meat for your esteemed guests, because nothing identifies the top tier of society like eating small fragrant bits of ancient humans:

Teasing out the secret recipes for mummification in ancient Egypt

Feb 2023, Ars Technica

https://arstechnica.com/science/2023/02/teasing-out-the-secret-recipes-for-mummification-in-ancient-egypt/

The results: “We could identify a large diversity of substances which were used by the embalmers,” co-author Maxime Rageot of the University of Tübingen told New Scientist. Those substances included oils or tars from juniper, cypress, or cedar; various resins, including some from Pistacia trees; and animal fats, beeswax, and plant oils. Most of those have been found before in mummies, but two resins—dammar and elemi—have not been previously identified anywhere in Egypt before. They also found bitumen from the Dead Sea. -via New Scientist

Stressed, Depressed, and Social Unrest

If you thought we had reached a new horizon of mass social behavior modification via electronic drugs  (ie social media and the consumer surveillance apparatus), then just wait until the smells show up. Smells have a direct line to the limbic system, which is called so because it controls your limbs; it literally makes you move, and it also controls your mood. 

Incorporating scents into a VR environment suitable for spacefarers

Jan 2023, phys.org

https://phys.org/news/2023-01-incorporating-scents-vr-environment-suitable.html

Building scents into a VR nature environment: A user could walk near a river in the VR environment and not only hear the sound of rushing water but also smell wet grass. This is accomplished by using hitboxes, which are invisible shapes in the VR environment that activate when the avatar collides with them.

When conducting their study, Abbott and Diaz Artiles measured users' anxiety levels before and after experiencing a stress-inducing event. The results showed that adding olfactory stimuli not only decreased users' anxiety levels after experiencing heightened stress but also reduced their stress and anxiety levels from their baseline.

via Texas A&M University College of Engineering: Renee (Woodruff) Abbott et al, The impact of digital scents on behavioral health in a restorative virtual reality environment, Acta Astronautica (2022). DOI: 10.1016/j.actaastro.2022.05.025

https://dx.doi.org/10.1016/j.actaastro.2022.05.025

Image credit: AI Art - Dog Smelling Roses on a Sunny Day - 2023

Dogs can smell when we're stressed, study suggests

Oct 2022, phys.org

https://phys.org/news/2022-09-dogs-stressed.html

 

93.75% accuracy detecting changes in breath and sweat, before and after a fast-paced arithmetic task, along with self-reported stress levels, heart rate and blood pressure.

via Animal Behaviour Centre at Queen’s University Belfast, and Newcastle University: Dogs can discriminate between human baseline and psychological stress condition odours, PLoS ONE (2022). DOI: 10.1371/journal.pone.0274143

https://dx.doi.org/10.1371/journal.pone.0274143

Chances are we can smell stress too, we're just not tuned-in to it. If you want proof, you can look at post-handshake-hand-sniffing behavior and think about how we're subconsciously measuring the stress levels of the people we shake hands with as a way to assess how we should react to them.  

And now for some thoughts about depression, anosmia and long covid:

Potential found to counter depression by restoring key brain rhythm

May 2023, phys.org

https://medicalxpress.com/news/2023-05-potential-counter-depression-key-brain.html

Effective communication between brain regions requires groups of neurons to synchronize their activity patterns in repetitive periods (oscillations) of joint silence followed by joint activity.

One such rhythm, called "gamma," repeats about 30 times or more in a second, and is an important timing pattern for the encoding of complex information, potentially including emotions.

Although its causes remain poorly understood, depression is reflected in gamma oscillation changes, according to past studies, as an electrophysiological marker of the disease in brain regions that manage the sense of smell, which have also been tied to emotions. 

"Our experiments revealed a mechanistic link between deficient gamma activity and behavioral decline in mice and rat models of depression, with the signal changes in the olfactory and connected limbic systems similar to those seen in depressed patients,"

Feeding an amplified olfactory bulb signal back into the brains of depressed rats restored normal gamma function in the limbic system, and reduced the depressive behaviors by 40 percent (almost to normal).

via NYU Grossman School of Medicine and University of Szeged in Hungary: Antal Berényi, Reinstating olfactory bulb derived limbic gamma oscillations alleviates depression-like behavioral deficits in rodents, Neuron (2023). DOI: 10.1016/j.neuron.2023.04.013.

https://dx.doi.org/10.1016/j.neuron.2023.04.013

Partially unrelated post script:

In case you're ever wondering how do they actually measure depression in mice, they get dunked in a bucket of water to see how long it takes for them to stop swimming -- the sooner they give up, the more depressed they are.