Summary: Study reveals how innate valence is encoded in the nervous system of mice.

Source: Stowers Institute for Medical Research

Since the beginning of the pandemic, a loss of smell has emerged as one of the telltale signs of COVID-19. Though most people regain their sense of smell within a matter of weeks, others can find that familiar odors become distorted. Coffee smells like gasoline; roses smell like cigarettes; fresh bread smells like rancid meat.

This odd phenomenon is not just disconcerting. It also represents the disruption of the ancient olfactory circuitry that has helped to ensure the survival of our species and others by signaling when a reward (caffeine!) or a punishment (food poisoning!) is imminent.

Scientists have long known that animals possess an inborn ability to recognize certain odors to avoid predators, seek food, and find mates.

Now, in two related studies, researchers from the Yu Lab at the Stowers Institute for Medical Research show how that ability, known as innate valence, is encoded. The findings, published in the journals Current Biology and eLife, indicate that our sense of smell is more complicated–and malleable–than previously thought.

Our current understanding of how the senses are encoded falls into two contradictory views–the labeled-line theory and the pattern theory. The labeled-line theory suggests that sensory signals are communicated along a fixed, direct line connecting an input to a behavior. The pattern theory maintains that these signals are distributed across different pathways and different neurons.

Some research has provided support for the labeled-line theory in simple species like insects. But evidence for or against that model has been lacking in mammalian systems, says Ron Yu, PhD, an Investigator at the Stowers Institute and corresponding author of the reports. According to Yu, if the labeled-line model is true, then the information from one odor should be insulated from the influence of other odors. Therefore, his team mixed various odors and tested their impact on the predicted innate responses of mice.

“It’s a simple experiment,” says Qiang Qiu, PhD, a research specialist in the Yu Lab and first author of the studies. Qiu mixed up various combinations of odors that were innately attractive (such as the smell of peanut butter or the urine of another mouse) or aversive (such as the smell of rotting food or the urine of a predator).

He then presented those odor mixtures to the mice, using a device the lab specially designed for the purpose. The device has a nose cone that can register how often mice investigate an odor. If mice find a particular mixture attractive, they poke their nose into the cone repeatedly. If they find the mixture aversive, they avoid the nose cone at all costs.

To their surprise, the researchers discovered that mixing different odors, even two attractive odors or two aversive odors, erased the mice’s innate behavioral responses. “That made us wonder whether it was simply a case of one odor masking another, which the perfume industry does all the time when they develop pleasant scents to mask foul ones,” says Yu.

However, when the team looked at the activity of the neurons in the olfactory bulb that respond to aversive and attractive odors, they found that was not the case.

Rather, the patterns of activity that represented the odor mixture were strikingly different from that for individual odors. Apparently, the mouse brain perceived the mixture as a new odor identity, rather than the combination of two odors. The finding supports the pattern theory, whereby a sensory input activates not just one neuron but a population of neurons, each to varying degrees, creating a pattern or population code that is interpreted as a particular odor (coyote urine! run!).

The study was published online March 1, 2021, in Current Biology.

But is this complicated neural code hardwired from birth, or can it be influenced by new sensory experiences? Yu’s team explored that question by silencing sensory neurons early in life, when mice were only a week old. They found that the manipulated mice lost their innate ability to recognize attractive or aversive odors, indicating that the olfactory system is still malleable during this critical period of development.

This shows the olfactory bulb of a mouse
Fluorescent immunochemistry staining of an olfactory bulb slice from mouse. Credit: Qiang Qiu, PhD, Stowers Institute for Medical Research

Interestingly, the researchers found that when they exposed mice during this critical period to a chemical component of bobcat urine called PEA, the animals no longer avoided that odor later in life. “Because the mice encountered this odor while they were still with their mothers in a safe environment and found that it did not pose a danger, they learned to not be afraid of it anymore,” says Yu. This study was published online March 26, 2021, in eLife.

Though the COVID-19 pandemic has warped the sense of smell in millions of people, Yu does not predict that it will have significant implications for most adults who recover from the disease. However, he thinks this altered sensory experience could have a major impact on affected infants and children, especially considering the role that many odors play in social connections and mental health.

“The sense of smell has a strong emotional component to it–it’s the smell of home cooking that gives you a feeling of comfort and safety,” says Yu. “Most people don’t recognize how important it is until they lose it.”

Other co-authors from Stowers include Yunming Wu, PhD Limei Ma, PhD, Wenjing Xu, PhD, Max Hills, and Vivekanandan Ramalingam, PhD.

Funding: The work was funded by the Stowers Institute for Medical Research and the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health (award numbers R01DC008003, R01DC014701, and R01DC016696). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Lay Summary of Findings

Animals possess an inborn ability to recognize certain odors to avoid predators, seek food, and find mates. Two new studies from the lab of Investigator Ron Yu, PhD, at the Stowers Institute for Medical Research uncover details about how this ability–known as innate valence–is encoded in the nervous system of mice.

In a study published online March 1, 2021, in the journal Current Biology, the researchers showed that whether a particular odor is attractive or aversive is communicated through a complicated computational code, in which different olfactory neurons are activated to varying degrees to spell out the odor’s valence. In a separate study published online March 26, 2021, in the journal eLife, the research team found that this coding for innate valence is not hardwired at birth, but rather is malleable and can be shaped by exposure to different odors during a critical period early in life.

About this olfaction research news

Source: Stowers Institue for Medical Research
Contact: Kimberly Bland – Stowers Institute for Medical Research
Image: The image is credited to Qiang Qiu, PhD, Stowers Institute for Medical Research

Original Research: Open access.
Encoding Innately Recognized Odors via a Generalized Population Code” by Qiang Qiu, Yunming Wu, Limei Ma, C. Ron Yu. Current Biology

Open access.
Acquisition of innate odor preference depends on spontaneous and experiential activities during critical period” by Qiang Qiu et al. eLife


Encoding Innately Recognized Odors via a Generalized Population Code


  • Odor mixture abolishes innate behavioral response to component odors
  • Change of odor preference is correlated with altered brain activity
  • Glomerular, but not mitral/tufted cell responses can be linearly decoded
  • Temporally displaced presentation allows odor segmentation


Odors carrying intrinsic values often trigger instinctive aversive or attractive responses. It is not known how innate valence is encoded. An intuitive model suggests that the information is conveyed through specific channels in hardwired circuits along the olfactory pathway, insulated from influences of other odors, to trigger innate responses.

Here, we show that in mice, mixing innately aversive or attractive odors with a neutral odor and, surprisingly, mixing two odors with the same valence, abolish the innate behavioral responses.

Recordings from the olfactory bulb indicate that odors are not masked at the level of peripheral activation and glomeruli independently encode components in the mixture.

In contrast, crosstalk among the mitral and tufted (M/T) cells changes their patterns of activity such that those elicited by the mixtures can no longer be linearly decoded as separate components. The changes in behavioral and M/T cell responses are associated with reduced activation of brain areas linked to odor preferences. Thus, crosstalk among odor channels at the earliest processing stage in the olfactory pathway leads to re-coding of odor identity to abolish valence associated with the odors.

These results are inconsistent with insulated labeled lines and support a model of a common mechanism of odor recognition for both innate and learned valence associations.


Acquisition of innate odor preference depends on spontaneous and experiential activities during critical period

Animals possess an inborn ability to recognize certain odors to avoid predators, seek food and find mates. Innate odor preference has been thought to be genetically hardwired.

Here we report that acquisition of innate odor recognition requires spontaneous neural activity and is influenced by sensory experience during early postnatal development.

Genetic silencing of mouse olfactory sensory neurons during the critical period has little impact on odor sensitivity, discrimination, and recognition later in life.

However, it abolishes innate odor preference and alters the patterns of activation in brain centers. Moreover, exposure to an aversive odor during the critical period abolishes aversion in adulthood in an odor-specific manner.

The loss of innate aversion is associated with broadened projection of OSNs. Thus, a delicate balance of neural activity is required during the critical period in establishing innate odor preference and ectopic projection is a convergent mechanism to alter innate odor valence.

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