How Does the Nose Know?

The answer may be more complicated than you think

By Anissa Anderson Orr

Of our five traditionally recognized senses, we often take our sense of smell for granted.

Sure, we enjoy breathing in the perfume of fresh-cut flowers, and appreciate being able to sniff out a gallon of sour milk. But many people don't truly value this helpful sense until they lose it.

"For humans, losing your sense of smell can be devastating, because you pretty much lose all your sense of taste as well," says Stowers Investigator Ron Yu, PhD. "That's why when you have a severe cold or flu and can't smell, food tastes like cardboard and you often lose your appetite."

Not only is smell linked with taste and appetite—a large part of flavors we taste actually come from our sense of smell—a declining ability to smell is also an early sign of degenerative diseases such as Parkinson's and Alzheimer's. And in the animal world, smell is critical for survival as it helps animals detect food, find mates, and avoid predators.

"We feel it's pretty important," explains Yu, whose lab focuses on identifying and mapping out the elaborate neural circuitry and processes involved in sensory systems. In particular, the Yu Lab studies the mouse olfactory system, which detects odors, and the related vomeronasal system, which detects pheromones.

Inside the olfactory system

At first glance, the olfactory system seems pretty straightforward. Odors are detected by proteins called receptors located on sensory neurons in the tissue that lines the inside of the nose. These neurons then pass information through their axons—the long, slender nerve fibers that conduct electrical impulses—on to the brain's olfactory bulb for further processing.

Then it gets more complicated. Humans have nearly 400 odorant receptors, and in mice, there are nearly 1,000. Neurons expressing these receptors are randomly distributed in the olfactory epithelia of the nasal lining, with each neuron expressing a single type of receptor.

From this seemingly disorganized jumble emerges an intricate neural network. Olfactory neurons with the same receptor reach out and connect to the same spot in the brain, called a glomerulus. This convergence forms an olfactory map, and it acts as a kind of a code book for the scents we encounter, helping us decide whether to respond by taking a big, juicy bite of an apple, or running for our lives from a hungry predator.

Glitches in the map's wiring affect how scents are perceived. Yu and his colleagues found that in mice, there's a brief window to fix problems—a window that lasts until about a week after mice are born, they reported in Science in 2014.

During that first week of life, the researchers showed that a scrambled olfactory map where neurons no longer converged onto the same glomeruli could be restored to the map's correct wiring. But, if they waited longer than seven days to attempt to restore order, the scrambled map could not be unscrambled.

This was a breakthrough discovery. A critical period was not thought to exist in the olfactory system. Unlike other sensory neurons, such as hair cells in the mammalian inner ear that can't be replaced once damaged, olfactory neurons regenerate and replace themselves throughout the life of an animal, and project their axons all the way to the brain to establish previous connections. Researchers thought that this lifelong regenerative ability of neurons coincided with the ability to re-establish correct connections.

"What this research indicates is that these maps are not maintained by a mechanism throughout the life of an animal," Yu says. "During that first week, whatever map is formed will last a lifetime." In other words, if the map doesn't get unscrambled during the critical period, the neurons are still able to regenerate but they connect to the wrong targets. This errant mapping alters odor perception.

Uncovering the mechanisms at work in olfactory map wiring could hold promise for regenerating and repairing olfactory neurons and neurons in other types of neural systems, such as those involved in spinal cord injury.

A closer look

Yu's research team is also testing how mice respond to scents emitted from a custom-designed device called an olfactometer, which can deliver 200 odors in one experiment. Depending on the scent, the reaction can be quite dramatic, Yu says.

"When the test mice sense predator-associated odors it can cause them to run away or even freeze," Yu says. "They will stop moving and become still for quite a long time—for minutes, sometimes perhaps half an hour, without moving at all."

When the olfactometer is coupled with a powerful microscope, the researchers can actually see what is happening in the mouse's brain as it reacts to the scent, and record how the neurons react to specific odors. Yu's team was among the first to capture these responses by establishing mice that express a genetically encoded sensor. These studies revealed important information about how the olfactory map's glomeruli are organized, and how the brain deciphers the response and creates a complex mental experience associated with different odors.

A product of the lab's collaborative atmosphere, the olfactometer was tweaked to perfection by a succession of lab members.

"The way my lab works is that we focus on a biological problem. Then we'll apply anything that is needed to try to solve it," he says. Yu also routinely utilizes experts from Stowers' core centers including Computational Biology, Molecular Biology, Microscopy, and Proteomics.

Next on his list is a tool that rapidly images the mouse brain, a project supported by a 2015 Neaves Award, which is presented to researchers pursuing innovative, high-risk research projects with the potential for broad impact.

Exploring the mysteries of pheromones

In mammals, the vomeronasal organ, located between the roof of the mouth and the nose, detects pheromones, the chemical signals that stimulate inborn social responses such as mating or attacking a threatening competitor. While humans don't have a functional vomeronasal system, the mechanisms that control our inborn behavior are similar to other mammals.

Yu and his team have identified two classes of pheromone receptors crucial for the mating process in mice, a landmark finding they reported in eLife in 2014. That study provides an important glimpse into the circuitry of the vomeronasal system, a sensory system just as complicated as the olfactory system.

"We are only scratching the surface at this moment," Yu says. "There are more than 300 receptors in the vomeronasal system, and we don't have a clue about most other receptors' function yet. We can identify many different pheromones and how they relate to specific behaviors."

Yu aims to trace the brain circuitry that passes sensory information from the vomeronasal organ all the way to behavior centers in the brain—from the moment a mouse first sniffs a pheromone to when it exhibits courtship responses.

Detailing the neural circuitry of both vomeronasal and olfactory systems is a monumental undertaking, but one Yu is well-equipped to pursue with backing from two National Institutes of Health R01 grants and continuous support from the Stowers Institute.

"I've been very fortunate to have talented people working with me in the lab, and collaborating with experts in Stowers core centers," Yu says. "With the support researchers get from the Institute, we are free to explore a lot of ideas and conduct experiments in new territories without constantly worrying about funding. We are able to push our research forward in ways we hadn't previously imagined."