A whiff of feline will send mice running for cover. That makes sense, given the propensity cats have for eating mice, but, in fact, it’s more than sensible: the behavior is built into the mouse genome. “Even a laboratory mouse that has never been exposed to cats will respond to their scent in fear,” says Gloria Choi, the Samuel A. Goldblith Career Development Professor of Brain and Cognitive Sciences, and an investigator at the McGovern Institute for Brain Research at MIT.

Most smells, however, have no intrinsic meaning to an animal. The connection has to be learned. This learning process intrigues Choi and has inspired her to study how mice link particular smells to specific behaviors. In her most recent work, she discovered that oxytocin, known as the “love hormone” because of its role in forming mother-child bonds, also plays a role in binding smells with social behaviors, such as mating or frightening off an intruder.

Early on in her career, Choi decided to study the senses because they act as gateways into the brain and make an ideal starting point for asking questions about how the brain works. Happenstance led her to join an olfaction lab, working with Richard Axel at Columbia University. Using mice, Axel had discovered the receptors in neurons that detect odors. “Smell is the primary sense mice use to interact with the world,” says Choi.

Choi stuck with olfaction because smell has deep meaning for humans. A familiar scent can be transcendent, taking one back in time or to faraway places. “It’s very personal,” says Choi, “and very experiential.”

To unlock the secrets of smell’s power to recall memories and guide action, Choi used optogenetics, a technique that uses laser light to stimulate and activate neurons selectively. Such artificial stimulation allowed her to simulate the sense of smell precisely so that she could study the neural circuits that respond to odor detection. In early experiments she did with Axel, this technique allowed her to zero in on a brain region called the piriform cortex as the seat of learning about a smell.

In more recent work, she and her team trained mice to associate a particular smell with a reproductively receptive female to illustrate a positive social interaction. To illustrate an aversive one, they associated a different smell with an aggressive male intruder. The team used both genetic and pharmacological techniques to manipulate the neurons involved in learning these associations to tease apart the neural circuitry.

Choi had hypothesized that special signaling molecules would drive learned associations between smell and behavior. When looking at the possible molecular candidates, she decided to zoom in on oxytocin based on previous research suggesting its strong role in directing social behavior. The research revealed that oxytocin is required for learning social associations, but not for other types of behaviors, such as craving food or feeling stressed. Choi speculates that an array of molecules, oxytocin included, may form a molecular code that governs different types of behavioral responses to smell.

To search for that molecular code, Choi is using single-cell RNA sequencing, a technique that reveals all of the molecules at work inside a cell. This technique will allow her to form a list of candidate molecules and the receptors that detect them to study in relation to learning. “If this mechanism exists, perhaps it exists not only for learning with smell, but also for learning with any other sense,” says Choi.

This work on neural signaling is dovetailing with Choi’s other work on immune signaling in the brain. Immune molecules may also influence behaviors linked to smell. For instance, immune signals present during illness can damp the association between smell and the desire to eat. “We want to understand how the immune system modulates the brain,” says Choi. “This is one of the most exciting emerging fields in neuroscience.

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