Scientists Taught Mice to Smell an Odor That Doesn’t Exist 1

When neuroscientists David Hubel and Torsten Wiesel wanted to figure out how the brain parses its visual environment, they went as simple as they could go. In a Harvard lab crammed with electrical equipment, they positioned cats in front of a screen and showed them extremely basic images: dots in particular locations, lines at various angles. At the same time, they used implanted electrodes to, quite literally, “listen” to neurons in the areas of the brain devoted to vision. By observing which neurons fired in response to which shapes, they were able to unlock a part of the brain’s “visual code,” the way in which it represents visual information about its environment. For their achievement, Hubel and Wiesel won the Nobel Prize in 1981, and their discoveries kick-started the rich, diverse field of visual neuroscience.

But scientists who want to study our sense of smell don’t have the same advantages. Smell “is much more, in a sense, mysterious,” says Edmund Chong, a graduate student in neuroscience at New York University. While complex images and shapes can be broken down into their constituent lines and angles, it’s not immediately obvious how to decompose smells, which are conveyed by airborne chemicals. When a person inhales these molecules, they travel through their nostrils and attach to receptor cells, which spark a pattern of activity in the olfactory bulb—a tiny, elongated brain structure right above the nasal cavity. The brain eventually recognizes this pattern as a particular scent. This system allows humans to detect as many as a trillion different odors, though we are much less gifted smellers than mice, whose olfactory bulbs take up a full 2 percent of their brain volume, compared to a hundredth of a percent in humans.

Because these odor-carrying chemicals aren’t easily broken up into their constituent parts, they are “hard to directly manipulate,” says Chong. So when he wanted to figure out how the brain represents smell, he couldn’t follow in Hubel and Wiesel’s steps. Instead of presenting his lab animals with real chemicals, he went straight into their brains. Last week, Chong and his colleagues published a study in the journal Science showing that they’d worked out some of the details of just how the olfactory bulb represents odors—by making mice smell scents that don’t actually exist in the real world.

“It’s a spectacular achievement, both from a technical perspective and conceptually,” says Sandeep Robert Datta, an associate professor of neurobiology at Harvard Medical School, who was not involved in the study. “They’ve taken advantage of advanced methods [to] trick the animal into thinking it’s smelling a particular smell.” By avoiding the issues of manipulating odor molecules entirely and instead going directly to the brain, Chong and his colleagues were able to investigate in detail the aspects of brain activity that matter most for our sense of smell.

Though making mice sense impossible odors might sound like something out of science fiction, Chong’s general approach—stimulating a part of the brain to figure out its logic—has been around since before Hubel and Wiesel did their cat experiments. Wilder Penfield, a neurosurgeon active in the middle of the 20th century, often used an electrical current to activate different areas on the surface of his patients’ brains. He soon discovered that he could cause his patients to feel a physical sensation on, say, their forearms by stimulating the correct brain region—even though they were not truly being touched.

To induce his mice to detect artificial scents, Chong had to be much more precise. Researchers who study the olfactory bulb know that distinct patterns of neural activity in the bulb correspond to different scents. So to make the mice smell odors that weren’t actually present, Chong used a technique called optogenetics, which allows scientists to stimulate groups of neurons using only light. Optogenetics experiments require mice who have been genetically engineered to make some of their neurons—olfactory bulb neurons, in this case—responsive to blue light. When researchers shine light on those neurons, the illuminated neurons become active. By shining different spots of light to stimulate clusters of olfactory neurons, Chong could generate an artificial smell—and train the mice to recognize that smell over time.