A mouse’s whiskers are more than just stiff, overgrown hairs. Exquisitely sensitive, they double as the animal’s eyes when it scurries through inky subterranean passages. Each whisker is controlled by a tiny muscle that allows its owner to palpate objects, relaying information about shape, texture, and location. “One way humans interact with the world is by moving our digits over objects to explore shapes or by moving our eyes over visual scenes,” explains neuroscientist Karel Svoboda. “Mice use their whiskers in the same way.”
When a whisker touches something, it flexes like a spring, putting pressure on the rich supply of nerve endings surrounding the follicle at its base. These nerve cells deliver an array of sensory information to the rodent’s brain, which then decides how the animal should react. Svoboda, a group leader at Janelia Research Campus, is interested in tracking the positions and angles of a mouse’s whiskers as it navigates its surroundings, so as to learn more about the information transmitted from object to whisker to brain.
But tracking whiskers is much easier said than done. Mice can whisk, or move their whiskers in a back-and-forth motion, up to 25 times per second. “To learn how mice use their whiskers, you have to track the tiny hairs with millisecond timescale precision,” says Svoboda. “This involves high-speed videography and a lot of computing.” It also involves either keeping the mouse still or following it closely with a camera as it feels its way along a tunnel. But with a little ingenuity and a lot of trial and error, anything is possible, including building a tactile virtual reality system for mice.
| Spend a day embedded in the Svoboda Lab as the team pushes itself to design a new type of microscope and uses a virtual reality system to learn how mice explore the world. Video produced by Robert Gutnikoff and Jim Keeley. |
A Virtual Burrow
Svoboda’s postdoc Nick Sofroniew was one of the least likely candidates to take on this virtual reality challenge. When he joined the lab as a graduate student, in 2010, Sofroniew had just completed a master’s degree in mathematics at the University of Cambridge. “A pencil-and-paper–style mathematician, he came to my lab pretty much knowing only the basics in experimental neuroscience,” recalls Svoboda. “So he had to learn all the necessary engineering skills and biology.”
Despite his lack of background knowledge, Sofroniew made the task the focus of his PhD thesis. “I was really attracted to the project’s engineering aspects,” he explains. “I saw it as a rich and interesting opportunity that would let me pick up a lot of skills, and that appealed to me.”
Fortunately, Sofroniew also got a lot of help – from his lab mates; from Janelia’s Instrument Design & Fabrication facility; and, importantly, from Janelia Group Leader Albert Lee and his postdoc Jeremy Cohen.
Lee and Cohen, who share an office space with Svoboda’s team, had just built a visual virtual reality system for rodents. Their rig, a modification of a concept used by other researchers, uses a spherical treadmill – a beach-ball–sized orb of Styrofoam floating on a cushion of air. A mouse is placed on the ball, its head held securely in a tiny metal helmet while it watches a video-game–like maze on a large screen (basically, the rodent equivalent of an IMAX theater). The movements of the ball are connected to the maze software, allowing the diminutive subject to dart through the virtual environment at will.
Sofroniew decided to try converting Lee and Cohen’s visual virtual reality system into a tactile one. It was clear that the spherical treadmill needed to be in the dark to ensure that the mice were using their whiskers rather than their eyes to explore. But how to simulate the narrow, twisting walls of a burrow? Sofroniew’s first idea was to glue pieces of foam to the ball, erecting a miniature, three-dimensional maze on the treadmill. It worked – the mice were able to navigate the labyrinth with ease – but Sofroniew quickly realized it wouldn’t be practical if he wanted to change the positions of the walls to create different corridors.
So Sofroniew replaced the glued-on foam with two motorized “walls” – glass microscope slides that are situated on either side of the mouse and hang from a platform suspended above the treadmill. “Initially,” says Sofroniew, “I purchased a very cheap, $20 hobbyist set of motors and a $50 microcontroller for pushing the walls around. The result was something very akin to pinball flippers.”
By moving the “flippers,” he could simulate the twists and turns of an underground tunnel. For example, shifting the left wall so it touched the mouse’s whiskers would make the animal think the tunnel was angling right. As a result, the animal would alter its course. “It’s like driving your car and staying in between the lane markers as you turn left and right,” explains Sofroniew. The mice took to the system readily and became experts at navigating the virtual corridors with little training.
Although the system was crude and the parts cheap, it was clear that the concept was going to work. That gave Sofroniew the confidence to invest in more reliable components and to write software to control the walls and couple their movements to the motion of the treadmill, allowing him to design winding corridors for the mice to explore. A strategically placed high-speed camera photographed the whiskers as they bent and flexed against the walls. Sofroniew, Cohen, Lee, and Svoboda published their design in The Journal of Neuroscience in July 2014.
With the kinks ironed out and his thesis project completed, Sofroniew has started using the virtual reality rig to understand how mice use their whiskers to see the world. For example, by recording a mouse’s brain activity as it explores a virtual maze, Sofroniew has homed in on the neurons involved in whisker-guided locomotion. He’s used this information to design experiments in which he turns these neurons on and off, and to alter the mouse’s activity. He’s also teamed up with Janelia Group Leader Jeremy Freeman to measure and analyze a rodent’s neural activity in real time, allowing him to change the nature of his experiments on the fly based on how he thinks a mouse’s brain is responding.
Eventually, Sofroniew hopes to put all these pieces together and come up with a model to explain just what a mouse is seeing – or, rather, feeling – as it goes about its life underground.
