Schnitzer’s group has also used the technique to study mouse models of glioma, the most common malignant brain tumor in humans. Aggressive gliomas usually occur deep in the brain, but previous studies in animals had examined tumors only on the brain’s surface, where conventional light microscopes work well.

They measured blood flow to deep tumors as well as growth of blood vessels. They found growth patterns similar to those in surface tumors, and, he says, demonstrated that the technique can be used to follow disease progression.

Schnitzer is planning with other research groups to disseminate the technology. “We think this ability to track on a microscopic scale the features of brain disease should be a broadly applicable approach to many different brain disorders in animal models,” he says.

For the previous studies, the mice had to be immobilized, but Schnitzer also wanted to image the brain cells of active mice. So he and his team designed a microscope that a mouse can wear—a tiny device with miniature lenses, filters, and other optics that weighs just a couple of grams. The mouse wears the miniature microscope on its head, like a hat, snapped into a base plate implanted in its skull. The mouse moves freely, tethered only by a fiber optic cable to the laser-light source.

Schnitzer opens his laptop to show a video of a mouse wearing the mini-microscope. On one half of the screen, a camera-wearing mouse explores its enclosure. The other side shows a network image of neurons fluorescing green.

“Putting it all together can be a challenge at the systems level, integrating mechanical features, optical features, and making the whole system work at a miniaturized scale.” Schnitzer says. His group includes mechanical engineers, electrical engineers, and applied physicists, all working closely with biologists and neuroscientists.

Down the road, Schnitzer plans to build on the group’s experience and develop grid-like microscopes to do “massively parallel brain imaging” on fruit flies. Such microscopes could dramatically increase the throughput of imaging for the systematic study of mutations that affect neural activity.

The ultimate goal is to connect behavior to what’s happening on a cellular level. “One thing that I’m keenly interested in is understanding how concerted activity at the level of hundreds to thousands of neurons influences behavior,” Schnitzer says.

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