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Karl Deisseroth: Brains and Behavior Are Revealed by Light and CLARITY


Stanford University bioengineer Karl Deisseroth at the 2015 AAAS Annual Meeting | Atlantic Photography Boston

SAN JOSE, California — Two transformative techniques from the lab of Stanford bioengineer Karl Deisseroth are helping scientists connect a complicated tangle of brain circuitry with behaviors like fear and addiction.

In his plenary address at the 2015 AAAS Annual Meeting, Deisseroth described the potential of a method called optogenetics, which uses flashes of light to probe and control brain cells in mice. About two years ago, Deisseroth and colleagues began pairing optogenetics with CLARITY, a technique that turns dense tissues like the brain transparent and clear enough to read through.

It's a cliché in science to say that new findings "shed light" on a particular problem, but Deisseroth's work has helped researchers see the brain with an unprecedented brilliance.

Optogenetics began with basic research on bacterial and algal opsins, proteins that form channels or pumps in the cell membrane and can be activated by light. Deisseroth and his colleagues have worked on ways to insert these opsins into the brain cells of a mouse and then to activate the proteins with a fiber optic attached to the mouse's head.

In 2007, the researchers used flashes of blue light through the fiber optic as a kind of remote control on the mice, which had the opsins placed in a part of the brain that controls motor activity. The scientists could make the mouse continually turn left by flicking on the light, returning the mouse to its own chosen pathway when the light went off. The experiment showed them which sets of neurons were activated during a particular behavior, with profound implications for examining and potentially controlling other types of behaviors.

"That's not the most complex behavior that you could imagine, but it was the beginning, and we've now gone from this moment in 2007 to where we can do very complex tasks…we've been able to use it to come to an understanding of aspects of anxiety, depression, drug abuse, social function and dysfunction, and fear memory" in mice, Deisseroth said.

Soon after that, Deisseroth and his colleagues realized they "were missing a key scientific piece, which is observing the natural patterns of activity in an animal during the course of its normal behavior," he said. To remedy this, they developed a way to insert a fluorescing gene into brain cells that would light up when the cells became active during certain behaviors. This technique helped them tease apart pathways in the brain that control similar but distinct behaviors — such as encountering a new and interesting mouse in a cage or examining a new and interesting toy.

In the past three years, the researchers have gone further in using the techniques to trace out some of the fragile connections between brain cells, and finding ways to zero in on the activity of a single cell at a time. But brain tissue is so dense, and the connections are so complex, that "to look at the detailed wiring, there's really only one option, and that's to cut [the brain] into millions of very thin slices, and then image each of those separately, and then try to reassemble them," Deisseroth explained.

Making thin slices is a time-consuming and expensive technique, and Deisseroth and his colleagues wanted to find a better way to look at an intact brain. Their solution was to invent CLARITY, a technique that locks in place all the important molecules in tissue cells — from DNA to proteins — with a special gel while removing the fat molecules that make the brain opaque.

Last year, the researchers used CLARITY to visualize the neural network activated in the mouse brain when it fears pain or anticipates a dose of cocaine. The fluorescent protein that lights up the brain cells involved in these behaviors shows up in distinct patterns that can be seen clearly in the brains once they are removed from the mice and washed clear with CLARITY.

Other scientists around the world have quickly adopted CLARITY to get a 3D look at protein tangles in brain tissue from people with Alzheimer's disease, mouse models of multiple sclerosis, and the circuitry of pain in the spinal cord, Deisseroth said.

He is gratified to see these techniques being adopted in thousands of labs around the globe, and urged the AAAS attendees to remember that the science started very small, in the cells of algae and bacteria.

"If you have a chance to influence a policymaker, this is a good anecdote for underscoring the value of basic science research," he said, "with these ancient and small organisms having an unanticipated but important impact on our world."