Karel Svoboda builds windows into the brain—literally, with tiny glass slides he places in the skulls of mice. He peers inside with sophisticated microscopes and watches individual neurons.

"What we've discovered is that new experiences spur new connections in the adult brain," he says. "And that's a mechanism for learning and memory."

While researchers already knew that the adult brain can reorganize in response to new experiences, until Svoboda developed his techniques, no one had seen the process in action.

"We follow individual synapses—the tiny junctions between neurons—day-by-day for a month or more to see if and how new connections form."

Svoboda, who prior to his move to Janelia was an HHMI investigator at Cold Spring Harbor Laboratory, has devised techniques so precise that he can count the number of calcium channels on the tiny spines that reach between neurons to form synapses. Calcium channels can trigger a series of chemical events that ultimately rewires the synapse. Watching the channels' openings and closings provides direct evidence of such activity.

"It's a very powerful technique that can look deep into the brain without disturbing it," he says. "There is something like a hundred billion synapses in the mouse brain and now we have some tricks to locate the same synapse each time we put the mouse under the microscope. It took a while to figure out, but now it's pretty routine."

In one set of experiments, Svoboda's team trimmed the whiskers of their mice. As the mice explored their environment, Svoboda saw "pronounced rewiring." New synapses formed and others disappeared in the part of the brain that receives input from the whiskers.

In Svoboda's experiments, fluorescent tags highlight brain activity for powerful microscopes that he designs and builds. Both tools—the fluorescent proteins and the instruments—require a diverse set of skills to develop, he says, one big reason he looks forward to working at Janelia Farm. "For a new microscope, you come up with an idea, you draw it up in your mind, and then you have to build a prototype. You need a machine shop, you need electronics, and all of a sudden you're out of your depth," he says. "Finding those kinds of resources is very, very difficult, but it's vital to developing the kind of sophisticated instruments we need."

As for the fluorescent proteins, Svoboda pins his hopes on a new generation of genetically engineered mice whose neurons make their own supply—an advance that will speed his brand of observational neuroscience. "We're just now starting to get mice that have these genetically encoded indicators of neuronal function in them. It's something we're really excited about," he says. "We want to look at the dynamics of neuronal ensembles—constellations of neurons, if you will. That's our goal for the next 5 to 10 years."

As he settles in at Janelia Farm, Svoboda anticipates finding new, unexpected uses for his expertise in optics and microscopy. "It's an ideal working environment, highly interactive with small groups focusing on interrelated problems." Even though individual groups will be relatively small, Svoboda envisions that, like the brain, they will constantly recombine and reorganize their efforts. "Brain circuitry or computation is so incredibly complex that it will require all kinds of expertise—physics, engineering, biology, and so on. Each of us will focus on what we're good at while working toward the larger common goal."

After working at two other research institutes—Bell Labs and Cold Spring Harbor Laboratory—Svoboda says the move to Janelia Farm will be natural. "What really clinched it for me was the overall research program—it overlaps smack-dab with my interests," he says, pausing for a pun. "It really was a no-brainer."

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RESEARCH ABSTRACT SUMMARY:

Karel Svoboda's lab is searching for the substrates of experience-dependent plasticity in the developing and adult neocortex. The functional properties of the brain must change in response to salient sensory experiences, but the nature of these changes at the level of synapses, neurons, and their networks (also known as the engram) is unknown.

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Photo: Paul Fetters