Crucially, the top of the fly’s head is open and bathed in saline under a microscope; a researcher removes a smidgen of the fly’s cuticle, and nudges a probe into the working brain. Harris’s improved probes should help Jayaraman get better measurements from neurons and understand more about how the brain makes decisions.

Illuminating Windows

The next step on the way up to the Empire State Building, Harris says, is the mouse. “The mouse brain is even bigger, with even more neurons. So you have to study smaller parts of it to understand what’s going on.”

Karel Svoboda, a group leader at Janelia Farm, studies mouse brains. His team builds a tiny glass window into each animal’s head. This doesn’t seem to bother the mice, and the researchers can follow one mouse for months as its brain changes to accommodate its new knowledge.

He uses GCaMP3 and other tools to measure electrical activity in mouse brains. But he says the tools available to do neuroscience today still aren’t good enough. “In brain research, we make up a lot of stories based on incomplete information,” Svoboda says. “We’re still looking at large populations of neurons, but we have only probed a small part of the brain. In many ways we’re still very much limited by measurements.”

As part of the GECI project at Janelia, Svoboda, Jayaraman, and Kerr are working with protein engineer Looger to develop improved versions of GCaMP3. The new proteins should be better at binding calcium, so they will respond when there’s less calcium. They hope newer versions will also light up sooner after calcium rushes into the cell. And while the current version can impair cells when it builds up, the next proteins may do less damage.

“The major discoveries of neuroscience in the modern era correlate directly with advances in measurement technology,” Svoboda says. Around the turn of the 20th century, Spanish physiologist Santiago Ramón y Cajal perfected a technique for looking at slices of brains and determined that brains were made of cells. Neuroscientists figured out some basics about how the visual cortex works because they invented a technique for recording electrical signals from cells.

This work continues at Janelia Farm, as its neuroscientists keep working to understand the brain. Harris thinks neuroscientists won’t understand the human brain for a thousand years, at least; but with new tools, they can keep chipping away at the problem—and make a little bit more sense of what goes on inside our heads.

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