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A new protein looks like Christmas lights and helps us track brain activity

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CaMPARI could help researchers get quick feedback when neurons fire

Eric Schreiter

Neuron activity is used as everything from an indicator of our most fundamental impulses to a model for computers, but our understanding of it is basic at best. The methods we use to detect brain activity are limited as well — even when researchers know what they're trying to track, the tools can only do so much, says Eric Schreiter, researcher at the Howard Hughes Medical Institute's Janelia research campus and co-author of a study released today in Science. But his team thinks it's found a way to help.

The most direct way to see what neurons are doing would be to just track the impulses as they fire. "It's possible to measure that electrical signal, but it turns out to be really difficult," Schreiter says. Instead, he cites two basic approaches, both of which come with a set of tradeoffs. One method uses fluorescent proteins — perhaps best known for producing glow-in-the-dark mice or rabbits — as sensors that get brighter when they bind to calcium and dim as it dissipates. Neuron activity is accompanied by a sudden spike in calcium, so if you introduce them into an animal and get a microscopic look at its brain, you’ll be able to see the proteins light up as it happens.

"It's actually quite beautiful."

But your view is limited to small areas, and there’s no permanent record of it. "As soon as you move your microscope or you turn your microscope off there's no way to know where that activity was," says Schreiter. If you’re looking for a wider view, on the other hand, it’s possible to track a subset of genes that are expressed during brain activity, but this measures neurons only over longer periods of time. To address these limitations, Schreiter and his team split the difference between the two: you can get a permanent record of activity across a whole brain, but it can capture things that happen over a span of seconds, not tens of minutes or hours.

Technically, it’s a twist on the calcium-tracking technique. The work started with an attempt to make a protein’s color change easier to detect — instead of going from green to more intense green, researchers created one that turned permanently from green to red when exposed to violet light. Modified to only respond in the presence of calcium as well as light, it becomes a neuron tracking tool. The designation — "calcium-modulated photoactivatable ratiometric integrator" — is a mouthful, but it shortens to the much more palatable name of CaMPARI.

The CaMPARI protein is still in 'version 1.0'

The team has so far tested the protein in mice, fruit flies, and zebrafish larvae to measure brain activity. Zebrafish, for example, were exposed to the protein and then set under violet light in various conditions: anesthetized, swimming freely, or put in extreme heat and cold. (A larval zebrafish’s skin is transparent, which makes flooding the brains with light easy; for animals like mice, researchers have to cut a window into the skull.) When their brains were imaged afterwards, they had permanently recorded the neural activity in a mix of green and magenta. "It's actually quite beautiful," Schreiter says.

While green fluorescent proteins were first isolated from jellyfish in the 1960s, Researcher Roger Tsien is credited with turning them into a range of tagging tools in the mid-’90s (he won a Nobel Prize in 2008 for his efforts.) Since then, scientists have been steadily refining and elaborating upon the technique, looking for new colors and new behaviors. MIT scientists, for example, developed a protein that responded to calcium only in specific cell types. Schreiter says it's too early to tell what CaMPARI's applications might be, but at the very least, real-time, flexible, but permanent imaging could give scientists a new way to get quick feedback when tracking an animal's actions. "We don't know what all of those applications are going to be," he says. "Our job is really to get these new tools into the hands of as many biologists as we can."

The CaMPARI method is in an early stage, Schreiter says. Right now, animals need to be flooded with more light than he’d like — it can affect their behavior and damage the brain tissue. And the group wants to adapt the protein to work with other signals, not just calcium, he says. "We've called this like, version 1.0 of a new tool."

Correction: A previous version of this article mischaracterized Schreiter's employer. The Howard Hughes Medical Institute is not a part of MIT. We regret the error.