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New technique gives see-through view into mouse brains

Replacing fatty molecules turns organs transparent

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To usher in a big advance in brain imaging, scientists simply had to cut the fat. By subbing out light-blocking fatty molecules, a new technique turns mouse brains almost fully transparent while retaining their structure and nearly all their important molecules, researchers report in the April 11 Nature.

The new method could help researchers image the whole brain and its circuitry while also doing detailed molecular and cellular analyses, says Clay Reid, a neurobiologist at Harvard University and the Seattle-based Allen Institute for Brain Science. “It’s a lovely paper, and it’s something that a lot of people will want to be using,” says Reid, who was not involved in the study.

There are tradeoffs in studying the brain. Typically researchers create thin slices of the brain for detailed looks at cellular and molecular anatomy. But that’s at the expense of learning how neurons are wired to far-away brain regions. Moreover, using light-based microscopes to look at the whole brain has its pitfalls. Light struggles to penetrate deep into organs mainly because lipids — the building blocks of fats — can block and scatter it. Lipids help maintain the brain’s structure, and removing them could cause the brain to fall apart.

Karl Deisseroth of Stanford University and colleagues devised a method that minimizes those tradeoffs. First, the researchers removed brains from mice and put those organs in a cocktail of chemicals, including a plastic-like substance. When heated, the chemical cocktail transformed into a clear gel that clung like glue to everything in the brain — cells, molecules and all — except the lipids.

To suck out the lipids, the researchers flushed a detergent through the brains. The result: The brains were see-through, yet the neurons, their connections, proteins, DNA and other crucial molecules remained in place.

The brains were so transparent that the researchers could use light microscopes to see fine details such as neurons and nerve fibers. The scientists could also measure levels of particular molecules in the brain using labeling techniques that stained certain types of molecules or made them glow.

With slight changes to the solution and detergent, researchers could use the technique, called CLARITY, in other organs, Deisseroth says. But he notes one limitation, at least for now: The method might not work well in organs where lipids play important roles besides structure. “It’s possible that some tweaks could allow particular lipids to be retained,” he says.

Showing its versatility and its promise for biomedical applications, the researchers also succeeded in using the method on a zebrafish and on preserved human brain samples, Deisseroth says.

It may take years before researchers can image all the brain’s connections, Harvard’s Reid says. But the new technique, which relies on light microscopes, may help neuroscientists tackle one of their major goals: mapping the long-distance connections between brain areas.

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