In April 2013, President Obama announced a multi-year, broad-based research program called the BRAIN—Brain Research through Advancing Innovative Neurotechnologies—Initiative  to help researchers find new ways to treat, cure, and even prevent brain disorders. Last December, one of the three federal agencies funding the “public” portion of this public-private collaboration—DARPA or the Defense Advanced Research Projects Agency—awarded its first research grants to support the Initiative’s goals.

Dr. Karl Deisseroth and his team at Stanford University received one of the grants, and the results of their work were published June 19th in Nature Protocols. Working to accelerate the dissemination and the practical usefulness of the new technology they unveiled last year called CLARITY, the researchers have made two important modifications to the technology to enable its use at diverse labs around the world.

The CLARITY technique enables researchers to image a whole, intact brain in three dimensions and obtain a virtually transparent view of its inner structure. By replacing the brain’s fatty molecules (or lipids), which provide support inside the brain to keep the structure intact, with a clear hydrogel, CLARITY turns the opaque and impenetrable brain transparent and permeable. The transparent hydrogel is first derived from the brain’s tissue; the gel is infused into the post-mortem brain and then the opaque lipids are flushed out with a combination of electrical current and detergent. Researchers are then able to use 3-D imaging technology for never-before-seen views of the brain’s internal mechanisms, ranging from single neurons to populations of neurons and how they project, to axons, dendrites, synapses, etc., all while still having a view of the global structure.

At some labs, however, the process of pulling out the opaque lipids with electrical current was damaging some other tissue. To avoid this, the researchers came up with a slower, but less risky method that does not rely upon electrical current. They call this method “passive” CLARITY. The original CLARITY technique “is important for cases where speed is critical, and for some tissues,” said Dr. Deisseroth, “but passive CLARITY is a crucial advance for the community, especially for neuroscience."  

The second important modification had to do with the imaging technology available in many labs that limited the extent to which the brain, even transparent, could be viewed. The Deisseroth team was able to advance this technology—called light sheet microscopy—so that fine wiring structures deep within an intact adult brain can be seen. They built their own microscope, but the procedures are described in the paper, and the key components are commercially available.

Read the Stanford press release.