brain initiative

As US science agencies firm up plans for a national ten-year neuroscience initiative, California is launching an ambitious project of its own. On 20 June, governor Jerry Brown signed into law a state budget that allocates US$2 million to establish the California Blueprint for Research to Advance Innovations in Neuroscience (Cal-BRAIN) project. Cal-BRAIN is the first state-wide programme to piggyback on the national Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative announced by US President Barack Obama in April 2013. The national project is backed this year by $110 million in public funding from the National Institutes of Health (NIH), the Defense Advanced Research Projects Agency (DARPA) and the National Science Foundation (NSF).

A new research protocol developed at Stanford University in California improves on their previous technological breakthrough and lets neuroscientists visualize a brain across multiple scales, says program manager Dr. Justin Sanchez. Stanford scientists earlier developed a method called Clear, Lipid-exchanged, Acrylamide-hybridized Rigid, Imaging/immunostaining compatible, Tissue hydrogel (CLARITY) to study brain tissue. The method uses a chemical to transform intact biological tissues into a hydrogel hybrid, which makes the brain tissues transparent. “Brains are not clear to begin with, therefore if you’re trying to use, let’s say, a microscope to study the volume of tissue of the brain, the light can’t transverse through all of the structure,” Sanchez explains. “However, if you do ‘clarify’ it using this very novel technique, then you are able to get through a volume of tissue and study all of the circuitry.” Under the CLARITY protocol, Sanchez says, it could take upwards of 80 years to conduct the imaging process for a complete human brain. But the new protocol accelerates the process so that the same technique now takes 220 days.

When you look at the brain, what you see is the fatty outer covering of the nerve cells within, which blocks microscopes from taking images of the intricate connections between deep brain cells. The idea behind CLARITY was to eliminate that fatty covering while keeping the brain intact, complete with all its intricate inner wiring. To help expand the use of CLARITY, the team devised an alternate way of pulling out the fat from the hydrogel-embedded brain – a technique they call passive CLARITY. It takes a little longer, but still removes all the fat, is much easier and does not pose a risk to the tissue. “Electrophoretic CLARITY is important for cases where speed is critical, and for some tissues,” said Deisseroth, who is also the D.H. Chen Professor. “But passive CLARITY is a crucial advance for the community, especially for neuroscience.” Passive CLARITY requires nothing more than some chemicals, a warm bath and time. Many groups have begun to apply CLARITY to probe brains donated from people who had diseases like epilepsy or autism, which might have left clues in the brain to help scientists understand and eventually treat the disease. But scientists, including Deisseroth, had been wary of trying electrophoretic CLARTY on these valuable clinical samples with even a very low risk of damage. “It’s a rare and precious donated sample, you don’t want to have a chance of damage or error,” Deisseroth said. “Now the risk issue is addressed, and on top of that you can get the data very rapidly.”

A connectome is essentially a wiring diagram. It shows how each of the millions or billions of neurons (gray matter) in a brain each connect to thousands of other neurons through projections called axons, the white matter, and thereby allow brain regions to communicate to produce behavior, intelligence, and personality. Such a diagram could reveal, say, how neurons that register the taste of a cookie fan out to circuits that store memories and unleash a torrent of remembrances of things past. And it could reveal what causes those circuits to malfunction in diseases such as Alzheimer’s.

The resulting map, which is available to anyone who wants to use it, has already led to at least two important findings, Lein says. “The first is that many genes that are associated with brain disorders are turned on early in development, which suggests that these disorders may have their origin from these very early time points.”

Researchers at the Allen Institute for Brain Science have generated a high-resolution blueprint for how to build a human brain, with a detailed map of where different genes are turned on and off during mid-pregnancy at unprecedented anatomical resolution. The data provide exceptional insight into diseases like autism that are linked to early brain development, and to the origins of human uniqueness.

US and EU initiatives have complementary missions: the BRAIN Initiative aims to create tools for imaging and controlling brain activity, while the HBP seeks to create a working computational model of the entire brain. And just as the HBP needs actual brain data to design its model, the BRAIN Initiative needs a system for integrating its massive amounts of biological data so that it can generate something meaningful.