In pursuit of mind map, slice by slice

Dr Lichtman and his team of researchers at Harvard have built some unusual contraptions that carve off slivers of mouse brains as part of a quest to understand how the mind works.

Their goal is to run slice after minuscule slice under a powerful electron microscope, develop detailed pictures of the brain’s complex wiring and then stitch the images back together. In short, they want to build a full map of the mind.

The field, at a very nascent stage, is called connectomics, and the neuroscientists pursuing it compare their work to early efforts in genetics. What they are doing, these scientists say, is akin to trying to crack the human genome—only this time around, they want to find how memories, personality traits and skills are stored. They want to find a connectome, or the mental makeup of a person.

“You are born with your genes, and they don’t change afterward,” said H Sebastian Seung, a professor of computational neuroscience at the Massachusetts Institute of Technology. “The connectome is a product of your genes and your experiences. It’s where nature meets nurture.”

The task is arduous and years from fruition, and even the biggest zealots acknowledge that their work may not pay off.

Since the 1970s, researchers have only had one connectome to play with—that of a worm with a measly 300 neurons. Now they are trying a mouse brain, with its 100 million neurons. So far the notion of creating a human-scale connectome — which would illuminate all of the connections among more than 100 billion neurons and unravel the millions of miles of wires in the brain—has proved too daunting.

And because the brain’s wiring is so densely packed, building a connectome stands as one of the most formidable data collection efforts ever concocted. About one petabyte of computer memory will be needed to store the images needed to form a picture of a one-millimeter cube of mouse brain, the scientists say.

Neuroscientists say that a connectome could give them myriad insights about the brain’s function and prove particularly useful in the exploration of mental illness.
Harvard recruited Dr Lichtman to push the connectome quest to its limits by tackling an entire mouse brain at the finest scale and allowed him to set up his own connectome research laboratory, staffed with four other people.

Lichtman Lab

In the basement quarters that house Lichtman Lab, the researchers go to work anesthetising mice, slicing open their rib cages and using the animals’ circulatory systems to spread concoctions that preserve the flesh and tune it for the electron microscope. With the body prepared, the slicing can begin.

Machines built by Kenneth J Hayworth, one of the researchers, can sheer off slices of a mouse brain just 29.4 nanometre thin using a diamond knife blade.

Hayworth devised techniques for floating the brain slivers across a tiny puddle of water where surface tension carries them to a clear plastic tape. The tape backing adds some sturdiness to the slivers and makes it possible to place scores of them on a silicon wafer that then goes under the electron microscope.

At Lichtman Lab, the researchers are marching across a mouse brain in linear fashion, gathering the slices, imaging them and then putting the puzzle back together. Once assembled by a computer, the images of the brain are beautiful.

Dr Lichtman and his colleagues give individual brain cells unique colours, making it easier to follow the wiring of a single neuron’s extensive axon and dendrite branches. The microscopes and computers they use can twist and turn these psychedelic images and zoom in and out at will.

Dr Lichtman estimates it will be several years before they can contemplate a connectome of a mouse brain, but there are some technological advances on the horizon that could cut that time significantly. Needless to say, a human brain would be far more complex and time-consuming.

As Bobby Kasthuri, one of the researchers, put it: “It will either be a great success story or a massive cautionary tale.”

The New York Times