2) Mapping

However researchers go about collecting data about neuronal activity and circuitry, it’ll be essential to map this onto a dependable and highly detailed anatomical atlas of the brain. It is like attempting to comprehend traffic flow in a city: the better the map (the anatomy), the better the predictions of how it is going to change during rush hour the {active circuits). For more than a hundred years, the method used to map neuroanatomy has been to cut a brain as thinly as is possible, stain the slices to render the cells visible then look at them under the light microscope. But, computationally, it is tremendously difficult to align large quantities of slices in order to rebuild the tangled web of neurons densely packed in a human brain. Even so, Katrin Amunts from the Research Centre Jülich in Germany and her team announced they had done it a month ago, when they published a three-dimensional reconstruction of a human brain in extraordinary detail. To build it, they painstakingly cut the brain of a sixty-five year-old woman in to 7, 400 layers 20 micrometres thick, stained them, imaged them using a light microscope and then utilized a thousand hours on two supercomputers to piece the terabyte of data together. The atlas reveals in fine detail folds of the human brain, which tend to get lost in two-dimensional cross-sections. The whole project took ten years, says Amunts, who has already started work with a second human brain to see variation between individuals; a project she expects to move much faster.

Wanting to take another leap farther, Jeff Lichtman at Harvard University, Cambridge, Massachusetts, and Winfried Denk of the Max Plank Institute for Neurobiology, Munich, Germany, are working using the German optics company Carl Zeiss using a new electron microscope that could image even thinner slices, 25 nanometres, or one-thousandth the thickness of your average cell. Then you are able to see every little part of the brain, from every neuron to every subcellular organelle, from each and every single synapse to every spine. Employing conventional electron microscopes, with their own single scanning beam of electrons, researchers have thus far been able to reconstruct merely a cubic millimetre of brain tissue. It would take many decades to scan an entire mouse brain’s worth of ultra-thin pieces, says Denk. The new equipment, which should be delivered to the two labs next year, should have sixty-one scanning beams operating in parallel and can shrink this time down to months. Denk predicts that this will allow them to manufacture a computational reconstruction of a mouse brain “inside a box,” as he puts it within five years. What Lichtman and Denk haven’t yet resolved is how to reconstruct a complete three-dimensional picture of the tissue from these images. In a trial project using a conventional electron microscope, Denk’s research laboratory scanned minuscule volumes of mouse retina, one of the simplest regions of the mammalian brain, But computing alone was unable to reconstruct the 300 gigabytes of image data the time and effort generated, so the lab enrolled 230 individuals to help to trace, by eyesight, the neurons as they wander over the slices. It won’t be practical to use that sort of crowd-sourcing on a greater scale, says Denk. We’ll have to develop algorithms to get machinery to do the job as well as the human eye.
There may be easier ways to undertake brain mapping at lower resolutions. One option is a method called CLARITY, which generated enthusiasm when it was unveiled in April. Karl Deisseroth at Stanford University and his colleagues have developed a method to chemically replace the opaque lipids within the brain with a clear gel solution, rendering the tissue transparent and allowing the inner arrangements of neurons to be seen with no need for slicing. Deisseroth has already applied the method to brain tissue from a boy who had autism spectrum, and found unusual ladder-like arrangements of neurons in his cortex. Other researchers are clamoring to make use of this method to trace circuitry in| normal brains.

However efficient the different activity-measuring and anatomy-mapping techniques develop into, many researchers hope that it’s not going to be necessary to view or record from every individual neuron to obtain a working picture of the entire brain. Patterns will emerge from which you’ll be able to extrapolate, says Newsome.

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