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New technologies that allow scientists to trace the fine wiring of the brain more accurately than ever before could soon generate a complete wiring diagram–including every tiny fiber and miniscule connection–of a piece of brain. Dubbed connectomics, these maps could uncover how neural networks perform their precise functions in the brain, and they could shed light on disorders thought to originate from faulty wiring, such as autism and schizophrenia.

“The brain is essentially a computer that wires itself up during development and can rewire itself,” says Sebastian Seung, a computational neuroscientist at MIT. “If we have a wiring diagram of the brain, that could help us understand how it works.” For example, scientists previously identified the part of the songbird’s brain that is important in the birds’ ability to generate songs. Seung would ultimately like to develop a wiring diagram of this structure in order to elucidate the features underlying its unique capability.

Only one organism’s wiring diagram currently exists: that of the microscopic worm C. elegans. Despite containing a mere 302 neurons, the C. elegans mapping effort took more than a decade to complete, in the 1970s. It has been an invaluable research resource and earned its creators a Nobel Prize.

With an estimated 100 billion neurons and 100 trillion synapses in the human brain, creating an all-encompassing map of even a small chunk is a daunting task. Using standard methods, it would take roughly three billion person years to generate the wiring diagram of a single cortical column, a narrow functional unit of neurons in the cortex, estimates Winfried Denk, a neuroscientist at the Max Planck Institute for Medical Research in Heidelberg, Germany.

Denk, Seung, and their collaborators are now developing sensitive new imaging techniques and machine-learning algorithms to automate the construction process. They have already generated a partial wiring diagram of part of the rabbit retina. But they’ll need to make their technique a million times faster to finally bring larger maps–like that of a cortical column–into the realm of reality.

Previous efforts to map the wiring of the brain have focused on larger anatomical features, such as the thick wiring tracts that connect different parts of the brain, or on the paths of single neurons, stained a particular color to distinguish them from their tangled multitude of neighbors. But to truly understand how a network of neurons can perform a particular function, scientists need a new kind of map. “A lot of properties of brain function are at the level of the circuit–information is being integrated, processed, extracted,” says Elly Nedivi, a neuroscientist at MIT who is not involved with the research. “To understand what that means, you need to be able to see who connects to who.”

Denk and his colleagues developed a new technique to make more fine-scaled wiring maps using electron microscopy. Starting with a small block of brain tissue, the researchers bounce electrons off the top of the block to generate a cross-sectional picture of the nerve fibers in that slice. They then take a very thin–30-nanometer–slice off the top of the block and repeat the process. Scientists go through the images slice by slice to trace the path of each nerve fiber. “Repeat this [process] thousands of times, and you can make your way through maybe the whole fly brain,” says Denk.

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Credit: Kevin Briggman, Moritz Helmstaedter, Winfried Denk Viren Jain, Joseph Murray, Srini Turaga, and Sebastian Seung.

Tagged: Biomedicine, MIT, neuroscience

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