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Jeff Lichtman hopes to elucidate brain development and disease with new technologies that illuminate the web of neural circuits.
February 19, 2008
BrainBows: Genetically engineering mice so that their brain cells express different combinations of fluorescent colors reveals the brain’s complicated anatomy. In the image round green neurons are interspersed with diffuse support cells called astrocytes.

Displayed on Jeff Lichtman’s computer screen in his office at Harvard University is what appears to be an elegant drawing of a tree. Thin multicolored lines snake upward in parallel, then branch out in twos and threes, their tips capped by tiny leaves. Lichtman is a neuroscientist, and the image is the first comprehensive wiring diagram of part of the mammalian nervous system. The lines denote axons, the long, hairlike extensions of nerve cells that transmit signals from one neuron to the next; the leaves are synapses, the connections that the axons make with other neurons or muscle cells.

The diagram is the fruit of an emerging field called “connectomics,” which attempts to physically map the ­tangle of neural circuits that collect, ­process, and archive information in the nervous system. Such maps could ultimately shed light on the early development of the human brain and on diseases that may be linked to 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, who is working with Lichtman. “If we have a wiring diagram of the brain, that could help us understand how it works.”

Although researchers have been studying neural connectivity for decades, existing tools don’t offer the resolution needed to reveal how the brain works. In particular, scientists haven’t been able to generate a detailed picture of the hundreds of millions of neurons in the brain, or of the connections between them.

Lichtman’s technology–developed in collaboration with Jean Livet, a former postdoc in his lab, and Joshua Sanes, director of the Center for Brain Science at Harvard–paints nerve cells in nearly 100 colors, allowing scientists to see at a glance where each axon leads. Understanding this wiring should shed light on how information is processed and transferred between different brain areas.

To create their broad palette, ­Lichtman and his colleagues genetically engineered mice to carry multiple copies of genes for three proteins that fluoresce in different colors–yellow, red, or cyan. The mice also carry DNA encoding an enzyme that randomly rearranges these genes so that individual nerve cells produce an arbitrary combination of the fluorescent proteins, creating a rainbow of hues. Then the researchers use fluorescence microscopy to visualize the cells.

“This will be an incredibly powerful tool,” says Elly Nedivi, a neuroscientist at MIT who is not involved in the research. “It will open up huge opportunities in terms of looking at neural connectivity.”

Lichtman and others hope that the ability to study multiple neural circuits simultaneously and in depth will provide unprecedented insight into how the wiring of the nervous system can go awry. “There’s a whole class of disorders of the nervous system that people suspect are due to defects in the connections between nerve cells, but we don’t have real tools to trace the connections,” says Lichtman. “It would be very useful to look at wiring in animal models of autism-spectrum disorders or psychiatric illness.”

In experiments so far, Lichtman’s group has used the technology to trace all the connections in a small slice of the cerebellum, the part of the brain that controls balance and movement. Other scientists have already expressed interest in using the technology to study neural connections in the retina, the cortex, and the olfactory bulb, as well as in non-neural cell types.

Generating maps of even a small chunk of the brain will be a huge challenge: the human brain consists of an estimated 100 billion neurons, with trillions of synapses. Scientists will need to find ways to store, annotate, and mine the volumes of data they create, and to meld information about connectivity with findings about the molecular and physiological characteristics of neurons in the circuits. But now, at least, they have a key tool with which to begin the massive effort of creating a wiring diagram of the brain.

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