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Old 09-27-2012, 10:22 PM   #262
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Controlling Brains With a Flick of a Light Switch
Using the new science of optogenetics, scientists can activate or shut down neural pathways, altering behavior and heralding a true cure for psychiatric disease.

by Amy Barth
From the September 2012 issue; published online September 25, 2012

Stopped at a red light on his drive home from work, Karl Deisseroth contemplates one of his patients, a woman with depression so entrenched that she had been unresponsive to drugs and electroshock therapy for years. The red turns to green and Deisseroth accelerates, navigating roads and intersections with one part of his mind while another part considers a very different set of pathways that also can be regulated by a system of lights. In his lab at Stanford University’s Clark Center, Deisseroth is developing a remarkable way to switch brain cells off and on by exposing them to targeted green, yellow, or blue flashes. With that ability, he is learning how to regulate the flow of information in the brain.

Deisseroth’s technique, known broadly as optogenetics, could bring new hope to his most desperate patients. In a series of provocative experiments, he has already cured the symptoms of psychiatric disease in mice. Optogenetics also shows promise for defeating drug addiction. When Deisseroth exposed a set of test mice to cocaine and then flipped a switch, pulsing bright yellow light into their brains, the expected rush of euphoria—the prelude to addiction—was instantly blocked. Almost miraculously, they were immune to the cocaine high; the mice left the drug den as uninterested as if they had never been exposed.

Today, those breakthroughs have been demonstrated in only a small number of test animals. But as Deisseroth pulls into his driveway he is optimistic about what tomorrow’s work could bring: Human applications, and the relief they could deliver, may not be far off.

For all its complexity, the brain in some ways is a surprisingly simple device. Neurons switch off and on, causing signals to stop or go. Using optogenetics, Deisseroth can do that switching himself. He inserts light-sensitive proteins into brain cells. Those proteins let him turn a set of cells on or off just by shining the right kind of laser beam at the cells.


That in turn makes it possible to highlight the exact neural pathways involved in the various forms of psychiatric disease. A disruption of one particular pathway, for instance, might cause anxiety. To test the possibility, Deisseroth engineers an animal with light-sensitive proteins in the brain cells lying along the suspected pathway. Then he illuminates those cells with a laser. If the animal begins cowering in a corner, he knows he is in the right place. And as Deisseroth and his colleagues illuminate more neural pathways, other researchers will be able to design increasingly targeted drugs and minimally invasive brain implants to treat psychiatric disease.

[...]

Crick’s idea was that light, with its unparalleled speed and precision, could be the ideal tool for controlling neurons and mapping the brain. “The idea of an energy interface instead of a physical interface to work with the brain was what was so exciting,” Deisseroth says. He thought creating a light-sensitive brain was probably impossible, but then an idea floated up: What about tapping the power of light-sensitive microbes, single-celled creatures that drift in water, turning toward or away from the sun to regulate energy intake? Such brainless creatures rely on signals from light-sensitive proteins called opsins. When sunlight hits the opsin, it instantly sends an electric signal through the microbe’s cell membrane, telling the tiny critter which way to turn in relation to the sun.

Deisseroth wondered if he could insert these opsins into targeted mammalian brain cells in order to make them light-sensitive too. If so, he could learn to control their behavior using light. Shining light into the brain could then become the tool Crick imagined, providing a way to control neurons without electric shocks or slow-acting, unfocused drugs.


Lighting the Brain

The necessary tools were already out there. The first opsin—the light-sensitive protein made by microbes—had been identified in 1971, the same year Deisseroth was born. Bacteriorhodopsin, as it was called, responded to green light, and scientists have since found it in microbes living in saltwater all over the world. The next opsin, halorhodopsin, which responds to yellow light, was discovered in 1977. Like bacteriorhodopsin, it was found in bacteria living in salty lakes and seas.

Deisseroth, who read everything he could about opsins, realized that light-sensitive microbes speak the same basic language as neurons: When light hits the opsin, gates in the cell membrane open, allowing charged particles called ions to flow in and out. In microbes, ion flow tells the organism which way to turn. In neurons, ions flowing through the cell wall initiate action, setting off a string of communications that tell organisms like us how to feel and behave. This similarity suggested to Deisseroth that opsins could be manipulated to switch brain cells on and off.

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