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Age of Enlightenment

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PHOTOGRAPH BY SAM KAPLAN

For years before optogenetics was invented, reports had circulated about microorganisms that produce proteins called opsins. An opsin spans the cell membrane and contains both a light-absorbing component—retinal, a vitamin A derivative—and a channel pore that is closed when the opsin is not illuminated. When the opsin’s retinal absorbs light, the protein changes form and temporarily opens up a pore that lets ions through. In effect, these naturally occurring opsins convert light into changes in cellular voltage. And because a voltage change is what causes neurons to fire, in 2000 Deisseroth and Boyden began brainstorming ways they might harness the special proteins to control neurons. In 2004, the team decided to focus on Channelrhodopsin-2 (ChR2), a protein from a one-celled alga that has an “eye” to guide the organism toward the daylight at the surface of a murky pond for photosynthesis. When exposed to blue light, a pore in the cell opens and positively charged ions flow in.

Deisseroth and Zhang, who is now a professor at MIT, used genetic engineering techniques to deliver the gene for ChR2 into the nucleus of rodent neurons they grew in cell cultures; the neurons then successfully produced the opsin. Boyden, who has an MIT degree in engineering and physics, rigged a system for directing blue light on those novel neurons.

Amazingly, the neurons fired instantly when illuminated. Also wonderful: The neurons immediately returned to their normal state when the light pulsed off, giving an unprecedented precision in timing neural activity. The process was perfectly simple, requiring only a single gene.

The team published its work in August 2005 in Nature Neuroscience, and they and other scientists adapted the system to try in living mice. Researchers insert the gene for ChR2 into a harmless virus, which is injected into a region of the mouse’s brain and “infects” the neurons there with the gene. The neurons then produce the light-activated protein all over their cell membranes. Next, implanted optic wires threaded to that brain region direct light there. When the light pulses on, only those cells bearing the opsin fire.

By 2007, Boyden—who by then had his own lab at MIT—Zhang, and Deisseroth independently showed that another naturally occurring opsin, halorhodopsin, responds to yellow or green light and inhibits neurons, preventing them from firing. Halorhodopsin allows researchers to zero in on particular kinds of neurons and control when they fire—in live, conscious animals. “People had been dreaming of this ability for decades,” says Wim Vanduffel, a neurophysiologist and radiologist at Massachusetts General Hospital who has begun using the technology in his research.

Optogenetics has clear advantages over electrophysiology, a technology that uses implanted electrodes to force neurons to fire. But a combination of the technologies can be particularly powerful. Electrophysiology can record how neurons fire both during normal activity and when optogenetically controlled. David Anderson, a neurobiologist at the California Institute of Technology, used this approach to explore aggression and sex in mice. With electrophysiology, he recorded electrical impulses from neurons in the hypothalamus as male mice fought potential male competitors and as they mated with females. “We were surprised that the nerve cells involved in both aggression and sex are closely intermingled in the same neighborhood,” Anderson says.

Normally, within a split second of an intruder male mouse entering a cage, the resident male streaks toward it and bites its neck. But the resident mouse will not attack a female—or a castrated male. When Anderson optogenetically activated neurons in the hypothalamus, however, the male would attack anything: a castrated male, an inflated rubber glove and even a female, unless he was in the midst of sex; then he wouldn’t go after her until after climaxing.

Anderson’s studies show not only that neurons involved in aggression and mating are intermingled, but also that interactions with females inhibit the neurons normally active in male aggression. “If this holds for humans, perhaps we’ll learn that something goes wrong with this inhibition in sexual pathologies when circuits get miswired,” he says. He’s planning experiments to trace that circuitry.

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Raising the Voltage

Scientist Walter Rudolf Hess conducted one of the first experiments to test whether neural activity in a defined part of a cat's brain causes specific actions.

What’s Next for Optogenetics?

Using flashes of light to control brain cells may be only the beginning for a remarkable research tool.

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hed-dossier

1. “A History of Optogenetics: The Development of Tools for Controlling Brain Circuits with Light,” by Edward S. Boyden, F1000 Biology Reports, May 3, 2011. This account of the development of optogenetics, by one of its inventors, includes middle-of-the-night “aha!” moments, with credit given to other researchers and to serendipity.

2. “Dopamine Neurons Modulate Neural Encoding and Expression of Depression-Related Behaviour,” by Kay M. Tye et al., Nature, January 2013. This study provided new insights into the role of dopamine in symptoms of depression by probing for the underlying neural circuits. The researchers integrated optogenetics with electrophysiology and pharmacology and used specially designed devices to precisely track behavior.

3. “Optogenetics, Sex, and Violence in the Brain: Implications for Psychiatry” by David J. Anderson, Biological Psychiatry, June 15, 2012. This study found a surprising neural link between aggression and sex, raising provocative questions about whether faulty wiring could account for some sexual pathologies.

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