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Optogenetics

Treating anxiety no longer requires pills or psychotherapy. At least, not for a certain set of bioengineered mice. In a study recently published in the journal Nature, neuroscientists turned these prey into bold explorers with the flip of a switch. The group, led by Karl Deisseroth, a psychiatrist and researcher at Stanford, employed an emerging technology called optogenetics to control electrical activity in a few carefully selected neurons.

First they engineered these neurons to be sensitive to light. Then, using implanted optical fibres, they flashed blue light on a specific neural pathway in the amygdala, a brain region involved in processing emotions. And the mice, which had been keeping to the sides of their enclosure, scampered freely across an open space.

While such tools are very far from being used or even tested in humans, scientists say optogenetics research is exciting because it gives them extraordinary control over specific brain circuits – and with it, new insights into an array of disorders, among them anxiety and Parkinson’s disease.

Mice are very different from humans, as Deisseroth acknowledged. But he added that because “the mammalian brain has striking commonalities across species,” the findings might lead to a better understanding of the neural mechanisms of human anxiety.

David Barlow, founder of the Center for Anxiety and Related Disorders at Boston University, cautions against pushing the analogy too far: “I am sure the investigators would agree that these complex syndromes can’t be reduced to the firing of a single small neural circuit without considering other important brain circuits, including those involved in thinking and appraisal.” But a deeper insight is suggested by a follow-up experiment in which Deisseroth’s team directed their light beam just a little more broadly, activating more pathways in the amygdala.This erased the effect entirely, leaving the mouse as skittish as ever. This implies that current drug treatments, could also in part be working against themselves.

Not on humans, anytime soon...

Optogenetics, which can focus on individual circuits with exceptional precision, may hold promise for psychiatric treatment. But Deisseroth and others caution that it will be years before these tools are used on humans, if ever. The procedure involves bioengineering that most people would think twice about. First, biologists identify an opsin, a protein found in photosensitive organisms like pond scum that allows them to detect light. Next, they fish out the opsin’s gene and insert it into a neuron within the brain, using viruses that have been engineered to be harmless “disposable molecular syringes,” as Anderson calls them.

There, the opsin DNA becomes part of the cell’s genetic material, and the resulting opsin proteins conduct electric currents – the language of the brain – when they are exposed to light. (Some opsins, like channelrhodopsin, which responds to blue light, activate neurons; others, like halorhodopsin, activated by yellow light, silence them.)

Understanding the nervous system

Finally, researchers delicately thread thin optical fibres down through layers of nervous tissue and deliver light to just the right spot. Thanks to optogenetics, neuroscientists can go beyond observing correlations between the activity of neurons and an animal’s behaviour; by turning particular neurons on or off at will, they can prove that those neurons actually govern the behaviour. “Sometimes before I give talks, people will ask me about my ‘imaging’ tools,” said Deisseroth, 39, a practicing psychiatrist who started a research laboratory in 2004 to develop and apply optogenetic technology.

In early experiments, scientists showed that they could make worms stop wiggling and drive mice around in manic circles as if by remote control. Now, laboratories around the world are using it to better understand how the nervous system works, and to study problems including chronic pain, Parkinson’s disease and retinal degeneration.

Dr Amit Etkin, a Stanford psychiatrist and researcher who collaborates with Deisseroth, is trying to translate the findings about anxiety in rodents to improve human therapy with existing tools.

Dr Jaimie Henderson, their colleague in the neurosurgery department, has treated more than 600 Parkinson’s patients using a standard procedure called deep brain stimulation. The treatment, which requires implanting metal electrodes in a brain region called the subthalamic nucleus, improves coordination and fine motor control. But it also causes side-effects, like involuntary muscle contractions and dizziness.

Moreover, as with any invasive brain surgery, implanting electrodes carries the risk of infection and life-threatening hemorrhage. What if you could stimulate the brain’s surface instead? A new theory of how deep brain stimulation affects Parkinson’s symptoms, based on optogenetics work in rodents, suggests that this might succeed. Henderson has recently begun clinical tests in human patients and hopes that this approach may also treat other problems associated with Parkinson’s.

Opsins in rhesus monkey brains

In the building next door, Krishna V Shenoy, a neuroscience researcher, is bringing optogenetics to work on primates. Extending the success of a similar effort by an MIT group led by Robert Desimone and Edward S Boyden, he recently inserted opsins into the brains of rhesus monkeys. They experienced no ill-effects from the viruses or the optical fibres, and the team was able to control selected neurons using light. Shenoy, who is part of an international effort financed by the Defense Advanced Research Projects Agency, says optogenetics has promise for new devices that could eventually help treat traumatic brain injury and equip wounded veterans with neural prostheses.

“Current systems can move a prosthetic arm to a cup, but without an artificial sense of touch it’s very difficult to pick it up without either dropping or crushing it,” he said. “By feeding information from sensors on the prosthetic fingertips directly back into the brain using optogenetics, one could in principle provide a high-fidelity artificial sense of touch.”

Boyden, who participated in the early development of optogenetics, points out that light, unlike drugs and electrodes, can switch neurons off – or as he put it, “shut an entire circuit down.” And shutting down overexcitable circuits is just what you’d want to do to an epileptic brain.

New York Times News Service

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