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Using light to probe the brain's self-repair after a stroke

Tim Murphy at the University of British Columbia shows off a new technique that allows researchers to turn specific brain circuitry on and off.


A revolutionary new technique is allowing Canadian researchers to map, with exquisite precision, how the brain repairs itself after a stroke.

Optogenetics gives neuroscientists the ability to control brain circuits in laboratory animals with lasers, to turn cells on or off with a flash of light. It offers a new way to probe what different parts of the brain do and could lead to new treatments for a variety of neurological conditions.

At the Brain Research Centre in British Columbia, Tim Murphy and his colleagues are using it to learn more about the critical period after a stroke. He and his team can chart how, in a mouse, damaged circuitry that once controlled movement of the right front paw is replaced with new wiring, in a different location, that does the same thing.

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"There is actual sprouting of connections and structural rearrangements," said Dr. Murphy. He can figure out the function of new circuitry by turning it on or off and watching how that affects an animal's ability to move.

Optogenetics - using a combination of genetics and optics to control cells - was developed in 2005 by Stanford University psychiatrist and bioengineer Karl Deisseroth and his colleagues. Neuroscientists in hundreds of labs around the world are now using it to investigate the neural circuitry involved in mental illnesses like depression and anxiety and to solve long-standing mysteries about the function of different types of brain cells.

Dr. Deisseroth's team took copies of one of the genes that make green algae extremely responsive to light and inserted them into the DNA of brain cells in a Petri dish. The scientists were then able to get the neurons to fire, or produce an electrical signal, with a pulse of blue light.

Next, researchers were able to insert the gene, essentially a new on-off switch, into the brain cells of living mice. They can activate these cells with laser light guided into the brain with a fibre-optic cable and have been able to make mice move their paws or run around in a circle.

It is similar to the technique used by Wilder Penfield in the 1930s, when he mapped the sensory and motor parts of the brain while performing surgery on patients with epilepsy. He would touch part of a patient's brain with an electric probe - turning cells on - and ask where it triggered a sensation in their body.

But using light rather than an electric probe to turn on brain cells is faster and far more precise and allows scientists to zero in on fine circuitry. In the future, the technique could be used in humans, says Dr. Murphy, but the challenge will be to transfer genes from algae into human brains.

Meanwhile, at the University of Alberta, Gregory Funkis using optogenetics to study how the brain controls breathing rhythm in hopes of helping premature babies, who often stop breathing.

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At the Samuel Lunenfeld Research Institute at Mount Sinai Hospital in Toronto, Kenichi Okamoto is working on what has been described as the next generation of optogenetics. He is using lasers to activate specific proteins in the brains of mice to determine which ones are involved in memory and learning. He will also investigate the role these proteins may play in Alzheimer's disease and autism.

In Dr. Murphy's lab, the focus is on stroke, and how to promote and capitalize on the brain's natural recovery process. Brain cells and circuitry die when they are suddenly cut off from the blood supply during a stroke, but in the days and weeks afterwards new connections form.

The team is mapping the parts of the brain that take on new functions. Usually, this occurs in areas adjacent to damaged neural pathways, but sometimes it is in the corresponding region in the other hemisphere of the brain.

"Is there a way we could stimulate those areas to promote this plasticity?" asked Dr. Murphy, a member of the University of British Columbia's department of psychiatry.

Researchers have already shown that they can help stroke patients overcome some kinds of brain damage with transcranial magnetic stimulation, which uses repetitive, precise magnetic signals delivered through the skull to either fire brain cells up or calm them down.

It is similar to using light to stimulate cells, says Dr. Murphy. He wants to test if particular patterns of stimulation are more effective in promoting the formation of new connections between brain cells.

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He recently was awarded $947,000 over five years from the Canadian Institutes of Health Research for his optogenetics research and is also funded by the Canadian Stroke Network and the Heart and Stroke Foundation of British Columbia and Yukon.

"It is going to be an incredible tool," Dr. Murphy said. "It is an entirely new aspect of neuroscience."


Brain storm

50,000 strokes occur in Canada each year. That's one every 10 minutes.

15 per cent of people who have a stroke die from it.

10 per cent recover completely.

25 per cent recover with a minor impairment or disability.

40 per cent are left with a moderate to severe impairment.

10 per cent are so severely disabled they require long-term care.

300,000 Canadians are living with the effects of stroke.

80 per cent of strokes are caused by the interruption of blood flow to the brain due to a blood clot.

20 per cent are caused by uncontrolled bleeding in the brain.

1.9 million: The number of brain cells the average patient loses for every minute of delay in treating a stroke.

$3.6-billion: What strokes cost the Canadian economy every year.

Source: Heart and Stroke Foundation of Canada

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