Optochemogenetics Tested for Neuronal Repair after Stroke

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Researchers at Emory University School of Medicine have developed optochemogenetics, a combinatorial approach based on optogenetics and chemogenetics, to enable the selective, noninvasive stimulation of brain cells using light. In a mouse model of stroke, neural progenitor cells that received light stimulation through optochemogenetics promoted functional recovery in the mice.

The Emory investigators wanted to remove the fiber optic cable that optogenetics approaches use to activate or inhibit neurons. The researchers created luminopsins — engineered proteins that are both light-sensitive and able to generate their own light when provided with coelenterazine (CTZ). They introduced genes encoding luminopsins into stem cells, which were cultured to form neural progenitor cells. The neural progenitor cells were delivered into the brains of mice a week after stroke. CTZ was provided intranasally twice a day for two weeks. Bioluminescence could be detected in the cell graft area and was visible for around one hour after CTZ administration.

Optochemogenetics for stroke research, Emory University School of Medicine.

Gaussia luciferase (GLuc) is fused to the ChR protein. ChR can be activated by blue light or by light emitted by GLuc when binding to its substrate coelenterazine (CTZ). ChR = channelrhodopsin. YFP = yellow fluorescent protein. Courtesy of Shan Ping Yu.

CTZ promoted an array of positive effects in the progenitor cells: more survival and intact axons, more connections within the brain, and better responses to electrical stimulation. It also promoted recovery of function in the affected limb in the mice. In young mice, CTZ and progenitor cells together could restore use of the stroke-affected limb back to normal levels and in older mice they produced partial recovery of function.

The team believes that optochemogenetics could represent a significant advance in light-based medicine. “Optogenetics is a fantastic technical tool, but it presents some barriers to clinical implementation,” professor Shan Ping Yu, M.D., said. “You have the invasive fiber optic light delivery, and the limited distance of light diffusion, especially on the larger scale of the human brain.”

Delivery of cells into the brain for light activation could offer scientists some flexibility when designing experiments: direct light application, which can be turned on and off quickly, or the steady support of CTZ stimulation. The noninvasive repeated CTZ stimulation of transplanted cells is feasible for clinical applications, the researchers believe.

Optochemogenetics for stroke research, Emory University School of Medicine.
As part of stroke research, Emory scientsts are making neural progenitor cells glow inside the brain. Bioluminescence from cells cultured in a multielectrode array, next to a fiber optic cable. Courtesy of Jack Tung.

“It is not sufficient to put the cells into the damaged brain and then not take care of them,” Yu said. “If we expect progenitor cells to differentiate and become functional neurons, the cells have to receive stimulation that mimics the kind of activity they will see in the brain. They also need growth factors and a supportive environment.”

Yu and his colleagues are also testing their approach for the delivery of neural progenitor cells in the context of traumatic brain injury.

The research was published in the Journal of Neuroscience (   

Published: July 2019
A discipline that combines optics and genetics to enable the use of light to stimulate and control cells in living tissue, typically neurons, which have been genetically modified to respond to light. Only the cells that have been modified to include light-sensitive proteins will be under control of the light. The ability to selectively target cells gives researchers precise control. Using light to control the excitation, inhibition and signaling pathways of specific cells or groups of...
Bioluminescence is a natural phenomenon in which living organisms produce and emit light through a chemical reaction occurring within their bodies. This light emission is typically the result of a biochemical reaction involving the oxidation of a light-emitting molecule called luciferin, catalyzed by an enzyme called luciferase. Bioluminescent organisms can be found across various taxa, including bacteria, fungi, algae, marine invertebrates, and some fish. Examples of bioluminescent...
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