Shining Lasers on Mouse Brains Advances Knowledge of Cells Central to Alzheimer’s, Schizophrenia

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WASHINGTON, D.C., April 11, 2019 — Alzheimer’s disease and schizophrenia are some of the most common brain disorders and have been associated with problems in cells that contain a type of protein, called parvalbumin. Those cells account for almost one-tenth of all brain cells, but relatively little is known about what they do. Researchers have started to make surprising findings about how those cells work by stimulating mouse brains with lasers.

Using their custom-built laser system, researchers in the Bauer Lab at Washington University in St. Louis discovered that increased activity in specific inhibitory neural circuits reduces cerebral blood flow and volume while excitatory activity causes blood flow and volume to increase.

Researchers in the lab of Dr. Adam Q. Bauer have found surprising changes in blood volume and flow when parvalbumin-containing cells are stimulated. The technique they used relies on specially bred mice whose brains can be stimulated with laser pulses.

Courtesy of Bauer Lab at Washington University in St. Louis.
One of the main types of the brain’s inhibitory cells, parvalbumin-expressing cells have been found to be responsible for keeping the endless signals of the brain in sync. Since proper nervous system development relies on nerves repeatedly firing in concert with one another over time, conducting this neural symphony has been found to be an important part of regulating the connections between brain cells that allow them to develop normally.

The technique of stimulating the brain with light signals, called optogenetics, has greatly advanced understanding of how the brain works, including how brains process fear and sense of smell, or what causes drug addiction.

“Optogenetics is convenient, less invasive and repeatable,” Joonhyuk Lee, one of the Bauer group researchers, said. “And it’s more straightforward. You don’t have to stick any probes into mouse brains.”

First, the researchers bred mice that expressed a special, light-sensitive protein called channelrhodopsin throughout the brain. Channelrhodopsin was originally found in algae, but scientists can use it to pick which parts of a mouse brain to turn on. By hitting that area of the mouse brain with the right colored laser, a desired neural circuit can be activated.

The team bred mice that had channelrhodopsin stuck to parvalbumin-expressing neurons and mice with channelrhodopsin on excitatory Thy1-expressing cells, for comparison. With each group, they were able to stimulate the mouse brains with lasers and compare the results.

When most neurons are stimulated, Lee said, the brain provides them with more blood and oxygen. This occurred with the excitatory Thy 1 cells, but the lab’s findings regarding blood flow and volume revealed the opposite response when parvalbumin-expressing cells were stimulated.

“How activity in specific neural populations is coupled to local changes in blood flow is fundamental to understanding how the brain regulates its blood supply,” Lee said.

The scientists concluded that parvalbumin-expressing cells have a way of pulling back and fine-tuning the blood supply in areas where they are activated.

Researchers measured the blood and oxygen levels by shining a separate laser system, called laser speckle contrasting imaging, on the brain. When the mice whiskers were touched, Lee and his colleagues first found that parvalbumin cells could scale down nearby available blood and oxygen when excited. The group then measured different areas of the brain and discovered that parvalbumin cells could help relay messages to faraway corners of the brain to change their hemodynamics, or blood flow, as well.

“We really weren’t expecting that activation of parvalbumin-expressing neurons would result in a reduction of local blood flow and volume,” Lee said. “Even more so, although it could be an indirect cause, the fact that we saw similar hemodynamic activity in more distant areas of the brain was very surprising.”

Eventually, Lee said, he hopes the findings and techniques will help lead to a better understanding of parvalbumin’s role in neurovascular coupling and provide another piece of the puzzle on how it influences brain development or formation of neurological disorders.

Published: April 2019
Research & TechnologyLasersbrain disordersparvalbumincellsOSAmouse brains

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