9 April 2019
Shining Lasers on Mouse Brains Sheds Light on Cells Important to Alzheimer’s, Schizophrenia
Technique that can turn on one of the brain’s most abundant inhibitory cells shows its role in curbing blood flow to different regions.
TUCSON, Ariz.–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. These parvalbumin-containing cells account for almost one-tenth of the cells in your brain, however, relatively little is known about what parvalbumin cells do. By stimulating mouse brains with lasers, researchers have started to make surprising findings about how they work.
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.
Credit: The Bauer Lab at Washington University in St. Louis
Researchers in the lab of Dr. Adam Q. Bauer, at Washington University in St. Louis, U.S.A., 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. They will present their findings at the OSA Biophotonics Congress: Optics in the Life Sciences meeting being held in Tucson, Ariz., U.S.A., 14-17 April 2019.
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 produced great leaps in our understanding of how the brain works, including how our brains process fear and our sense of smell, or what causes us to become addicted to drugs.
“Optogenetics provides a convenient method for repeatedly probing brain circuits with light,” Joonhyuk Lee, one of the Bauer group researchers said. “You can do it relatively non-invasively, because you don’t have to stick any physical probes into the brain.”
First, the researchers bred mice that expressed a special, light-sensitive protein called channelrhodopsin in certain cells of the brain. Channelrhodopsin was originally found in algae, but scientists can use it to pick which parts of a mouse brain to turn on or off. Hit that area of the mouse brain with the right colored laser and you can activate or deactivate a desired neural circuit.
The team bred mice that expressed channelrhodopsin in inhibitory parvalbumin interneurons or in excitatory Thy1 pyramidal cells. With each group, they were able to stimulate the mouse brains with lasers and compare the results.
When most neurons are active, Lee said, blood flow increases in the active region. This occurred when the excitatory Thy 1 cells were stimulated, but the lab’s findings regarding blood flow and volume revealed the opposite response when parvalbumin-expressing cells were stimulated.
“Our results demonstrate a critical role of parvalbumin-expressing interneurons in how the brain regulates its blood supply,” said Lee.
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 blood oxygenation and flow using combined imaging techniques, called optical intrinsic signal imaging and laser speckle contrast imaging. When the mouse whiskers were touched, Lee and his colleagues first observed that parvalbumin cells can 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 more distant regions 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. Lee also hopes that his results will provide insight on how aberrant activity in PV-based cells influences brain development or the onset of neurological disorders.
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Authors: Joonhyuk Lee, Annie R. Bice, Zachary P. Rosenthal, Jin-Moo Lee and Adam Q. Bauer
Author Affiliations: Washington University in St. Louis School of Medicine