University of Utah Study Reveals Key Role of Microglia in Controlling Anxiety and OCSD Behavior

University of Utah medical scientists have discovered a key role for microglia, a subtype of brain cells, in controlling anxiety and obsessive-compulsive disorder (OCSD) behavior. By stimulating specific populations of microglia, researchers can enable or inhibit this behavior in mice. This new insight challenges the belief that neurons are the only controllers of behavior and offers a promising therapeutic avenue for dealing with anxiety.

The pandemic and its consequences have raised anxiety to new levels. But the roots of anxiety-related conditions, including obsessive-compulsive disorder (OCSD), are still unclear. In a new study, University of Utah health scientists have uncovered insight into the importance of a secondary cell type in the brain – microglia – in controlling anxiety-related behavior in laboratory rats. Traditionally, neurons—the dominant type of brain cell—are thought to control behavior.

The researchers demonstrated that, like buttons on a game controller, certain groups of microglia activate anxiety and OCSD behaviors while others inhibit them. Moreover, microglia communicate with neurons to elicit behavior. The results are published in a journal Molecular PsychiatryThis may eventually lead to new approaches to targeted therapy.

“A little anxiety is a good thing,” says Nobel Prize winner Mario Capecci, Ph. D., distinguished professor of human genetics at the University of Utah’s Spencer Fox Eccles School of Medicine and senior author of the study. “Anxiety stimulates us, motivates us, gives us that extra push that says, ‘I can.’ But a large dose of anxiety overwhelms us. We become mentally paralyzed, our hearts beat faster, we sweat, and confusion settles in our minds. ”

“This work is unique and challenges current dogma about the role of microglia function in the brain.”

The newly identified mechanisms could be important for keeping behavior within a healthy range under normal conditions. In pathological conditions, says Capecchi, mechanisms can drive debilitating behavior.

“This work is unique and challenges current dogma about the role of microglia function in the brain,” said Naveen Nagajaran, PhD, geneticist and neuroscientist at U of U Health and lead author of the study.

microglia treatment

Mice with OCSD-like behavior are unable to withstand grooming on their own. They lick their bodies in such a way that their fur peels off, and they get blisters. Previously, Capecchi’s team found that mutations in a gene called Hoxb8 caused mice to show signs of chronic anxiety and overcondition themselves. Unexpectedly, they determined that the source of this behavior was a type of immune cell called microglia. Representing only 10% of cells in the brain, microglia are considered the brain’s “garbage collectors” that have scavenged dying neurons – the most common brain cells – and abnormally shaped proteins. Their findings are also among the first to reveal that Hoxb8 microglia are important for controlling behavior by communicating with specific neural circuits.

The Honorable Professor Mario Capecci, Ph.D. and Naveen Nagagaran, Ph.D., University of Utah. Credit: Charlie Ellert, University of Utah Health

But how microglia accomplish this task remains a mystery. To find out more, Nagajaran turned to optogenetics, a technique that combines laser light with genetic engineering. Like playing a video game, use a laser to stimulate specific groups of microglia in the brain.

To the surprise of the researchers, they could trigger anxiety-related behaviors at the push of a button. When they used the laser to stimulate the subpopulation, Hoxb8 microglia, the mice became more agitated. When the laser awakened Hoxb8 microglia in other parts of the brain, the mice readied themselves. Targeting Hoxb8 microglia elsewhere had multiple effects: Mice increased anxiety, braced themselves, and then froze, an indicator of fear. Every time the scientists turn off the laser, the behavior stops.

“It was a big surprise for us,” Nagarajan said. “It has traditionally been believed that only neurons can generate behavior. The current findings highlight the way the two brains generate behavior using microglia.” Indeed, stimulating microglia with a laser caused neighboring neurons to fire more intensely, suggesting that the two cell types communicate with each other to trigger different behaviors.

The Honorable Professor Mario Capecchi, Ph.D. and Naveen Nagagaran, Ph.D., University of Utah. Credit: Charlie Ellert, University of Utah Health

Further experiments revealed another control layer by a group of microglia not expressing Hoxb8. Simultaneous stimulation of ‘non-Hoxb8’ and Hoxb8 microglia prevented the onset of anxiety and OCSD-like behavior. These results indicate that the two populations of microglia act like brakes and accelerators. They balance each other under normal conditions and create pathology when the signals are unbalanced.

Research suggests that the location and type of microglia are two characteristics that appear to be important for regulating anxiety and OCSD behavior. From there, microglia communicate with specific neurons and neural circuits that ultimately control behavior, says Capecchi. “We wanted to learn more about the two-way relationship between neurons and microglia,” he said. “We want to know what is responsible for that.” Identification of this interaction in rats could lead to therapeutic targets for controlling excessive anxiety in patients.

Reference: “Hoxb8 mice optogenetic stimulation of certain brain regions leads to anxiety, grooming, or both” By Naveen Nagarajan and Mario R Capechi, 10 Apr. 2023, Available here. Molecular Psychiatry.
DOI: 10.1038/s41380-023-02019-w