A newly discovered brain mechanism linked to anxiety and obsessive-compulsive disorder has been discovered

University of Utah health scientists have discovered a key role for microglia, a subtype of brain cell, in controlling anxiety and obsessive-compulsive disorder (OCSD) behaviors. By stimulating specific populations of microglia, researchers can activate or inhibit these behaviors in mice. This new insight challenges the belief that neurons are the sole controllers of behavior and offers a promising avenue for therapies to treat anxiety.

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

The researchers showed that, like the buttons on a game controller, certain groups of microglia activate anxiety and OCSD behaviors while others inhibit them. Moreover, microglia communicate with neurons to invoke behaviours. The results published in the journal Molecular PsychiatryIt could eventually lead to new approaches to targeted therapies.

University of Utah health scientists have discovered insights into the importance of a secondary cell type in the brain — microglia — in controlling anxiety-related behaviors. The findings could lead to new approaches for targeted therapies. Credit: Charlie Ellert, University of Utah Health

“A little bit of 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 boost that says, ‘I can.’ But a heavy dose of anxiety overwhelms us. We get mentally paralyzed, the heart beats faster, we sweat, and confusion settles in our minds.”

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

The newly identified mechanisms could be important for maintaining behaviors within the healthy range under normal circumstances. Under pathological conditions, Capecchi says, mechanisms can drive behaviors that become debilitating.

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

Microglia treatment

Mice with OCSD-like behaviors cannot resist grooming on their own. They lick their bodies so much that their fur sloughs off, and they get blisters. Previously, Capecchi’s team discovered that a mutation in a gene called Hoxb8 caused mice to show signs of chronic anxiety and to condition themselves excessively. Unexpectedly, they determined that the source of these behaviors was a type of immune cell called microglia. Representing only 10% of cells in the brain, microglia are thought to be the brain’s “garbage collectors” that have scavenged dying neurons – the most common brain cells – and abnormally shaped proteins. Their findings were also among the first to reveal that Hoxb8 microglia were important for controlling behavior by communicating with specific neural circuits.

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

But how microglia accomplish these tasks has remained 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 researchers’ surprise, they can trigger anxiety-related behaviors by flipping a switch. When they used a laser to stimulate a subpopulation, Hoxb8 microglia, the mice became more restless. When the laser excited Hoxb8 microglia in other parts of the brain, the mice prepared themselves. Targeting Hoxb8 microglia elsewhere had multiple effects: The mice increased anxiety, braced themselves, and then froze, an indicator of fear. Whenever the scientists turn off the lasers, the behaviors stop.

“It was a big surprise for us,” says Nagarajan. “It has traditionally been believed that only neurons can generate behaviors. The current findings highlight a second way the brain generates behaviors using microglia.” Indeed, stimulating microglia with the laser caused neurons next to them to fire more vigorously, suggesting that the two types of cells communicate with each other to trigger distinct behaviors.

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

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

The research shows that the location and type of microglia are two characteristics that appear to be important for the regulation of anxiety and behaviors of OCSD. From there, the microglia communicate with specific neurons and neuronal circuits that ultimately control behavior, Capecci says. “We want to learn more about the bidirectional connections between neurons and microglia,” he says. “We want to know what is responsible for it.” Identification of these interactions in mice could lead to therapeutic targets for controlling excessive anxiety in patients.

Reference: “Optogenetic stimulation of mouse Hoxb8 in specific brain regions causes anxiety, grooming, or both” By Naveen Nagarajan and Mario R Capechi, Apr 10, 2023, Available here. Molecular Psychiatry.
DOI: 10.1038/s41380-023-02019-w