The pandemic and its aftermath have raised anxiety to recent levels. However the roots of anxiety-related conditions, including obsessive-compulsive spectrum disorder (OCSD), are still unclear. In a recent study, University of Utah Health scientists discovered insights into the importance of a minor cell type within the brain-;microglia-;in controlling anxiety-related behaviors in laboratory mice. Traditionally, neurons-;the predominant brain cell type-;are thought to regulate behavior.

The researchers showed that, like buttons on a game controller, specific microglia populations activate anxiety and OCSD behaviors while others dampen them. Further, microglia communicate with neurons to invoke the behaviors. The findings, published in Molecular Psychiatry, could eventually result in recent approaches for targeted therapies.

A small amount of tension is nice. Anxiety motivates us, spurs us on, and offers us that extra little bit of push that claims, ‘I can.’ But a big dose of tension overwhelms us. We turn out to be mentally paralyzed, the center beats faster, we sweat, and confusion settles in our minds.”

Nobel Laureate Mario Capecchi, Ph.D., a distinguished professor of human genetics on the Spencer Fox Eccles School of Medicine at University of Utah and senior writer of the study

The newly identified mechanisms may very well be necessary for maintaining behaviors throughout the healthy range under normal conditions. Under pathological conditions, the mechanisms could drive behaviors that turn out to be debilitating, Capecchi says.

“This work is exclusive and has challenged the present dogma in regards to the role of microglia function within the brain,” says Naveen Nagajaran, Ph.D, a geneticist and neuroscientist at U of U Health and the study’s lead writer.

Manipulating microglia

Mice with OCSD-like behaviors cannot resist grooming themselves. They lick their bodies a lot that their fur sloughs off, and so they develop welts. Previously, Capecchi’s team discovered that a mutation in a gene called Hoxb8 caused mice to point out signs of chronic anxiety and to groom themselves excessively. Unexpectedly, they identified that the source of those behaviors was a variety of immune cell called microglia. Accounting for less than 10% of cells within the brain, microglia had been regarded as the brain’s “trash collectors” that disposed of dying neurons-;essentially the most common brain cell-;and abnormally shaped proteins. Their discoveries were also among the many first to disclose that Hoxb8 microglia were necessary for controlling behavior by communicating with specific neuronal circuits.

But how microglia completed these tasks remained a mystery. To learn more, Nagajaran turned to optogenetics, a way that mixes laser light and genetic engineering. Like playing a video game, he used the laser to stimulate specific populations of microglia within the brain.

To the researchers’ amazement, they may activate anxiety-related behaviors with the flip of a switch. Once they used the laser to stimulate one subpopulation, Hoxb8 microglia, the mice became more anxious. When the laser triggered Hoxb8 microglia in other parts of the brain, the mice groomed themselves. Targeting Hoxb8 microglia in one more location had multiple effects: the mice’s anxiety increased, they groomed themselves, and so they froze, an indicator of fear. At any time when the scientists turned the laser off, the behaviors stopped.

“That was a giant surprise for us,” Nagarajan says. “It’s conventionally thought that only neurons can generate behaviors. The present findings make clear a second way that the brain generates behaviors using microglia.” In reality, stimulating microglia with the laser caused the neurons sitting next to them to fireplace more strongly, suggesting that the 2 cell types communicate with each other to drive distinct behaviors.

Further experiments revealed one more layer of control by a population of microglia that don’t express Hoxb8. Stimulating “non-Hoxb8” and Hoxb8 microglia at the identical time prevented the onset of tension and OCSD-like behaviors. These results suggested that the 2 populations of microglia act like a brake and an accelerator. They balance one another out under normal conditions and induce a disease state when the signals are off-balance.

The research shows that location and variety of microglia are two characteristics that seem like necessary for fine-tuning anxiety and OCSD behaviors. From there, microglia communicate with specific neurons and neural circuits that ultimately control behavior, Capecchi says. “We wish to learn more in regards to the two-way communications between neurons and microglia,” he says. “We wish to know what’s accountable for that.” Defining these interactions in mice could lead on to therapeutic targets for controlling excessive anxiety in patients.

Source:

Journal reference:

Nagarajan, N., & Capecchi, M. R. (2023). Optogenetic stimulation of mouse Hoxb8 microglia in specific regions of the brain induces anxiety, grooming, or each. Molecular Psychiatry. doi.org/10.1038/s41380-023-02019-w.