Salt Lake City: The epidemic and its effects have raised anxiety to unprecedented proportions. However, the causes of anxiety-related disorders such as obsessive-compulsive spectrum disorder (OCSD) remain unknown. In a new study, researchers at the University of Utah Health identified the role of a small cell in the brain called microglia in modulating anxiety-related behaviors in laboratory mice. Traditionally, neurons, the most common type of brain cells, have been assumed to control behavior. Certain microglia populations, like the buttons on a gaming controller, trigger anxiety and OCSD behaviors, while others suppress them, the researchers suggest. Microglia communicate with neurons to initiate behaviors. The results, published in the journal Molecular Psychiatry, could lead to new techniques for targeted drugs.
“A small amount of anxiety is good,” said Nobel laureate Mario Capecchi, distinguished professor of human genetics at the University of Utah’s Spencer Fox Eccles School of Medicine and senior author of the study. “Anxiety motivates us, energizes us, and gives us that extra push to say ‘I can.’
Newly identified mechanisms are important for maintaining behavior within healthy limits under normal conditions. Under pathological conditions, the mechanisms can drive debilitating behaviors, Capecchi said.
“This work is unique and challenges current theory about the role of microglia function in the brain,” says Naveen Nagajaran, Ph.D., a geneticist and neuroscientist at U of U Health and lead author of the study.
Rats with OCSD-like behaviors cannot resist self-grooming. They lick their bodies a lot, their hair falls out, and they develop welts. Previously, Capecchi’s team found that a mutation in the gene Hoxb8 caused mice to show symptoms of chronic anxiety and engage in excessive self-grooming. Unexpectedly, they identified the source of these behaviors as a type of immune cell called microglia. Microglia, which make up only 10 percent of the brain’s cells, are considered the brain’s “trash collectors,” removing dying neurons, most common brain tissue, and abnormally shaped proteins. Their findings are among the first to reveal that Hoxb8 microglia are important for controlling behavior by communicating with specific neuronal circuits.
But how microglia accomplished these tasks remained a mystery. To learn more, Nagajaran turned to optogenetics, a technique that combines laser light and genetic engineering. He used lasers to stimulate specific populations of microglia in the brain, much like playing a video game.
To the researchers’ amazement, they could turn on anxiety-related behaviors with the flip of a switch. When they used a laser to stimulate a subpopulation of Hoxb8 microglia, the mice became more anxious. When the laser induced Hoxb8 microglia in other parts of the brain, the mice maintained themselves. Elsewhere targeting Hoxb8 microglia had multiple effects: the mice increased anxiety, they groomed themselves, and they froze, a sign of fear. Whenever the scientists turned off the laser, the behavior stopped.
“It was a big surprise for us,” says Nagarajan. “It has traditionally been thought that only neurons can generate behavior. The current findings shed light on a second way the brain generates behaviors using microglia.” In fact, stimulating microglia with a laser caused neurons sitting near them to fire more vigorously, suggesting that the two cell types communicate with each other to drive different behaviors.
Further experiments revealed another layer of regulation of a population of microglia that does not express Hoxb8. Simultaneous stimulation of “Non-Hoxb8” and Hoxb8 microglia prevented the development of anxiety and OCSD-like behaviors. These results suggest that the two populations of microglia act like a brake and an accelerator. Under normal conditions they balance each other and when the signals are imbalanced they trigger a disease state.
Research shows that the location and type of microglia are two characteristics that appear to be important for anxiety and OCSD behaviors. From there, microglia communicate with specific neurons and neural circuits that ultimately control behavior, Capecchi says. “We want to learn more about the two-way communication between neurons and microglia,” he says. “We want to know who is responsible for that.” Defining these interactions in mice may lead to therapeutic targets for controlling excessive anxiety in patients.
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