Anxiety, OCD Brain Mechanism Revealed

The pandemic and its effects have heightened 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 from the University of Utah Health identified the role of a minor cell type in the brain called microglia in modulating anxiety-related behaviors in laboratory mice. Traditionally, neurons—the most common type of brain cell—were assumed to control behavior.

Specific microglia populations, like buttons on a gaming controller, trigger anxiety and OCSD behaviors while others dampen them, according to the researchers. Microglia also communicate with neurons to initiate the behaviors. The findings, which were published in the journal Molecular Psychiatry, may potentially lead to new techniques for targeted medicines.

“A small amount of anxiety is good,” says Nobel Laureate Mario Capecchi, Ph.D., a distinguished professor of human genetics at the Spencer Fox Eccles School of Medicine at University of Utah and senior author of the study. “Anxiety motivates us, spurs us on, and gives us that extra bit of push that says, ‘I can.’ But a large dose of anxiety overwhelms us. We become mentally paralyzed, the heart beats faster, we sweat, and confusion settles in our minds.”

The newly discovered systems may be helpful for maintaining healthy behaviors under regular situations. Under pathological situations, the systems could drive debilitating behaviors, according to Capecchi.

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

Microglia manipulation
Mice with OCSD-like habits are unable to stop grooming themselves. They lick themselves so excessively that their fur sloughs off and welts form. Previously, Capecchi’s team revealed that a mutation in a gene called Hoxb8 caused mice to exhibit chronic anxiety and compulsive grooming.

Surprisingly, they discovered that the root of these actions was a type of immune cell known as microglia. Microglia, which account for barely 10% of brain cells, were assumed to be “trash collectors” who disposed of dying neurons (the most common brain cell) and improperly shaped proteins. They were also among the first to uncover that Hoxb8 microglia were critical for behavior control via connecting with certain neural circuits.

But how microglia fulfilled these jobs was unknown. Nagajaran resorted to optogenetics, a technology that combines laser light and genetic engineering, to learn more. He utilized the laser to excite specific populations of microglia in the brain, much like a video game.

The researchers were astounded to discover that they could activate anxiety-related behaviors with the flip of a switch. The mice got more apprehensive when they used the laser to excite one subset, Hoxb8 microglia. The mice brushed themselves when the laser activated Hoxb8 microglia in other sections of the brain. When Hoxb8 microglia were targeted in yet another region, the mice’s anxiety rose, they combed themselves, and they froze, indicating fear. When the scientists turned off the laser, the behaviors ceased.

“That was a big surprise for us,” Nagarajan says. “It is conventionally thought that only neurons can generate behaviors. The current findings shed light on a second way that the brain generates behaviors using microglia.” In fact, stimulating microglia with the laser caused the neurons sitting next to them to fire more strongly, suggesting that the two cell types communicate with one another to drive distinct behaviors.

Further research found an additional layer of control by a population of microglia that does not express Hoxb8. Simultaneous stimulation of “non-Hoxb8” and Hoxb8 microglia reduced the emergence of anxiety and OCSD-like behaviors. These findings suggested that the two populations of microglia function as a brake and an accelerator, respectively. Under normal settings, they balance each other out and create sickness when the signals are out of sync.

The research shows that location and type of microglia are two characteristics that appear to be important for fine-tuning 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 communications between neurons and microglia,” he says. We want to know what’s responsible for that.” Defining these interactions in mice could lead to therapeutic targets for controlling excessive anxiety in patients.

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