Researchers at the University of Utah have found that anxiety in mice is regulated by two groups of microglia, immune cells that act as accelerators and brakes. This discovery challenges the traditional focus on neurons for mental health issues. The findings, published in Molecular Psychiatry, suggest potential new approaches to treating anxiety disorders.
Anxiety disorders affect roughly one in five people in the United States, yet the mechanisms behind them remain poorly understood. A new study from the University of Utah Health reveals that two subsets of microglia—brain immune cells—play opposing roles in controlling anxious behavior in mice, rather than neurons which typically handle signaling.
The research identified Hoxb8 microglia as functioning like brakes, preventing anxiety, while non-Hoxb8 microglia act as accelerators, promoting it. Earlier experiments showed that disrupting Hoxb8 microglia led to anxious behaviors, but blocking all microglia resulted in normal behavior, hinting at their balancing act.
To test this, scientists transplanted specific microglia types into mice lacking them entirely. Mice receiving only non-Hoxb8 microglia exhibited strong anxiety signs, such as excessive grooming and avoidance of open spaces. In contrast, those with only Hoxb8 microglia showed no anxiety. When both types were present, Hoxb8 cells neutralized the anxiety-promoting effects of non-Hoxb8 cells.
"These two populations of microglia have opposite roles," says Mario Capecchi, PhD, distinguished professor of human genetics at University of Utah Health and senior author. "Together, they set just the right levels of anxiety in response to what is happening in the mouse's environment."
"This is a paradigm shift," adds Donn Van Deren, PhD, who conducted the work at Utah. "It shows that when the brain's immune system has a defect and is not healthy, it can result in very specific neuropsychiatric disorders."
The study, titled "Defective Hoxb8 microglia are causative for both chronic anxiety and pathological overgrooming in mice," appears in Molecular Psychiatry (2025; DOI: 10.1038/s41380-025-03190-y). Researchers note that humans have similar microglia populations, and current treatments target neurons, not immune cells. Future therapies could modulate these cells to restore anxiety control, though Van Deren cautions that such applications remain distant. The work was supported by the National Institutes of Health and others.