Anxiety disorders are a prevalent mental health concern, impacting approximately one in five individuals across the United States. Despite this, the underlying causes of anxiety within the brain remain largely shrouded in mystery. However, groundbreaking research conducted at the University of Utah has unveiled a surprising discovery: two distinct groups of brain cells in mice that act as catalysts and inhibitors of anxiety.
The revelation is particularly intriguing because these regulatory cells are not neurons, the traditional messengers of the brain. Instead, a type of immune cell known as microglia emerges as a key player in determining anxiety levels. One group of microglia appears to promote anxiety, while another group acts as a buffer, keeping anxiety in check.
"This finding is a game-changer," remarks Donn Van Deren, PhD, a postdoctoral research fellow at the University of Pennsylvania, who conducted the research during his fellowship in human genetics at the University of Utah Health. "It highlights the critical role of the brain's immune system in maintaining mental health. When this system is compromised, it can lead to specific neuropsychiatric disorders."
The study's results, published in Molecular Psychiatry, shed light on the complex interplay between brain immune cells and anxiety.
Researchers had previously established that microglial immune cells play a role in anxiety regulation. However, they believed that all microglia functioned similarly. When they interfered with a specific group of microglia called Hoxb8 microglia, mice exhibited anxious behavior. Surprisingly, when they suppressed the activity of all microglia, including both Hoxb8 and non-Hoxb8 microglia, the mice behaved normally.
This led researchers to hypothesize that the two groups of microglia have opposing roles. To confirm their theory, they needed to observe the behavior of each group independently.
The researchers' experiment was unconventional: they transplanted different types of microglia brain cells into mice that lacked microglia altogether.
They found that non-Hoxb8 microglia act as an accelerator for anxiety. When these cells were transplanted into microglia-deficient mice, the mice displayed classic signs of heightened anxiety, such as compulsive grooming and avoidance of open spaces. With only non-Hoxb8 microglia present, the anxiety accelerator was constantly engaged, with no brake to control it.
In contrast, Hoxb8 microglia act as a brake pedal for anxiety. Mice transplanted with only Hoxb8 microglia did not exhibit anxious behavior. Importantly, mice with both types of microglia - the accelerator and the brake - also remained anxiety-free. The non-Hoxb8 microglia may drive anxiety, but this is counterbalanced by the anxiety-preventing activity of Hoxb8 microglia, resulting in a balanced response.
"These two populations of microglia have opposite roles, working together to set the appropriate anxiety levels in response to environmental cues," explains Mario Capecchi, PhD, distinguished professor of human genetics at University of Utah Health and senior author of the study.
The researchers believe that their findings could pave the way for significant advancements in the understanding and treatment of anxiety disorders. "Humans also possess two populations of microglia that function similarly," Capecchi notes. "However, current medications for psychiatric conditions primarily target neurons."
By uncovering the role of these microglia in driving anxiety, researchers can develop therapies that focus on these cells, either activating the brakes or reducing the accelerator's impact. "This knowledge will empower patients who have lost control over their anxiety levels to regain it," Capecchi asserts.
"We are still a long way from therapeutic applications," cautions Van Deren. "But in the future, we may be able to target specific immune cell populations in the brain and correct their function through pharmacological or immunotherapeutic approaches. This would represent a paradigm shift in the treatment of neuropsychiatric disorders."
The research, published in Molecular Psychiatry, is titled "Defective Hoxb8 microglia are causative for both chronic anxiety and pathological overgrooming in mice."
The study was supported by the National Institutes of Health, specifically the National Institute of Mental Health (R01 MH093595), as well as the Dauten Family Foundation and the University of Utah Flow Cytometry Facility. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
