New research from the University of Utah reveals that two distinct groups of immune cells in the brain, called microglia, have opposing roles in regulating anxiety. Unlike neurons which transmit signals, microglia act as an anxiety “accelerator” and “brake.” One subset, non-Hoxb8 microglia, increases anxious behaviors like repetitive grooming and avoidance, while Hoxb8 microglia reduce anxiety and counterbalance this effect.
Anxiety disorders affect over 300 million people worldwide and represent one of the fastest-growing mental health challenges globally. Factors such as increased stress, urbanization, and social isolation contribute to its rising prevalence. Despite its commonality, many cases remain undiagnosed or untreated, highlighting an urgent need for improved awareness and interventions.
Anxiety affects the brain by overactivating the amygdala, which processes fear and emotions, and impairing the prefrontal cortex responsible for regulation and decision-making. Chronic anxiety leads to structural and functional changes in these areas, disrupting emotional control and increasing stress sensitivity. This can result in difficulties with focus, memory, and emotional regulation.
To study this, researchers transplanted each microglial type separately into mice that lacked these cells. Mice receiving only non-Hoxb8 microglia showed heightened anxiety behaviors, while those with Hoxb8 microglia acted normally. Importantly, mice with both microglial types displayed balanced anxiety levels, showing these cells work together to regulate anxiety precisely.
This finding challenges the traditional view that anxiety is mainly controlled by neurons, highlighting the immune system’s crucial role in brain function and mental health. It also opens the door to novel treatments, focusing on microglia to either enhance their calming effects or inhibit their anxiety-promoting activity.
Since humans also have these microglial populations, this discovery could lead to more targeted therapies for anxiety disorders in the future, moving beyond current psychiatric drugs that primarily target neurons. Though clinical applications are still forthcoming, this study marks a major shift in understanding and potentially treating anxiety by modulating the brain’s immune cells rather than just neural circuits.
REFERENCE: Donn A. Van Deren, Ben Xu, Naveen Nagarajan, Anne M. Boulet, Shuhua Zhang, Mario R. Capecchi. Defective Hoxb8 microglia are causative for both chronic anxiety and pathological overgrooming in mice. Molecular Psychiatry, 2025; DOI: 10.1038/s41380-025-03190-y
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