The future of psychiatric treatment approaches may be revolutionized with this groundbreaking scientific discovery.
A new preclinical study on mice revealed that two distinct teams of microglia may apply the brakes or even trigger anxiety levels.
To date, we have a good understanding of the role of neurons in anxiety management. But what if someone tells us it’s not just neurons but the entire mechanics of anxiety may lie in a dynamic system hidden and embedded in our brains?
This is what this new study has revealed. It has disclosed two pedals, calling them microglia groups having a rivalry.
One group induces anxiety while the other opposes it. This is how mental health is managed. Anxiety-provoking team triggers restlessness, while the relaxing group eases out the situation and gives a sigh of relief.
These findings suggest a potential role for these immune cells in regulating anxiety. Their mutual coordination maintains a dynamic balance, keeping the person sane and lively.
Why should we even bother about anxiety?
Research says that one in five individuals is impacted by anxiety around the globe. The scientists work relentlessly to map the brain switchboard controlling anxious conduct. The surprising outcome is that neurons may not be the sole regulators of anxiety in the human body.
The specialized immune cells inside the brain, known as microglia, may maintain, modulate, and monitor the environment dominated by billions of nerve cells.
The current study called out a lineage of microglia. It said that it may have a significant role in amplifying the anxiety-like behaviors. Paradoxically, another lineage may suppress the anxiety fluxes.
Until both these lineages coordinate well, the individual may retain a balanced state of mind. Dominance of any lineage over its opponent may lead to an imbalance. The anxious responses due to the hyperactivation of one microglial team could have the power to downgrade the mental health and wellness perceptions.
The microglia teams
A recent study examined the Hoxb8 and non-Hoxb8 microglia lineages, building on earlier assumptions about their potential role in anxiety. The mice with exclusive presence of non-Hoxb8 microglia had a rapid acceleration in their anxiety levels. Alternatively, greater calm was observed in mice with Hoxb8 microglia.
The results may transform our current understanding of psychology
The psychiatric drugs prescribed by today’s physicians specifically impact neurons, including their circuits, receptors, and synapses. However, the latest preclinical results state that microglia are not mere spectators but the actual drivers of anxiety.
So the behaviors in individuals with anxiety may be calibrated by knocking down the accelerating non-Hoxb8 microglia or boosting the breaking Hoxb8 microglia.
The current findings pertain to mice, but similar microglia-anxiety mechanisms may also be at play in human populations. That provides a concrete basis for retesting these results in humans and understanding the potential of prospective immune-centric strategies against anxiety.
The accelerator-brake model
The anxiety control mechanism, as determined by this preclinical study, is similar to a bipedal driving model. Mice with non-Hoxb8 microglia were found to exhibit more avoidance of open spaces and self-grooming behavior. In contrast, Hoxb8-based mice exhibited normal behaviors, particularly when Hoxb8 was coordinated with non-Hoxb8 microglia.
Another remarkable finding was that the double-tuned microglia acted across the neuronal circuitry, optimizing the anxiety patterns. Previous studies that did not consider both Hoxb8 and non-Hoxb8 microglia could not unlock their potential for anxiety management. This is because both these pedals are simultaneously needed to appropriately control the anxiety levels.
Establishing causality
To avoid any scope of biased outcomes, the researchers in this preclinical study transplanted microglial progenitors into newborn mice. These mice were first operated upon to deactivate their natural microglia. The next step was to observe the behaviors in both groups of mice that were or were not administered with Hoxb8/non-Hoxb8 microglia. The best outcomes (i.e., normal behaviors) were observed in those mice with the blend of both microglia.
Scientists have now performed another unique test wherein they retransplanted mutant Hoxb8-lineage microglia to the same mouse populations. What they observed was that the patterns of overgrooming and chronic anxiety were repeated in the mutant mice. They concluded that anxiety pathology was mainly driven by the defective Hoxb8 microglia.
The missing signals
Although mice that had a complete loss of Hoxb8 brakes and incorporated non-Hoxb8 microglia exclusively exhibited increased grooming, this did not supersede that of complete Hoxb8 mutants.
What this means is that mutations in Hox8 microglia can really deteriorate anxiety levels even more than non-Hoxb8 microglia. So those mice with non-Hoxb8 microglia and mutated Hoxb8 microglia had peaked their anxiety levels. The future research studies, therefore, have the scope of investigating the missing signals based on the absence of normal Hoxb8 microglia.
Scope of transplanted microglia
Following transplantation, a high level of maturity was observed in Hoxb8 microglia. The level of grooming behavior was more predictable and reciprocated with the type of microglia. Extra grooming correlated with the medial prefrontal cortex responses following its optogenetic stimulation. The integration of mature microglial cells into the brain circuitry led to region-specific behavioral outputs.
Key takeaways
The outcomes of this preclinical study suggest that the behavioral baseline for anxiety may be influenced by microglia. Accordingly, future anxiety treatments can target these over and above serotonin and synapses.
So the psychological balance could be restored either by disrupting the non-Hoxb8 acceleration or triggering the Hoxb8 microglial brakes. Studies testing the tuning of these immune cells against anxiety may provide further hints regarding the future of anxiety treatments, which will more likely be focused on immune cell targeting.
References
University of Utah Health. Your anxiety may be controlled by hidden immune cells in the brain. ScienceDaily. 2025 Nov 13
Van Deren, D.A., Xu, B., Nagarajan, N. et al. Defective Hoxb8 microglia are causative for both chronic anxiety and pathological overgrooming in mice. Mol Psychiatry (2025). DOI: 10.1038/s41380-025-03190-y
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Truly yours,
Dr. Khalid Rahman
Health Scientist | Scholarly Communicator | Licensed Integrative Medicine Practitioner PhD (Clinical Research) | MSc (Bioinformatics) | MSc (Clinical Research & Regulatory Affairs) | P.G.D.C.A. | Bachelor of Unani Medicine & Surgery
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