Summary: Researchers identified a precise calcium-based signaling mechanism inside a subset of brain immune cells—Hoxb8 microglia—that directly regulates anxiety and grooming behaviors in mice. These behaviors model core symptoms of autism spectrum disorders and obsessive-compulsive disorder (OCD).
This study demonstrates that internal calcium dynamics in Hoxb8 microglia act as a biological switch: transient calcium signals produce acute anxiety and grooming, while sustained, unregulated calcium drives chronic anxiety and pathological over-grooming.
Key research findings
- The Hoxb8 connection: Mice missing the Hoxb8 gene develop chronic anxiety and compulsive over-grooming, providing a model for related human conditions.
- Calcium as the trigger: Optogenetic activation of Hoxb8 microglia elevates intracellular calcium and immediately elicits anxiety-like and grooming behaviors.
- Loss of calcium regulation: Hoxb8-deficient microglia cannot regulate intracellular calcium, producing sustained calcium signaling that underlies persistent anxiety and compulsive grooming.
- Miniature microscopy in behaving animals: Researchers recorded calcium signals from individual microglia (10–15 µm) in awake, behaving mice using a 2.4 g miniaturized microscope (miniscope).
- Direct causal proof: Blocking calcium entry into Hoxb8 microglia with a light-activated channel (ChRmine) prevented anxiety-related behaviors, confirming calcium’s causal role.
Source: University of Louisville
A team led by Naveen Nagarajan, assistant professor in the University of Louisville School of Medicine Department of Pediatrics and child neurology, together with University of Utah geneticist Mario R. Capecchi (2007 Nobel laureate), published these findings in Molecular Psychiatry. The work focuses on how Hoxb8 microglia—specialized brain immune cells—use calcium signaling to control behaviors relevant to neuropsychiatric disorders.
Previous studies showed that activating Hoxb8 microglia can produce grooming and anxiety-like behaviors in healthy mice. This study probed what intracellular signals drive those behaviors. Using optogenetics to raise calcium inside Hoxb8 microglia, researchers recorded the resulting effects with a lightweight miniscope while mice were awake and behaving. Those calcium elevations produced immediate anxiety and/or grooming responses.
In contrast, Hoxb8 mutant mice showed a different profile: their microglia displayed abnormally high baseline levels of free intracellular calcium and lacked further calcium transients in response to behavior induction. That persistent calcium signaling appears to perpetuate chronic anxiety and pathological over-grooming in mutant animals.
To directly test whether calcium itself drives these behaviors, the team used a genetic approach combining a light-activated channel, ChRmine, to block calcium influx into Hoxb8 microglia. When calcium entry was prevented, anxiety-related behaviors were abolished, demonstrating a direct mechanistic link between microglial calcium signaling and behavioral outcomes.
Implications for neuropsychiatric research and treatment
These results reveal microglial calcium homeostasis as a potential therapeutic target for anxiety-related disorders and repetitive behaviors seen in autism spectrum and OCD conditions. Identifying and stabilizing calcium signaling in microglia may offer a route to treatments that act on specific cellular mechanisms rather than broad-acting central nervous system drugs. The findings also expand our understanding of how immune cells interact with neural circuits during development and behavior.
Key questions answered
A: Microglia were once considered passive housekeeping cells. This study shows they actively influence neural circuits. Rapid rises in microglial intracellular calcium trigger signaling that changes behavior, such as initiating grooming or anxiety-like responses.
A: Pathological over-grooming in mice models human body-focused repetitive behaviors commonly associated with OCD and some autism presentations. In this study, unregulated calcium in Hoxb8 microglia produced that compulsive grooming.
A: The findings suggest it may be possible. By restoring calcium homeostasis in microglia, future therapies might reduce anxiety and compulsive behaviors with greater cellular specificity and fewer off-target effects than current medications.
Editorial notes
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full.
- Additional context was added by editorial staff.
About this microglia and anxiety research news
Author: Betty Coffman
Source: University of Louisville
Contact: Betty Coffman – University of Louisville
Image credit: Neuroscience News
Original research (open access): “Microglia respond to and induce anxiety and grooming in mice using calcium signaling” by Naveen Nagarajan & Mario R. Capecchi. Journal: Molecular Psychiatry. DOI: 10.1038/s41380-026-03572-w
Abstract (concise)
Microglia respond to and induce anxiety and grooming in mice using calcium signaling
Disruption of the Hoxb8 gene in mice leads to chronic anxiety and pathological over-grooming driven by defective Hoxb8 microglia. Optogenetic activation of Hoxb8 microglia increases intracellular calcium, which induces anxiety and grooming in wild-type mice. Behaviorally induced anxiety and grooming also produce microglial calcium transients in wild-type animals. Hoxb8 mutant microglia lack these transients because they maintain elevated constitutive free calcium, creating a persistent signal that sustains pathological behaviors. These findings demonstrate that microglial calcium signaling can both trigger and maintain anxiety and compulsive grooming, offering a cellular mechanism relevant to neuropsychiatric conditions.