Summary: Researchers have identified a calcium-based signaling mechanism in a subset of brain immune cells (Hoxb8 microglia) that directly regulates anxiety and pathological grooming behaviors in mice—behaviors that model key features of autism spectrum and obsessive-compulsive disorders.
This study demonstrates that intracellular calcium signals within Hoxb8-expressing microglia act as a biological switch for anxiety and repetitive grooming. When calcium increases in these cells, mice display immediate anxiety-like and grooming behaviors; when calcium entry is blocked, those behaviors are prevented.
Key Research Findings
- The Hoxb8 Connection: Mice lacking the Hoxb8 gene show chronic anxiety and pathological over-grooming, modeling symptoms relevant to human neuropsychiatric conditions.
- Calcium as the Driver: Optogenetic activation of Hoxb8 microglia increases intracellular calcium and immediately triggers anxiety-related and grooming behaviors.
- Loss of Regulation in Mutants: Hoxb8-deficient microglia fail to regulate calcium properly, maintaining persistently elevated intracellular calcium that sustains chronic anxiety and compulsive grooming.
- Miniature Microscopy: Researchers recorded calcium signals from 10–15 µm microglia in awake, behaving mice using a 2.4 g miniaturized microscope (miniscope), enabling direct observation of microglial activity during behavior.
- Direct Causality Demonstrated: Using the light-activated channel ChRmine to block calcium entry into Hoxb8 microglia prevented anxiety-like and grooming behaviors, confirming calcium signaling as the direct mediator.
Source: University of Louisville
Study overview
A team led by Naveen Nagarajan, Assistant Professor in Pediatrics and Child Neurology at the University of Louisville School of Medicine, together with geneticist Mario R. Capecchi (2007 Nobel laureate), published the findings in Molecular Psychiatry. The paper describes how Hoxb8 microglia use calcium signaling to both respond to and induce anxiety-like states and repetitive grooming in mice. The methods combine optogenetics, miniature in vivo microscopy, and targeted genetic tools to establish a causal link between microglial calcium dynamics and behavior.
Previous work showed that activating Hoxb8 microglia can produce grooming and anxiety behaviors in healthy mice. This new study probes which intracellular signals drive those behaviors and whether dysregulation of those signals explains the extreme anxiety and pathological grooming observed in Hoxb8-deficient animals.
By optogenetically elevating calcium in Hoxb8 microglia, the researchers produced immediate increases in anxiety-like behavior and grooming. Conversely, when ChRmine was used to prevent calcium entry into these cells, the behaviors did not occur. In Hoxb8 mutant mice, microglia exhibited chronically high free calcium levels and failed to generate normal transient calcium responses to induced behavior, supporting the interpretation that constitutive calcium elevation drives the persistent pathological phenotype.
Methods and technical advances
A notable technical achievement in this work is the use of a 2.4 g miniscope to record calcium transients in individual microglia (10–15 µm) in awake, freely behaving mice. Combining miniscope imaging with optogenetic control of microglial activity allowed direct correlation of cellular calcium events with observable anxiety and grooming behaviors. Genetic approaches, including targeted expression of the light-activated channel ChRmine, permitted reversible manipulation of calcium entry to test causality.
Implications for neuropsychiatric disorders
These results identify microglial calcium homeostasis as a potential mechanism underlying anxiety and repetitive behaviors. That discovery opens several avenues: development of therapies aimed at stabilizing microglial calcium signaling, new diagnostic markers based on calcium dysregulation in immune cells, and improved understanding of how immune–neural interactions shape behavior during development. While translation to human clinical treatment requires further research, the findings offer a specific cellular target and a measurable signaling pathway for future investigation.
Key Questions Answered:
A: Microglia were once thought to be passive “clean-up” cells. This study shows they actively participate in neural circuits: when their internal calcium levels rise, they send signals that alter circuit function and can trigger behaviors such as repetitive grooming and anxiety-like responses.
A: Pathological over-grooming refers to excessive, repetitive grooming behaviors that can damage tissue and mirror human body-focused repetitive behaviors seen in obsessive-compulsive disorder and some presentations of autism. In this study, unregulated microglial calcium produced this behavior in mice.
A: The findings support that possibility. By demonstrating that blocking calcium entry into Hoxb8 microglia prevents anxiety-like and grooming behaviors, the study suggests therapies that restore calcium balance in microglia could be a promising, more targeted approach to treat certain neuropsychiatric symptoms.
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: The image is credited to 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. Molecular Psychiatry. DOI: 10.1038/s41380-026-03572-w
Abstract
Microglia respond to and induce anxiety and grooming in mice using calcium signaling
Disruption of the mouse Hoxb8 gene causes chronic anxiety and pathological over-grooming resulting from defective Hoxb8 microglia. Optogenetic stimulation of Hoxb8 microglia in specific brain regions induces elevated anxiety and/or grooming through intracellular calcium signals. Conversely, behavioral induction of grooming and anxiety produces calcium transients within wild-type microglia. Hoxb8 mutant microglia, however, show high constitutive levels of free calcium and fail to generate normal calcium transients in response to induced behaviors. These persistent calcium elevations act as relentless signals that increase anxiety and grooming, producing the chronic phenotype observed in Hoxb8 mutants.
In summary, microglial calcium signaling: 1) can induce anxiety and grooming when Hoxb8 microglia are optogenetically activated in wild-type mice; 2) is produced in microglia in response to induced behaviors in wild-type mice; and 3) is the causative agent for chronic anxiety and pathological over-grooming in Hoxb8 mutant mice.