Summary: Researchers have identified a specific signaling mechanism in brain immune cells that regulates anxiety and grooming behaviors.
The study focuses on Hoxb8 microglia and reveals that internal calcium signals within these cells act as a biological switch for core symptoms of autism and obsessive-compulsive (OCD) spectrum disorders.
Key Research Findings
- The Hoxb8 Connection: Mice lacking the Hoxb8 gene are highly susceptible to chronic anxiety and pathological over-grooming, mimicking conditions that affect millions of people worldwide.
- Calcium as the Driver: Using optogenetics (light-activated cellular control), researchers discovered that increasing calcium levels inside Hoxb8 microglia immediately triggered anxiety and grooming behaviors.
- Loss of Regulation: In mice without the Hoxb8 gene, the cells lose their ability to regulate calcium, resulting in a constant “stream” of signaling that sustains chronic anxiety and compulsive actions.
- Miniature Microscopy: To record these tiny signals (10–15 µm) in awake, behaving mice for the first time, researchers used a 2.4 g miniaturized microscope (miniscope).
- Direct Correlation: By using a light-activated channel (ChRmine) to block calcium entry into the cells, researchers were able to prevent all anxiety-related behaviors, confirming that calcium is the direct driver of these symptoms.
Source: University of Louisville
A study led by a University of Louisville School of Medicine pediatrics and child neurology researcher reveals how a specific signaling mechanism in microglia, the brain immune cell, can regulate anxiety and grooming behaviors. These behaviors are core symptoms of autism and obsessive-compulsive spectrum disorders.
The research was conducted by Naveen Nagarajan, assistant professor in the UofL Department of Pediatrics, alongside University of Utah geneticist Mario Capecchi, 2007 Nobel laureate in Physiology/Medicine, and was published in Molecular Psychiatry, a Nature Publishing Journal, one of the top scientific journals.
The research centers on Hoxb8 microglia, a specialized group of brain immune cells. These cells use calcium signaling to help regulate anxiety and grooming behaviors in mice. Nagarajan’s previous work showed that a healthy mouse can generate these behaviors if activated.
Mice lacking the Hoxb8 gene are susceptible to developing extreme anxiety and pathological overgrooming, a condition that is observed in humans who suffer from chronic anxiety (nearly 4.4% of the global population) and obsessive-compulsive disorders that affect nearly 1% to 3% worldwide. Phase two of this study questioned what signals in those cells drive those behaviors.
Using optogenetics, a technique that activates cells with light, the researchers increased calcium levels inside Hoxb8 microglia in mice. To measure these tiny calcium signals in a 10-15 µm microglia cell, Nagarajan used a 2.4 g weighing miniaturized microscope, or miniscope, to record the signals in an awake behaving mouse for the first time.
The increase in calcium levels triggered anxiety and/or grooming behaviors. They also found that mice without Hoxb8 gene lose the capacity to regulate calcium resulting in a constant stream of calcium causing chronic anxiety and compulsive over-grooming.
To test whether calcium itself was the driver of these behaviors, Nagarajan and Capecchi used the light activating channel ChRmine that prohibits calcium entry into Hoxb8 microglia using elegant genetic techniques. This manipulation prevented any anxiety-related behaviors, confirming the direct correlation between calcium and anxiety-driven behaviors.
The discovery of these specific calcium signals opens the opportunity for future therapies for anxiety-related disorders, the ability to identify calcium homeostasis when diagnosing neuropsychiatric conditions, and a new understanding of how immune cells influence brain circuits during development.
Key Questions Answered:
A: We used to think microglia were just the brain’s “trash collectors”. This study shows they are active participants in brain circuits. When their internal calcium levels spike, they send signals that fundamentally change behavior, like triggering an obsessive need to groom.
A: In humans, this manifests as body-focused repetitive behaviors often seen in OCD or autism spectrum disorders. In the study’s mice, it was a direct result of unregulated calcium in the Hoxb8 cells.
A: That is the hope. By identifying that calcium homeostasis is the key, future therapies could focus on stabilizing these levels in microglia to treat neuropsychiatric conditions without the broad side effects of current medications.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our 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.
Furthermore, optogenetic stimulation of Hoxb8 microglia in specific regions of the brain induces elevated anxiety and/or grooming. Herein we show that the molecular signals for inducing anxiety and/or grooming in response to optogenetic activation are calcium ions.
Conversely, induction of grooming and anxiety in mice produces calcium transients within microglia. Unexpectedly, calcium transients are not produced in Hoxb8 mutant mice in response to the induction of these behaviors.
The likely cause for this lack of response by Hoxb8 mutant mice to induced grooming is the presence of high constitutive levels of free calcium within Hoxb8 mutant microglia resulting from the gene disruption.
These calcium ions, in turn, serve as relentless signals to increase anxiety and grooming leading to chronic anxiety and pathological overgrooming in Hoxb8 mutant mice.
Thus, we have shown that calcium signaling is used by microglia: 1) to induce anxiety and/or grooming by optogenetic stimulation of Hoxb8 microglia in WT mice, 2) to respond by microglia to the induction of both behaviors in WT mice and 3) as the causative agent for producing chronic anxiety and pathological overgrooming in Hoxb8 mutant mice.
