IMPACT: The results open the door to novel anxiety treatments that target calcium in brain immune cells.
Researchers had previously discovered a population of immune cells within the brain that can act as accelerators and brakes for anxiety in mice. Now, new research from the lab of Mario Capecchi, PhD, professor of human genetics at University of Utah Health and 2007 Nobel laureate in Physiology or Medicine, has identified calcium as a key chemical signal that triggers these immune cells during obsessive-compulsive and anxiety-related behaviors in healthy mice, as well as in a mouse model of obsessive compulsive spectrum disorder (OCSD) and chronic anxiety. This discovery establishes a new framework to study how anxiety arises and persists through calcium signals in microglia.
The results are published in Molecular Psychiatry.
"Microglia are not just passive immune cells but actively control anxiety-, grooming-, and obsessive-compulsive-related behaviors through specific molecular signals like calcium," explains Naveen Nagarajan, PhD, assistant professor of pediatrics at the Pediatric Research Institute at the University of Louisville and first author on the paper, who conducted this research during his postdoctoral work in Capecchi's lab. "This makes microglia a key target to understand and treat neuropsychiatric disorders."
Calcium signaling linked to anxiety-related behaviors
A specific group of microglia, called Hoxb8 microglia, seem to be able to trigger obsessive grooming anxiety-related behaviors in mice. When researchers used genetic tools combined with precise light-based cell stimulation to temporarily activate Hoxb8 microglia in a healthy mouse, the mice performed grooming and anxiety-like behaviors. But until now, scientists didn't know what was going on within Hoxb8 microglia cells that trigger these changes. Researchers found that calcium signaling within microglia is pivotal.
High levels of calcium within microglia act as a critical molecular signal that triggers obsessive grooming and anxiety, the researchers found. Calcium ions enable microglia cells to encode and transmit instructions that shape behavioral output. When normal mice performed grooming, freezing in place, or other anxiety-like behaviors, calcium levels spiked in Hoxb8 microglia. When the behaviors stopped, calcium returned to normal levels. In mice with chronic anxiety and OCSD, calcium is always high in Hoxb8 mutant microglia.
To figure out what was going on in microglia during anxiety and grooming behaviors, the research team used a combination of genetic tools and a miniaturized microscope half the size of a fingernail. Calcium signaling caused genetically engineered microglia to light up green, and the mini microscope watched as calcium levels changed within individual microglia cells for the first time in the brain in freely behaving mice.
Opening the door to new anxiety treatments
If drugs could be targeted to reduce overactive calcium signaling in Hoxb8 microglia, that could potentially provide a new avenue for treating anxiety disorders and OCSD. "Ultimately, this knowledge supports the development of targeted and potentially preventative therapies that are still missing in the clinical settings," Nagarajan says.
The researchers say that the implications of their discovery are far-reaching. Anxiety disorders and OCSD affect hundreds of millions of individuals worldwide and often co-occur with autism spectrum disorders. Current treatments, which tend to cause wide-scale modulation of chemicals related to neurons, don't work for everyone.
By identifying calcium within microglia as a central anxiety-regulating mechanism, this research opens the door to a new class of therapies that target the brain's immune cells and precisely modulate calcium signaling pathways. Such approaches may hold the potential for more effective, targeted, and durable treatments.
The researchers say that beyond their clinical impact, this work represents a turning point in how the brain is understood. Consistent with prior results, their work underscores that behaviors emerge not solely from neurons but from interactions between neural and immune systems. The researchers add that their findings bridge disciplines, uniting neuroscience, immunology, and psychiatry into a more integrated view of the human mind.
"This discovery compels us to rethink the fundamental architecture of brain function," Nagarajan says. "It uncovers a hidden layer of control that directly governs OCSD- and anxiety-related behavioral states and offers a new path toward understanding and treating psychiatric disease."
