University of Louisville Pediatric Researcher Dr. Naveen Nagarajan uncovers new signaling mechanism in microglia to address anxiety and overgrooming

A groundbreaking study led by University of Louisville School of Medicine pediatrics and child neurology researcher Dr. Naveen Nagarajan alongside University of Utah geneticist Dr. Mario Capecchi, 2007 Nobel laureate in Physiology/Medicine reveals how 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 paper 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. Dr. 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, Dr. 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 loose 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, Drs. 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. 

Click here to read the full study.