Brain immune cells found to regulate anxiety and grooming behaviors

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's 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 the 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.