Unveiled Brain Function Associated with Anxiety and OCD

A recent research study emphasizes the importance of brain cells, known as microglia, in managing anxiety and obsessive-compulsive behaviors. This study challenges the traditional belief that neurons solely govern behavior and introduces the concept of microglia-neuron communication as a prospective therapeutic opportunity.

The rise in anxiety levels due to the ongoing pandemic is unparalleled. However, the root cause of anxiety disorders, such as obsessive-compulsive spectrum disorder (OCSD), remains undetermined. Researchers at the University of Utah Health have highlighted the vital role that microglia, a commonly neglected cell type in the brain, play in controlling anxiety-related behaviors in lab mice. This deviates from the traditional notion that neurons, the primary brain cells, regulate behavior.

The scientists demonstrated that specific populations of microglia activate or suppress anxiety and OCSD behaviors, much like buttons on a game controller. Moreover, microglia interact with neurons to elicit these behaviors. These findings, published in Molecular Psychiatry, could pave the way for innovative targeted therapy methods in the future.

Distinguished Professor Mario Capecchi, Ph.D., and Naveen Nagajaran, Ph.D, University of Utah. Photo: Charlie Ehlert, University of Utah Health

“A modest amount of anxiety can be beneficial,” comments Nobel Laureate Mario Capecchi, Ph.D., a renowned professor of human genetics at the Spencer Fox Eccles School of Medicine at the University of Utah and the primary author of the research. “Anxiety can drive us and provide that extra push that says, ‘I can.’ However, an overwhelming level of anxiety can incapacitate us. Our hearts beat faster, we sweat, and our minds become confused.”

The recently discovered mechanisms could play a crucial role in keeping behaviors within a healthy range under typical circumstances. In pathological conditions, these mechanisms could lead to debilitating behaviors, according to Capecchi.

“This research is unique and challenges the current belief about the function of microglia in the brain,” remarks Naveen Nagajaran, Ph.D., a geneticist and neuroscientist at U of U Health and the main author of the study.

Scientists at the University of Utah Health have found the crucial role of a less prominent cell type in the brain—microglia—in managing anxiety-related behaviors. These discoveries could lead to novel methods for targeted therapies. Photo: Charlie Ehlert, University of Utah Health

Manipulation of Microglia

Mice exhibiting OCSD-like behaviors can’t resist excessive grooming. They lick their bodies excessively, causing their fur to shed and welts to form. Earlier, Capecchi’s team found that a mutation in the Hoxb8 gene led to mice showing chronic anxiety and excessive grooming behaviors. Interestingly, they found that the origin of these behaviors was a type of immune cell called microglia, previously seen as the brain’s “garbage collectors,” responsible for eliminating dying neurons and abnormal proteins. Their findings were also among the first to demonstrate that Hoxb8 microglia were crucial in controlling behavior by communicating with specific neuronal circuits.

Distinguished Professor Mario Capecchi, Ph.D., and Naveen Nagajaran, Ph.D, University of Utah. Photo: Charlie Ehlert, University of Utah Health

However, the way microglia achieved these functions was not clear. Nagajaran employed optogenetics, a combination of laser light and genetic engineering, to stimulate specific microglia populations in the brain.

To the researchers’ astonishment, they were able to induce anxiety-related behaviors at will. They could increase the mice’s anxiety by using the laser to stimulate one subpopulation, Hoxb8 microglia. When they used the laser to trigger Hoxb8 microglia in other brain regions, the mice excessively groomed themselves. Targeting Hoxb8 microglia in another location led to increased anxiety, excessive grooming, and freezing, an indication of fear. Turning off the laser caused these behaviors to cease.

“That was quite surprising,” Nagajaran notes. “It was widely accepted that only neurons could produce behaviors. These findings unveil a second way for the brain to generate behaviors using microglia.” Notably, stimulating microglia with the laser made the adjacent neurons fire more robustly, suggesting that the two cell types communicate to trigger distinct behaviors.

Subsequent experiments exposed another layer of control by a population of microglia that do not express Hoxb8. Stimulating “non-Hoxb8” and Hoxb8 microglia simultaneously hindered the onset of anxiety and OCSD-like behaviors. These results suggested that the two populations of microglia acted as brakes and accelerators, respectively. Under normal conditions, they counterbalance each other and induce a disease state when the signals are misaligned.

The research indicates that the location and type of microglia are two characteristics that seem crucial for regulating anxiety and OCSD behaviors. Microglia then interact with specific neurons and neural circuits to ultimately control behavior, Capecchi explains. “We aim to further understand the bidirectional communication between neurons and microglia,” he says. “We want to uncover what drives that.” Determining these interactions in mice could lead to therapeutic targets for managing excessive anxiety in patients.

Reference: “Optogenetic stimulation of mouse Hoxb8 microglia in specific regions of the brain induces anxiety, grooming, or both” by Naveen Nagarajan and Mario R. Capecchi, 10 April 2023, Molecular Psychiatry.
DOI: 10.1038/s41380-023-02019-w

Frequently Asked Questions (FAQs) about Microglia and Anxiety

More about Microglia and Anxiety

• Molecular Psychiatry Journal
• University of Utah Health Research
• Information on Anxiety Disorders
• Introduction to Optogenetics
• Information on Obsessive-Compulsive Spectrum Disorders