Scientists may have found the root of anxiety, opening a door to treatment

When anxiety takes hold, it’s a full-body experience. It’s hard to imagine that these all-encompassing symptoms could emanate from a few specific cells, but new research points to just such a neural home for anxiety in the brain.

Using a specific class of cells as a target, researchers hope that they’ll be able to develop more precise and effective treatments for anxiety.

A new treatment that could prevent anxiety symptoms may be lurking in a small population of microglia is described in a paper published this week in Cell Reports.

In a series of mouse experiments, scientists at the University of Utah noted that a “lineage” of cells called Hoxb8 microglia had specific effects on anxiety. In mice with dysfunctional Hoxb8 microglia cells, they nervously over-groomed and displayed symptoms similar to human anxiety and obsessive compulsive disorder, but when these cells were functioning normally, the symptoms abated.

Dimitri Traenkner, Ph.D., assistant professor of biology at the University of Utah, tells Inverse the finding offers biological answer for why people with acute anxiety feel the way they do. The identification of these cells is a big step forward for developing new anxiety treatments.

“For people suffering from anxiety, this news should give hope. Maybe simply because it might not be your fault if you are anxious. There is an underlying disease mechanism,” Traenkner says.

The National Institute of Mental Health’s statistic maintain that that about 19.1 percent of adults in the United States struggled with an anxiety disorder between 2001 and 2003 (these adults were asked to report the past year anxiety symptoms, and the NIH still uses these stastics to estimate the prevalence of anxiety disorders) That mean their anxiety was so acute that it affected their jobs, schoolwork, and relationships.

“An underlying disease mechanism”

Before Traenkner’s team revealed the connection between microglia and anxiety symptoms in mice, scientists knew these cells had both a good side and a bad side. Microglia act as maintenance cells in the brain that seek out pathogens and destroy them. However, the activation of microglia has also been traced to neurodegenerative diseases, like Alzheimer’s, suggesting that we don’t fully understand how their benefits compare to their potential for harm.

That strange dichotomy made it even more surprising when this team found that microglia may have a protective effect on anxiety symptoms. In the paper, they explain that these cells have “the ability to suppress obsessive compulsive and anxiety symptoms.”

The researchers also seem to have solved another piece of the microglia puzzle: Only microglia that develop a specific way seem to have this protective effect of suppressing anxiety symptoms. All microglia start out as a common precursor cell — similar to the way that all living creatures descended from a common ancestor. The cells then follow certain pathways of development that make them distinct from each other. These specific microglia develop according to the whims of the Hoxb8 gene, which is why they’re named Hoxb8 microglia.

To test whether these cells affected anxiety symptoms, the team messed with that development pathway, making it impossible for those cells to follow the garden path from common precursor to fully differentiated microglia. Getting off track in this way led to higher rates of anxiety and OCD.

"…we are getting closer to defining the cells and molecules producing or preventing anxiety.

“The main positive aspect is that our study, and many recent studies done in other labs, show that we are getting closer to defining the cells and molecules producing or preventing anxiety,” says Traenkner.

Supporting this claim, they noticed another way that human anxiety is mirrored in these cells deep in mouse brains: in how anxiety symptoms are linked to male and female hormones.

Hormones and symptom severity

People of both sexes struggle with anxiety, but more females tend to struggle with it, statistically speaking. The NIH has noted that 23.4 percent of women were diagnosed with an anxiety order compared to 14.3 percent of men. This team suggests that if the microglia play a role in the development of symptoms in the first place, hormones appear to control how severe those symptoms are.

In this study, female mice who had abnormal Hoxb8 microglia showed more severe symptoms than their male counterparts. Both male and female mice started showing coat loss due to over-grooming when they were three weeks old (a sign of anxiety), but the females started losing their hair rapidly when they were between six and eight weeks old, which is when they started to reach sexual maturity and were producing more estrogen and progesterone.

To test whether those primary female sex hormones could increase anxiety symptoms, they actually reduced the mice’s production of those hormones. In response, over-grooming plummeted to levels similar to those seen in male mice.

Their experiment suggests that it’s the high levels of estrogen and progesterone that could ratchet up the volume of anxiety symptoms in females, particularly around the onset of puberty. Though this was only seen in their mouse models, we do see higher levels of anxiety in adolescent girls compared to boys. According to the NIH, 38 percent of adolescent girls reported anxiety disorders compared to 26.1 percent of adolescent boys.

Taken together, Traenkner is most excited about the potential that his team’s early research has for explaining anxiety, a condition that feels overwhelming and hard to explain for both patients and physicians. This model, he says is just at the beginning, but he has plans to keep probing at it:

“At this point, I have only a vision,” he says. “But experiments will tell.”

Summary: Aberrant microglia activity is associated with many neurological and psychiatric disorders, yet our knowledge about the pathological mechanisms is incomplete. Here, we describe a genetically defined microglia sublineage in mice which has the ability to suppress obsessive compulsion and anxiety symptoms. These microglia derive from precursors expressing the transcription factor Hoxb8. Selective ablation of Hoxb8-lineage microglia or the Hoxb8 gene revealed that dysfunction in this cell type causes severe over-grooming and anxiety-like behavior and stress responses. Moreover, we show that the severity of the pathology is set by female sex hormones. Together, our findings reveal that different microglia lineages have distinct functions. In addition, our data suggest a mechanistic link between biological sex and genetics, two major risk factors for developing anxiety and related disorders in humans.