Summary: Researchers at the University of Utah identified a distinct sublineage of microglia—Hoxb8-lineage microglia—that protects mice from obsessive-compulsive-like overgrooming and anxiety. When these cells are dysfunctional, mice show excessive grooming behaviors reminiscent of human trichotillomania. The team also found that female sex hormones amplify these OCD-like and anxiety symptoms.
Source: University of Utah
Overview
Anxiety disorders and obsessive-compulsive behaviors affect millions of people worldwide and disproportionately impact women. Despite their prevalence, the biological mechanisms that drive these conditions remain incompletely understood. A new study from the University of Utah links a genetically defined microglial sublineage to the control of compulsive grooming and anxiety-like traits in mice, and it shows that female sex hormones can worsen these behaviors.
Microglia are the brain’s resident immune cells and play key roles in neural development and circuit maintenance. The research team discovered that microglia are not uniform: a Hoxb8-expressing sublineage makes up roughly 30% of brain microglia and performs distinct, protective functions. When Hoxb8-lineage microglia are selectively disabled, mice develop pronounced overgrooming. This behavior mirrors human trichotillomania—a form of obsessive-compulsive disorder in which people compulsively pull out hair—and is accompanied by other anxiety-like responses.
Lead author Dimitri Traenkner, a research assistant professor in the School of Biological Sciences at the University of Utah, explained that identifying this protective microglia population provides a new biological entry point for studying anxiety. “We linked anxiety and compulsive behavior to dysfunction in a specific type of microglia and to female sex hormones,” Traenkner said. “This model gives us a platform to test potential therapies that could eventually help people.”
Discovery of a unique microglia sublineage
This study is the first to demonstrate that a genetically defined microglia sublineage influences compulsive and anxiety-like behavior. Nobel laureate Mario Capecchi, senior author of the study, had long suspected that Hoxb8-lineage microglia were functionally distinct. Earlier work disabling Hoxb8 did not reveal obvious developmental defects, but the research team later observed striking behavioral changes: mice lacking functional Hoxb8-lineage microglia groomed excessively and for longer durations than normal.
Rather than contributing to neuronal damage, as some had feared, these microglia appear to protect neural circuits from developing compulsive and anxiety-related behaviors. “Researchers have long suspected that microglia might drive neuropsychological disorders because they can release potentially neurotoxic substances. We were surprised to find that a specific microglia lineage actually guards against anxiety,” Traenkner added.
Female sex hormones increase symptom severity
The study revealed a clear sex difference in symptom severity. Female mice lacking Hoxb8-lineage microglia consistently showed more pronounced compulsive grooming than males and displayed an additional anxiety-related physiological response: marked pupil dilation in response to stress, a validated indicator of a heightened fight-or-flight reaction.
To test the role of sex hormones, researchers manipulated estrogen and progesterone levels. When female mice were treated to approximate male hormone levels, their compulsive and anxiety-like behaviors became similar to those of males. Conversely, increasing female-level hormones in male mice intensified compulsive grooming and produced anxiety-related signs. These results indicate that female sex hormones modulate the severity of pathology caused by Hoxb8-lineage microglia dysfunction.
“Our findings strongly argue for a mechanistic link between biological sex and genetic family history in the risk to develop anxiety disorders,” Traenkner said.
Implications for human anxiety and OCD
Although this work was conducted in mice, it highlights a cellular mechanism that could be relevant to human anxiety disorders and obsessive-compulsive conditions. Linking dysfunctional Hoxb8-lineage microglia to compulsive grooming and anxiety provides a new biological target for further study. These findings may inspire clinical research focused on microglia in patients with anxiety or OCD, and they establish a preclinical model for testing microglia-targeted therapeutic approaches.
“We did not identify a treatment for anxiety in people, but we created a platform to discover new drugs that might reduce anxiety,” Traenkner noted.
Source:
University of Utah
Media Contacts:
Lisa Potter – University of Utah
Image Source:
Image credited to Ann Martin.
Original Research: Closed access. Title: “A Microglia Sublineage Protects from Sex-Linked Anxiety Symptoms and Obsessive Compulsion.” Dimitri Traenkner et al. Published in Cell Reports. DOI: 10.1016/j.celrep.2019.09.045.
Abstract (summary)
Aberrant microglia activity is associated with many neurological and psychiatric disorders, but the underlying mechanisms are not fully known. This study identifies a genetically defined microglia sublineage derived from Hoxb8-expressing precursors that suppresses obsessive-compulsive and anxiety-like behaviors in mice. Selective removal of Hoxb8-lineage microglia or loss of the Hoxb8 gene produced severe overgrooming, anxiety-like behavior, and exaggerated stress responses. Female sex hormones increased the severity of these symptoms. The results reveal that distinct microglia lineages have different functions and suggest a mechanistic link between biological sex and genetic risk factors for anxiety-related disorders.