Mario Capecchi

We have recently turned our attention to the role of microglia, the immune cell of the brain, in maintaining brain homeostasis and in protecting us from acquisition of anxiety disorders.  Anxiety disorders affect ~20% of adults.  These statistics are even more alarming for adolescents, with 38% of females and 26% of males reporting disabling anxiety.  The levels of anxiety disorders are currently rapidly arising even higher as a consequence of the COVID-19 pandemic.  The strong sex bias of anxiety disorders is observed at all age levels in humans.  We have shown in mice that a genetic disruption in a subpopulation of microglia (Hoxb8 microglia) causes chronic anxiety and, as in humans, females exhibit more severe pathology than males.  Moreover, the more severe pathology in females can be reduced to male levels by treatments that lowers their female hormone levels.  In contrast, the pathology in mutant males can be increased to female levels by the introduction of female hormones.  Since we can induce the behavioral pathologies through optogenetic stimulation we are positioned to map the brain circuitry that cause these disorders and determine how microglia communicate with specific brain neural circuits to modulate their output.

Anxiety disorders show extremely high comorbidity with a number of neuropsychiatric disorders.  Why such high comorbidity exists has not been answered nor why different choices, such as major depression, OCD or schizophrenia are made.  Our mouse model shows very high comorbidity with OCD spectrum disorder.  Why?  Can this choice be changed?  Many questions can now be addressed genetically and molecularly and the tools to address these questions are here. In terms of explanation of the pathology, we have been able to extend causation to the molecular level.