Regulatory Elements Controlling Anxiety States

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PROJECT SUMMARY About one in three U.S. Americans experiences disabling anxiety at some point in life, and about 60% of those affected are women. Available anxiety treatments only temporarily improve mood with variable success, underscoring the need for new paths in the combat against anxiety disorders. Gene regulatory mechanisms are emerging as major drivers of mental health risks. Understanding how gene regulatory mechanisms influence anxiety phenotypes is essential for the development of more precise assessment of genetic risk, diagnosis, and targeted treatments of anxiety disorders. We recently showed that disruption of the transcription factor HoxB8 produces severe anxiety symptoms in mice likely due to the dysfunction in a subset of microglia and that the pathology scales with levels of female sex hormones. Since Hox transcription factors have highly conserved functions across all vertebrate species, our findings in mice likely apply to some extend to humans. In fact, our preliminary study revealed that in humans HoxB8-binding sites are disproportionally often in contact with promotors of anxiety-risk genes, but it is unclear how these genes are linked to microglia. Here, we test the hypothesis that HoxB8-activity is associated with genetic risk factors for anxiety disorders and that these risk factors act via microglia. Based on the strong sex-linked and hormone-controlled phenotype in mice, our expanded hypothesis is that HoxB8 enables microglia to tune brain circuits for cautious versus risk-taking behaviors during the reproductive cycle. Two aims proposed here address our immediate hypothesis. Aim 1 defines HoxB8-dependent gene regulatory elements and genes at several developmental stages and Aim 2 explores the expression of HoxB8-linked anxiety-risk genes in microglia of mice. Identified regulatory elements and associated genes will be aligned with genome-wide association study (GWAS) data to evaluate their role in anxiety disorders. The expression tests will further substantiate the role of microglia in HoxB8-controlled anxiety, shed first light on the underlying molecular mechanisms, and set stage for direct functional studies in the future.