# Regulatory Elements Controlling Anxiety States

> **NIH NIH R21** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $230,313

## Abstract

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.

## Key facts

- **NIH application ID:** 10371661
- **Project number:** 1R21MH126241-01A1
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Dimitri Traenkner
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $230,313
- **Award type:** 1
- **Project period:** 2022-08-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10371661

## Citation

> US National Institutes of Health, RePORTER application 10371661, Regulatory Elements Controlling Anxiety States (1R21MH126241-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10371661. Licensed CC0.

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