Regulatory Elements Controlling Anxiety States

项目总结 大约三分之一的美国人在生活中的某个时候经历过令人无法忍受的焦虑，其中约60%的人 受影响的是女性。现有的焦虑症治疗方法只能暂时改善情绪，效果各不相同， 强调在与焦虑症的斗争中需要新的途径。基因调控机制有 成为心理健康风险的主要驱动因素。了解基因调控机制如何影响 焦虑表型对于开发更精确的遗传风险评估、诊断和 焦虑症的靶向治疗。我们最近发现，转录因子HoxB8的破坏 在小鼠中产生严重的焦虑症状，可能是由于小胶质细胞亚群功能障碍所致 病理与女性性激素水平有关。因为HOX转录因子高度保守 在所有脊椎动物物种中，我们在老鼠身上的发现可能在一定程度上适用于人类。事实上，我们的 初步研究表明，在人类中，HoxB8结合部位不成比例地经常与 焦虑风险基因的启动子，但还不清楚这些基因是如何与小胶质细胞联系在一起的。在这里，我们测试 假设HoxB8活性与焦虑症的遗传风险因素有关，并且这些风险 因子通过小胶质细胞发挥作用。基于小鼠强烈的性别连锁和激素控制的表型，我们的 扩展的假说是，HoxB8使小胶质细胞能够调节大脑回路，以谨慎对待冒险行为 生殖周期中的行为。这里提出的两个目标解决了我们的直接假设。目标1 定义几个发育阶段的HoxB8依赖基因调控元件和基因，以及目标2 探索HoxB8相关焦虑风险基因在小鼠小胶质细胞中的表达。已确定的监管要素 相关基因将与全基因组关联研究(GWAS)数据进行比对，以评估它们在 焦虑症。表达测试将进一步证实小胶质细胞在HoxB8控制的焦虑中的作用， 首先阐明潜在的分子机制，并为未来的直接功能研究奠定基础。

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.