Epigenetic regulation of brain and behavior by the estrous cycle

发情周期对大脑和行为的表观遗传调节

• 批准号: 10549358
• 负责人: Marija Kundakovic
• 金额: $ 38.28万
• 依托单位: FORDHAM UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549358
• 关键词: 3-Dimensional; ATAC-seq; Address; Affect; Age; Animal Model; Animals; Anxiety; Automobile Driving; Behavior; Binding Sites; Bioinformatics; Biological Assay; Brain; Cell Nucleus; Cells; ChIP-seq; Chromatin; Chromatin Loop; Complement; Data; Development; Diestrus; Disease; Distant; Drops; Enhancers; Epigenetic Process; Estrogens; Estrous Cycle; Etiology; Event; Exhibits; Female; Fright; Gene Expression; Gene Expression Regulation; Gene Family; Genes; Genetic Transcription; Genomics; Goals; Gonadal Steroid Hormones; Hi-C; Hippocampus; Hormonal; Hormonal Change; Hormone Receptor; Hormones; In Situ Hybridization; Life; Link; Maps; Mediating; Menstrual cycle; Mental Depression; Mental disorders; Methods; Modeling; Molecular; Mus; Nature; Neurons; Ovarian Cycles; Perimenopause; Periodicity; Phase; Phenotype; Physiological; Postpartum Period; Proestrus; RNA; Regulation; Regulator Genes; Regulatory Element; Reproductive Periods; Research; Risk; Role; Specificity; Structure; Testing; Variant; Woman; anxiety-related behavior; candidate identification; chromatin remodeling; design; disorder risk; emotion regulation; emotional behavior; epigenetic regulation; epigenomics; estrogenic; experience; experimental study; genetic manipulation; genomic locus; histone modification; in vivo; male; men; mouse model; neuropsychiatric disorder; neuropsychiatry; overexpression; programs; promoter; reproductive; sex; sex cycle; single nucleus RNA-sequencing; synaptic function; transcription factor; transcriptome sequencing; transcriptomics

Project Summary/Abstract Sex-hormone fluctuations across the ovarian cycle exert powerful effects on female brain and behavior, and are likely contributors to female-specific risks for neuropsychiatric conditions. This is exemplified by anxiety and depression, disorders twice as prevalent in women of reproductive age compared to their male counterparts. However, the mechanisms underlying the dynamic nature of the female brain remain poorly understood, limiting our ability to design sex-specific treatments for female-biased disorders. The goal of our research is to address this critical need, and to reveal the molecular mechanisms through which sex hormones dynamically impact female brain structure and behavior. To this end, we recently made the important discovery that chromatin organization, a major epigenetic mechanism controlling gene expression, is highly dynamic in the female ventral hippocampus (vHIP) of mouse, as a function of the estrous cycle stage. We linked these chromatin dynamics to changes in neuronal gene expression and to variation in vHIP-dependent, anxiety-related behaviors in mice. Based on these findings, we hypothesize that rhythmic sex-hormone changes induce extensive chromatin re- organization in vHIP neurons across the ovarian cycle, resulting in cyclic changes in gene activity and contributing to increased female vulnerability to anxiety-related phenotypes associated with the varying estrogen state. To address this hypothesis, we designed the current study with three independent aims to reveal estrous cycle- and sex-specific epigenetic gene regulation in vHIP neurons in mice, and to provide a mechanistic link between vHIP chromatin dynamics and anxiety-related behavior. In Aim 1, we will use cutting-edge epigenomics methods to identify estrous cycle- and sex-specific cis-regulatory elements and chromatin mechanisms driving transcriptional programs in vHIP neurons. In Aim 2, we will use a single-cell transcriptomic analysis and RNA in situ hybridization to reveal vHIP neuronal clusters that are transcriptionally responsive to cycling hormones and possible drivers of cyclic changes in chromatin and behavior. In Aim 3, we will genetically manipulate a candidate epigenetic regulator identified by bioinformatics approaches, to identify a functional role of these sex-specific chromatin dynamics in gene regulation and anxiety-related behavior. Overall, these studies will reveal chromatin- dependent molecular mechanisms controlling neuronal gene expression and anxiety-related behavior across the estrous cycle. These findings will provide a necessary first step to identify candidate, sex-specific targets for the treatment of female-biased disorders such as anxiety and depression.

项目总结/摘要 卵巢周期中的性激素波动对女性的大脑和行为产生强大的影响， 可能导致女性神经精神疾病风险。焦虑就是一个例子， 抑郁症，这种疾病在育龄妇女中的发病率是男性的两倍。 然而，女性大脑动态本质的机制仍然知之甚少， 我们设计针对女性偏见疾病的性别特异性治疗方法的能力。我们研究的目标是解决 这一关键需求，并揭示性激素动态影响的分子机制， 女性的大脑结构和行为为此，我们最近有了一个重要发现， 组织是控制基因表达的主要表观遗传机制，在雌性腹侧肌中具有高度动态性， 小鼠的海马（vHIP），作为动情周期阶段的函数。我们将这些染色质动力学与 神经元基因表达的变化以及小鼠中vHIP依赖性焦虑相关行为的变化。 基于这些发现，我们假设节律性的性激素变化诱导广泛的染色质重排， 组织在整个卵巢周期的vHIP神经元，导致基因活性的周期性变化， 导致女性对与不同雌激素相关的焦虑相关表型的易感性增加， 状态为了解决这一假设，我们设计了三个独立的目的，以揭示发情期 小鼠vHIP神经元中周期和性别特异性表观遗传基因调控，并提供一种机制联系 vHIP染色质动力学和焦虑相关行为之间的关系。在目标1中，我们将使用尖端的表观基因组学 鉴定发情周期和性别特异性顺式调节元件和染色质机制的方法 vHIP神经元中的转录程序。在目标2中，我们将使用单细胞转录组学分析和RNA， 原位杂交以揭示对循环激素有转录响应的vHIP神经元簇， 染色质和行为周期性变化的可能驱动因素。在目标3中，我们将对候选人进行基因操作， 通过生物信息学方法鉴定表观遗传调节因子，以确定这些性别特异性的功能作用。 基因调控和焦虑相关行为中的染色质动力学。总体而言，这些研究将揭示染色质- 控制神经元基因表达和焦虑相关行为的依赖性分子机制 发情周期这些发现将为确定候选的性别特异性靶点提供必要的第一步， 治疗女性偏见的疾病，如焦虑和抑郁。