Epigenetic regulation of brain and behavior by the estrous cycle

项目摘要/摘要 性激素在卵巢周期中的波动对女性的大脑和行为产生强大的影响，而且 可能是女性神经精神疾病风险的贡献者。这一点以焦虑和 抑郁症在育龄妇女中的流行程度是男性的两倍。 然而，女性大脑动态特性背后的机制仍然知之甚少，限制了 我们为女性偏见障碍设计针对性别的治疗方法的能力。我们研究的目标是解决 这一迫切需要，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，即染色质 组织是控制基因表达的主要表观遗传机制，在雌性腹侧是高度动态的 小鼠的海马体(VHip)，作为发情周期阶段的一个功能。我们将这些染色质动力学与 神经元基因表达的变化以及VHIP依赖和焦虑相关行为的变化。 基于这些发现，我们假设性激素节律性变化会引起广泛的染色质再释放。 VHip神经元在卵巢周期中的组织，导致基因活性和 增加女性对与不同雌激素相关的焦虑相关表型的易感性 州政府。为了解决这个假设，我们设计了目前的研究，有三个独立的目的来揭示发情 小鼠VHip神经元的周期和性别特异性表观遗传基因调控，并提供机制联系 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 确定动情周期和性别特异性顺式调控元件和染色质驱动机制的方法 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分析和RNA 原位杂交揭示VHip神经元簇对循环激素和 染色质和行为周期性变化的可能驱动因素。在目标3中，我们将从基因上操纵一名候选人 通过生物信息学方法确定表观遗传调节因子，以确定这些性别特异性的功能作用 染色质动力学在基因调控和焦虑相关行为中的作用。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分子机制 发情周期。这些发现将为确定候选的、特定于性别的目标提供必要的第一步 治疗女性偏向的疾病，如焦虑和抑郁。

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.