Epigenetic regulation of brain and behavior by the estrous cycle

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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.