STRESS RESHAPES GENOMIC AND CIRCUIT-LEVEL ESTROGEN SIGNALING IN A SEX-DEPENDENT MANNER

Sex differences are evident in the prevalence and mechanisms of stress-related psychiatric disorders. Women experience these disorders at higher rates than men, and fluctuations in ovarian hormones are associated with changes in symptomatic prevalence and severity. These differences are mirrored in animal models, in which females exhibit greater stress susceptibility and behavioral responses vary across the estrous cycle. Despite this, our understanding of the mechanisms driving sex- and hormone-dependent differences in stress responses remains limited.
Estrogen regulates transcriptional programs in the brain through its nuclear receptors; however, the role of estrogen’s genomic pathway in shaping stress responses is poorly understood. To address this, we used CUT&RUN to investigate estrogen receptor alpha (ERα) binding in multiple stress-responsive brain regions at baseline and following chronic stress. Our analyses reveal region-, sex-, and estrous-stage-specific ERα binding patterns and demonstrate that stress markedly alters ERα regulatory activity, with particularly strong effects in the nucleus accumbens (NAc).
Estrogen can also influence neuronal activity through non-genomic mechanisms. Given the pronounced impact of stress on ERα binding in the NAc, we next examined how stress influences activity within estrogen-responsive circuits projecting to this region. Following chronic stress, we virally labeled ERα-positive cells that project to the NAc and performed brain clearing with immunolabeling for the viral marker and c-Fos. These analyses identify regions with sex-specific activity responses to stress and highlight those that are NAc-projecting and estrogen-responsive.
Together, these molecular and circuit approaches provide a framework for understanding how estrogen signaling contributes to sex-dependent stress vulnerability.