Project Summary/Abstract Binge alcohol drinking and high stress reactivity are leading risk factors for anxiety and alcohol use disorders, and women are at twice the risk for co-expression of these diseases. The sex hormone estrogen has been implicated in playing a modulatory role in anxiety and alcohol/drug use and may be related to the telescoping of addiction observed in women by amplifying the positive and negative components of binge alcohol consumption and withdrawal. Further, alcohol consumption itself may be able to stimulate estrogen synthesis to promote drinking behavior, suggesting that estrogen signaling may be an important mechanism in addiction for both males and females. However, the mechanisms by which estrogen regulates neuronal function to control these behaviors is unknown. We hypothesize that estrogen signals at membrane-bound receptors located at discrete synaptic nodes of limbic circuitry to modulate their control of behavior, and that this mechanism is prominent at baseline in females but becomes more important in males across alcohol drinking exposure. In the proposed work, we examine the locus and mechanism of endogenous estrogen signaling, its effect on circuit function and corresponding behavior, and alcohol-induced plasticity in estrogen modulation in both males and females.