PROJECT SUMMARY Women display higher incidence of gastrointestinal disorders, including functional dyspepsia (FD), and report a higher severity of dyspeptic symptoms compared to men. Although physiological mechanisms that mediate this sex disparity in gastrointestinal (GI) disorders are not fully understood, it has been suggested that they may be mediated by circulating estrogen. Gastric motility is modulated by neurons of the dorsal motor nucleus of the vagus (DMV) and the activity of these neurons is regulated by a robust tonic GABAergic input. Estrogen has been shown to increase GABA expression and release in several regions of the central nervous system (CNS), as well as to modulate neuronal morphology and synaptic activity. Based on our preliminary studies that indicate an estrogen-dependent modulation of vagal output to the stomach, we will test the following novel hypothesis: “Functional gastrointestinal disorders are increased in severity and incidence in females due, in part, to an estrogen mediated decrease in vagal outflow to the stomach”. To investigate this novel hypothesis, we will use a combination of in vitro and in vivo electrophysiological, behavioral, chemogenetic, and anatomical approaches in a rodent model aimed at interrogating the role of stress and estrogen on the brain-gut axis. The results of the experiments outlined in this proposal will provide a deeper understanding of the cellular and neural mechanisms by which estrogen influences the etiology of FD, help identify potential targets for more effective therapeutic interventions directed specifically towards women, and provide novel insights into changes in GI functions that occur in the perimenopausal period.