PROJECT SUMMARY/ABSTRACT Prenatal alcohol use (PAU) is associated with increased likelihood of obstetric complications, including preterm labor, miscarriage, and stillbirth, and is also the direct cause of Fetal Alcohol Spectrum Disorders, a collection of neurodevelopmental disorders that cause lifelong neurobehavioral and craniofacial abnormalities. In 2020, the Center for Disease Control and Prevention reported that approximately 1 in 7 pregnant women had consumed alcohol in the past month, which is in line with increasing trends since 2011. Thus, PAU is a major and growing public health problem, so it is imperative to understand the risk factors for PAU to inform prevention and intervention. Stress is one such key risk factor. Pregnant women with frequent stress have a 3- fold higher risk of binge drinking than pregnant women without frequent stress. Furthermore, pre-pregnancy alcohol use is consistently associated with PAU, suggesting that understanding the etiology of alcohol misuse outside of pregnancy is essential for preventing PAU. Correspondingly, stress plays a crucial role in Alcohol Use Disorder (AUD) in women outside of pregnancy, as women are more vulnerable to relapse following stressful triggers relative to men. This vulnerability may in part be driven by sex/gender (SG) differences in neurocircuitry related to processing stress in AUD. Increased stress vulnerability has been linked to dysfunction in the “salience network” (SN), which is a collection of brain regions, primarily the insula, the dorsal anterior cingulate cortex, and inferior parietal lobule, that responds to salient, potentially stressful stimuli and is also highly reactive to substance use cues, including alcohol. Furthermore, social support may serve as a resilience factor against stress-related alcohol misuse, particularly in women. If and how social support can also buffer the brain’s heightened vulnerability to stress in AUD, and if there are SG differences in this effect, remains to be examined. Moreover, whether stress and social support similarly affect PAU is unclear. My overarching hypothesis is that women, relative to men, are more vulnerable to stress-related alcohol misuse via enhanced SN reactivity; however, social support will have a stronger buffering effect on this relationship in women. The specific aims of this project are to (1A) assess SG differences in the role of the SN on the relationship between stress reactivity and alcohol use levels in people with AUD, (1B) assess SG differences in whether social support protects against alcohol misuse by altering stress-related SN reactivity, and (2) determine risk and protective factors for prenatal alcohol use. Achieving these goals will inform scientifically- grounded treatments for AUD in women during and outside of pregnancy, as well as prepare me for a successful career as a physician-scientist in academic medicine.