PROJECT SUMMARY/ABSTRACT Evidence that anxious smokers experience lower cessation success and account for a greater proportion of tobacco-related disease and disability underscores the need to identify common factors that underlie this comorbidity and improve outcomes in this vulnerable population. Research initiatives addressing cigarette use and anxiety have largely overlooked physiological mechanisms that facilitate body-brain communication, despite their promise as malleable intervention targets. To address this gap, study designs are needed that characterize (1) the effects of cigarette use on physiological processes that support body-brain communication and (2) how these impairments confer anxiety risk in human models. This application proposes that the baroreflex, a well-delineated feedback loop through which body-brain communication occurs, is likely to be impaired in cigarette smokers and, as a result, may undermine core learning processes that confer anxiety risk. The proposed study will involve a single in-person laboratory visit during which 66 participants (n=33 smokers; n=33 non-smokers) will complete a fear conditioning paradigm while baroreflex function assessed. Dependent variables include: (1) baroreflex function indexed via electrocardiograph and blood pressure data and (2) fear inhibition indexed via skin conductance response during the paradigm’s extinction training phase. Analysis of variance, linear regression, and mediation modeling will be used to examine group differences in baroreflex function between smokers and non-smokers (Aim 1), the relationship between baroreflex function and fear inhibition (Aim 2), and the direct and indirect effects of smoking status on fear inhibition through the baroreflex (Aim 3), respectively. Findings will refine knowledge of physiological processes implicated in anxiety, smoking, and their high comorbidity. The applicant is applying for an F31 award to receive high caliber training in the design and implementation of mechanism-focused addiction research (Goal 1), translational models of anxiety pathology (Goal 2), psychophysiological interpretation and analysis (Goal 3), and professional development (Goal 4). The research and training plan will lay the foundation for the applicant’s future line of research to examine how substance- related impairments in physiological function promote anxiety risk and maintain substance use behavior. Receiving an F31 fellowship will relieve the applicant from her time-intensive teaching assistant position to effectively to conduct research and establish a strong interdisciplinary network in the addiction science field.