PROJECT SUMMARY/ABSTRACT This K99/R00 NIH Pathway to Independence Award will provide Dr. Cofresí, trained as a preclinical neuroscientist, with a two-year intensive, mentored training and research experience in translational neuroscience and three-years of research support that will launch his career as an independent investigator. The training and research program focuses on bidirectional translation between preclinical and human laboratory models of neurobehavioral mechanisms that promote alcohol use disorder (AUD). The K99 career development plan will provide training in AUD psychopathology, human alcohol administration, human cognitive/affective neuroscience, and human functional neuroimaging methods. Training will include coursework, conferences, individualized one-on-one mentoring, seminars, and workshops. The K99 research focuses on a neurobehavioral domain of the Addictions Neuroclinical Assessment believed to be critical to the Addiction/AUD Cycle: the attribution of incentive salience (IS) to alcohol cues. Preclinical and human neurobehavioral evidence suggests that repeated alcohol intoxication can sensitize IS attribution to alcohol cues, which may drive the Addiction/AUD Cycle in some individuals. To begin testing this possibility, Dr. Cofresí will translate a preclinical model of individual differences in propensity to attribute IS to reward- predictive cues into a human laboratory model of individual differences in propensity to attribute IS to alcohol intoxication-predictive vs. natural reward-predictive cues, and examine how these individual differences are associated with future problematic alcohol use. Dr. Cofresí’s development will be facilitated by a team with collective expertise spanning the areas of training (Drs. Bruce Bartholow, Shelly Flagel, Brett Froeliger, David Kareken, Denis McCarthy, Ed Merkle, Thomas Piasecki, Kenneth Sher, Todd Schachtman). The K99 phase will take place at the University of Missouri, a world-class research institution, in the Department of Psychological Sciences, home to renowned faculty in alcohol and addiction research with human participants and a premier alcohol research training program (T32-AA013526). The R00 research will take place at a to-be- determined R1 institution, and will focus on continued testing of IS attribution to alcohol-predictive cues and its sensitization in the human laboratory. This K99/R00 award will produce research that advances Goal 1 Objective 1a of the 2017-2021 NIAAA Strategic Plan, which involves identifying behavioral and neurobiological mechanisms underlying AUD, and explaining heterogeneity in how people progress through the Addiction/AUD Cycle, in order to inform the development of AUD prevention and treatment. This K99/R00 award will also produce an independent scientist able and committed to conducting basic behavioral and neurobiological research with human participants that will continue to advance NIAAA’s mission to improve diagnosis, prevention, and treatment of alcohol-related problems, including AUD.

PROJECT NARRATIVE In any given year, over 10% of the adult population in the United States engages in excessive alcohol use, which has myriad negative personal and public health consequences. One reason why certain individuals develop disordered and excessive alcohol use may be that their brains’ reward system is primed to learn about cues that predict rewards and is especially sensitive to alcohol reward, such that these individuals lose the ability to control themselves when confronted with cues that their brain has learned are signals for alcohol. This project will begin develop different ways to measure this between-person difference in the laboratory and test if these laboratory measures can predict changes in problematic alcohol use over time.