PROJECT SUMMARY/ABSTRACT This proposal leverages recent advancements in translational neuroscience and represents a critical step in the effort to further our understanding of individual differences in addiction liability, one of the most challenging and important questions in substance use research. This question is particularly relevant during emerging adulthood because that is when risk factors and rates of substance use and substance use disorder are high relative to other age groups. One of the most well-validated models of addiction based on animal models, incentive-sensitization theory, holds great promise for elucidating individual differences in human addiction liability. Incentive-sensitization theory describes the process of reward-associated cues acquiring incentive salience, a mechanism that has been well-studied in animals with sign-/goal-tracking paradigms. These processes have not yet been well-characterized in humans at the neurobehavioral level, however. To address this need, the overall objectives in this mechanistic investigation are to further validate a human sign-/goal- tracking paradigm and identify neurobehavioral signatures of sign- and goal-tracking. Preclinical studies have identified differences between sign-tracking and goal-tracking animals in three key domains that are already well-established correlates of human substance use—reward responsivity, attentional control, and impulse control. The central hypothesis is that a stronger sign-tracking bias will be associated with a bottom-up processing style characterized by less adaptive attentional- and impulse-control as well as hyperactive reward processing, whereas a stronger goal-tracking bias will be associated with a top-down processing style characterized by strong attentional- and impulse-control as well as normative reward processing. 294 18–20- year-olds, in whom substance use is free to vary, will be recruited. At baseline, participants will be assessed for sign-/goal-tracking bias with an interactive Pavlovian conditioned approach task and undergo psychometric assessment and functional magnetic resonance imaging. The psychometric assessment will include measures of approach and avoidance, attention, and impulsivity. The neuroimaging protocol will comprise tasks probing sign-/goal-tracking, substance cue reactivity, sustained attention, and inhibitory control. Participants will also be assessed for substance use, problems, and diagnoses at baseline and every three months through the end of the study. This will allow for the delineation of associations between sign-/goal-tracking bias and: (1) trait constructs, (2) brain function, and (3) substance-related clinical outcomes. This innovative, mechanistic work will provide further validation of a translated human sign-/goal-tracking paradigm through delineation of trait, neural, and substance use correlates of sign- and goal-tracking. The long-term goal of this line of work is to identify early those who are at t...