PROJECT SUMMARY/ABSTRACT Extensive research has documented the physical and mental health benefits of social support, yet large swaths of the population experience social disconnection and do not derive these benefits. Roughly 73% of adolescents report they needed more emotional support than they received in the past year (1), and 39% of high school seniors describe themselves as lonely (2). The prevalence of loneliness has increased during the COVID-19 pandemic (3, 4), further highlighting the importance of understanding this phenomenon. Why are so many adolescents experiencing social disconnection? A key underlying process may be adolescents’ heightened biological stress reactivity (5), which can profoundly affect their social behavior. Taylor (6) theorized that the stress response can activate two primary social-behavioral profiles: (a) “fight-or-flight” (i.e., an increase in conflict or social withdrawal) or (b) “tend-and-befriend” (i.e., an increase in prosocial and affiliative behavior). This theory raises the possibility that the biological stress response activates behavioral repertoires that either increase social disconnection or facilitate social connection after stress exposure. However, most prior research testing Taylor’s model has been cross-sectional and with adults, creating a gap in our understanding of when and why these profiles emerge in development. Adolescence is a key period during which average rates of loneliness rise steeply, but we know little about why some youth respond to social challenges with socially distancing behaviors whereas other youth respond by strengthening their social connections. This project aims to fill these critical gaps by identifying the biological, personality, and relationship characteristics that differentiate these two social-behavioral stress response profiles. We hypothesize a vicious cycle whereby some youth who experience social disconnection will show heightened social-behavioral and physiological reactivity in response to social evaluation or social exclusion, which fosters further social disconnection. At a biological level, we propose this cycle is perpetuated by altered oxytocin, adrenocortical, autonomic, and inflammatory activity. We propose both a new data collection effort and secondary analyses of a rich existing longitudinal dataset to test the two aims of this project. This project will advance our understanding of the development of social disconnection in youth and the biobehavioral targets that can be modified to increase social connectedness in adolescence and beyond.