PROJECT SUMMARY Biological females develop psychotic disorders later than males. One leading theory that explains this phenomenon is the estrogen hypothesis, which proposes that rising estrogen during the pubertal period may impact mechanisms of psychosis onset until estrogens normatively decline (8-10 years later) and the risk for psychosis is unmasked. The premorbid psychosis period, during the transition from childhood to adolescence, is of high significance with regard to early mechanisms of psychosis as it marks a time where liability for psychosis interacts with hormonal and brain development while subtle psychosis symptoms, i.e., psychotic-like experiences (PLEs), emerge. This developmental period is also marked by the initiation and rising estrogen levels in biological females which has a powerful impact on the hippocampus- increasing volumes, connectivity, and improving hippocampal-related cognitive function- a region critically implicated in psychosis vulnerability and course. However, the estrogen hypothesis has never been examined longitudinally in the developmental context of the premorbid period. Instead, prior literature has often focused on late decreases in estrogen or retrospective accounts of puberty in individuals along the psychosis spectrum. As a result, many questions remain regarding the mechanisms of the estrogen hypothesis in adolescence. Individual variability in late childhood and early adolescent development provides a natural experiment for testing the mechanisms through which estrogen interacts with vulnerability to psychosis. This variability allows for the modeling of changes in estrogen (in terms of rising levels and menarche), brain structure and function, cognition, and course of symptoms both across and between biological females within their developmental context. This approach has significant potential to provide an entirely new perspective on our mechanistic understanding of psychosis. The proposed analyses will leverage the strengths of the ABCD study, capturing this rich variability in estrogen in late childhood and early coupled with critical neural, cognitive, and symptom longitudinally within biological females. This rich dataset will allow us to examine estrogen comprehensively within biological females and whether there is sex specificity to the impact of estrogen levels on PLEs by examining biological males for whom estrogen levels are available. Although not everyone with PLEs will transition to psychosis, these symptoms do reflect underlying psychosis vulnerability in the premorbid period, and tracking changes in PLE levels in the premorbid period may be informative in the early mechanism that may modulate vulnerability related to formal psychotic disorders as a function of adolescent development. Understanding the mechanisms of these estrogen effects within their developmental context will provide insights into how (structural, functional, cognitive, direct clinical impact), when (timing/developm...