PROJECT SUMMARY Oral contraceptives (OCs), the most common type of hormonal contraceptives, are taken by more than 150 million people worldwide at any given time. For approximately 10% of users, OCs trigger severe mood-related adverse consequences, including depression and anxiety. The current project will use a mouse model to identify how OCs modulate the hypothalamic-pituitary-adrenal (HPA) axis and contribute to increased vulnerability – or resilience – to depression. A dysregulated stress response is a key aspect of depression, and there is consistent evidence that OCs blunt the HPA axis. Central mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) activity control the stress response via negative feedback loops. FK506-binding protein 51 (FKBP5) regulates the balance between MR and GR, and is expressed throughout the hypothalamus, an essential part of the stress response; and the hippocampus, which is implicated in the effects of stress on affective regulation and depression. Therefore, this project will determine changes in hypothalamic and hippocampal FKBP5, GR, and MR activity, their causal role in blunting systemic stress responses, and how stress and OCs interact in individuals at risk for depression. We will integrate biochemical, molecular, behavioral, and CRISPR/Cas9 genetic techniques to address these questions. The overall goal of this project is to systematically study the impact of OCs on specific psychological and physiological components of stress and depression using a mouse model of OC exposure. The central hypothesis of this project is that OC-triggered depression is caused by molecular changes that regulate the stress response, only in individuals with a pre-existing vulnerability to depression. At the end of this project, a molecular basis for more targeted interventions will be delineated to understand the mechanisms of OCs effects on the stress response and depression. This research can be applied directly to the improvement of contraceptives for all hormonal contraceptive users and will transform the understanding and treatment of OC-induced mental illness, including depression and anxiety. Furthermore, the current project will pave the way for a personalized approach for prescribing OCs to limit adverse effects and enhance benefits.