PROJECT SUMMARY/ABSTRACT: Major depressive disorder (MDD) is a leading cause of disability worldwide with a paucity of personalized, efficacious treatments. Life stressors have long been shown to potently predict depressive symptomatology and onset of major depressive episodes. Despite this, the neurobiological mechanisms underlying stress regulation in depression are not yet fully understood in humans. Preclinical and initial human studies implicate kappa-opioid receptor (KOR) deficits in the pathogenesis of MDD and suggest that stress reactivity might contribute to these KOR deficits. The innovative study proposed in this K01 represents a first step to determine if KOR binding deficits and heightened dynorphin/KOR-mediated stress reactivity are observed in MDD relative to healthy controls (HCs). If shown to be so, then the second step will be to determine whether these deficits represent a state effect that it is present in currently depressed and not in euthymic subjects with MDD or a trait effect present in both currently depressed and remitted MDD (to be tested in a follow-up R01). Therefore, we seek to evaluate KOR binding at rest and endogenous dynorphin release to a laboratory stressor in unmedicated, currently depressed participants with MDD vs. HCs. KOR binding and dynorphin release will be quantified in vivo in humans with functional positron emission tomography (PET) with the new tracer [11C]EKAP, already reliably synthesized and used in rodents at the Columbia PET Center, that targets KOR with high sensitivity and specificity. A brief, validated stress task with physiologic and psychologic components will be given during the PET scan that elicits hypothalamic-pituitary-adrenal (HPA) axis activation. Physiologic markers of HPA activation will be acquired proximal to the task, e.g., cortisol, to be compared with KOR binding at rest and stress-induced endogenous dynorphin release in MDD vs. HCs. Further, the Principal Investigator’s (PI) preliminary studies suggest that smartphone-administered ecological momentary assessment (EMA) of daily stressors is greater in depressed relative to control participants and has distinct structural and functional neural correlates. In this study, EMA of daily stressors will be acquired and evaluated to determine if daily stress preceding the PET scan, as well as preceding a structural magnetic resonance imaging (MRI) scan, modulate brain structure, KOR binding, and stress-induced endogenous dynorphin release in depression. This will be the first study to investigate KOR’s role in stress-reactivity in vivo in MDD, and will combine multimodal neuroimaging, peripheral markers of HPA activation, and EMA daily stress. Regardless of the outcome of this study, it will increase our understanding of KOR’s role in MDD and in dysregulated stress reactivity in MDD, potentially suggesting KOR-regulated, stress-sensitive depression subtypes. This award will measurably advance the PI’s training in conducting highly i...