The overarching goal of this translational project is to investigate the neurobehavioral responses to rewards and to acute stress as key neurobiological mechanisms underlying individual differences in the risk of developing depressive symptoms at different ages (young and older adults) after early life stress experiences (ELS), a well-documented environmental risk factor for psychopathology. We hypothesize that an imbalance between striatal sensitivity to reward and amygdala reactivity to stress may constitute a predictor for the development of psychopathological symptoms resp. for resilience. Our multi-modal project combines A) preclinical models of ELS and stress exposure on reward-related and depression-like behaviors in rats and mice (WP1), this will serve to as models for human behaviour; B) fMRI and EEG studies in human participants at risk, using existing datasets and cohorts of individuals exposed to ELS (such as the Mannheim Psychoepidemiological Center cohort, an accelerated cohort study of 700 children, juveniles and young adults with varying degrees of ELS exposure), and extending them with targeted data collection in young and older adults exposed to ELS (WP2), in combination with HPA axis, genetic, and ecological momentary assessment measures; C) Studies in a sample of currently depressed participants (WP3); and D) computational analysis of brain network properties using fMRI and EEG data collected under WP2 and WP3, to unravel their relation to different stress measures (WP4), and ultimately lead to a common FAIR database to probe our overarching hypotheses using large-scale analyses (WP5). This multi-modal translational approach combining neurobiological, behavioral, genetic and neuro-endocrine data, and measures from everyday life to increase ecological validity, is highly innovative and brings a bench-to bedside methodology with direct clinical implications. Targeting specific and well-defined mechanisms of interest will support the identification of biomarkers and advance towards a transdiagnostic and dimensional approach of psychopathology, making it possible to transfer our framework to other mental disorders. We expect our project to lead to the identification of evidence-based behavioral markers. Such biomarkers should be easily accessible and transferable in clinical settings. Creating a database with large samples of individuals at risk and individuals with current depression will allow defining norms for behavioral results and increase their interest for clinical use. And the creation of a FAIR database specific for ELS available in open-access after the end of project will be an important deliverable. The introduction of a developmental, life-time perspective is cutting-edge, especially in the context of ELS and depression, and we strongly believe that it will yield major advances in the understanding of depression in a life-long perspective, sparkling important new insight for the understanding of late-life depression and the long-term effects of ELS. Our consortium includes a very strong and multidisciplinary group of investigators with excellent research and publication records. We are therefore convinced that our project will lead to major high-impact publications on neurobiological mechanisms of vulnerability and resilience in mental health, and thus pave the way to novel clinical perspectives in the management of patients
