Affective disorders result from a gene-environment interaction with stress as a risk factor that may precipitate their emergence. Every individual experiences stressful life events. In some cases acute or repeated stress leads to affective disorders, but most people are resilient to such effects. The ability to adapt during stress has a significant impact on the functional outcome and long-term health of each individual. However, there are only a few studies in humans focusing on adaptive and maladaptive response to stress. A number of human and animal studies have reported the physiological and behavioral effects of stress. Recent studies combining behavioural, molecular and electrophysiological techniques and the use of animal models reveal that stress may induce memory impairment, neuroplastic changes in specific neural circuits and at the cellular level drastic effects, including cell death. The study of the temporal order of stress-induced events at individual level requires diachronic approaches; thus, the use of longitudinal in vivo magnetic resonance imaging (MRI) combined to ex vivo characterization (molecular and imaging) becomes critical for the analysis of the neurobiology of stress. In this project, we plan to investigate changes in the function and structure of the brain that are associated to the normal and pathological response to repeated stress in two rat strains using multimodal in vivo and ex vivo MRI methods. Concomitantly, we will explore the potential correlations between the quantitative MRI parameters and molecular markers of stress and their differences between high and low stress-sensitive rat strains. Brain imaging data will be acquired at NeuroSpin on a Bruker PharmaScan 7T. Using a defined stress paradigm (Task 1), we will quantify the stress-associated changes on different MRI parameters: cerebral structure (Task 2), function (Task 3), white matter microstructure and connectivity (Task 4), and on molecular correlates (markers of functional and structural brain activity, inflammatory signalling) of these stress-induced changes in the brain (Task 5). This longitudinal design will be used to assess significant brain changes at different times of exposure to stress and between high and low stress-sensitive rat strains: 1) Comparison between baselines will provide biomarkers of vulnerability to stress; 2) Comparison before and after exposure to acute stress will provide biomarkers of acute stress effects 3) Comparison before and after exposure to repeated stress will provide biomarkers of habituation. This project is a collaboration between internationally known groups, one of which specialized in stress mechanisms systems-level translational research (Partner 1), the pathogenesis of stress-related brain disorders (Partner 2) and translational brain imaging (Partner 3). Investigating the neural circuits and molecular pathways of resilience will not only provide a tool for mechanistic investigation of neural systems but also potentiate MRI to in vivo monitor the response to stress in preclinical and clinical research. Understanding the mechanisms of resilience to stress will offer a crucial new dimension for the development of fundamentally novel treatments to the protection of stress effects.