– REJUVENATE

Childhood adversities have long-lasting consequences in terms of mental health and well-being, and, exposure to childhood adversities (Juvenile stress [JS]) significantly increases vulnerability to mood and anxiety disorders later in life. Yet, not all show an increased risk of adulthood psychopathology. Some individuals develop resilience, helping them to better cope with later life challenges. Our primary objectives
are (1) To elucidate mechanisms relating JS to vulnerability and resilience to stressful challenges in adulthood, and (2) To test the therapeutic/preventive potential of translational life-style interventions on the negative impact of JS later in life (i.e., boosting resilience). Our secondary objective is to systematically address sex-related differences in sensitivity, in related mechanisms underlying stress vulnerability or resilience, and in the effectiveness of life-style interventions for enhancing mental health resilience. Previous
findings and our preliminary data suggest that the modulation of hippocampal functioning along its ventral- dorsal axis plays a pivotal role in mediating vulnerability or resilience following JS. Results hint to alterations
of GABAergic functions, which alter excitability and immediate early gene expression, leading to alterations in memory-related engrams, and sleep patterns. We thus aim to test the following specific hypotheses: (i) JS leads to different behavioural and cognitive outcomes in resilient vs susceptible individuals. Resilience and vulnerability will be reflected in the molecular, cellular and network level process in a sex-dependent fashion. (ii) Life-style interventions can bias the outcome at the behavioural level, of JS towards resilience (intermittent fasting) or vulnerability (high-fat diet), by influencing the identified processes. The outcomes of life-style interventions are sex dependent. (iii) The long-term outcomes of JS and the effect of lifestyle interventions will be predicted by early neural and behavioural biomarkers (e.g., sleep patterns, spatial/social code in hippocampal units, maturation rate of performance in learning and social tasks). In this collaborative project,
we will team advanced expertise in behavioural neuroscience together with systems, cellular and molecular methodologies to comprehensively unravel the neural bases of the impact of JS on vulnerability and resilience later in life. We will establish multimodal predictive and descriptive biomarkers that can identify risk
and resilience outcomes of JS. Furthermore, we will examine the impact of life-style interventions, on behaviour and related mechanisms, with the aim of establishing such highly translational interventions as a
potential approach to enhance mental health resilience following JS exposure.