Early life stress and psychopathology: unraveling the mechanisms of vulnerability and resilience

Several lines of evidence have shown that adverse experiences early in life, especially in the prenatal period, but also in childhood, can induce long-lasting modifications of physiological functions, which may result in embedded biological traces determining an increased vulnerability to the development of psychiatric conditions. However, there are important qualitative and quantitative differences in the outcome of early life stress (ELS). Indeed, some individuals exposed to ELS are susceptible and develop a pathological condition, while others appear to be resilient. Interestingly, a sub-set of the early stressed individuals may develop a psychiatric condition only if re-exposed to a second stressful event. Importantly, a stress-induced full-blown condition is often observed in the period of transition from adolescence to adulthood, being this time window a crucial period for negative outcomes, but also an important phase for preventive interventions. In this scenario, major challenges concern the identification of molecular pathways underlying the development of vulnerable or resilient states following ELS, the definition of specific mechanisms leading to the development of a vulnerable state in previously resilient subjects and the identification of specific strategies to normalize the pathological condition induced by the stressful event. Given the ethical and time-related limitations of human studies aimed to solve these challenges, animal models represent unique tools of investigation, allowing both a detailed characterization of stress exposure-induced alterations and the observation, in a reasonable amount of time, of long-lasting modifications caused by adverse experiences. On these bases, the main aims of this project will be to identify mechanisms mediating the development of vulnerability or resilience to ELS, to investigate the persistence of alterations induced by ELS, to evaluate if ELS exposure may predispose to psychopathological states in adulthood following a second traumatic experience and, finally, to analyze the impact of pharmacological and non-pharmacological strategies aimed to prevent or counteract the effects of ELS exposure. To address these aims, we will use a prenatal stress model (PNS) obtained by exposing pregnant females to a stressful condition during the last week of gestation. We will then perform specific behavioral (to assess anhedonia, emotional and cognitive functions), functional (related to neuroendocrine neurochemical and redox state maintenance functions) and molecular investigations (genome-wide analysis, molecular markers related to neuroplasticity, neuroinflammation and oxidative stress), to identify vulnerable or resilient subjects in the obtained litters (both males and females). After the initial phenotyping at adolescence, a subset of PNS-exposed animals will be grown until adulthood, in order to assess possible long-term consequences of exposure to PNS (rats, vulnerable at adolescence, with persistent pathological phenotype into adulthood; rats, resilient at adolescence, that develop their alterations only at adulthood or rats resilient both at adolescence and adulthood). While the initial studies will be carried out in male and female progeny, we will next focus on one gender to address further questions related to PNS exposure. Indeed, using a new batch of rats, we will identify animals resilient to PNS, which will be exposed to different types of stressors in order to establish if, despite the initial resilience, they will be more ‘vulnerable’ to the second hit. Moreover, we will also try to establish if the functional consequences of the second hit will depend on the type and timing of stress/trauma to which the animals will be exposed. Finally, we will evaluate the effects of pharmacologic (modulation of endocannabinoid system, supplementation with the antioxidant compound N-acetylcysteine and treatment with the antid