Stress has important effects on brain functions inducing long-lasting effects on both cognition and emotions. On one hand, these effects depend on individual's ability to cope with stress, wherein coping is defined as the behavioral, psychological and physiological effort to master a stressful situation. Therefore, coping strategies are the major determinant of stress resilience or vulnerability. In general, resilient or hardy individuals use active coping strategies when facing stressful life experiences. The appraisal and development of stress-coping strategies is controlled by cortico-limbic areas. On the other hand, stress-coping behavior style depends on genetic, epigenetic and environmental factors. Among epigenetic modulators of gene expression, microRNAs (miRs) have emerged as key regulators of the neurobiological processes controlling the stress response. In particular, miRs belonging to the miR-34 family have been linked to pathogenesis of psychopathologies, including depression, characterized by alterations in coping strategies to stress. Thus, genetic differences in miR-34 expression may contribute to individual stress coping response, making circulating levels of this specific miR a useful biomarker for identifying vulnerable/resilient individuals. Accordingly, we have shown that down-regulation miR-34 expression is associated to resilience to the effects of stress and with a significant reduction of the prefrontal-cortex-amygdala neurochemical response in mouse.Using a translational approach, this project aims to investigate in the animal model and in healthy humans: i) whether individual differences in miR-34 expression are able to predict differences in behavioral response to stress, as determined by their cognitive performance following stress exposure; ii) the role of the prefrontal-cortex-amygdala circuit in mediating the relationship between individuals' coping style, their s¿ miR-34 expression and cognitive performance.
Stress exposure represents the most important risk factor for the expression of psychopathologic and cognitive outcome. Individual's ability to cope with stress is critical for setting vulnerability or resilience.
Individuals¿ coping strategy is a complex phenotype depending on a strong interaction between genetic, environmental and epigenetic factors. Among epigenetic factors, MicroRNAs (miRs), have been in recent years proposed to play a critical role due to their ability to act as modulators of expression of hundreds of genes, thus regulating various and important biological functions. They have been found to be important in the pathogenesis of several disorders related to stress and are emerging as diagnostic and prognostic biomarkers.
Based on this evidence, it is intriguing to speculate that miR may epigenetically regulate differences in coping strategies with the consequence of predisposing individuals to vulnerability or resilience to stress effects.
Non-coding RNAs have been found to be important in the pathogenesis of several disorders related to stress, so by offering the possibility to operate as diagnostic and prognostic biomarkers.
Using an innovative translational approach, this project aims to investigate the role of miRs-34 in mediating the stress coping style. We hypothesize that miR-34 levels could be a reliable biomarker to identify the preferential coping style to stress, and therefore act as a predictor of susceptibility or resilience to stress effects. The identification of predictors of resistance and vulnerability to stress effects would represent a very useful tool to an early assessment of risk factors, to planning and monitoring both pharmacological and psychotherapeutic interventions. This would significantly reduce the very high costs borne by the National Health System. Furthermore, by using evidence from the animal model to guide research on humans we plan to identify the contribution of prefrontal-amygdala network in mediating the ability to perform decisions under stress and link the role of this network to individuals¿ level of peripheral miR-34. This might indicate that cognitive mechanisms associated to stress coping may be tackled via non-invasive brain stimulation/modulation approaches.
According to the European guidelines dictated by the Horizon 2020 program, the objective of Social Challenge SC1 (Health, demographic change and well-being) consists to improve health and well-being throughout life. In particular, the specific objectives in the guidelines of Horizon 2020 are:
1) Effective health promotion to prevent disease, improve well-being with the objective of cost-efficiency.
2) Improve the decision-making process in terms of prevention and treatment offerings, to
aim to identify and support the dissemination of best practices in the health sectors and
assistance, as well as integrated forms of assistance through the use of innovations technology.
Thus, the present research program is part of the objectives and challenges proposed in Horizon 2020 program and will have the possibility of obtaining an important amount of data, both a preclinical and clinical level, regarding the important interaction between individual differences and environment. Based on this approach the research group plans to apply for external fundings and establish a stronger collaborations among the different specialties of the components.