Early adversities are known to represent the major risk factor for psychopathologies expression, such as depression, when individuals are exposed to stressful conditions later in life. Stress-coping behavior style depends on genetic, epigenetic and environmental factors. Among epigenetic factors, 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.
Interestingly, recent studies suggested a link between altered peripheral miR-34a expression and adverse childhood experiences in depressed.
Based on these premises, using a translational approach here we propose miR-34 as an objective, reliable peripheral biological marker of risk to develop a depression-like phenotype (inducing a preferential passive coping style) in adult mice previously exposed to Early-life Adversity. Moreover, using an innovative pharmacological approach we will try to prevent the behavioral consequences of early adversity.
Finally, we propose to translate our preclinical results to human by investigating peripheral miR-34 levels in individuals with a story of early adversities.
Exposure to an adverse environment during early life is reported to modulate sensitivity to future challenges, potentially producing dysfunctional coping responses and pathological outcomes. 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 pivotal 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 set individual stress coping response (O'Connor et al. 2012; Zurawek et al., 2016; Cohen et al., 2017) and to be important players in the pathogenesis of several disorders related to stress exposure. Based on this evidence, they are emerging as diagnostic and prognostic biomarkers to evaluate the impact of stressful events on the brain and to forecast preferential coping strategies used to cope with stressful events (Serafini et al., 2021).
The miR-34 family consists of three miRNAs: miR-34a, transcribed on human chromosome 1p36, and miR-34b/c, co-transcribed on human chromosome 11q23. The central role of this family in the regulation of stress response is suggested by the great number of miR-34 target genes that are associated with stress and mental disorders (Haramati et al., 2011; Andolina et al., 2016; 2018; Bavamian et al., 2015; Zhou et al., 2009; Bocchio-Chiavetto et al., 2013). In particular, miR-34 family has been linked to pathogenesis of psychopathologies, including depression, characterized by alterations in coping strategies to stress. Thus, 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 to personalized medicine aim of H2020 (https://ec.europa.eu/info/research-and-innovation/research-area/health-r...), unrevealing and manipulating this biological marker in our preclinical model and by translating the results in clinical field may help to develop suitable pharmacological treatment in order to prevent and/or reduce the risk of long-term psychological consequences of early adversities.
Using a translational approach, this project aims to investigate in our animal model of early adversity and in healthy humans exposed to early stress: i) whether peripheral differences (which reflect brain levels) in miR-34 expression are able to forecast coping stress style (in human) and stress-induced depression-like phenotype (in animals); ii) whether interfering with miR-34 increase (by a cutting-edge pharmacological treatment) in our animal model of early stress is possible to prevent the adult pathological outcomes.
Another innovative aspect of this project is the use of ANN for the identification of prognostic biomarkers, an approach that could have the advantage to unveil potential non-linear relationships between the levels of miRNA and those of many psychological measures.