STRESS EXPOSURE AS RISK FACTOR FOR PSYCHIATRIC DISORDERS: FROM FUNCTIONAL CHARACTERIZATION TO PHARMACOLOGICAL INTERVENTION

Stress response involves several mechanisms and mediators that allow individuals to adapt to a changing environment. The effects of stress may be adaptive or maladaptive, based on the timing and intensity of exposure as well as the individual vulnerability. Indeed, while acute stress induces the activation of the hypothalamic pituitary adrenal (HPA) axis to ensure the normal homeostasis and mediates adaptive reactions to cope with such challenges, chronic stress exposure has detrimental and long-lasting effects on brain functions. Actually, stress represents a major susceptibility element for psychiatric disorders and stressful life events are among the environmental factors that contribute to the etiology of major depressive disorder (MDD). However, there are differences in individual susceptibility to develop stress-related disorders, with some person displaying vulnerability to stressful event and others showing resistance to the same adversities. Moreover, it has to be considered that exposure to an adverse situation may leave a permanent \u2018scar\u2019 in the individual, which confer enhanced vulnerability for relapse. In this context, the overall goal of my studies was to characterize the effects of both chronic and acute stressors on adult male rats to better understand the behavioral outcomes of stressful events as well as the molecular changes that may sustain the pathologic phenotype emerging as a consequence of stress exposure. Furthermore, we investigated if the pharmacological treatment with lurasidone, a drug approved by the Food and Drug Administration for the treatment of different psychiatric conditions, may modulate the behavioral and molecular alterations induced by stress exposure. In particular, lurasidone acts, with high affinity, as antagonist of dopamine D2 receptor, serotonin 5-HT2A and 5-HT7 receptors, with moderate affinity as antagonist of adrenergic \uf0612Aand \uf0612C and as partial agonist of the HT1A receptors. Here, by employing the chronic mild stress (CMS) paradigm to induce a depressive like behavior in rodents, we identified two populations of stressed animals: one was susceptible to stress whereas the other was resilient to stress, in term of anhedonia. Moreover, independently from the vulnerable and resilient phenotype, we found that all stressed rats developed cognitive deficits. Among the mechanisms underlying the link between cognitive impairment and MDD, we found that the cognitive decline associated with stress exposure may be due to alterations in de-novo protein synthesis at synaptic levels. Interestingly, we highlighted the ability of the antipsychotic lurasidone to normalize not only the anhedonic phenotype, but also the cognitive impairment induced by the CMS paradigm. Furthermore, known that the function of the HPA axis is altered in psychiatric disorders, we provided evidence for the involvement of lurasidone in counteracting the molecular abnormalities induced by chronic stress on glucocorticoids receptor function and responsiveness. Additionally, considering that recently epigenetics have been well characterized as potential mechanisms by which environmental factors can lead to the development of different psychiatric disorders, we demonstrated that the chronic stress exposure had long lasting consequences on the HPA axis activity, by acting as modulators of the DNA methylation of key players of the glucocorticoid receptor signaling, and that lurasidone was able to counteract such abnormalities, suggesting that some of its long-term effects may also be related to epigenetic mechanisms. Subsequently, since a high percentage of depressant patients experience relapse after a period of recovery, we assessed differences in molecular responsiveness to a challenging event, in animals that were originally exposed to a chronic stress paradigm and had received the pharmacological treatment. In particular, we highlight the different ability of prefrontal cortex and dorsal hippocampus to cope with the new challenge, in terms of neuroplastic mechanisms, known to be involved in the adaptation of the brain structures to different demand, including environmental challenges. In addition, in the field of adaptive response to stress, we demonstrated that a single session of acute restraint stress was able to enhance the cognitive performance with a specific temporal profile, by inducing the activation of selected brain players involved in neuroplasticity, including the immediate early genes and the neurotrophic factor Brain Derived Neurotrophic Factor. These findings support the fundamental impact of stress exposure during adult life, highlighting its critical effect on systems and pathways through which stress can contribute to the development of stress related disorders. Furthermore, the ability of lurasidone to counteract stress-induced abnormalities provide support to the notion that drugs characterized by a multi receptor profile may be effective in counteracting different pathologic alterations and, speculatively, suggest that such compounds may hold a powerful indication for the treatment of different stress-related disorders