Early-age stress exposure and psychopathology development: vulnerability mechanisms and resilience

Stress is a general term describing the altered physiological response of humans or animals to any physical, emotional or mental request. Stress could be “acute”, if it occurs for a short time period, or “chronic” if it lasts for a long time, finally resulting in a maladaptive response with harmful effects on the body. In this context, several lines of evidence have shown that exposure to chronic stress, especially during early phases of life in which key neurodevelopmental steps occur, is significantly involved in the onset and progression of different psychiatric disorders, including psychosis. Moreover, it has been reported that psychotic patients frequently experience other mental disturbances, such as anxiety and depression. However, so far, mechanisms underlying psychosis comorbidities have not been clarified. Furthermore, while the detrimental effects of the exposure to stressful events during pregnancy have been extensively investigated, the impact of preconceptional chronic stress exposure on the offspring still remains unexplored. In this context, animal models of chronic stress- induced psychiatric disorders are very useful research tools. Here, we used an environmental animal model of chronic stress exposure, i.e. the rat social isolation model which has been widely described to induce behavioural, neurochemical, neuroendocrine, metabolic and biomolecular alterations reminiscent of what observed in psychotic patients. In particular, in the first part of this study we investigated whether exposure to social isolation from weaning (postnatal day-PND21) to young adulthood (PND70) could induce depressive- and anxiety-like behaviours, as well as neurochemical and neuroendocrine alterations in rats. In the second part of the study, we evaluated whether female exposure to social isolation before pregnancy could determine cognitive, neurochemical and redox-related dysfunctions in the offspring, reared, in its turn, in group or in isolation condition from PND21 to PND70. Results of the first part of the study showed that socially isolated rats developed a depressive-like behaviour, as demonstrated by the significant increase in the immobility frequency and the reduction of the swimming frequency in the forced swimming test. Moreover, exposure to social isolation also induced an anxious-like state, as evidenced in the elevated zero maze test by a significant decrease in the time spent in the open corridors and an enhanced time spent in the closed ones, and in the open field test by the elevation of the grooming time. Those behavioural alterations were accompanied by a significant decrease of noradrenaline (NA) and serotonin (5- HT) levels, as well as an increase of 5-HT turnover, in amygdala. Seven weeks of isolation also led to a reduction of gamma aminobutyric acid (GABA) amount and an elevation of glutamate (GLU) amount in amygdala and hippocampus. Following social isolation exposure, central neurochemical alterations also reflected at peripheral levels, with a significant increase of kynurenine and a reduction of 5-HT concentrations. Neurochemical alterations were accompanied by a decrease of plasmatic oxytocin, prolactin, ghrelin and melatonin amounts, while plasmatic levels of Neuropeptide S were not modified. Results of the second part of the study showed that the offspring of socially isolated females developed cognitive alterations, as evidenced in the novel object recognition test, where it was not able to discriminate between a familiar and a novel object, and in the passive avoidance task, in which it showed a significant reduction of the latency time. Behavioural dysfunctions were accompanied by increased NA levels and reduced 5-HT amounts in the prefrontal cortex. In this same area, a significant decrease of GABA levels was found, whereas no significant differences in GLU content were observed. Furthermore, chronic social stress exposure led to redox-related alterations in terms of cortical increase of reactive oxygen species amount, reduced expression of Nf-kB, NOX2 and NOX1, as well as altered expression of antioxidant enzymes, such as SOD1 and CoQ10. In conclusion, our findings provide novel insights in the understanding of the neurochemical and neuroendocrine alterations underlying the comorbidity among different stress-induced neuropsychiatric disorders, such as psychosis, anxiety and depression. In addition to this, preconceptional exposure to chronic social stress might have a profound influence on the offspring neurodevelopment in terms of cognitive, neurochemical and redox-related alterations. Therefore, our results open new perspectives for targeted therapies acting on neurobiological pathways, also identifying specific time points for possible preventive and therapeutic strategies against chronic stress-induced neuropsychiatric disorders.