Efeitos de modelos experimentais de estressores precoces ao longo do desenvolvimento nos comportamentos ansiosos e na cognição

Abstract

Early life stress (ELS) exposure during sensitive periods of development has been discussed over the last decade as an environmental factor able to influence multiple brain developmental processes. ELS negative consequences and its influence over neurodevelopment could be observed through the emergence of different behavioral and cognitive phenotypes. Also, exposure to stress early in life is considered to be a risk factor to the development of different psychiatric disorders, such as Anxiety, Mood and Substance Related Disorders. Several molecular and neurobiological mechanisms have been investigated and pointed out as potential mediators for the behavioral changes and of the increased vulnerability in individuals to manifest psychiatric conditions later in life. Specific brain regions have become the focus of these investigations especially as they are extremely sensitive to stress effects. The prefrontal cortex, in this sense, appears as one of the key regions affected by stress effects, being involved in the pathophysiology of several of these disorders. Another important factor that has received special attention is the fact that not all individuals exposed to ELS respond in the same way. It is known that some individuals exposed to stressors are more prone to develop deleterious and negative effects in a long term, while a significant portion does not manifest negative effects. The investigation of possible mechanisms and factors responsible for leading to both vulnerable and resilience stress response became a thematic of studies in the field. However, it is still unclear which targets and central pathways are responsible for mediate distinct stress effects. For this reason, the current thesis aimed to investigate experimentally the ELS effects in different periods of developmental vulnerability, such as childhood and adolescence, on behavioral outcomes related to anxiety, cognitive functions related to working memory and recognition memory, as well as neuroendocrine stress response in adult male mice. In addition, we sought to investigate possible mechanisms underlying vulnerability and resilience to stress response through gene expression analyses in specific targets. For this, two different experimental studies were carried out based on ELS paradigms. The Study 1 aimed to investigate the ELS effects during childhood and adolescence, using a second hit model, on anxiety-like behaviors and on neuroendocrine stress response in adult mice. The Study 2 aimed to investigate the ELS effects, through maternal separation (MS), on the working memory and recognition memory and dopamine receptors gene expression in the medial prefrontal cortex (mPFC). Further to that, it sought to investigate possible differences in stress response through an experimental design that split stress responsive and non-responsive animals (vulnerable and resilient). Overall, our results revealed deleterious stress effects on behavioral and cognitive outcomes at different developmental periods. Study 1 showed, for example, pronounced adolescence stress effects on anxiety-like behaviors and neuroendocrine response. The second hit stress effects, in its turn, appears to induce a blunted response on these parameters in those animals exposed to childhood stress through MS. In the Study 2, we found working memory and recognition memory impairments in animals considered vulnerable to MS stress effects. Biomolecular changes in gene expression of specific targets in the mPFC region were found in both studies. GR and MR gene expression showed a significant cumulative effect of second hit model in Study 1, as observed by an increase in both gene expression parameters; while in Study 2 increased gene expression of dopaminergic receptors (DRD1 and DRD2) was observed in animals vulnerable to early stress effects. Based on our findings from both experimental studies, this thesis was able to conclude that ELS effects at different time-points of development have distinct effects, combined or isolated, on behavioral and gene expression outcomes. It suggests that specific developmental period and/or cumulative effects of repeated exposures are contributing factors to the variability in stress response. In addition, our results reinforce individual differences in stress response, which could point to potential mechanisms of vulnerability and resilience to ELS effects over the development.