Project Portugal 2030

Summary

Childhood exposure to adversity, in the form of abuse or neglect, is the most common and preventable cause of abnormal brain development (1) and constitutes a significant risk factor for childhood psychiatric disorders (2), which often progress to life-long chronic psychiatric and medical conditions. Despite our growing awareness of this problem, precisely how ELS causes such diverse and disabling clinical outcomes is not well understood. Therefore, there is an urgent need for research directly exploring the molecular and cellular mechanisms underlying the impact of ELS on mental health. Given that many mental disorders have been associated with changes in the microbiome and immune system, our current hypothesis, which we plan to explore in this project, is that ELS can trigger changes in the levels of circulating cytokines, sexual hormones, and microbiome-derived metabolites that will directly impact the brain, particularly during sensitive periods of neurodevelopment. These vulnerability intervals, which include early childhood, largely overlap with periods of intense microglia-mediated refinement of specific neuronal circuits and development of hub regions and myelin tracts, which are critical for the establishment of secure attachment, adult personality, and emotional control. Therefore, it stands to reason that preventive interventions focusing on these periods may be more effective and produce longer-lasting results. In this context, we propose to test dietary supplementation approaches, designed to decrease stress-induced dysbiosis and to reduce both systemic and local inflammation in ELS models, to understand to what extent they can constitute novel promising approaches for universal prevention in mental health. Another relevant issue that we plan to address is related to the pathways through which sex modulates the outcomes of ELS. Although it has been observed that early differences in the levels of sexual hormones translate into disparities in microglia number and activity between males and females, as well as in different behavioral outcomes following ELS, very few studies have addressed the link between the observed sexual dysmorphisms and brain wiring and physiology. However, we believe that the clear sex bias associated with several of the most prevalent neurodevelopmental and neuropsychiatric disorders is unarguably the best reason to focus our research on exploring the intrinsic and ELS-triggered sex differences in neuroimmune parameters. By addressing this issue, we will undoubtedly gain important insights into the pathophysiology of these conditions, which may also have significant treatment implications. Taking all this into consideration, we can summarize the main goals of this proposal as follows: 1) identify fundamental sex-dependent structural and functional differences in cognitive and emotion-related brain circuits and clarify how they influence behavioral outcomes following different types of ELS; 2) understand how ELS exposure impacts circulating microbiome-derived metabolites, sexual hormones and inflammatory cytokines and how, in turn, these molecules contribute to microglia maturation/function during early childhood and adolescence; 3) recognize what are the local and systemic triggers of microglia dysfunction following ELS and 4) validate the potential of anti-inflammatory nutrition-based approaches to reduce ELS-associated microbiome and neuroimmune changes and avoid ELS-triggered behavior outcomes.