EXPOSURE TO STRESS EARLY IN LIFE AND ENHANCED RISK TO DEVELOP MOOD AND METABOLIC DISORDERS LATER IN LIFE: IDENTIFICATION OF THE COMMON PERIPHERAL AND CENTRAL MECHANISMS

The intricate relationship between mental and physical health, particularly the co-occurrence of psychiatric disorders and metabolic conditions, has become a focus of recent research. Early-life stress (ELS) is recognized as a key factor that heightens the risk of developing mood and metabolic disorders, often resulting in comorbidities during adolescence and adulthood. This study investigates the role of ELS in contributing to psycho-metabolic comorbidities, with a focus on disruptions in the brain-liver axis, which is crucial for regulating metabolic and inflammatory processes. Using a rat model of prenatal stress (PNS), we explored five biological questions. First, we examined whether dysregulation of the inflammatory state within the brain-liver axis could mediate vulnerability to PNS exposure in adolescence by assessing microglial activation and pro-inflammatory cytokine expression in the dorsal and ventral hippocampus and liver, focusing on leptin's role in inflammation. We found strong microglia activation in the dorsal hippocampus of animals vulnerable to PNS exposure, along with increased transcription of pro- inflammatory markers in the liver. Moreover, an upregulation of leptin receptor expression was found in the same animals and it correlates with the inflammatory status in the liver. Second, we explored other biological mechanisms involved in PNS-induced vulnerability in adulthood, investigating disruptions in the hypothalamic-pituitary-adrenal (HPA) axis and metabolic functions and identifying candidate genes associated with psycho-metabolic comorbidities. Vulnerable males showed more pronounced metabolic issues, including weight loss, inflammation and insulin resistance, as well as upregulation of stress-related markers (FoxO1, 11β- HSD1) in the brain and liver. In contrast, resilient males demonstrated better metabolic and anti-inflammatory responses, such as increased ADIPOR1 and IL4R expression, indicating effective stress management. Additionally, the liver of vulnerable males exhibited upregulated insulin and leptin signaling, alongside decreased glucocorticoid receptor expression, linking stress response to metabolic dysregulation. Third, we assessed potential sex differences in central and peripheral responses to PNS, considering the different developmental trajectories of mood and metabolic disorders in males and females. Females do not respond to PNS exposure in the same way as males; a less pronounced effect was observed, at least in the systems analyzed. This difference in stress response could be attributed to sex hormones and their ability to buffer stress consequences. Fourth, we investigated whether PNS leads to common molecular alterations in the liver and brain of male adult offspring by conducting transcriptomic analyses to identify commonly altered differentially expressed genes and modulated pathways. Molecular analyses showed that vulnerable animals had significant disruptions in neurotransmission and inflammatory signaling pathways, particularly downregulation of CREB signaling, which is crucial for memory and synaptic plasticity. This may contribute to cognitive and behavioral vulnerabilities, such as depression-like symptoms. Lastly, we evaluated the long-term metabolic impact of PNS by analyzing glucose metabolism and plasma biomarkers, hypothesizing potential dysregulation in PNS-exposed animals. PNS-exposed animals showed different glycemic levels after glucose or insulin injection, indicating a possible dysregulation in the insulin system and in glucose metabolism. Moreover, levels of metabolic hormones in plasma of PNS exposed animals, such as leptin, insulin, ghrelin and incretins, were significantly different compared to controls. Taken together, these results could suggest a possible dysregulation of insulin signaling and glucose metabolism, hallmark of metabolic syndrome. Our findings shed light on the biological mechanisms linking ELS to increased vulnerability to psycho-metabolic comorbidities, underscoring the importance of the brain-liver axis as a critical mediator. Overall, the study highlights the central role of inflammation in the comorbidity of mental and physical health conditions following early life stress and underscores the importance of sex-specific approaches in understanding and addressing these vulnerabilities.