Activation of the kynurenine pathway and mitochondrial respiration to face allostatic load in a double-hit model of stress

Allostasis is the process by which the body's physiological systems adapt to environmental changes. Chronic stress increases the allostatic load to the body, producing wear and tear that could, over time, become pathological. In this study, young adult male Wistar Kyoto rats were exposed to an unpredictable chronic mild stress (uCMS) protocol to increase allostatic load. First, physiological systems which may be affected by extended uCMS exposure were assessed. Secondly, 5 weeks of uCMS were used to investigate early adaptations in the previously selected systems. Adverse experiences during developmentally sensitive periods like adolescence are known to severely alter the individual stress vulnerability with long-lasting effects. To elucidate how early life adversity impacts stress reactivity in adulthood, an additional group with juvenile single-housing (JSH) prior to uCMS was included in the second cohort. The aim of this work was to assess the impact of chronic stress with or without adversity during adolescence on two domains known to be impacted in numerous stress-related disorders: mitochondria! energy metabolism and the immune system. Both, uCMS and adolescence stress increased kynurenine and kynurenic acid in plasma, suggesting a protective, anti-oxidant response from the kynurenine pathway. Furthermore, uCMS resulted in a down-regulation of immediate early gene expression in the prefrontal cortex and hippocampus, while only rats with the double-hit of adolescent stress and uCMS demonstrated increased mitochondria! activity in the hippocampus. These results suggest that early life adversity may impact on allostatic load by increasing energetic requirements in the brain.