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

• Published in: Psychoneuroendocrinology 2019-09, Vol.107, p.148-159
• Main Authors: Nold, V., Sweatman, C., Karabatsiakis, A., Böck, C., Bretschneider, T., Lawless, N., Fundel-Clemens, K., Kolassa, I.-T., Allers, K.A.
• Format: Article
• Language: English
• Subjects: Adaptation, Physiological - physiology; Allostasis; Allostasis - physiology; Animals; Brain - metabolism; Cell Respiration - physiology; Chronic stress; Energy Metabolism - physiology; Hippocampus - metabolism; Immune system; Immunity - physiology; Kynurenine - metabolism; Kynurenine - physiology; Male; Mitochondria; Mitochondria - metabolism; Plasticity; Prefrontal Cortex - metabolism; Rats; Rats, Inbred WF; Stress, Physiological - physiology; Stress, Psychological - metabolism; Tryptophan catabolism
• ISSN: 0306-4530; 1873-3360
• DOI: 10.1016/j.psyneuen.2019.04.006

•The combination of juvenile single housing and unpredictable chronic mild stress increases the routine electron transport chain activity.•In the double-hit group of stress, mitochondrial respiration produces more energy via electron transport chain complex II than in controls and after uCMS alone.•Juvenile single housing activates the anti-oxidative side of tryptophan catabolism.•Unpredictable chronic mild stress reduces immediate early gene expression in the pre- frontal cortex and hippocampus.•After 5 weeks of uCMS, more immune cells are present in peripheral blood with a tendency to favor the innate over the adaptive immune system. 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: mitochondrial 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 mitochondrial activity in the hippocampus. These results suggest that early life adversity may impact on allostatic load by increasing energetic requirements in the brain.