Rethinking resilience to stress as floating between a stable state and a veiled vulnerability: focus on the metabolic plasticity in the rat ventral hippocampu

The consequences of stress exposure on the brain are not unique, indeed it can cope with stress and activate adaptive mechanisms and resilience or can be damaged by persistent negative stimuli thus resulting in vulnerability to stress-related disorders. Moreover, a previous history of chronic stress can alter the response to novel stressor by opening a window of plasticity. Brain metabolism is a fundamental process involved in the maintenance of the main higher functions in humans and an imbalance of bioenergetics has been observed in patients with depression. Because we observed that chronic mild stress (CMS) exposure differently affected bioenergetics in the ventral hippocampus of vulnerable and resilient animals, with the latter preferring glycolysis over -oxidation to sustain energy demand, here we studied whether the energetic strategy set in motion to foster resilience is a stable trait or veils a feature of vulnerability when challenged by a novel and unexpected event. Sucrose consumption test (SCT) was performed to discriminate among vulnerable (rats showing an anhedonic-like behavior) and resilient (rats not showing an anhedonic-like behavior) adult male Wistar rats exposed to 6-weeks of CMS. At the end, half of the rats were exposed to 1 hour of acute restrain stress (ARS) and sacrificed 1 hour later whereas the other half was sacrificed 24 hours after the last stressor. Ventral hippocampus (vHip) was dissected for the targeted metabolomic analysis. Data were analyzed with the two-way ANOVA followed by Tukey multiple comparison test. Two-way ANOVA with repeated measures showed a significant effect of stress on sucrose intake (F2-44=62.9, p<0.001) with vulnerable animals showing a significant reduction of sucrose intake (week6: -7.49g, p<0.001 vs No stress/same week). Considering the major classes of metabolites investigated, two-way ANOVA revealed a significant effect of CMS X ARS interaction on the class of amino acids (AA) (F2-44=3.15, p=0.05), of glycolysis CMS X ARS (F2-44=3.28, p<0.05) and of acylcarnitines (F2-44=9.83, p<0.001). Focusing on the effect of ARS on metabolites, Tukey multiple comparison test revealed that the AA Asp, Met and Trp were modulated by ARS specifically in the No stress group, whereas in resilient rats ARS led to decreased levels of the glycolysis intermediates and to an increase of many acylcarnitines. These results suggest that acute stress exposure negatively affects the vHip fuel utilization in rats resilient to 6 weeks of CMS. Indeed, while they increase glycolysis to sustain the non-hedonic phenotype when exposed to CMS, they shift to fatty acid -oxidation after ARS, as vulnerable animals did after CMS alone, suggesting that an unfamiliar stressor may change the energy strategy that sustains resilience. Strengthening resilience to foster individuals to bounce back from stressful life events may represent a strategy to decrease or prevent the risk of stress-related disorders.