Changes in brain metabolites related to stress resilience: Metabolomic analysis of the hippocampus in a rat model of depression

The ability to cope successfully with stress is known as 'resilience', and those with resilience are not prone to developing depression. One preclinical animal model for depression is the chronic mild stress (CMS) model. There are CMS-resilient (do not manifest anhedonia) and CMS-susceptible (manifest anhedonia) rats. This study aimed to investigate the differences in the profiles of hippocampal metabolites between susceptible and resilient rats, and to identify a biomarker that can distinguish the two. We divided stress-loaded rats into susceptible and resilient types based on their sucrose preference values. We then conducted brain-derived neurotrophic factor (BDNF) quantification and metabolomic analysis in the hippocampus. Compared to the controls, no significant differences were observed in the hippocampal BDNF levels of susceptible and resilient rats. However, the control rats were clearly distinguishable from the susceptible rats in terms of their brain metabolite profiles; the control rats were difficult to distinguish from the resilient rats. CMS model rats showed an increase in the levels of N-acetylaspartate and glutamate, and a decrease in the levels of aspartate and gamma-aminobutyric acid in the hippocampus. Of the 12 metabolites measured in the present study, N-acetylaspartate was the only one that could differentiate the three types (control, susceptible, and resilient) of rats. Thus, brain metabolomic analyses can not only distinguish CMS model rats from control rats, but also indicate stress susceptibility. The variation in the levels of N-acetylaspartate in the hippocampus of control, resilient, and susceptible rats demonstrated that it could be a biomarker for stress susceptibility.