Metabolic stress-response in female rats: β-oxidation-induced vulnerability vs adaptive resilience

Major depressive disorder (MDD) is characterized by substantial sex differences in its prevalence, with women having double the risk to experience MDD compared to men. One of the major goals of research is to understand the sex-specific factors that confer vulnerability or resilience to stress, which represents one of the most prominent risk factors for MDD. In this study, we performed a targeted metabolomic analysis in the ventral hippocampus of adult vulnerable or resilient female rats to unravel metabolic differences underlying the different susceptibility to stress. From a behavioral standpoint, female rats started to develop anhedonic-like symptoms after 2 weeks of stress. Interestingly, we observed that the anhedonic like behavior, an indicator of vulnerability, was associated to several metabolic pathways, among which it is evident clearly the enhancement of fatty acid β-oxidation, a feature previously observed in vulnerable male rats. Conversely, resilient female rats seem to set in motion a metabolic adaptation, since they do not activate any specific metabolic pathway to sustain resilience, although enrichment pathway analysis highlighted the modulation of antioxidant and neuroprotective mechanisms specifically for the maintenance of resilience. Taken together, our findings indicate that the mechanisms underlying vulnerability in female rats are similar with those we previously observed in males, while those underlying resilience clearly differ. These results reinforce the importance of pursuing the study of sex-specific molecular mechanisms characterizing the gender gap in developing depression.