Metabolic stress-response in female rats: b-oxidation-induced vulnerability vs adaptive resilie

Major depressive disorder (MDD) is characterized by substantial sex differences in its prevalence, with women having double the risk of experiencing 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 the last years we demonstrated that the different susceptibility to develop a depressive-like behavior in adult male rats was associated with different metabolic and energetic strategies to face with stress in the ventral hippocampus (vHip). In this study, for the first time we investigated in adult female rats the contribution of brain metabolism in the vulnerability and resilience to chronic stress exposure. To this aim, adult female Wistar Han rats were exposed to 6-weeks of chronic mild stress (CMS) and sucrose consumption test was performed at weekly intervals to discriminate between vulnerable (rats showing an anhedonic-like behavior) and resilient (rats not showing an anhedonic-like behavior). 24 hours after the last stressor rats were sacrificed and vHip was dissected for the targeted metabolomic analysis. Data were analyzed with the one-way ANOVA followed by Tukey multiple comparison test. From a behavioral standpoint, one-way ANOVA with repeated measures showed a significant effect of CMS (F2-16=14.85, p<0.001) and of CMS X week (F12-6=3.99, p<0.001) on sucrose intake, with vulnerable animals showing a significant reduction of sucrose intake (week 6: -9,7g, p<0.001 vs No stress/same week). At metabolic level, Partial Least Squares Discriminant Analysis revealed a different metabolic profile between unstressed and stressed animals, with further separation among CMS vul and CMS res groups. Indeed, we observed that the anhedonic like behavior, was associated to changes in several metabolic pathways, among which it was evident the enhancement of fatty acid  -oxidation. Accordingly, we found a significant increase of the C2/C0 ratio (+52%, p<0.05), a commonly used marker of fatty acid β-oxidation activity, and of the sum of short-chain acylcarnitines (+55%, p<0.05) in CMS vul compared to No stress group. Moreover, the enhancement of C5/(leu+ile+val) ratio (+30%, p<0.05) in CMS vul vs No stress animals suggested an alteration in branched-chain amino acids catabolism. Differently to what we previously observed in male (Brivio et al. 2023), resilient female rats came off as being more resistant to the adverse effects of stress since they did not activate any specific metabolic pathway to sustain resilience. Taken together, our findings indicate that vulnerable female rats preferentially use fatty acids in the vHip as a primary energy source, in line with our recent findings in males exposed to the same experimental protocol. These results reinforce the importance of pursuing the study of sex-specific molecular mechanisms characterizing the gender gap in developing depression.