Validation of the Targeted Metabolomic Pathway in the Hippocampus and Comparative Analysis with the Prefrontal Cortex of Social Defeat Model Mice.

The proportion of major depressive disorder (MDD) patients around the world has increased remarkably. Although many studies of MDD have been conducted based on classic hypotheses, like alteration of the hypothalamic-pituitary-adrenal axis or monoamine neurotransmitters, the mechanisms underlying MDD remain unclear. Aiming to further investigate the mechanisms of MDD, liquid chromatography-tandem mass spectrometry was employed to measure target metabolites in the hippocampus (HIPPO) of chronic social defeat stress model mice. Compared with control mice, stress-susceptible mice showed a reduction of 5-hydroxyindoleacetic acid and kynurenic acid in the tryptophan pathway, and an increased level of dopamine in the catecholamine pathway, while stress-resilient mice displayed a reduction of 5-hydroxytryptamine in the tryptophan pathway. The altered levels of key molecules related to the tryptophan or dopamine metabolic pathways were validated by real-time quantitative polymerase chain reaction or western blotting. Comparative analysis with previous targeted metabolomics results in the prefrontal cortex (PFC) of chronic social defeat stress mice revealed that the altered metabolites manifested in specific brain areas, and only the dopamine metabolic pathway was perturbed in both the HIPPO and PFC after stress. Additionally, correlation analysis validated that levels of kynurenic acid in the HIPPO, along with glutamic acid, L-3, 4-dihydroxyphenylalanine, and vanillylmandelic acid in the PFC, were correlated with depression-like behaviors. This study provides a unique perspective on the potential molecular mechanisms of stress susceptibility and stress resilience.