Decoding depression: stress-derived formaldehyde initiates depressive symptoms in mouse and human

Stress is a high-risk factor for major depressive disorder (MDD) with hippocampal damage and monoamine deficiency. Surprisingly, the administration of gaseous or aqueous formaldehyde (FA) causes depressive symptoms in both animals and humans, though whether endogenous FA induces depression is unclear. Here, we report that stress-derived FA promotes depression onset. In this study, endogenous FA concentrations in mice and human induced by acute or chronic stress were quantified by a FA-sensitive fluorescence probe. Acute infusion and chronic FA injection were used to mimic depressive behaviors in mice under chronic unpredictable mild stress (CUMS). Patch clamp recorded FA-inhibited hippocampal CA1 discharges, while mass spectrometry and spectrophotometry examined FA-inactivated monoamine. The software of magnetic resonance imaging (MRI) was used to quantify hippocampal CA1 atrophy in adolescents with MDD. Biochemical tests were applied for evaluating the link between FA levels and depression severity in MDD patients. Various bioinformatics methods were used to explore FA's connection to depression-related pathways. Metabolomics data from MENDA were used to identify FA accumulation and monoamine deficiency in depression models and MDD patients. Our results showed that in cellular and mouse models, glutamic acid and both acute and chronic stress triggered FA production in hippocampal CA1 neurons. Excessive FA indued depressive behaviors due to FA buildup and decreased serotonin, dopamine, and melatonin levels in the extracellular space. Especially, excessive FA deactivated these monoamines, damaged hippocampal CA1 structure, and reduced neuroexcitability. Remarkably, adolescent MDD patients showed hippocampal CA1 atrophy and monoamine deficiencies, with blood FA levels predicting depression severity. These findings suggest that stress-derived FA serves as a critical trigger of depression by inactivating monoamines and impairing hippocampal CA1.