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Life sciences · Journal article
Theoretical and Natural Science · September 22, 2026
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Major depressive disorder (MDD) lacks objective neuroimaging biomarkers under DSM-5 and ICD-11 diagnostic criteria, while the ventral hippocampus-medial prefrontal cortex (vHipp-mPFC) circuit dominates reward processing and negative emotion regulation. The NIMH RDoC framework urgently requires circuit-level objective indicators for standardized mental illness assessment. This review systematically synthesizes peer-reviewed literature published between 2020 and 2025 and retrieved from PubMed and PMC, focusing on chronic unpredictable mild stress (CUMS)-induced structural and functional impairments of the vHipp–mPFC circuit. The included studies are organized around four experimental modalities: behavioral phenotyping, ex vivo immunofluorescence synaptic quantification, in vivo resting-state fMRI, and translational psychiatry analysis. Consistent results from existing validated studies confirm that CUMS treatment reduces vHipp-mPFC synaptic density by 28%-35% and lowers resting-state functional connectivity. And the degree of circuit impairment is positively correlated with depressive-like behaviors. This paper further discusses the inherent limitations of rodent CUMS models, defects of fMRI BOLD signals, and prominent translational gaps between preclinical and clinical research. Finally, it proposes a multimodal validation experiment using both male and female mice to address the sex bias and limitations of single‑modality detection in existing studies.