Breakdown of the blood-brain barrier in depressed mice induced by chronic unpredictable mild stress

Background: Recent studies have suggested potential impairment of the blood-brain barrier (BBB) in depression. However, due to the limited research and variability in animal models, further investigation using diverse and stable models is necessary. Methods: A male mouse model of depression was established using the chronic unpredictable mild stress (CUMS) protocol. Following model establishment, depression-like behaviors were assessed using the sucrose preference test, tail suspension test, and forced swimming test. Morphological changes in the hippocampus were examined through hematoxylin-eosin staining. BBB permeability was evaluated using the Evans blue leakage test, fluorescein sodium (NaF) leakage test, and serum S100B content assessment. Gene and protein expression levels of BBB-related proteins in the hippocampus were determined via real-time PCR, western blotting, and immunofluorescence assays. Results: CUMS exposure induced depression-like behaviors, including reduced body weight gain, diminished sucrose preference, and prolonged immobility in both the tail suspension test and forced swimming test. While no significant pathological changes were observed in the hippocampus of either group, increased BBB permeability was noted in the CUMS group, as evidenced by enhanced NaF leakage into the brain parenchyma and elevated serum S100B levels. Gene expression analysis revealed downregulation of angiogenesis-related genes and tight junction proteins in the CUMS group. Additionally, protein levels of tight junction proteins Claudin-5 and ZO-1 were lower in the CUMS group compared to controls. Limitations: This study is limited to a male mouse model, and the BBB in females is worth exploring in the future. Conclusions: Increased BBB permeability and decreased expression of tight junction proteins Claudin5 and ZO-1 were observed in mice with CUMS-induced depression.