Psychological stress induces depressive-like behavior associated with bone marrow-derived monocyte infiltration into the hippocampus independent of blood–brain barrier disruption

Abstract

Abstract Background Psychological stress is one of the most important factors that trigger emotional disorders, such as depression and anxiety. Emerging evidence suggests that neuroinflammation exacerbated by bidirectional communication between the peripheral immune system and the central nervous system facilitates abnormal psychiatric symptoms. This study aimed to investigate the hippocampal migration of bone marrow (BM)-derived monocytes and its role in regulating depressive-like behaviors using the chronic psychological stress (CPS) mouse model. More importantly, whether the central migration of these peripheral BM-derived cells depend on the disruption of the blood–brain barrier (BBB) was also investigated. Methods and findings Green fluorescent protein-positive (GFP+) BM chimeric mice were used to distinguish BM-derived monocytes within the brain. A CPS mouse model was established to explore the effect of CPS on hippocampal migration of BM-derived monocytes and its role in the regulation of depressive-like behaviors. The results revealed that BM-derived GFP+ cells accumulated in the hippocampus and differentiated into microglia-like cells after exposure to CPS. Interestingly, this migration was not associated with BBB disruption. Furthermore, treatment with C–C chemokine receptor 2 (CCR2) antagonist (RS102895) suppressed the recruitment of BM-derived monocytes to the hippocampus and alleviated depressive-like symptoms. Conclusion These findings indicate that monocyte recruitment to the hippocampus in response to psychological stress may represent a novel cellular mechanism that contributes to the development of depression.

Keywords

• Psychological stress
• Depression
• Bone marrow transplantation
• Monocytes
• Blood–brain barrier
• Hippocampus