Hilar mossy cell oxytocin receptor signaling regulates adult hippocampal neurogenesis and context discrimination in mice

Background: Neurogenesis is a crucial form of neuroplasticity in the adult mammalian brain. Hilar mossy cells (MCs) in the dentate gyrus show a uniquely high expression of oxytocin receptors (OXTRs) and are implicated in the regulation of adult hippocampal neurogenesis (AHN). However, it remains unclear whether MCs contribute to regulating AHN through OXTR signaling. Here, we sought to investigate whether the loss of MC OXTR signaling may affect AHN and its related cognitive function. Methods: We used a calcitonin receptor-like receptor (Crlr)-Cre mouse line to selectively remove Oxtrin MCs. 5-Bromo-2'-deoxyuridinelabeling, immunofluorescence staining, and retrovirus-mediated strategies were used to trace newborn cells. The contextual fear discrimination task was employed to evaluate learning and memory functions mediated by AHN. Results: We found that conditional deletion of MC Oxtrleads to impaired AHN by reducing the proliferation, differentiation, survival, and maturation of neural stem/progenitor cells (NSPCs). MC Oxtr deletion reduces cell cycle re-entry and promotes cell cycle exit and death of NSPCs. Furthermore, MC Oxtr deletion results in the reduction of type 1, type 2b, and type 3 NSPC populations. By using a retrovirus-mediated birthdating and cell labeling approach, we demonstrate that the deletion of MC Oxtr retards dendritic development without affecting the migration or positioning of newly generated dentate granule cells. Functionally, MC OXTR-deficient mice exhibited impaired performance in the contextual fear discrimination task, indicating impaired fear memory specificity. Conclusions: These results uncover a previously unknown role of MC OXTR signaling in regulating the dynamic process of AHN and related context discrimination abilities.