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

TL;DR

This study shows that oxytocin receptor signaling in hilar mossy cells affects adult hippocampal neurogenesis and context discrimination in mice.

Contribution

It identifies a novel role for oxytocin receptors in hilar mossy cells in regulating neurogenesis and cognitive function.

Findings

Conditional deletion of MC Oxtr impairs adult hippocampal neurogenesis by reducing NSPC populations.

MC Oxtr deletion reduces cell cycle re-entry and increases NSPC death.

OXTR-deficient mice show impaired contextual fear discrimination, indicating memory specificity deficits.

Abstract

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 regulate AHN through OXTR signaling. Here, we sought to investigate whether loss of MC OXTR signaling affects AHN and its associated cognitive function.

We used a calcitonin receptor-like receptor (Crlr)-Cre mouse line to selectively remove Oxtr in MCs. 5-Bromo-2'-deoxyuridine labeling, 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.

We found that conditional deletion of MC Oxtr impairs AHN by reducing the number, but not the rate, of 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 NSPC death. Furthermore, MC Oxtr deletion reduces the populations of type 1, type 2b, and type 3 NSPCs. Using a retrovirus-mediated birthdating and cell-labeling approach, we demonstrate that 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 a deficit in fear memory specificity.

These results uncover a previously unknown role for MC OXTR signaling in regulating the dynamic processes of AHN and context discrimination.

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