Neuropeptides Modulate Local Astrocytes to Regulate Adult Hippocampal Neural Stem Cells

Highlights

• Stimulating dentate CCK release promotes rNSC depolarization and proliferation

• CCK modulates local astrocytes to regulate rNSCs via glutamatergic gliotransmission

• CCK interneuron stimulation recruits GABAergic inputs onto excitatory neurons

• Reduced CCK induces reactive astrocytes and impairs neurogenic potential of rNSCs

Summary

Neural stem cells (NSCs) in the dentate gyrus (DG) reside in a specialized local niche that supports their neurogenic proliferation to produce adult-born neurons throughout life. How local niche cells interact at the circuit level to ensure continuous neurogenesis from NSCs remains unknown. Here we report the role of endogenous neuropeptide cholecystokinin (CCK), released from dentate CCK interneurons, in regulating neurogenic niche cells and NSCs. Specifically, stimulating CCK release supports neurogenic proliferation of NSCs through a dominant astrocyte-mediated glutamatergic signaling cascade. In contrast, reducing dentate CCK induces reactive astrocytes, which correlates with decreased neurogenic proliferation of NSCs and upregulation of genes involved in immune processes. Our findings provide novel circuit-based information on how CCK acts on local astrocytes to regulate the key behavior of adult NSCs.