Septo-dentate gyrus cholinergic circuits modulate function and morphogenesis of adult neural stem cells through granule cells in mice

Dentate gyrus (DG) is a critical structure for spatial memory and adult neurogenesis, and both processes are dynamically regulated by neural circuit activity. It remains unknown how neural circuits orchestrate the molecular landscape of the highly heterogeneous DG to regulate these distinct functions. Here we first report that activation of a cholinergic circuit from Diagonal Band of Broca to DG promotes both neural stem cell (NSC) activation and spatial memory. Furthermore, using single-nucleus RNA-sequencing of DG, we report broad transcriptomic changes across multiple types of mature and adult-born cells in response to cholinergic circuit activation. Notably, various neuronal populations exhibit abundant molecular changes that support synaptic functions crucial for spatial memory; while NSCs exhibit molecular changes that support their structural development and neurogenic proliferation. Interestingly, our electrophysiology and NicheNet analyses reveal granule cells, endothelial cells, and astrocytes as potential intermediaries for cholinergic activity-dependent NSC regulation. Our findings provide cell-type specific molecular mechanisms underlying cholinergic circuit activity-dependent regulation of distinct DG functions. Overall design: Single-nucleus RNA-seq (SPLiT-seq) of mouse dentate gyrus from stimulated (Chr2) and sham (yfp) stimulated animals. FASTQs represent two sublibraries comprised of cells from all 10 biological samples