A Cholinergic Signaling Pathway underlying Cortical Circuit Regulation of Lateral Ventricle Quiescent Neural Stem Cells

Neurogenesis and proliferation of neural stem cells (NSCs) in the subventricular zone (SVZ) are controlled by both intrinsic molecular pathways and extrinsic signaling cues, including neural circuits. One such circuit, the ACC-subep-ChAT+ circuit, has been identified as a regulator of ventral SVZ neurogenesis by modulating the proliferation of LV NSCs. However, the specific neural signals that promote the proliferation activity of LV NSCs have remained largely unknown. In this study, we uncover a molecular mechanism underlying the cellular activation and proliferation of quiescent NSCs (qNSCs) in the lateral ventricle SVZ (LV-SVZ) mediated by the cortical circuit. Our findings demonstrate that postnatal and adult LV qNSCs are triggered by the cortical circuit through ChAT+ neuron stimulation, consequently resulting in the activation of muscarinic 3 receptors (M3) expressed on LV qNSCs. This, in turn, triggers inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) activation, causing intracellular calcium release. Subsequently, the proliferation of LV qNSCs occurs through the downstream regulation of the calcium/calmodulin dependent protein kinase II delta (CAMK2D) and the MAPK10 signaling pathway. These findings shed light on the molecular regulatory mechanisms that govern LV qNSCs and emphasize the significant role of the cortical circuit in promoting their proliferative activation within the ventral LV-SVZ.