Regulation Of Adult Hippocampal Neurogenesis By Neural Activity:Critical Roles Of SFRP3 And Acetylcholine

In the adult mammalian brain, active neurogenesis occurs in the subgranular zone(SGZ) of the dentate gyrus. Radial glia-like precursors(RGLs) within the SGZ serve as one type of quiescent neural stem cell and continuously give rise to both dentate granule neurons and astrocytes in the adult mouse dentate gyrus. Adult hippocampal neurogenesis proceeds concurrently with the ongoing activity of existing neuronal circuits and is regulated by many physiological and pathological stimuli. However, the niche mechanism underlying the activity-dependent modulation of adult hippocampal neurogenesis remains largely unknown.We found a activity-dependent niche regulator of adult neurogenesis by performing RNA-sequencing(RNA-seq) analysis. We reported that electroconvulsive stimulation(ECS)as well as exercise and direct neuronal stimulation, via optogenetic activation decreased the expression of secreted frizzled-related protein 3(sFRP3), a naturally secreted Wnt inhibitor highly expressed by adult dentate gyrus granule neurons. Adult knockdown of sFRP3 via lentiviral injection of shRNA in the dentate gyrus resulted in increased Wnt signaling and neural progenitor proliferation. We then generated sFRP3knockout(KO) mice, and observed that sfrp3 deletion activated quiescent radial neural stem cells and promoted newborn neuron maturation in the adult mouse hippocampus.In addition, ECS and exercise-induced increase of progenitor proliferation appeared to be attenuated in sFRP3 knockout mice. These data suggested that sFRP3 regulated multiple phases of adult hippocampal neurogenesis and at least in part, mediated activity-induced neurogenesis in the adult dentate gyrus.Besides, we investigated the effect of cholinergic projections from medial septum and diagonal band of Broca(MSDB) on neural stem cells. We found cholinergic projection terminals are closely associated with PV interneuron terminals in the adult dentate gyrus. Functionally, the calcium imaging analysis demonstrated that neurotransmitter ACh reduced calcium levels of GCaMP-expressing PV interneurons.We are investigating whether optogenetic suppression of cholinergic neurons suppresses the activation of quiescent radial glia-like cells(RGL), an opposite effect from suppression of local PV interneurons. Our model is that long-distance cholinergicneuronal activity may exert an indirect effect on adult neurogenesis through inhibiting the local PV interneuron activity.Here we focused our study on two major types of molecular mediators for activity dependent adult neurogenesis: a secreted protein from hippocampus local neural circuit--sFRP3 and a neurotransmitter from long-distance neural projection--acetylcholine. Our study provided future insights into understanding the function of adult hippocampal neurogenesis.