The Mechanism Study Of Septohippocampal Gabaergic Projections Regulating Adult Hippocampal Neural Stem Cells And Neurogenesis

For decades,people believed that there was no neural regeneration in adult mammalian nerve system and loss of neurons were irrevocable.Until 1990 s,with the development of cell labeling technologies,the concept of adult neurogenesis started to be gradually accepted and followed by numerous of exciting studies in this new field of neuroscience.Studies have shown that subgranular zone(SGZ)of dentate gyrus(DG)in hippocampus and subventricular zone(SVZ)of lateral ventricle are the main adult neurogenesis niches in mammalian.There are neural stem cells lying in these two niches,and they share the same properties of other stem cells: self-renew,and potential to differentiate.Our study is mainly focused on the hippocampal neurogenesis.Numbers of researches have shown that hippocampus is a critical brain region related to cognitive functions and learning memory,and the disruption of hippocampal neurogenesis could lead to neuropathological conditions,such as schizophrenia,or Alzheimer's disease.Therefore,it is important to study the mechanism that regulates the neural stem cells(NSCs)and adult neurogenesis.PV+(parvalbumin)interneurons locating at SGZ were identified as a major GABAergic component regulating NSCs activities and adult neurogenesis.However,little is known about how local PV+ interneurons communicate with distal brain regions to regulate NSCs and hippocampal neurogenesis.In this study,we first used pseudorabies virus to specifically label those PV+ interneurons in DG and retrogradely traced back to their monosynaptic input cells.We found this forebrain region named medial septum(MS)had a major input contribution to those DG PV+ cells.This septohippocampal pathway had been well addressed in other studies,and it mainly included two types of projection neurons: GABAergic and cholinergic.Both of our retrograde and anterograde tracing data showed the majority of the input cells in medial septum are GABAergic,therefore we focused this study on septohippocampal GABAergic projections.By using optogenetics and chemogenetics approaches,we were able to specifically manipulate the activities of the projection terminals in hippocampus bi-directionally.We found that when we activated these GABAergic projection terminals in DG,the neural stem cells were more likely maintaining in quiescent status.While inhibiting these projections terminals,more neural stem cells started to transit into activated status.Surprisingly,when we applied Ca2+ imaging to study local DG PV+ interneurons,they turned out to be the main intermediators in this circuit by their unique property of depolarizing to GABA.Furthermore,in order to study the chronic effects of interference to this pathway,we used Caspase3 virus to induce apoptosis of MS GABAergic neurons,which eventually ablated this long-rang projections to DG.We found neural stem cells pool depletion and impaired neurogenesis after the chronic ablation of GABAergic inputs from MS.Overall,our findings identified this long-range septohippocampal GABAergic projection is both necessary and sufficient to regulate adult neural stem cells and substantial neurogenesis in hippocampus by the intermediation of local DG-PV+ interneurons.