Communication, Cross Talk, and Signal Integration in the Adult Hippocampal Neurogenic Niche

Radial glia-like neural stem cells (RGLs) in the dentate gyrus subregion of the hippocampus give rise to dentate granule cells (DGCs) and astrocytes throughout life, a process referred to as adult hippocampal neurogenesis. Adult hippocampal neurogenesis is sensitive to experiences, suggesting that it may represent an adaptive mechanism by which hippocampal circuitry is modified in response to environmental demands. Experiential information is conveyed to RGLs, progenitors, and adult-born DGCs via the neurogenic niche that is composed of diverse cell types, extracellular matrix, and afferents. Understanding how the niche performs its functions may guide strategies to maintain its health span and provide a permissive milieu for neurogenesis. Here, we first discuss representative contributions of niche cell types to regulation of neural stem cell (NSC) homeostasis and maturation of adult-born DGCs. We then consider mechanisms by which the activity of multiple niche cell types may be coordinated to communicate signals to NSCs. Finally, we speculate how NSCs integrate niche-derived signals to govern their regulation. Radial glia-like neural stem cells (RGLs) in the dentate gyrus subregion of the hippocampus give rise to dentate granule cells (DGCs) and astrocytes throughout life, a process referred to as adult hippocampal neurogenesis. Adult hippocampal neurogenesis is sensitive to experiences, suggesting that it may represent an adaptive mechanism by which hippocampal circuitry is modified in response to environmental demands. Experiential information is conveyed to RGLs, progenitors, and adult-born DGCs via the neurogenic niche that is composed of diverse cell types, extracellular matrix, and afferents. Understanding how the niche performs its functions may guide strategies to maintain its health span and provide a permissive milieu for neurogenesis. Here, we first discuss representative contributions of niche cell types to regulation of neural stem cell (NSC) homeostasis and maturation of adult-born DGCs. We then consider mechanisms by which the activity of multiple niche cell types may be coordinated to communicate signals to NSCs. Finally, we speculate how NSCs integrate niche-derived signals to govern their regulation. Radial glia-like neural stem cells (RGLs) in the dentate gyrus subregion of the hippocampus give rise to dentate granule cells (DGCs) and astrocytes throughout life, a process referred to as adult hippocampal neurogenesis (Bonaguidi et al., 2012Bonaguidi M.A. Song J. Ming G.L. Song H. A unifying hypothesis on mammalian neural stem cell properties in the adult hippocampus.Curr. Opin. Neurobiol. 2012; 22: 754-761Crossref PubMed Scopus (105) Google Scholar, Garcia et al., 2004Garcia A.D. Doan N.B. Imura T. Bush T.G. Sofroniew M.V. 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Experience is conveyed to RGLs, neuroblasts, and immature adult-born DGCs via signals sensed by the hippocampal neurogenic niche that is composed of diverse local cell types, including astrocytes, DGCs, inhibitory interneurons, endothelial cells, extracellular matrix (ECM), and subcortical neurons that project to the DG. Thus, the local and extended niche enables NSCs to listen and respond to changes in neural activity and systemic factors (Guo and Sahay, 2017Guo N. Sahay A. Neural circuits serve as periscopes for NSCs.Cell Stem Cell. 2017; 21: 557-559Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Understanding how the niche performs its functions may guide strategies to maintain its health throughout the lifespan and provide a permissive milieu for adult hippocampal neurogenesis. A swath of evidence generated over several decades describes how different kinds of experiences affect neural stem cell and progenitor proliferation and differentiation and survival of adult-born DGCs (Cope and Gould, 2019Cope E.C. Gould E. Adult neurogenesis, glia, and the extracellular matrix.Cell Stem Cell. 2019; 24: 690-705Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, Dranovsky et al., 2011Dranovsky A. Picchini A.M. Moadel T. Sisti A.C. Yamada A. Kimura S. Leonardo E.D. Hen R. Experience dictates stem cell fate in the adult hippocampus.Neuron. 2011; 70: 908-923Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, Encinas et al., 2008Encinas J.M. Vazquez M.E. Switzer R.C. Chamberland D.W. Nick H. Levine H.G. Scarpa P.J. Enikolopov G. Steindler D.A. Quiescent adult neural stem cells are exceptionally sensitive to cosmic radiation.Exp. Neurol. 2008; 210: 274-279Crossref PubMed Scopus (0) Google Scholar, Gonçalves et al., 2016bGonçalves J.T. 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Not surprisingly, NSCs do not act autonomously but instead sense and integrate a plethora of niche-derived signals communicated by local, distal, and systemic actors. Transplantation studies exemplify the role of niche in instructing and respecifying fate of biased progenitors (Gage et al., 1995Gage F.H. Coates P.W. Palmer T.D. Kuhn H.G. Fisher L.J. Suhonen J.O. Peterson D.A. Suhr S.T. Ray J. Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain.Proc. Natl. Acad. Sci. USA. 1995; 92: 11879-11883Crossref PubMed Scopus (850) Google Scholar, Seidenfaden et al., 2006Seidenfaden R. Desoeuvre A. Bosio A. Virard I. Cremer H. Glial conversion of SVZ-derived committed neuronal precursors after ectopic grafting into the adult brain.Mol. Cell. Neurosci. 2006; 32: 187-198Crossref PubMed Scopus (100) Google Scholar). Additionally, many of these local niche cell types also govern the maturation and synaptic integration of adult-born DGCs. Here, we first discuss representative contributions of distinct niche cell types to regulation of NSC homeostasis and maturation of adult-born DGCs, with each section conveying outstanding questions. We then consider mechanisms by which the activity of multiple niche cell types may be coordinated to communicate signals to NSCs. Finally, we speculate how NSCs integrate these multiple niche-derived signals to make decisions. Ultrastructural analysis and high-resolution imaging provide a ground truth for understanding how NSCs and immature adult-born DGCs may respond to local niche signals. The subgranular zone of the DG, where neural stem cells differentiate into DGCs, is highly vascularized (Palmer et al., 2000Palmer T.D. Willhoite A.R. Gage F.H. Vascular niche for adult hippocampal neurogenesis.J. Comp. Neurol. 2000; 425: 479-494Crossref PubMed Scopus (1465) Google Scholar). Electron microscopy (EM) analysis has revealed that RGL cell bodies have concave edges presumably reflecting the convex curvature of adjacent DGC bodies. The primary (apical) processes of RGLs navigate the granule cell layer to branch extensively in the inner molecular layer (Moss et al., 2016Moss J. Gebara E. Bushong E.A. Sánchez-Pascual I. O’Laoi R. El M’Ghari I. Kocher-Braissant J. Ellisman M.H. Toni N. Fine processes of Nestin-GFP-positive radial glia-like stem cells in the adult dentate gyrus ensheathe local synapses and vasculature.Proc. Natl. Acad. Sci. USA. 2016; 113: E2536-E2545Crossref PubMed Google Scholar). Secondary and tertiary processes contact DGC dendritic spines and apposing axon terminals of entorhinal cortical and subcortical projections and mossy cells. RGL processes do not establish synaptic contacts but, much like astrocytes, wrap around or form tight appositions with axon terminals and spines (Moss et al., 2016Moss J. Gebara E. Bushong E.A. Sánchez-Pascual I. O’Laoi R. El M’Ghari I. Kocher-Braissant J. Ellisman M.H. Toni N. Fine processes of Nestin-GFP-positive radial glia-like stem cells in the adult dentate gyrus ensheathe local synapses and vasculature.Proc. Natl. Acad. Sci. USA. 2016; 113: E2536-E2545Crossref PubMed Google Scholar). Larger diameter processes, like astrocytic endfeet, wrap local blood vessels, creating a blanket of coverage along with astrocytic processes. Basal processes project along the subgranular zone axis and into the hilus, where they are positioned to sense signals from hilar neurons (Moss et al., 2016Moss J. Gebara E. Bushong E.A. Sánchez-Pascual I. O’Laoi R. El M’Ghari I. Kocher-Braissant J. Ellisman M.H. Toni N. Fine processes of Nestin-GFP-positive radial glia-like stem cells in the adult dentate gyrus ensheathe local synapses and vasculature.Proc. Natl. Acad. Sci. USA. 2016; 113: E2536-E2545Crossref PubMed Google Scholar). 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In each section, we begin with the relationship between niche cell type and NSCs prior to transitioning to dialog between niche cell type and adult-born DGCs. DGCs are abundant niche cells and ensconce the cell bodies of NSCs located in the subgranular zone (Figure 1). DGCs receive excitatory inputs from diverse cortical and subcortical circuits and other hippocampal subregions and, as such, are well positioned to relay signals to NSCs and immature adult-born DGCs (Miller and Sahay, 2019Miller S.M. Sahay A. Functions of adult-born neurons in hippocampal memory interference and indexing.Nat. Neurosci. 2019; 22: 1565-1575Crossref PubMed Scopus (0) Google Scholar). Growing evidence suggests that neuronal activity may recruit DGCs to modulate NSC homeostasis via secretion of factors. Several studies have identified activity-dependent production of pro-neurogenic secreted factors. A pioneering study found that electroconvulsive shock treatment induced a transient increase in GADD45b expression in DGCs (Ma et al., 2009Ma D.K. Jang M.H. Guo J.U. Kitabatake Y. Chang M.L. Pow-Anpongkul N. Flavell R.A. Lu B. Ming G.L. Song H. Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis.Science. 2009; 323: 1074-1077Crossref PubMed Scopus (646) Google Scholar). Gadd45b functions as a DNA demethylase and promotes expression of secreted factors, such as brain-derived neurotrophic factor (BDNF) and fibroblast growth factor (FGF), to stimulate neural progenitor proliferation and dendritic maturation of adult-born DGCs. Neural activity and running were shown to decrease levels of sFRP3, secreted frizzled-related protein 3, an extracellular Wnt inhibitor, in DGCs (Jang et al., 2013Jang M.H. Bonaguidi M.A. Kitabatake Y. Sun J. Song J. Kang E. Jun H. Zhong C. Su Y. Guo J.U. et al.Secreted frizzled-related protein 3 regulates activity-dependent adult hippocampal neurogenesis.Cell Stem Cell. 2013; 12: 215-223Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). Reduction of sFRP3 levels promoted NSC activation without affecting lineage choice. Additionally, loss of sFRP3 also accelerated dendritic growth and spine formation, suggesting that it normally functions as a brake that calibrates the tempo of neuronal differentiation. DGCs also express other neurogenic ligands, such as vascular endothelial growth factor C (VEGF-C), which signals through VEGFR3 in NSCs to promote neurogenesis (Han et al., 2015Han J. Calvo C.F. Kang T.H. Baker K.L. Park J.H. Parras C. Levittas M. Birba U. Pibouin-Fragner L. Fragner P. et al.Vascular endothelial growth factor receptor 3 controls neural stem cell activation in mice and humans.Cell Rep. 2015; 10: 1158-1172Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Exercise, enriched environment, and administration of selective serotonin reuptake inhibitors have been shown to decrease bone morphogenetic protein (BMP) signaling by either reducing BMP levels or increasing expression of noggin, an extracellular BMP inhibitor, in DGCs (Brooker et al., 2017Brooker S.M. Gobeske K.T. Chen J. Peng C.Y. Kessler J.A. Hippocampal bone morphogenetic protein signaling mediates behavioral effects of antidepressant treatment.Mol. Psychiatry. 2017; 22: 910-919Crossref PubMed Scopus (14) Google Scholar, Gobeske et al., 2009Gobeske K.T. Das S. Bonaguidi M.A. Weiss C. Radulovic J. Disterhoft J.F. Kessler J.A. BMP signaling mediates effects of exercise on hippocampal neurogenesis and cognition in mice.PLoS ONE. 2009; 4: e7506Crossref PubMed Scopus (0) Google Scholar). Viral overexpression of noggin in DGCs (Gobeske et al., 2009Gobeske K.T. Das S. Bonaguidi M.A. Weiss C. Radulovic J. Disterhoft J.F. Kessler J.A. BMP signaling mediates effects of exercise on hippocampal neurogenesis and cognition in mice.PLoS ONE. 2009; 4: e7506Crossref PubMed Scopus (0) Google Scholar) or genetic ablation of BMP signaling in neural stem and progenitor cells (NSPCs) (when neither population is selectively targeted) promoted proliferation (Mira et al., 2010Mira H. Andreu Z. Suh H. Lie D.C. Jessberger S. Consiglio A. San Emeterio J. Hortigüela R. Marqués-Torrejón M.A. Nakashima K. et al.Signaling through BMPR-IA regulates quiescence and long-term activity of neural stem cells in the adult hippocampus.Cell Stem Cell. 2010; 7: 78-89Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar). Interestingly, inducible elimination of dendritic spines of mature DGCs is accompanied by robust activation of NSCs (McAvoy et al., 2016McAvoy K.M. Scobie K.N. Berger S. Russo C. Guo N. Decharatanachart P. Vega-Ramirez H. Miake-Lye S. Whalen M. 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