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

Abstract

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.

Figure 1.. Local DG circuits regulate NSC homeostasis and integration of adult-born neurons.

Local hilar inhibitory interneurons, mossy cells and potentially, astrocytes relay local and distal inputs onto NSCs and differentiating adult-born DGCs. NSCs summate GABAergic and Glutamatergic inputs to mediate quiescence-activation and self-renewal decisions. Tonic GABA release onto NSCs promotes quiescence (grey arrow) whereas mossy cell dependent glutamate release promotes activation of NSCs (blue arrow). Afferent and efferent synaptogenesis of adult-born DGCs occurs at pre-existing synapses and astrocytes and microglia may modulate synaptic competition through vesicular release of D-serine and secreted synaptogenic factors and trogocytosis. MSDB: medial septum/diagonal band, M/DRN: median/dorsal raphe, EC: entorhinal cortex. See text for details.

Figure 2.. NSCs integrate secreted and juxtacrine signals from diverse niche cell-types to maintain homeostasis.

a. NSCs integrate signals from astrocytes, DGCs, semilunar granule cells, inhibitory interneurons, blood vessels, extracellular matrix (ECM) and inhibitory interneurons to mediate quiescence-activation and self-renewal decisions. Different niche actors may release ligands onto discrete domains of NSCs. Receptors in the apical process of RGLs may sense ligands released by axon terminals of DG afferents or of semilunar granule cells in the inner molecular layer. Competition for niche-derived factors may trigger microglial dependent pruning of NSC numbers to maintain homeostasis. b. Magnification of RGL in dashed line box in a. conveying niche derived secreted ligands [astrocyte derived factors (blue): IL1b, Wnt3a; vasculature derived factors (brown): IGF; mature DGC derived factors (Green): sFRP3, VEGF-C, Noggin, BMP, Fracktalkine, microglia derived factors (purple)] signal in paracrine or juxtacrine modes. DGCs may regulate NSC behavior through recruitment of microglia via release of phospholipids and fracktalkine. NSCs and progenitors may regulate their fate choices by autocrine signaling [(red): VEGF, Mfge8]. Extracellular matrix (ECM) regulates NSC behavior through ligands such as laminin, reelin and stiffness dependent modulation of Piezo signaling in NSCs. Within NSCs, mRNAs encoding ligands maybe transported along the radial apical process for local translation in response to physiological signals. See text for details.

Figure 3.. Inter-cellular cross talk in the niche

Neuronal activity may recruit multiple modes of signaling to coordinate activity of diverse niche actors and NSCs. a. Parallel mode: A single niche derived signal (light blue) may act simultaneously on cognate receptors present on astrocytes (green), microglia (orange), endothelial cells (red) and NSCs (pink). b. One-on-one mode: NSCs may receive a signal from only one cell-type. c. Sequential mode: This mode invokes communication across a cascade of niche actors such that signals are sequentially transmitted to ultimately reach NSCs. See text for details.

Figure 4.. Signal integration in NSCs

NSCs filter and integrate a wide-range of signals to make activation and division decisions. a. Master TFs may couple maintenance of NSC quiescence with repression of asymmetric stem cell renewal or symmetric stem cell renewal. b. Distinct physiological signals may converge onto the same cis regulatory element (purple) to regulate expression of master transcription factors (black) and influence the expression of target genes (white) involved in NSC quiescence-activation, fate choice and self-renewal (top). Distinct signals may recruit different coactivators (orange, green, yellow, blue) that bias master TF occupancy (black circle) at target gene promoters resulting in differential expression of genes (middle). Levels of intracellular calcium may mediate different biological responses in NSCs. Ca²⁺ influx into the cytoplasm from the extracellular environment (grey, green, red blue and orange receptors) and from the endoplasmic reticulum [G protein coupled receptors (dark green and yellow) and ER (light orange)] contribute to intracellular levels of calcium that, through the activation of second messengers, can mediate distinct cellular behaviors (bottom). c. The spatial organization of the niche can influence signal integration in NSCs. For example, a signal released by a DGC (grey) proximal to the NSC (pink) outcompetes an antagonistic signal released by distally located microglia (orange). d. Phenotypic and functional diversity of NSCs in the niche may support distinct fate choices i.e. bias towards asymmetric neurogenic or astrogenic stem cell renewal or symmetric stem cell renewal. See text for details.