Neuropeptides modulate local astrocytes to regulate adult hippocampal neural stem cells and neurogenesis
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ABSTRACT:
PROVIDER: PRJNA564331 | ENA |
REPOSITORIES: ENA
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Project description:It has been well established that parvulbumin (PV) interneurons in the adult dentate gyrus (DG) regulate radial-glia like neural stem cells (rNSCs) through tonic GABA signaling. However, several major local interneuron subtypes co-release GABA and neuropeptides. Virtually nothing is known about whether and how endogenous neuropeptides regulate rNSCs. Here we demonstrate an unprecedented role of endogenous CCK in regulating rNSCs and hippocampal neurogenesis through distinctive states of the local astrocytes. Specifically, stimulating CCK release leads to increased Ca2+ transients in local astrocytes, and the subsequent astrocytic glutamate release promotes rNSC proliferation and neurogenesis via glutamate receptor mediated MAPK/ERK signaling cascade. In contrast, suppression of CCK synthesis switches resident astrocytes to a reactive state, which leads to decreased proliferation of rNSCs by regulating a gene network that negatively regulates rNSC proliferation. These findings have broad implications in multiple neuropathological conditions associated with altered CCK level, neuroinflammation, and impaired hippocampal neurogenesis.
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Project description:During adult hippocampal neurogenesis, the majority of newborn cells undergo apoptosis and are rapidly phagocytosed by resident microglia in order to avoid disturbing the surrounding neurons. Here, we propose that phagocytosis is not merely a passive process of corpse removal but has an active role in maintaining adult hippocampal neurogenesis. First, we found that neurogenesis was disrupted in three defective microglial phagocytosis KO models in vivo (P2Y12, MerTK/Axl , GPR34). We then followed an in vitro approach to perform a transcriptomic analysis of microglial phagocytosis and identified genes involved in metabolism, chromatin remodeling, and neurogenesis-related functions. Finally, we determined that the phagocytic microglia secretome limits the production of new neurons both in vivo and in vitro. Our data suggest that reprogrammed phagocytic microglia acts as a sensor of local cell death, modulating the balance between cell proliferation and cell survival in the neurogenic niche, supporting the long-term maintenance of adult hippocampal neurogenesis.
2020-04-09 | GSE129569 | GEO
Project description:Astrocytes are highly abundant cells in the mammalian brain and their numerous functions are of vital importance for all aspects of development, adaption and aging of the central nervous system (CNS). Mounting evidence indicates the astrocytes’s cardinal contribution to a wide range of neuropathies, still, our understanding of astrocyte development significantly lags behind those of other CNS cells. Using the dentate gyrus (DG) as a model system, we here combine genetic fate-mapping, behavioral paradigms, single cell transcriptomics and in vivo two-photon imaging, to assess the generation and proliferation of astrocytes across the lifespan of a mouse in great detail. Astrogenesis in the DG is initiated by perinatal radial glia-like neural stem cells (rNSCs) giving rise to locally dividing astrocytes that enlarge the astrocyte compartment in an outside-in-pattern. This process occurs simultaneously to neurogenesis and likewise continues life-long. In the adult DG, rNSCs occasionally give rise to newborn astrocytes, but the vast majority of astrogenesis is mediated through proliferation of local astrocytes. Interestingly, locally dividing astrocytes revealed an unexpected plasticity and were able to adapt their proliferation to environmental and behavioural stimuli. Our study thus establishes astrocytes as enduring plastic elements in DG circuits, implicating a vital contribution of astrocyte dynamic to hippocampal plasticity.
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Project description:Neural stem cells, located in discrete niches in the adult brain, generate new neurons throughout life. These stem cells are specialized astrocytes, but astrocytes in other brain regions (parenchymal astrocytes) do not generate neurons under physiological conditions. After stroke, however, astrocytes in the mouse striatum undergo neurogenesis, triggered by decreased Notch signaling. Notch signaling can be experimentally depleted in mice by deleting the Notch-mediating transcription factor Rbpj. This dataset consists of single-cell RNA sequencing data of astrocytes isolated from the striatum (where astrocytes undergo neurogenesis in response to Rbpj deletion) or somatosensory cortex (where astrocytes don't complete neurogenesis in response to Rbpj deletion) of 4 mice. Cells were isolated from Cx30-CreER; R26-tdTomato; Rbpj(fl/fl) mice at three time points after tamoxifen-induced Rbpj deletion (2, 4, 8 weeks), and from Cx30-CreER; R26-tdTomato mice with intact Rbpj 3 days after tamoxifen. These time points span the transition from astrocyte through transit-amplifying cells to neuroblasts. The dataset contains 1) astrocytes from the striatum that initiate a neurogenic transcriptional program in response to Rbpj deletion and generate transit-amplifying cells and neuroblasts, and 2) astrocytes from the somatosensory cortex that initiate a neurogenic program in response to Rbpj deletion but fail to generate transit-amplifying cells or neuroblasts.
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Project description:We sought to find molecular signatures of the SGZ cell types, and to characterize the molecular pathways and transcription factor cascades that define the neurogenic niche. We used laser capture microdissection and DNA microarrays to profile gene expression in the inner (SGZ) and outer portions of the dentate gyrus (DG). Since the vast majority of the cells in the DG are mature granule cells, we compared the expression of the inner and outer portions to reveal molecular markers for the less numerous populations of the SGZ. This data set is part of a larger study assessing conserved molecular signatures of neurogenesis in the hippocampal subgranular zone of rodents and primates. Using a combination of selective SGZ transcriptional profiling with laser microdissection and DNA microarrays as well as in situ hybridization (ISH), we developed an extensive molecular characterization of the mouse SGZ, identifying 367 genes enriched in the SGZ compared to mature granule neurons. These genes displayed a wide range of cellular expression patterns reflecting the cellular milieu of the SGZ, including progenitor and dividing cells, immature granule cells, astrocytes, oligodendrocytes, and GABAergic interneurons. We next used a comparable microarray data set in rhesus monkey that profiled the SGZ across postnatal development to identify genes related to developmentally regulated granule cell neurogenesis. The rhesus monkey SGZ showed highly significant similarity to mouse, whereas network analysis of these data identified SGZ-enriched gene sets with different temporal profiles reflecting differential time-courses for maturation of glia and granule neurons. One neurogenesis-related gene network showed a steady decrease in expression across postnatal rhesus development from birth to adulthood. This temporal pattern is highly correlated with the number of proliferating cells in the dentate gyrus, and the neurogenic transcription factors Sox4 and Sox11 are central hub genes for this gene network. A number of the genes in this network showed a similar postnatal downregulation in mouse, suggesting a general conservation of molecular mechanisms underlying developmental and adult neurogenesis in rodents and primates. Primate data available at: http://www.blueprintnhpatlas.org/ Brains from 10- to 11-week-old C57BL/6 male mice housed in three conditions (no running, 4 days of running, 30 days of running) were sectioned and the dentate gyrus was isolated. For each brain, the inner granule cell layer (containing the subgranular zone) and outer GCL were separated using laser capture microdissection, and RNA from each region was collected and processed as described in the protocols.
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Project description:Transcriptomics analysis of neurogenesis by striatal astrocytes upon Rbpj-K deletion
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