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Astrogenesis in the murine dentate gyrus is a life-long and dynamic process

ABSTRACT: Astrocytes are highly abundant in the mammalian brain and their functions are of vital importance for all aspects of development, adaption and aging of the central nervous system (CNS). Mounting evidence indicates the important contributions of astrocytes to a wide range of neuropathies. Still our understanding of astrocyte development significantly lags behind that of other CNS cells. We here combine immunohistochemical approaches with genetic fate-mapping, behavioural paradigms, single cell transcriptomics and in vivo two-photon imaging, to comprehensively assess the generation and proliferation of astrocytes in the dentate gyrus (DG) across the lifespan of a mouse. Astrogenesis in the DG is initiated by radial glia-like neural stem cells giving rise to locally dividing astrocytes that enlarge the astrocyte compartment in an outside-in-pattern. Also in the adult DG, the vast majority of astrogenesis is mediated through proliferation of local astrocytes. Interestingly, locally dividing astrocytes were able to adapt their proliferation to environmental and behavioural stimuli revealing an unexpected plasticity. Our study establishes astrocytes as enduring plastic elements in DG circuits, implicating a vital contribution of astrocyte dynamics to hippocampal plasticity.

SUBMITTER: Ms. Julia Schneider

PROVIDER: S-SCDT-EMBOJ-2021-110409 | biostudies-other |

REPOSITORIES: biostudies-other

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Astrogenesis in the murine dentate gyrus is a life-long and dynamic process.

Project description:Astrocytes are highly abundant in the mammalian brain, and their functions are of vital importance for all aspects of development, adaption, and aging of the central nervous system (CNS). Mounting evidence indicates the important contributions of astrocytes to a wide range of neuropathies. Still, our understanding of astrocyte development significantly lags behind that of other CNS cells. We here combine immunohistochemical approaches with genetic fate-mapping, behavioural paradigms, single-cell transcriptomics, and in vivo two-photon imaging, to comprehensively assess the generation and the proliferation of astrocytes in the dentate gyrus (DG) across the life span of a mouse. Astrogenesis in the DG is initiated by radial glia-like neural stem cells giving rise to locally dividing astrocytes that enlarge the astrocyte compartment in an outside-in-pattern. Also in the adult DG, the vast majority of astrogenesis is mediated through the proliferation of local astrocytes. Interestingly, locally dividing astrocytes were able to adapt their proliferation to environmental and behavioral stimuli revealing an unexpected plasticity. Our study establishes astrocytes as enduring plastic elements in DG circuits, implicating a vital contribution of astrocyte dynamics to hippocampal plasticity.

| S-EPMC9156974 | biostudies-literature

Astrogenesis in the murine dentate gyrus – a life-long and plastic process mediated by proliferation of neural stem cells and local astrocytes

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.

2021-12-12 | GSE190399 | GEO

Long-term potentiation expands information content of hippocampal dentate gyrus synapses.

Project description:An approach combining signal detection theory and precise 3D reconstructions from serial section electron microscopy (3DEM) was used to investigate synaptic plasticity and information storage capacity at medial perforant path synapses in adult hippocampal dentate gyrus in vivo. Induction of long-term potentiation (LTP) markedly increased the frequencies of both small and large spines measured 30 minutes later. This bidirectional expansion resulted in heterosynaptic counterbalancing of total synaptic area per unit length of granule cell dendrite. Control hemispheres exhibited 6.5 distinct spine sizes for 2.7 bits of storage capacity while LTP resulted in 12.9 distinct spine sizes (3.7 bits). In contrast, control hippocampal CA1 synapses exhibited 4.7 bits with much greater synaptic precision than either control or potentiated dentate gyrus synapses. Thus, synaptic plasticity altered total capacity, yet hippocampal subregions differed dramatically in their synaptic information storage capacity, reflecting their diverse functions and activation histories.

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Transcriptome analysis of long term potentiation in rat dentate gyrus

Project description:In vivo high frequency stimulated of left dentate gyrus was performed on anaesthetised rats followed by RNA-seq to study long-term potentiation. Both left and right dentate gyrus was collected, sequenced and compared against each other for naive rats and for rats 30 min, 2 hours, and 5 hours post-HFS.

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Acute and long-term effects of electroconvulsive therapy on human dentate gyrus.

Project description:Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, although the underlying mechanisms remain unclear. Animal studies have consistently shown that electroconvulsive stimulation induces neuroplastic changes in the dentate gyrus. To date, few studies have investigated the effect of ECT on human hippocampal subfields. In the current study, structural magnetic resonance imaging (MRI) was conducted in 25 patients with major depressive episodes at 3 time points: before ECT (TP1), after 1 week of the last ECT (TP2) and after 3 months of the last ECT (TP3). Twenty healthy controls were scanned twice with an interval similar to patients between TP1 and TP2. Volumetric analyses of the cornu ammonis (CA)4/dentate gyrus (DG) were performed using the MAGeT-Brain (Multiple Automatically Generated Templates) algorithm. Clinically remitted patients after ECT showed larger volume increases in the right CA4/DG than non-remitted patients. Volume increases in the right CA4/DG were negatively associated with age. Increased CA4/DG volumes after ECT returned to baseline levels after 3 months irrespective of clinical state. ECT-induced volume increase in the CA4/DG was associated with age and clinical remission. These findings are consistent with the neurotrophic processes seen in preclinical studies. Neuroplastic change in the CA4/DG might mediate some of the short-term antidepressant effects of ECT.

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Effect of methanol fixation on single-cell RNA sequencing of the murine dentate gyrus.

Project description:Single-cell RNA sequencing (scRNA-seq) provides a powerful tool to evaluate the transcriptomic landscape and heterogeneity of thousands of cells in parallel. However, complex study designs or the unavailability of in-house instruments require the temporal disconnection between sample preparation and library construction, raising the need for efficient sample preservation methods which are compatible with scRNA-seq downstream analysis. Several studies evaluated the effect of methanol fixation as preservation method, yet none of them deeply assessed its effect on adult primary dissociated brain tissue. Here, we evaluated its effect on murine dentate gyrus (DG) single cell suspensions and on subsequent scRNA-seq downstream analysis by performing SOrting and Robot-assisted Transcriptome SEQuencing (SORT-seq), a partially robotized version of the CEL-seq2 protocol. Our results show that MeOH fixation preserves RNA integrity and has no apparent effects on cDNA library construction. They also suggest that fixation protects from sorting-induced cell stress and increases the proportion of high-quality cells. Despite evidence of mRNA leakage in fixed cells, their relative gene expression levels correlate well with those of fresh cells and fixation does not significantly affect the variance of the dataset. Moreover, it allows the identification of all major DG cell populations, including neural precursors, granule neurons and different glial cell types, with a tendency to preserve more neurons that are underrepresented in fresh samples. Overall, our data show that MeOH fixation is suitable for preserving primary neural cells for subsequent single-cell RNA profiling, helping to overcome challenges arising from complex workflows, improve experimental flexibility and facilitate scientific collaboration.

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Developmental profiling of postnatal dentate gyrus progenitors provides evidence for dynamic cell-autonomous regulation.

Project description:The dentate gyrus of the hippocampus is one of the most prominent regions in the postnatal mammalian brain where neurogenesis continues throughout life. There is tremendous speculation regarding the potential implications of adult hippocampal neurogenesis, though it remains unclear to what extent this ability becomes attenuated during normal aging, and what genetic changes in the progenitor population ensue over time. Using defined elements of the nestin promoter, we developed a transgenic mouse that reliably labels neural stem and early progenitors with green fluorescent protein (GFP). Using a combination of immunohistochemical and flow cytometry techniques, we characterized the progenitor cells within the dentate gyrus and created a developmental profile from postnatal day 7 (P7) until 6 months of age. In addition, we demonstrate that the proliferative potential of these progenitors is controlled at least in part by cell-autonomous cues. Finally, to identify what may underlie these differences, we performed stem cell-specific microarrays on GFP-expressing sorted cells from isolated P7 and postnatal day 28 (P28) dentate gyrus. We identified several differentially expressed genes that may underlie the functional differences that we observe in neurosphere assays from sorted cells and differentiation assays at these different ages. These data suggest that neural progenitors from the dentate gyrus are differentially regulated by cell-autonomous factors that change over time.

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TRPV1 activation by endogenous anandamide triggers postsynaptic long-term depression in dentate gyrus.

Project description:The transient receptor potential TRPV1 is a nonselective cation channel that mediates pain sensations and is commonly activated by a wide variety of exogenous and endogenous, physical and chemical stimuli. Although TRPV1 receptors are mainly found in nociceptive neurons of the peripheral nervous system, these receptors have also been found in the brain, where their role is far less understood. Activation of TRPV1 reportedly regulates neurotransmitter release at several central synapses. However, we found that TRPV1 suppressed excitatory transmission in rat and mouse dentate gyrus by regulating postsynaptic function in an input-specific manner. This suppression was a result of Ca(2+)-calcineurin and clathrin-dependent internalization of AMPA receptors. Moreover, synaptic activation of TRPV1 triggered a form of long-term depression (TRPV1-LTD) mediated by the endocannabinoid anandamide in a type 1 cannabinoid receptor-independent manner. Thus, our findings reveal a previously unknown form of endocannabinoid- and TRPV1-mediated regulation of synaptic strength at central synapses.

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Transient increases in dendritic spine density contribute to dentate gyrus long-term potentiation.

Project description:Dendritic spines are the primary sites for excitatory neurotransmission in the adult brain and exhibit changes in their number and morphology with experience. The relationship between spine formation and synaptic activity has been best characterized along the apical dendrites of pyramidal neurons in the hippocampal CA1 subfield. However, less is known about the structural mechanisms at the spine that mediate plasticity in other hippocampal subfields. The dentate gyrus is the predominant point of entry for synaptic input to the hippocampus, and dentate granule cells differ from CA1 pyramidal neurons in terms of their morphology and biophysical properties. In order to understand the structural mechanisms for plasticity in the dentate gyrus, we measured dendritic spine density in hippocampal slice preparations at different intervals following synaptic stimulation. We observed that transient increases in dendritic spine density are detectable 30 min after induction of long-term potentiation (LTP). By 60 min poststimulation, dendritic spine density has returned to basal levels. Both early LTP and enhancements in dendritic spine density could be blocked by destabilizing actin filaments, but not by inhibitors of transcription or protein synthesis. These results indicate that spine formation is a transient event that is required for dentate gyrus LTP.

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Nonrandom local circuits in the dentate gyrus.

Project description:The dentate hilus has been extensively studied in relation to its potential role in memory and in temporal lobe epilepsy. Little is known, however, about the synapses formed between the two major cell types in this region, glutamatergic mossy cells and hilar interneurons, or the organization of local circuits involving these cells. Using triple and quadruple simultaneous intracellular recordings in rat hippocampal slices, we find that mossy cells evoke EPSPs with high failure rates onto hilar neurons. Mossy cells show profound synapse specificity; 87.5% of their intralamellar connections are onto hilar interneurons. Hilar interneurons also show synapse specificity and preferentially inhibit mossy cells; 81% of inhibitory hilar synapses are onto mossy cells. Hilar IPSPs have low failure rates, are blocked by the GABA(A) receptor antagonist gabazine, and exhibit short-term depression when tested at 17 Hz. Surprisingly, more than half (57%) of the mossy cell synapses we found onto interneurons were part of reciprocal excitatory/inhibitory local circuit motifs. Neither the high degree of target cell specificity, nor the significant enrichment of structured polysynaptic local circuit motifs, could be explained by nonrandom sampling or somatic proximity. Intralamellar hilar synapses appear to function primarily by integrating synchronous inputs and presynaptic burst discharges, allowing hilar cells to respond over a large dynamic range of input strengths. The reciprocal mossy cell/interneuron local circuit motifs we find enriched in the hilus may generate sparse neural representations involved in hippocampal memory operations.

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