JNK1 controls adult hippocampal neurogenesis and imposes cell-autonomous control of anxiety behaviour from the neurogenic niche

Microglia, the resident immune cells of the brain, are crucial in the development of the nervous system. Recent evidence demonstrates that microglia modulate adult hippocampal neurogenesis by inhibiting cell proliferation of neural precursors and survival both in vitro and in vivo, thus maintaining a balance between cell division and cell death in the neural stem cell pool. There are increasing reports suggesting these microglia found in neurogenic niches differ from their counterparts in non-neurogenic areas. Here, we present evidence that microglia in the hippocampal neurogenic niche are a specialized population that express genes known to regulate neurogenesis. By comprehensively profiling myeloid lineage cells in the hippocampus using single cell RNA-sequencing, we resolve transcriptomic differences in microglia originating from the subgranular zone. These cells have lower expression of genes associated with homeostatic microglia and increased expression of genes associated with phagocytosis. Intriguingly, this small yet distinct population expresses a gene signature with substantial overlap with previously characterized phenotypes, including disease associated microglia (DAM), a particularly unique and compelling microglial state.

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Neuroinflammation and physical exercise as modulators of adult hippocampal neural precursor cell behavior

Reviews in the Neurosciences ◽

10.1515/revneuro-2017-0024 ◽

2017 ◽

Vol 29 (1) ◽

pp. 1-20 ◽

Cited By ~ 6

Author(s):

Martha Pérez-Domínguez ◽

Luis B. Tovar-y-Romo ◽

Angélica Zepeda

Keyword(s):

Stem Cells ◽

Physical Exercise ◽

Neural Stem Cells ◽

Cell Fate ◽

Bone Morphogenetic Proteins ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Adult Neural Stem Cells ◽

Neurogenic Niche ◽

Glial Lineage

Abstract The dentate gyrus of the hippocampus is a plastic structure where adult neurogenesis constitutively occurs. Cell components of the neurogenic niche are source of paracrine as well as membrane-bound factors such as Notch, Bone Morphogenetic Proteins, Wnts, Sonic Hedgehog, cytokines, and growth factors that regulate adult hippocampal neurogenesis and cell fate decision. The integration and coordinated action of multiple extrinsic and intrinsic cues drive a continuous decision process: if adult neural stem cells remain quiescent or proliferate, if they take a neuronal or a glial lineage, and if new cells proliferate, undergo apoptotic death, or survive. The proper balance in the molecular milieu of this neurogenic niche leads to the production of neurons in a higher rate as that of astrocytes. But this rate changes in face of microenvironment modifications as those driven by physical exercise or with neuroinflammation. In this work, we first review the cellular and molecular components of the subgranular zone, focusing on the molecules, active signaling pathways and genetic programs that maintain quiescence, induce proliferation, or promote differentiation. We then summarize the evidence regarding the role of neuroinflammation and physical exercise in the modulation of adult hippocampal neurogenesis with emphasis on the activation of progression from adult neural stem cells to lineage-committed progenitors to their progeny mainly in murine models.

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Chronic stress induces significant gene expression changes in the prefrontal cortex alongside alterations in adult hippocampal neurogenesis

Brain Communications ◽

10.1093/braincomms/fcaa153 ◽

2020 ◽

Vol 2 (2) ◽

Author(s):

Ksenia Musaelyan ◽

Selin Yildizoglu ◽

James Bozeman ◽

Andrea Du Preez ◽

Martin Egeland ◽

...

Keyword(s):

Gene Expression ◽

Prefrontal Cortex ◽

Chronic Stress ◽

Molecular Mechanisms ◽

Dendritic Tree ◽

Hippocampal Neurogenesis ◽

Stress Disorders ◽

Adult Hippocampal Neurogenesis ◽

Mild Stress ◽

Neurogenic Niche

Abstract Adult hippocampal neurogenesis is involved in stress-related disorders such as depression, posttraumatic stress disorders, as well as in the mechanism of antidepressant effects. However, the molecular mechanisms involved in these associations remain to be fully explored. In this study, unpredictable chronic mild stress in mice resulted in a deficit in neuronal dendritic tree development and neuroblast migration in the hippocampal neurogenic niche. To investigate molecular pathways underlying neurogenesis alteration, genome-wide gene expression changes were assessed in the prefrontal cortex, hippocampus and the hypothalamus alongside neurogenesis changes. Cluster analysis showed that the transcriptomic signature of chronic stress is much more prominent in the prefrontal cortex compared to the hippocampus and the hypothalamus. Pathway analyses suggested huntingtin, leptin, myelin regulatory factor, methyl-CpG binding protein and brain-derived neurotrophic factor as the top predicted upstream regulators of transcriptomic changes in the prefrontal cortex. Involvement of the satiety regulating pathways (leptin) was corroborated by behavioural data showing increased food reward motivation in stressed mice. Behavioural and gene expression data also suggested circadian rhythm disruption and activation of circadian clock genes such as Period 2. Interestingly, most of these pathways have been previously shown to be involved in the regulation of adult hippocampal neurogenesis. It is possible that activation of these pathways in the prefrontal cortex by chronic stress indirectly affects neuronal differentiation and migration in the hippocampal neurogenic niche via reciprocal connections between the two brain areas.

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Mathematical modelling of adult hippocampal neurogenesis: effects of altered stem cell dynamics on cell counts and bromodeoxyuridine-labelled cells

Journal of The Royal Society Interface ◽

10.1098/rsif.2014.0144 ◽

2014 ◽

Vol 11 (94) ◽

pp. 20140144 ◽

Cited By ~ 21

Author(s):

Frederik Ziebell ◽

Ana Martin-Villalba ◽

Anna Marciniak-Czochra

Keyword(s):

Granule Cells ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Initial Increase ◽

Model Parameters ◽

Multiple Time ◽

Cell Dynamics ◽

Asymmetric Cell Divisions ◽

Neurogenic Niche ◽

Cell Counts

In the adult hippocampus, neurogenesis—the process of generating mature granule cells from adult neural stem cells—occurs throughout the entire lifetime. In order to investigate the involved regulatory mechanisms, knockout (KO) experiments, which modify the dynamic behaviour of this process, were conducted in the past. Evaluating these KOs is a non-trivial task owing to the complicated nature of the hippocampal neurogenic niche. In this study, we model neurogenesis as a multicompartmental system of ordinary differential equations based on experimental data. To analyse the results of KO experiments, we investigate how changes of cell properties, reflected by model parameters, influence the dynamics of cell counts and of the experimentally observed counts of cells labelled by the cell division marker bromodeoxyuridine (BrdU). We find that changing cell proliferation rates or the fraction of self-renewal, reflecting the balance between symmetric and asymmetric cell divisions, may result in multiple time phases in the response of the system, such as an initial increase in cell counts followed by a decrease. Furthermore, these phases may be qualitatively different in cells at different differentiation stages and even between mitotically labelled cells and all cells existing in the system.

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Fine processes of Nestin-GFP–positive radial glia-like stem cells in the adult dentate gyrus ensheathe local synapses and vasculature

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1514652113 ◽

2016 ◽

Vol 113 (18) ◽

pp. E2536-E2545 ◽

Cited By ~ 54

Author(s):

Jonathan Moss ◽

Elias Gebara ◽

Eric A. Bushong ◽

Irene Sánchez-Pascual ◽

Ruadhan O’Laoi ◽

...

Keyword(s):

Stem Cells ◽

Dentate Gyrus ◽

Radial Glia ◽

Molecular Layer ◽

Cell Activity ◽

Local Environment ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Granule Cell Layer ◽

Neurogenic Niche

Adult hippocampal neurogenesis relies on the activation of neural stem cells in the dentate gyrus, their division, and differentiation of their progeny into mature granule neurons. The complex morphology of radial glia-like (RGL) stem cells suggests that these cells establish numerous contacts with the cellular components of the neurogenic niche that may play a crucial role in the regulation of RGL stem cell activity. However, the morphology of RGL stem cells remains poorly described. Here, we used light microscopy and electron microscopy to examine Nestin-GFP transgenic mice and provide a detailed ultrastructural reconstruction analysis of Nestin-GFP–positive RGL cells of the dentate gyrus. We show that their primary processes follow a tortuous path from the subgranular zone through the granule cell layer and ensheathe local synapses and vasculature in the inner molecular layer. They share the ensheathing of synapses and vasculature with astrocytic processes and adhere to the adjacent processes of astrocytes. This extensive interaction of processes with their local environment could allow them to be uniquely receptive to signals from local neurons, glia, and vasculature, which may regulate their fate.

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Influences of prenatal and postnatal stress on adult hippocampal neurogenesis: The double neurogenic niche hypothesis

Behavioural Brain Research ◽

10.1016/j.bbr.2014.12.036 ◽

2015 ◽

Vol 281 ◽

pp. 309-317 ◽

Cited By ~ 17

Author(s):

Sylvia Ortega-Martínez

Keyword(s):

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Neurogenic Niche ◽

Postnatal Stress

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Impaired adult hippocampal neurogenesis in Alzheimer’s disease is mediated by microRNA-132 deficiency and can be restored by microRNA-132 replacement

10.1101/2020.03.12.988709 ◽

2020 ◽

Author(s):

Evgenia Salta ◽

Hannah Walgrave ◽

Sriram Balusu ◽

Elke Vanden Eynden ◽

Sarah Snoeck ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Memory Decline ◽

Human Neural Stem Cells ◽

Neurogenic Niche

SummaryAdult hippocampal neurogenesis (AHN) plays a crucial role in memory processes and is impeded in the brains of Alzheimer’s disease (AD) patients. However, the molecular mechanisms impacting AHN in AD brain are unknown. Here we identify miR-132, one of the most consistently downregulated microRNAs in AD, as a novel mediator of the AHN deficits in AD. The effects of miR-132 are cell-autonomous and its overexpression is proneurogenic in the adult neurogenic niche in vivo and in human neural stem cells in vitro. miR-132 knockdown in wild-type mice mimics neurogenic deficits in AD mouse brain. Restoring miR-132 levels in mouse models of AD significantly restores AHN and relevant memory deficits. Our findings provide mechanistic insight into the hitherto elusive functional significance of AHN in AD and designate miR-132 replacement as a novel therapeutic strategy to rejuvenate the AD brain and thereby alleviate aspects of memory decline.

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Glial PAMPering and DAMPening of Adult Hippocampal Neurogenesis

Brain Sciences ◽

10.3390/brainsci11101299 ◽

2021 ◽

Vol 11 (10) ◽

pp. 1299

Author(s):

Luke Parkitny ◽

Mirjana Maletic-Savatic

Keyword(s):

Cell Fate ◽

Glial Cells ◽

Cognitive Disorders ◽

Hippocampal Neurogenesis ◽

Innate Immune ◽

Adult Hippocampal Neurogenesis ◽

Sterile Inflammation ◽

System Response ◽

Danger Signals ◽

Neurogenic Niche

Adult neurogenesis represents a mature brain’s capacity to integrate newly generated neurons into functional circuits. Impairment of neurogenesis contributes to the pathophysiology of various mood and cognitive disorders such as depression and Alzheimer’s Disease. The hippocampal neurogenic niche hosts neural progenitors, glia, and vasculature, which all respond to intrinsic and environmental cues, helping determine their current state and ultimate fate. In this article we focus on the major immune communication pathways and mechanisms through which glial cells sense, interact with, and modulate the neurogenic niche. We pay particular attention to those related to the sensing of and response to innate immune danger signals. Receptors for danger signals were first discovered as a critical component of the innate immune system response to pathogens but are now also recognized to play a crucial role in modulating non-pathogenic sterile inflammation. In the neurogenic niche, viable, stressed, apoptotic, and dying cells can activate danger responses in neuroimmune cells, resulting in neuroprotection or neurotoxicity. Through these mechanisms glial cells can influence hippocampal stem cell fate, survival, neuronal maturation, and integration. Depending on the context, such responses may be appropriate and on-target, as in the case of learning-associated synaptic pruning, or excessive and off-target, as in neurodegenerative disorders.

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A role for Lin28a in aging-associated decline of adult hippocampal neurogenesis

10.1101/2022.01.03.474756 ◽

2022 ◽

Author(s):

Zhechun Hu ◽

Jiao Ma ◽

Huimin Yue ◽

Xiaofang Li ◽

Chao Wang ◽

...

Keyword(s):

Progenitor Cells ◽

Neural Progenitor Cells ◽

Rna Binding ◽

Functional Integration ◽

Neural Progenitor ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Pattern Separation ◽

Neurogenic Niche ◽

Newborn Neurons

Hippocampal neurogenesis declines with aging. Wnt ligands and antagonists within the hippocampal neurogenic niche regulate the proliferation of neural progenitor cells and the development of new neurons, and the changes of their levels in the niche mediate aging-associated decline of neurogenesis. We found that RNA-binding protein Lin28a remained existent in neural progenitor cells and granule neurons in the adult hippocampus, and decreased with aging. Loss of Lin28a inhibited the responsiveness of neural progenitor cells to niche Wnt agonist and reduced neurogenesis, thus impairing pattern separation. Overexpression of Lin28a increased the proliferation of neural progenitor cells, promoted the functional integration of newborn neurons, restored neurogenesis in Wnt-deficient dentate gyrus, and rescued the impaired pattern separation in aging mice. Our data suggest that Lin28a regulates adult hippocampal neurogenesis as an intracellular mechanism by responding to niche Wnt signals, and its decrease is involved in aging-associated decline of hippocampal neurogenesis as well as related cognitive functions.

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