Cited by 102Neurogenesis and neuroplasticity mechanismsNeuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology Research

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Adult hippocampal neurogenesis inversely correlates with microglia in conditions of voluntary running and aging

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Gebara, Elias, Sultan, Sebastien, Kocher-Braissant, Jacqueline, Toni, Nicolas·2013·Frontiers in Neuroscience

Abstract

Adult hippocampal neurogenesis results in the formation of new neurons and is a process of brain plasticity involved in learning and memory. The proliferation of adult neural stem or progenitor cells is regulated by several extrinsic factors such as experience, disease or aging and intrinsic factors originating from the neurogenic niche. Microglia is very abundant in the dentate gyrus (DG) and increasing evidence indicates that these cells mediate the inflammation-induced reduction in neurogenesis. However, the role of microglia in neurogenesis in physiological conditions remains poorly understood. In this study, we monitored microglia and the proliferation of adult hippocampal stem/progenitor cells in physiological conditions known to increase or decrease adult neurogenesis, voluntary running and aging respectively. We found that the number of microglia in the DG was strongly inversely correlated with the number of stem/progenitor cells and cell proliferation in the granule cell layer. Accordingly, co-cultures of decreasing neural progenitor/glia ratio showed that microglia but not astroglia reduced the number of progenitor cells. Together, these results suggest that microglia inhibits the proliferation of neural stem/progenitor cells despite the absence of inflammatory stimulus.

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Crossref · 10.3389/fnins.2013.00145

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Figure 1 Effect of running and aging on cell proliferation in the dentate gyrus. (A) Experimental timeline. (B) Histogram of the density (cells/μ m2) of Ki-67–expressing cells in the granule cell layer of the dentate gyrus of 8-week-old animals (8 W) and 8-month-old animals (8 M) housed with (R), or without (NR) a running wheel. (C) Confocal maximal projection micrographs of hippocampal sections immunostained for Ki-67. Inset: Higher magnification confocal micrograph of a Ki-67-expressing cell. (D) Histogram of the density of BrdU-positive cells in the granule cell layer of the dentate gyrus. (E) Confocal maximal projection micrographs of hippocampal sections immunostained for BrdU. (F) Quantification of the density of RGL cells in the granule cell layer of the dentate gyrus. (G) Confocal maximal projection micrographs of hippocampal sections. Inset: Higher magnification confocal micrograph of a RGL cell. (H) Histogram showing the density of Tbr2-expressing cells in the granule cell layer of the dentate gyrus. (I) Confocal maximal projection micrographs of hippocampal sections immunostained for Tbr2. Inset: Higher magnification confocal micrograph of a Tbr2-expressing cell. (J) Histogram of the density of DCX-immunolabeled cells in the granule cell layer of the dentate gyrus. (K) Confocal micrographs of hippocampal sections immunostained for DCX. Inset: Higher magnification confocal micrograph of a DCX-immunolabeled group of cells. Blue: Dapi staining. Animals, n = 4 per group. Scale bars: 100 μm, insets 10 μm, post-hoc Tukey HSD test *p < 0.05; **p < 0.01; ***p < 0.001; NS: p > 0.05. Each value represents the mean ± SEM.
Figure 1 Effect of running and aging on cell proliferation in the dentate gyrus. (A) Experimental timeline. (B) Histogram of the density (cells/μ m2) of Ki-67–expressing cells in the granule cell layer of the dentate gyrus of 8-week-old animals (8 W) and 8-month-old animals (8 M) housed with (R), or without (NR) a running wheel. (C) Confocal maximal projection micrographs of hippocampal sections immunostained for Ki-67. Inset: Higher magnification confocal micrograph of a Ki-67-expressing cell. (D) Histogram of the density of BrdU-positive cells in the granule cell layer of the dentate gyrus. (E) Confocal maximal projection micrographs of hippocampal sections immunostained for BrdU. (F) Quantification of the density of RGL cells in the granule cell layer of the dentate gyrus. (G) Confocal maximal projection micrographs of hippocampal sections. Inset: Higher magnification confocal micrograph of a RGL cell. (H) Histogram showing the density of Tbr2-expressing cells in the granule cell layer of the dentate gyrus. (I) Confocal maximal projection micrographs of hippocampal sections immunostained for Tbr2. Inset: Higher magnification confocal micrograph of a Tbr2-expressing cell. (J) Histogram of the density of DCX-immunolabeled cells in the granule cell layer of the dentate gyrus. (K) Confocal micrographs of hippocampal sections immunostained for DCX. Inset: Higher magnification confocal micrograph of a DCX-immunolabeled group of cells. Blue: Dapi staining. Animals, n = 4 per group. Scale bars: 100 μm, insets 10 μm, post-hoc Tukey HSD test *p < 0.05; **p < 0.01; ***p < 0.001; NS: p > 0.05. Each value represents the mean ± SEM.CC BY · PubMed Central
Figure 2 Effect of running and aging on the density of microglia. (A) Histogram showing the density (cells/μ m2) of Iba1-expressing cells in the dentate gyrus (including hilus, granule cell layer and molecular layer). (B) Histogram of the density of Iba1-expressing cells in the cortex. (C) Confocal maximal projection micrographs of hippocampal sections immunostained for Iba1. Inset: Higher magnification confocal micrograph of an Iba1-immunolabeled cell. (D) Histogram of the density of MHC II-expressing cells in the dentate gyrus. (E) Confocal maximal projection micrographs of hippocampal sections immunostained for MHC II. Inset: Higher magnification confocal micrograph of a MHC II-immunolabeled cell. (F) Histogram of the density of GFAP-expressing astrocytes in the dentate gyrus of mice for each experimental condition. (G) Confocal maximal projection micrographs of hippocampal sections immunostained for GFAP. Inset: Higher magnification confocal micrograph of a GFAP-immunolabeled cell. Blue: Dapi staining. Animals: n = 4 per group. Scale bars: 100 μm, insets 10 μm. post-hoc Tukey HSD test: N.S.: p > 0.05; ***p < 0.001. Each value represents the mean ± SEM.
Figure 2 Effect of running and aging on the density of microglia. (A) Histogram showing the density (cells/μ m2) of Iba1-expressing cells in the dentate gyrus (including hilus, granule cell layer and molecular layer). (B) Histogram of the density of Iba1-expressing cells in the cortex. (C) Confocal maximal projection micrographs of hippocampal sections immunostained for Iba1. Inset: Higher magnification confocal micrograph of an Iba1-immunolabeled cell. (D) Histogram of the density of MHC II-expressing cells in the dentate gyrus. (E) Confocal maximal projection micrographs of hippocampal sections immunostained for MHC II. Inset: Higher magnification confocal micrograph of a MHC II-immunolabeled cell. (F) Histogram of the density of GFAP-expressing astrocytes in the dentate gyrus of mice for each experimental condition. (G) Confocal maximal projection micrographs of hippocampal sections immunostained for GFAP. Inset: Higher magnification confocal micrograph of a GFAP-immunolabeled cell. Blue: Dapi staining. Animals: n = 4 per group. Scale bars: 100 μm, insets 10 μm. post-hoc Tukey HSD test: N.S.: p > 0.05; ***p < 0.001. Each value represents the mean ± SEM.CC BY · PubMed Central
Figure 3 Correlation between cell proliferation and Iba1-expressing microglia. (A–E) Plots showing the density of Ki-67-expressing cells (A), BrdU-labeled cells (B), RGL cells (C), Tbr2-expressing cells (D) and DCX-expressing cells (E), as a function of the density of Iba1-expressing cells, in the dentate gyrus. Each point represents the density of cells for one animal. Spearman's correlation test was used to study the correlation, ρ: coefficient of Spearman; p: value of significance.
Figure 3 Correlation between cell proliferation and Iba1-expressing microglia. (A–E) Plots showing the density of Ki-67-expressing cells (A), BrdU-labeled cells (B), RGL cells (C), Tbr2-expressing cells (D) and DCX-expressing cells (E), as a function of the density of Iba1-expressing cells, in the dentate gyrus. Each point represents the density of cells for one animal. Spearman's correlation test was used to study the correlation, ρ: coefficient of Spearman; p: value of significance.CC BY · PubMed Central
Figure 4 Effect of microglia on progenitor cells in vitro. (A) Histogram of the change in NPCs number when cultured with microglia or astrocytes (% from the number of plated cells). N = 3 culture wells per group. (B) Confocal maximal projection micrographs of NPCs-microglia co-cultures. (C) Confocal maximal projection micrographs of NPCs-astrocytes co-cultures. N.S.: p > 0.05, ***p < 0.001. Each value represents the mean ± SEM.
Figure 4 Effect of microglia on progenitor cells in vitro. (A) Histogram of the change in NPCs number when cultured with microglia or astrocytes (% from the number of plated cells). N = 3 culture wells per group. (B) Confocal maximal projection micrographs of NPCs-microglia co-cultures. (C) Confocal maximal projection micrographs of NPCs-astrocytes co-cultures. N.S.: p > 0.05, ***p < 0.001. Each value represents the mean ± SEM.CC BY · PubMed Central

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Authors
Gebara, E., Sultan, S., Kocher-Braissant, J., & Toni, N.
Affiliations
University of Lausanne (CH)
Corresponding author
Toni, Nicolas
Venue
Frontiers in Neuroscience
Published
2013
Volume
7
Pages
145-145
ISSN
1662-453X (ISSN-L)
OpenAlex
W2074643664
Cited by
102
References
55
Citations by year
2026: 3 · 2025: 4 · 2024: 7 · 2023: 2 · 2022: 2 · 2021: 8 · 2020: 7 · 2019: 4 · 2018: 6 · 2017: 13 · 2016: 14 · 2015: 17 · 2014: 13 · 2013: 2
FWCI
5.69
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • IRIS (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • SERVAL (Université de Lausanne) (submittedVersion, other-oa)
Funders
  • National Science Foundation
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
  • Fondation Leenaards
  • Université de Lausanne
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
adult hippocampal neurogenesis, microglia, neural stem/progenitor cells, voluntary running, aging, dentate gyrus, granular layer, cell proliferation, astrocyte-microglia interaction, neurogenic niche, neuroinflammation, neuroplasticity

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