Adult murine hippocampal neurogenesis is inhibited by sustained IL-1β and not rescued by voluntary running - PubMed (original) (raw)

Adult murine hippocampal neurogenesis is inhibited by sustained IL-1β and not rescued by voluntary running

Michael D Wu et al. Brain Behav Immun. 2012 Feb.

Abstract

Acute neuroinflammation reduces adult hippocampal neurogenesis but the role of chronic neuroinflammation, which may be more representative of ongoing processes in CNS disorders, remains relatively unknown. Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that has been shown to acutely impair neurogenesis. To further investigate the relationship between sustained IL-1β expression and adult neurogenesis, a mouse model with an IL-1β excisionally activated transgene, IL-1β(XAT), was utilized. Upon exposure to Cre recombinase, IL-1β overexpression in this model results in chronic neuroinflammation, which persists up to 12 months and causes glial activation, cellular recruitment, and deficits in learning and memory. We hypothesized that adult neurogenesis would be reduced by sustained hippocampal IL-1β overexpression and rescued by voluntary running, which has been shown to enhance neurogenesis. Hippocampal inflammation in the IL-1β(XAT) model severely impaired doublecortin (DCX) positive cells at 1 and 3 months after IL-1β induction. Furthermore, BrdU labeling demonstrated a shift in cell lineage from neuronal to astroglial in the context of sustained hippocampal IL-1β overexpression. Deletion of the IL-1 receptor prevented the decrease in DCX(+) cells. Voluntary running did not attenuate the effects of IL-1β expression demonstrated by DCX staining. These results suggest that chronic neuroinflammation severely impairs adult hippocampal neurogenesis and voluntary running is not beneficial as a therapy to rescue these effects.

Copyright © 2011 Elsevier Inc. All rights reserved.

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Conflict of interest statement

Conflict of Interest Statement: All authors declare that there are no conflicts of interest.

Figures

Figure 1

Figure 1. Sustained IL-1β overexpression causes focal activation of MHC-II+ cells in the inflamed hippocampus

Staining for MHC-II in the IL-1βXAT model 1 month post-injection of FIV(Cre). Scale bars = 50μm.

Figure 2

Figure 2. Chronic hippocampal IL-1β overexpression ablates adult neurogenesis

(A) Doublecortin staining (green) and Hoechst-stained nuclei (blue) of hippocampal sections from adult IL-1βXAT and control WT mice one month after unilateral FIV(Cre) injection into the dentate gyrus. Scale bars = 50μm. (B,C) Quantification of DCX+ cells in inflamed hippocampi revealed significant decreases at 1 month and 3 months post-induction. n = 11–15 animals/group, 2-way ANOVA for 1 month, and n = 8–9 animals/group, 1-way ANOVA for 3 months. No significant difference was seen between IL-1βXAT + FIV(GFP) and WT + FIV(Cre) groups (C). Data represent means ± SEM. * = p<0.05, ** = p<0.01, *** = p<0.001.

Figure 3

Figure 3. Staining for activated Iba-1+ microglia as well as DCX+ cells in the presence of sustained IL-1β expression

FIV(Cre)-injected hippocampus of IL-1βXAT showed robust microglial activation as shown by increased numbers of Iba-1+ cells with thicker processes 1 month after injection. No direct association with DCX+ cells was seen. Iba-1 = red, DCX = green, Hoechst-stained nuclei = blue. Scale bars = 5μm.

Figure 4

Figure 4. Newborn cells in the SGZ fail to develop into neurons and instead become astroglia in the context of IL-1β overexpression

Experimental design for pulse-labeling with intracerebroventricular BrdU (A,D). IL-1βXAT mice received two intrahippocampal injections, one on each side: FIV(Cre) and FIV(lacZ). Quantification of BrdU+ cells labeled 29 days and 8 weeks previously that colocalize with neuronal (NeuN) and astroglial (GFAP) markers (B,E). Representative immunofluorescent images of BrdU+GFAP+ cells and BrdU+NeuN+ cells (C,F). Images taken at 60X. n = 4 animals per time point, 2-way ANOVA or Student’s t-test. Data represent means ± SEM. * = p<0.05, *** = p<0.001.

Figure 5

Figure 5. The negative effect of IL-1β on DCX+ cells is dependent on the type 1 IL-1 receptor

Quantification of DCX+ cells from FIV(Cre)-injected IL-1βXAT animals 2 weeks post-injection that are wild-type (+/+), heterozygote (+/−), or knockouts (−/−) for the type 1 IL-1 receptor, n = 3 animals/group, 2-way ANOVA. Data represent means ± SEM. ** = p<0.01, *** = p<0.001.

Figure 6

Figure 6. Voluntary running does not alleviate the detrimental effect of IL-1β on DCX+ cells in the SGZ

Experimental design for IL-1βXAT animals that were given access to non-functional (controls) or functional running wheels for 6 weeks prior to sacrifice (A). Quantification of DCX staining demonstrated that voluntary running increased cell numbers only on the contralateral, uninjected hippocampi (B). n = 6–8 animals/group, 2-way ANOVA. Data are means ± SEM. ** = p<0.01.

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