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. 2008 Mar;22(3):301-11.
doi: 10.1016/j.bbi.2007.08.014. Epub 2007 Oct 24.

Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system

Jing Chen  1 , Jessica B Buchanan, Nathan L Sparkman, Jonathan P Godbout, Gregory G Freund, Rodney W Johnson
Affiliations

Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system

Jing Chen et al. Brain Behav Immun. 2008 Mar.

Abstract

Acute cognitive disorders are common in elderly patients with peripheral infections but it is not clear why. Here, we injected old and young mice with Escherichia coli lipopolysaccharide (LPS) to mimic an acute peripheral infection and separated the hippocampal neuronal cell layers from the surrounding hippocampal tissue by laser capture microdissection and measured mRNA for several inflammatory cytokines (IL-1 beta, IL-6, and TNFalpha) that are known to disrupt cognition. The results showed that old mice had an increased inflammatory response in the hippocampus after LPS compared to younger cohorts. Immunohistochemistry further showed more microglial cells in the hippocampus of old mice compared to young adults, and that more IL-1 beta-positive cells were present in the dentate gyrus and in the CA1, CA2, and CA3 regions of LPS-treated old mice compared to young adults. In a test of cognition that required animals to effectively integrate new information with a preexisting schema to complete a spatial task, we found that hippocampal processing is more easily disrupted in old animals than in younger ones when the peripheral innate immune system is stimulated. Collectively, the results suggest that aging can facilitate neurobehavioral complications associated with peripheral infections probably by allowing the over expression of inflammatory cytokines in brain areas that mediate cognitive processing.

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Figures

Figure 1
Figure 1
Laser capture microdissection (LCM) of hippocampal tissue. Prior to determination of steady-state levels of inflammatory cytokine mRNA the DG and CA regions were separated from surrounding hippocampal tissue by LCM. (A) An intact cresyl violet-stained coronal brain section that reveals the CA neuronal cell layer and DG in a young adult mouse brain; (B) the same section after the CA regions and DG were outlined using a 15 μm laser spot with a power setting of 35 mW and pulse duration of 6 ms; (C) the section after the CA regions and DG were captured on to an Arturus CapSure HS LCM cap (note the surrounding tissue remains intact); and (D) the CA regions and DG that were captured. Increasing numbers of hippocampal neuronal cell layers (D) were pooled to determine the minimum needed to measure inflammatory cytokine mRNA by real-time PCR without RNA amplification. (E) The number of LCM sections pooled was positively correlated with the amount of RNA extracted (r=0.9782, p < 0.01). (F) In real-time PCR, as the amount of starting RNA (logarithm) increased, the Ct values for GAPDH (r=0.9991, p < 0.001) and IL-6 (r=0.9956, p < 0.001) decreased. As described in the results it was determined that a minimum of four LCM sections were needed to provide enough RNA for our real-time PCR protocol.
Figure 2
Figure 2
Inflammatory cytokine mRNA in hippocampal tissue that was separated by laser capture microdissection. Young and old mice were injected i.p. with LPS or saline and killed 4 h later for tissue collection. Inflammatory cytokine mRNA levels in hippocampal neuronal cell layers (DG and CA regions) (A) and surrounding hippocampal tissue (B) were determined by real-time PCR. Bars represent mean ±S.E.M. Means with different letters are significantly different from each other, p < 0.05.
Figure 3
Figure 3
Immunohistochemical staining of IL-1β-positive cells in hippocampus. Young and old mice were injected i.p. with LPS or saline and 4 h later their brains were collected. Bar graphs summarize the number of IL-1β-positive cells per 100μm2 (A). Bars represent mean ±S.E.M. Means with different letters are significantly different from each other, p < 0.05. Pictures are representative photomicrographs of the DG for an old and young mouse given LPS or saline at a magnification of 40×. (B) Scale bar = 25 μm.
Figure 4
Figure 4
Tomato lectin staining of microglia in hippocampi of young adult and old mice. Representative photomicrographs showing at 40×magnification microglia stained with tomato lectin in the DG of young adult (A) and old (B) mice. Scale bar = 25 μm. The bar graph (C) summarizes the number of microglia that stained with tomato lectin per 100μm2 for both the DG and CA3 regions in young and old mice. Data are presented as mean ± S.E.M. Means with different letters are significantly different from each other, p < 0.05. The photomicrographs to the lower right show a tomato lectin stained microglial cell (D) and an IL-1β-positive cell (E) at 100× magnification within the DG. Scale bar = 10 μm.
Figure 5
Figure 5
Effects of LPS on performance of young and old mice in the matching-to-place test. Young and old mice were trained in the radial arm water maze for 8 d. After the 8 d acquisition training mice were injected with saline or LPS and performance in the matching-to-place test was evaluated 4 h later. Performance of acquisition and test phase in young (white circles) and old (black circles) mice was shown in mean distance (A and D), latency to find the platform (B and E) and swim speed (C and F). Data are presented as mean±S.E.M. * - denotes significant difference between groups as determined by Fisher’s PLSD (p < 0.05).
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Comment in

  • The risky business of ageing.
    Lynch MA. Lynch MA. Brain Behav Immun. 2008 Mar;22(3):299-300. doi: 10.1016/j.bbi.2007.10.008. Epub 2007 Nov 26. Brain Behav Immun. 2008. PMID: 18042344

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