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. 2012 Mar;33(3):603-616.e3.
doi: 10.1016/j.neurobiolaging.2010.04.002. Epub 2010 May 14.

Systemic inflammation induces acute working memory deficits in the primed brain: relevance for delirium

Carol Murray  1 , David J Sanderson, Chris Barkus, Robert M J Deacon, J Nicholas P Rawlins, David M Bannerman, Colm Cunningham
Affiliations

Systemic inflammation induces acute working memory deficits in the primed brain: relevance for delirium

Carol Murray et al. Neurobiol Aging. 2012 Mar.

Abstract

Delirium is an acute, severe neuropsychiatric syndrome, characterized by cognitive deficits, that is highly prevalent in aging and dementia and is frequently precipitated by peripheral infections. Delirium is poorly understood and the lack of biologically relevant animal models has limited basic research. Here we hypothesized that synaptic loss and accompanying microglial priming during chronic neurodegeneration in the ME7 mouse model of prion disease predisposes these animals to acute dysfunction in the region of prior pathology upon systemic inflammatory activation. Lipopolysaccharide (LPS; 100 μg/kg) induced acute and transient working memory deficits in ME7 animals on a novel T-maze task, but did not do so in normal animals. LPS-treated ME7 animals showed heightened and prolonged transcription of inflammatory mediators in the central nervous system (CNS), compared with LPS-treated normal animals, despite having equivalent levels of circulating cytokines. The demonstration that prior synaptic loss and microglial priming are predisposing factors for acute cognitive impairments induced by systemic inflammation suggests an important animal model with which to study aspects of delirium during dementia.

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Figures

Figure S1
Figure S1
Rate of learning of correct responding (alternation) in the shallow water T-maze in ME7 versus NBH animals late or early in disease. a) Alternation performance of ME7 and NBH animals was examined daily starting from 18 weeks post-inoculation for four successive days. b) Alternation performance of ME7 and NBH animals was examined daily starting from 10 weeks post-inoculation for 10 successive days. Data are shown as mean ± SEM and were analysed by repeated measures ANOVA using training block as the within subjects factor and disease as the between subjects factor. n = 10 for ME7 and n = 9 for NBH at 18 weeks and n = 20 for ME7 and n = 15 for NBH at 12 weeks.
Figure S2
Figure S2
Effect of LPS or saline on mRNA expression of inflammatory receptors in ME7 and NBH animals as assessed by quantitative PCR. Transcripts a) TLR4, b) IL-1RI, c) TNFRp55, d) IFNAR2, e) CD68 and f) TREM2 were assessed 4 hours post intraperitoneal challenge with LPS (100 μg/kg) or sterile saline. Data are shown as mean ± SEM and data were analysed by two-way ANOVA using disease (ME7 vs NBH) and treatment (LPS vs saline) as factors for main effects. Results of statistical analysis are presented in full in the text. n = 5 for both ME7 groups and n = 4 for both NBH groups.
Fig. 1
Fig. 1
Hippocampal vulnerability: synaptic loss and inflammatory priming. Presynaptic terminals in the stratum oriens (so), stratum radiatum (rad) and stratum lacunosum moleculare (lac) of the hippocampus, visualized by immunostaining with sy38 anti-synaptophysin in NBH (a and c, ×20 and ×40, respectively) and ME7 animals at 12 weeks postinoculation (b and d, ×20 and ×40, respectively). Increased microglial numbers and activation state in the same region of NBH (e) and ME7 animals (f), labeled using anti-IBA-1 antibody against microglia and visualized at ×20. (g) Hippocampal expression of the inflammatory receptors TLR4, IL-1R1, TNFR p55, and IFNAR2, microglial CD68 and uPAR and the myeloid-restricted anti-inflammatory markers TREM2 and CD200R in ME7 and NBH animals at 12 weeks. Significant differences by Student t test are denoted by * (p < 0.05), ** (p = 0.0027), and *** (p < 0.001). n = 9, ME7; and n = 4, NBH. Scale bar = 100 μm in a and b and 50 μm in c-f.
Fig. 2
Fig. 2
LPS-induced working memory deficits and validation of T-maze alternation. (a) Performance of ME7+LPS (n = 12), ME7+saline (n = 11), NBH+LPS (n = 13) and NBH+saline (n = 11) animals in the novel T-maze alternation task at baseline (−22, −24 hours), posttreatment with saline or LPS (3, 5, 7 hours) and upon recovery (24, 26 hours). Schematic representation of this T-maze is shown on right, illustrating forced entry to 1 arm on the sample run and alternation on the choice run. Simple main effects analysis revealed an effect of LPS specifically in the ME7 group and this is denoted by * (p < 0.001). (b) Performance of similar groups in the egocentric Y-maze (shown on right), 3 hours posttreatment, assessed as 2 blocks of 6 trials. Repeated measures analysis of variance (ANOVA) revealed no effect of treatment, but a main effect of block (denoted as *, p < 0.0001). n = 15, ME7+LPS; n = 13, NBH+LPS; n = 9, ME7+saline, and NBH+saline. (c) Performance of the T-maze alternation spatial working memory task (after training: 10 blocks of 10 trials) in normal C57BL6 mice treated with LPS 200 μg/kg (n = 9) or sterile saline (n = 9). There were no effects of treatment. (d) Training of hippocampal-lesioned (n = 8) and sham-operated animals (n = 12) on the spatial working memory T-maze task. A main effect of lesion group (p = 0.0021) in a 2-way ANOVA analysis is denoted by *. (e) Cresyl violet-stained coronal sections from representative sham-operated and hippocampal-lesioned animals.
Fig. 3
Fig. 3
Comparison of systemic and hippocampal cytokine responses. Plasma was prepared from whole blood of NBH and ME7 animals 1, 2, 4, or 8 hours posttreatment with LPS or saline and samples were analyzed for (a) TNF-α, (b) IL-6, and (c) IL-1β protein levels. Two-way analysis of variance (ANOVA) of NBH+LPS versus ME7+LPS revealed no effect of disease for any cytokine (F ≤ 2.22, df, 1,7, p ≥ 0.18). There were significant interactions of treatment and time and significant pair-wise comparisons by Bonferroni posthoc are denoted by * (p < 0.05) or ** (p < 0.01). NBH+LPS (n = 4) and ME7+LPS (n = 5). Saline-treated groups did not show detectable levels of these cytokines (n = 4–5). (d–g) CNS cytokine transcription was assessed at the same time points by quantitative PCR. All genes were elevated after LPS treatment. ME7+LPS animals were compared with NBH+LPS group by repeated measures, 2-way ANOVA. Statistical significance by Bonferroni posthoc tests after a significant main effect is denoted by * (p < 0.05), ** (p < 0.01), or *** (p < 0.001). n = 5 for all ME7 groups and n = 4 for all NBH groups.
Fig. 4
Fig. 4
Microglial priming and further activation. IBA-1 immunolabelling has been used to demonstrate increased numbers of microglia and morphological changes in the hippocampus of ME7 animals (b) and ME7+LPS animals (c) compared with NBH animals (a) photographed at ×20 magnification. Morphological changes can be seen in insets (a–c) (×100). Immunostaining with anti-IL-1β antibody, photographed at ×40 magnification, shows perivascular and parenchymal IL-1β-positive cells at 3 hours post-LPS in the hippocampus (d) and the thalamus (f) of ME7+LPS animals, with morphology indicative of microglial cells (e; ×100). IL-1β was not detected in ME7+saline (g) or in NBH+LPS (h). Scale bar (a) represents 100 μm in pictures a, b, and c, and 20 μm in the insets. Scale bar (d) represents 100 μm in (d) and 125 μm in (f, g, and h) and 12.5 μm in (e).
Fig. 5
Fig. 5
Expression of transcripts for downstream or effector molecules. Expression of microglial (uPAR, CD200R, COX-2), endothelial (VCAM-1, COX-2), NF-kB-dependent (iNOS, MCP-1, PTX3, COX-2, VCAM-1), and stat 1/2 dependent (IRF7) transcripts was examined at 1, 2, 4, and 8 hours postchallenge with LPS in NBH and ME7 animals and compared with ME7 or NBH animals treated with saline (4 hours). ME7+LPS and NBH+LPS were compared by 2-way analysis of variance (ANOVA) with treatment and time post-LPS as factors. Main effects are described in the main text. Significant differences, by Bonferroni posthoc tests, between ME7+LPS and corresponding time point in NBH+LPS, are denoted by * (p < 0.05), and ** (p < 0.01).
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