Systemic inflammation impairs attention and cognitive flexibility but not associative learning in aged rats: possible implications for delirium - PubMed (original) (raw)

Systemic inflammation impairs attention and cognitive flexibility but not associative learning in aged rats: possible implications for delirium

Deborah J Culley et al. Front Aging Neurosci. 2014.

Abstract

Delirium is a common and morbid condition in elderly hospitalized patients. Its pathophysiology is poorly understood but inflammation has been implicated based on a clinical association with systemic infection and surgery and preclinical data showing that systemic inflammation adversely affects hippocampus-dependent memory. However, clinical manifestations and imaging studies point to abnormalities not in the hippocampus but in cortical circuits. We therefore tested the hypothesis that systemic inflammation impairs prefrontal cortex function by assessing attention and executive function in aged animals. Aged (24-month-old) Fischer-344 rats received a single intraperitoneal injection of lipopolysaccharide (LPS; 50 μg/kg) or saline and were tested on the attentional set-shifting task (AST), an index of integrity of the prefrontal cortex, on days 1-3 post-injection. Plasma and frontal cortex concentrations of the cytokine TNFα and the chemokine CCL2 were measured by ELISA in separate groups of identically treated, age-matched rats. LPS selectively impaired reversal learning and attentional shifts without affecting discrimination learning in the AST, indicating a deficit in attention and cognitive flexibility but not learning globally. LPS increased plasma TNFα and CCL2 acutely but this resolved within 24-48 h. TNFα in the frontal cortex did not change whereas CCL2 increased nearly threefold 2 h after LPS but normalized by the time behavioral testing started 24 h later. Together, our data indicate that systemic inflammation selectively impairs attention and executive function in aged rodents and that the cognitive deficit is independent of concurrent changes in frontal cortical TNFα and CCL2. Because inattention is a prominent feature of clinical delirium, our data support a role for inflammation in the pathogenesis of this clinical syndrome and suggest this animal model could be useful for studying that relationship further.

Keywords: CCL2; aging neuroscience; frontal cortex; inflammation; lipopolysaccharides; rats; set-shifting.

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Figures

Figure 1

Figure 1

Lipopolysaccharide (LPS) produces a robust but transient increase in plasma TNFα and CCL2. Plasma was sampled at the time of sacrifice from aged Fisher 344 rats 2, 24, and 48 h after administration of 50 μg/kg LPS (N = 5 per group) or a control group (N = 5) that received an equal volume of saline intraperitoneally. There was a marked increase in both TNFα (A) and CCL2 (B) 2 h after LPS but the effect resolved completely by 24 or 48 h, respectively. Data are mean ± SEM. ***P < 0.001 by one-way ANOVA.

Figure 2

Figure 2

Lipopolysaccharide (LPS) produces a robust but transient increase in TNFα and CCL2 in the frontal cortex. Rats (N = 5 per group) were treated as described in Figure 1 and frontal cortex harvested at the time of sacrifice. There was no change in TNFα in the frontal cortex at any time compared to control animals (A). CCL2 was elevated nearly threefold above control 2 h after LPS but this resolved by 24 h after treatment (B). Data are mean ± SEM. ***P < 0.001 by one-way ANOVA.

Figure 3

Figure 3

Lipopolysaccharide selectively impaired attention/executive function in aged rats. Twenty-four-month-old Fischer-344 rats (N = 11) were tested on two simple discrimination (SD) tasks, one from each dimension (medium and shape) prior to receiving LPS 50 μg/kg or an equal volume of saline i.p. They were tested on the compound discrimination (CD) task and compound discrimination reversal (CD-R) on day 1 after LPS, the intradimensional shift (IDS) and intradimensional shift reversal (IDS-R) on day 2 after LPS, and the extradimensional shift (EDS) on day 3 after LPS. There were no differences between the groups at baseline. LPS did not affect performance on the CD or IDS task but impaired performance on the CD-R and the EDS. This indicates LPS had no effect on simple discrimination learning but did impair attention/executive function for at least 3 days. Data are mean ± SEM. *P ≤ 0.05, **P ≤ 0.01 by two-way ANOVA.

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