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

Trinity College Institute of Neuroscience, School of Biochemistry & Immunology, Trinity College Dublin, Dublin, Ireland.
Neurobiology of aging (Impact Factor: 5.01). 03/2012; 33(3):603-616.e3. DOI: 10.1016/j.neurobiolaging.2010.04.002
Source: PubMed


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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    • "Thus far, few animal models related to the study of delirium have been established. Murray et al. reported that the " paddling " T-maze alternation task might be used to detect acute working memory deficits induced by systemic administration of bacterial endotoxin lipopolysaccharide (LPS), which might be utilized to study delirium (Murray et al., 2012). The attentional setshifting task (AST), another potential animal model that could be used to study delirium (Culley et al., 2014), includes tests of discrimination problems, which are based on stimulus dimensions (e.g., odor and intra-and extra-dimensional cues). "
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    • "However, some recent evidences suggest that at least microglia and leukocytes infiltration could be involved in this effect. Amplified central inflammatory response following immune challenge may be related to microglial priming, which induces stronger cytokine production and/or impairments in resolving the inflammation (Chen et al., 2008; Field et al., 2012; Murray et al., 2012). This could also be mediated by the transmigration of cytokines-expressing leukocyte to the brain following systemic LPS injection (Rummel et al., 2010). "
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    • "The pathogenesis of delirium is poorly understood, in part because there is no widely accepted animal model for examining mechanisms of the disorder. There are a multitude of putative causes of delirium but inflammation is a prime suspect based on clinical studies that reveal it is often precipitated in elderly patients by proinflammatory events such as infectious illness or surgery and laboratory evidence that cytokines and chemokines impair memory and leaning directly (Marcantonio et al., 2006; Rudolph et al., 2008; van Gool et al., 2010; Murray et al., 2012). "
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