Article

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

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.

Download full-text

Full-text

Available from: sciencedirect.com · License: CC BY
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: There is a need to develop animal models to study postoperative delirium. Inattention is one of the symptoms of delirium. Increases in the levels of α-synuclein and S100β have been reported to be associated with delirium. Therefore, we set out to determine the effects of surgery plus general anesthesia on the behavioral changes (including loss of attention) in mice and on the levels of α-synuclein and S100β in the brain tissues of these mice. C57BL/6J mice (2- to 8-months-old) had a simple laparotomy plus isoflurane anesthesia. The behavioral changes, including attention level and the speed of movements, were determined 12, 24, and 48 h after the surgery plus anesthesia in the mice. The levels of α-synuclein and S100β in the cortex of these mice following the surgery plus anesthesia were determined by Western blot analysis. We found that there was a loss of attention at 24, but not 12 or 48 h following the surgery plus anesthesia (49% ± 5 vs. 33% ± 2.9, P = 0.011, N = 12) in the mice without significantly affecting the speed of their movements. There were increases in the levels of total α-synuclein (139% ± 33.5 vs. 100% ± 13.7, P = 0.037, N = 6) and S100β (142% ± 7.7 vs. 100% ± 6, P = 0.002, N = 6) in the cortex of the mice 12 h following the surgery plus anesthesia. These findings suggested that the surgery plus isoflurane anesthesia might induce behavioral and biochemical/cellular changes associated with delirium. We could use the surgery plus anesthesia in mice to develop an animal model to study postoperative delirium.
    Full-text · Article · Sep 2015 · Frontiers in Cellular Neuroscience
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In addition to metabolic and cardiovascular disorders, obesity pandemic is associated with chronic low-grade inflammation as well as adverse cognitive outcomes. However, the existence of critical periods of development that differ in terms of sensitivity to the effects of diet-induced obesity remains unexplored. Using short exposure to a high-fat diet (HFD) exerting no effects when given to adult mice, we recently found impairment of hippocampal-dependent memory and plasticity after similar HFD exposure encompassing adolescence (from weaning to adulthood) showing the vulnerability of the juvenile period (Boitard et al., 2012). Given that inflammatory processes modulate hippocampal functions, we evaluated in rats whether the detrimental effect of juvenile HFD (jHFD) on hippocampal-dependent memory is associated with over-expression of hippocampal pro-inflammatory cytokines.
    Full-text · Article · Aug 2014 · Brain Behavior and Immunity
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Jun 2014 · Frontiers in Aging Neuroscience
Show more