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.

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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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    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. jHFD exposure impaired long-term spatial reference memory in the Morris water maze without affecting acquisition or short-term memory. This suggests an effect on consolidation processes. Moreover, jHFD consumption delayed spatial reversal learning. jHFD intake did neither affect basal expression of pro-inflammatory cytokines at the periphery nor in the brain, but potentiated the enhancement of Interleukin-1-beta and Tumor Necrosis Factor-alpha expression specifically in the hippocampus after a peripheral immune challenge with lipopolysaccharide. Interestingly, whereas the same duration of HFD intake at adulthood induced similar weight gain and metabolic alterations as jHFD intake, it did neither affect spatial performance (long-term memory or reversal learning) nor lipopolysaccharide-induced cytokine expression in the hippocampus. Finally, spatial reversal learning enhanced Interleukin-1-beta in the hippocampus, but not in the frontal cortex and the hypothalamus, of jHFD-fed rats. These results indicate that juvenile HFD intake promotes exaggerated pro-inflammatory cytokines expression in the hippocampus which is likely to contribute to spatial memory impairment.
    Brain Behavior and Immunity 08/2014; 40. DOI:10.1016/j.bbi.2014.03.005 · 5.89 Impact Factor
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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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    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.
    Frontiers in Aging Neuroscience 06/2014; 6:107. DOI:10.3389/fnagi.2014.00107 · 4.00 Impact Factor
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    • "Mullington et al. (2000) found that a small nocturnal dose of endotoxin increases cytokines (TNF-a, IL-6, IL-1Ra) but also induces increased NREM sleep, while a high dose of endotoxin disrupts sleep, concluding that sleep–wake behaviour is very sensitive to levels of inflammatory cytokines [81]. Other studies have highlighted the significant role of inflammatory mechanisms in delirium pathogenesis [72] [82]. Patients with active delirium have low levels of anti-inflammatory markers such as IL-1Ra and Insulin-like growth factor and significantly elevated levels of inflammatory markers such as IFN-gamma and C-reactive protein [83] [84]. "
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    ABSTRACT: Delirium is a serious neuropsychiatric syndrome of acute onset that occurs in approximately one in five general hospital patients and is associated with serious adverse outcomes that include loss of adaptive function, persistent cognitive problems and increased mortality. Recent studies indicate a three-domain model for delirium that includes generalised cognitive impairment, disturbed executive cognition, and disruption of behaviours that are under circadian control such as sleep-wake cycle and motor activity levels. As a consequence, attention has focused upon the possible role of the circadian timing system (CTS) in the pathophysiology of delirium. We explored this possibility by reviewing evidence that (1) many symptoms that occur in delirium are influenced by circadian rhythms, (2) many features of recognised circadian rhythm disorders are similar to characteristic features of delirium, (3) common risk factors for delirium are known to disrupt circadian systems, (4) physiological disturbances of circadian systems have been noted in delirious patients, and (5) positive effects in the treatment of delirium have been demonstrated for melatonin and related agents that influence the circadian timing system. A programme of future studies that can help to clarify the relevance of circadian integrity to delirium is described. Such work can provide a better understanding of the pathophysiology of delirium while also identifying opportunities for more targeted therapeutic efforts.
    Medical Hypotheses 07/2013; 81(4). DOI:10.1016/j.mehy.2013.06.032 · 1.07 Impact Factor
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