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: 4.85). 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 · 6.13 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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    • "Acute exacerbation of function: Delirium, depression, and cognitive impairment It is now clear that systemic inflammation can induce acute working memory changes in aged animals (Chen et al., 2008) and those with prior neurodegenerative disease (Murray et al., 2012) or cholinergic neuronal loss (Field et al., 2012). These cognitive changes are comparable to the cognitive deficits observed in episodes of delirium in the elderly and demented according to DSM-IV and ICD-10 descriptions (American Psychiatry Association, 1994; WHO, 1992) and microglial priming as observed in these model systems has gained acceptance as a contributor to this clinical scenario (van Gool et al., 2010). "
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    ABSTRACT: It is well accepted that CNS inflammation has a role in the progression of chronic neurodegenerative disease, although the mechanisms through which this occurs are still unclear. The inflammatory response during most chronic neurodegenerative disease is dominated by the microglia and mechanisms by which these cells contribute to neuronal damage and degeneration are the subject of intense study. More recently it has emerged that systemic inflammation has a significant role to play in the progression of these diseases. Well-described adaptive pathways exist to transduce systemic inflammatory signals to the brain, but activation of these pathways appears to be deleterious to the brain if the acute insult is sufficiently robust, as in severe sepsis, or sufficiently prolonged, as in repeated stimulation with robust doses of inflammogens such as lipopolysaccharide (LPS). Significantly, moderate doses of inflammogens produce new pathology in the brain and exacerbate or accelerate features of disease when superimposed upon existing pathology or in the context of genetic predisposition. It is now apparent in multiple chronic disease states, and in ageing, that microglia are primed by prior pathology, or by genetic predisposition, to respond more vigorously to subsequent inflammatory stimulation, thus transforming an adaptive CNS inflammatory response to systemic inflammation, into one that has deleterious consequences for the individual. In this review, the preclinical and clinical evidence supporting a significant role for systemic inflammation in chronic neurodegenerative diseases will be discussed. Mechanisms by which microglia might effect neuronal damage and dysfunction, as a consequence of systemic stimulation, will be highlighted. © 2012 Wiley Periodicals, Inc.
    Glia 01/2013; 61(1). DOI:10.1002/glia.22350 · 6.03 Impact Factor
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