Acute inflammation alters energy metabolism in mice and humans: Role in sickness-induced hypoactivity, impaired cognition and delirium.

Abstract

Systemic infection triggers a spectrum of metabolic and behavioral changes, collectively termed sickness behavior, that while adaptive for the organism, can affect mood and cognition. In vulnerable individuals, acute illness can also produce profound, maladaptive, cognitive dysfunction including delirium, but our understanding of delirium pathophysiology remains limited. Here we used bacterial lipopolysaccharide (LPS) in C57BL/6J mice and acute hip fracture in humans to address whether disrupted energy metabolism contributes to inflammation-induced behavioral and cognitive changes. LPS (250 μ/kg) induced hypoglycemia, which was mimicked by IL-1β (25 μg/kg) but not prevented in IL-1RI-/- mice, nor by IL-1RA (10 mg/kg). LPS suppression of locomotor activity correlated with blood glucose concentration, was mitigated by exogenous glucose (2 g/kg) and was exacerbated by 2-deoxyglucose glycolytic inhibition, which prevented IL-1β synthesis. Using the ME7 model of chronic neurodegeneration, to examine vulnerability of the diseased brain to acute stressors, we showed that LPS (100 μg/kg) produced acute cognitive dysfunction, selectively in those animals. These acute cognitive impairments were mimicked by insulin (11.5 IU/kg) and mitigated by glucose, demonstrating that acutely reduced glucose metabolism impairs cognition in the vulnerable brain. To test whether these acute changes might predict altered carbohydrate metabolism during delirium, we assessed glycolytic metabolite levels in cerebrospinal fluid (CSF) in humans during delirium, triggered by acute inflammatory trauma. Hip fracture patients showed elevated CSF lactate and pyruvate during delirium, consistent with altered brain energy metabolism. Collectively the data suggest that disruption of energy metabolism drives behavioral and cognitive consequences of acute systemic inflammation.

Footnotes

* This version of the manuscript has been revised to update the following: 1) We have performed further correlations of plasma glucose with locomotor activity to illustrate that this correlation becomes stronger when vehicle-treated animals are omitted from the analysis and only LPS-treated animals are included (Fig. 2A). 2) We have included data to show that while LPS induced decreased locomotor activity, these animals were still capable of movement. There decreased activity represented a suppression of spontaneous activity (Figure 2B) 3) We have included analyses of the time course of glucose elevation after i.p. injection of glucose at 2g/Kg (Figure 2G). 4) We included data to show that 2-deoxyglucose, in the absence of LPS does not significant affect locomotor activity or plasma glucose (Figure 2 J,K).