Kealy, John and Murray, Carol and Griffin, Éadaoin W. and Lopez-Rodriguez, Ana Belen and Healy, Dáire and Tortorelli, Lucas Silva and Lowry, John P. and Watne, Leiv Otto and Cunningham, Colm (2020) Acute Inflammation Alters Brain Energy Metabolism in Mice and Humans: Role in Suppressed Spontaneous Activity, Impaired Cognition, and Delirium. The Journal of Neuroscience, 40 (29). pp. 5681-5696. ISSN 0270-6474

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Abstract

Systemic infection triggers a spectrum of metabolic and behavioral changes, collectively termed sickness behavior, which while adaptive, 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 female 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 µg/kg) induced hypoglycemia, which was mimicked by interleukin (IL)-1β (25 µg/kg) but not prevented in IL-1RI-/- mice, nor by IL-1 receptor antagonist (IL-1RA; 10 mg/kg). LPS suppression of locomotor activity correlated with blood glucose concentrations, was mitigated by exogenous glucose (2 g/kg), and was exacerbated by 2-deoxyglucose (2-DG) glycolytic inhibition, despite preventing IL-1β synthesis. Using the ME7 model of chronic neurodegeneration in female mice, 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 selectively in the vulnerable brain. To test whether these acute changes might predict altered carbohydrate metabolism during delirium, we assessed glycolytic metabolite levels in CSF in humans during inflammatory trauma-induced delirium. Hip fracture patients showed elevated CSF lactate and pyruvate during delirium, consistent with acutely altered brain energy metabolism. Collectively, the data suggest that disruption of energy metabolism drives behavioral and cognitive consequences of acute systemic inflammation.SIGNIFICANCE STATEMENT Acute systemic inflammation alters behavior and produces disproportionate effects, such as delirium, in vulnerable individuals. Delirium has serious short and long-term sequelae but mechanisms remain unclear. Here, we show that both LPS and interleukin (IL)-1β trigger hypoglycemia, reduce CSF glucose, and suppress spontaneous activity. Exogenous glucose mitigates these outcomes. Equivalent hypoglycemia, induced by lipopolysaccharide (LPS) or insulin, was sufficient to trigger cognitive impairment selectively in animals with existing neurodegeneration and glucose also mitigated those impairments. Patient CSF from inflammatory trauma-induced delirium also shows altered brain carbohydrate metabolism. The data suggest that the degenerating brain is exquisitely sensitive to acute behavioral and cognitive consequences of disrupted energy metabolism. Thus "bioenergetic stress" drives systemic inflammation-induced dysfunction. Elucidating this may offer routes to mitigating delirium.

Item Type:	Article
Additional Information:	This work was supported by The Wellcome Trust Grant CC SRF 090907 and by the National Institutes of Health Grant R01AG050626. J.P.L. was supported by the Health Research Board Grant EQ/2004/12. L.O.W. was supported by the Norwegian Health Association and by the South-Eastern Norway Regional Health Authorities. We thank Prof. Stuart Allan for the gift of IL-1RA and Prof. Kingston Mills for the gift of IL-1RI/mice. A prior version of this article was made available as a preprint on BioRxiv (https://doi.org/10.1101/642967). *J.K. and C.M. contributed equally to this work. The authors declare no competing financial interests. Correspondence should be addressed to Colm Cunningham at colm.cunningham@tcd.ie. https://doi.org/10.1523/JNEUROSCI.2876-19.2020 Copyright © 2020 Kealy, Murray et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License Creative Commons Attribution 4.0 International, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Keywords:	IL-1; cognitive; delirium; dementia; hypoglycemia; sepsis;
Academic Unit:	Faculty of Science and Engineering > Chemistry
Item ID:	15055
Identification Number:	https://doi.org/10.1523/JNEUROSCI.2876-19.2020
Depositing User:	John Lowry
Date Deposited:	23 Nov 2021 17:20
Journal or Publication Title:	The Journal of Neuroscience
Publisher:	Society for Neuroscience
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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