Acute Inflammation Alters Brain Energy Metabolism in Mice and Humans: Role in Suppressed Spontaneous Activity, Impaired Cognition, and Delirium

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 mg/kg) induced hypoglycemia, which was mimicked by interleukin (IL)-1b (25 mg/kg) but not prevented in IL-1RI 2/2 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-1b 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 mg/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.

Acute colitis during chronic experimental traumatic brain injury in mice induces dysautonomia and persistent extraintestinal, systemic, and CNS inflammation with exacerbated neurological deficits

“…Sustained systemic inflammation initiated by an enteric challenge likely enhances the risk of neurodegenerative and neuropsychiatric diseases. Our findings are consistent with literature regarding clinically relevant sickness behavior [ 127 , 128 ], which occurs in response to systemic inflammation and includes changes in brain energy metabolism and neuroinflammation, affecting mood and cognition [ 129 ].…”

Delirium

“…In small studies in patients, delirium was associated with decreased cerebral blood flow (30-50%) that resolved at the time of recovery 92 and with impaired autoregulation in patients with sepsis 93 . Consistent with a possible role for hypoxia, cerebrospinal fluid (CSF) lactate levels were significantly elevated in hip fracture and general medical patients with delirium 94,95 . Brain tissue hypoxia can be assessed in patients using near infrared spectroscopy.…”

“…Hypoglycaemia is not commonly observed in patients with delirium but infection, surgery and trauma can all trigger insulin insensitivity 104,105 , which limits glucose uptake and use. Glucose utilization 106 and insulin signalling 107 are markedly reduced in patients with Alzheimer disease and these individuals might, therefore, be particularly susceptible to the effects of limited glucose availability, as was shown in an animal model of delirium 95 . FDG-PET imaging data revealed that glucose uptake is substantially reduced in rats with lipopolysaccharide-induced sepsis 108 and human FDG-PET imaging data showed reduced glucose metabolism during delirium 109 .…”

“…Hypoglycaemia also substantially increases the risk of delirium in ICU patients 103 . In mice, both lipopolysaccharide and IL-1β trigger hypoglycaemia, selectively causing acute cognitive dysfunction in animals with prior neurodegeneration, and glucose treatment mitigated these cognitive deficits 95 . Hypoglycaemia is not commonly observed in patients with delirium but infection, surgery and trauma can all trigger insulin insensitivity 104,105 , which limits glucose uptake and use.…”

Sex-specific metabolic alterations in the type 1 diabetic brain of mice revealed by an integrated method of metabolomics and mixed-model

“…Systemic inflammation has been associated with the pathogenesis of diabetes and its complications [72] , [73] , [74] . Furthermore, of note, inflammation can affect brain metabolism, such as glucose metabolism [75] , energy metabolism [76] , [77] and tryptophan metabolism [78] . The limitation of this study is that inflammation-induced metabolic alterations were not investigated.…”