Abstract
Systemic infection can result in a spectrum of metabolic and behavioral changes, termed sickness behavior, an organismal reprioritization that suppresses activity, conserves energy, and maximizes the probability of recovery. In vulnerable individuals, acute sickness can include profound acute cognitive impairments including delirium. The molecular mechanisms driving the acute suppression of activity and the acute cognitive deficits arising remain unclear. Here, we hypothesized that disruption of energy metabolism during acute inflammation is a significant contributor to behavioral changes after bacterial endotoxin in mice, and to delirium after inflammatory trauma. LPS (250 μg/kg) and IL-1β (25 μg/kg) markedly decreased blood glucose in c57BL6J mice. LPS-induced decreases in glucose still occurred in IL-1R1−/− mice and in animals treated with IL-1RA (100 μg/kg). Locomotor activity correlated with blood glucose concentration and treatment with glucose (2 g/kg) prevented the suppression of spontaneous activity. Inhibition of glycolysis using 2-deoxyglucose completely suppressed locomotor activity despite preventing IL-1β synthesis. Selectively in ME7 animals with chronic hippocampal and thalamic synaptic loss, LPS (100 μg/kg) produced robust cognitive dysfunction and this could be mimicked with insulin and significantly mitigated with glucose treatment, demonstrating that reduced glucose levels are a major driver cognitive impairment in the vulnerable brain. Analysis of glycolytic metabolites in human CSF from hip fracture patients showed that there is also a significant alteration of brain energy metabolism (elevated lactate and pyruvate) during delirium. Collectively the data suggest that behavioral impacts of acute systemic inflammation are strongly influenced by disruption of energy metabolism.