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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-1b (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-1b 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. Introduction:Systemic infection can result in a spectrum of metabolic and behavioral changes, termed sickness behavior, which includes fever, lethargy, loss of appetite, anhedonia, and impairments in cognitive function (1). Sickness behavior is an evolutionarily conserved response to illness and is thought to represent a reprioritization by the organism to conserve energy and maximize the probability of recovery (2). Systemic administration of the bacterial endotoxin lipopolysaccharide (LPS), can induce sickness behavior in humans (3, 4) and rodents (1, 5) and although peripheral LPS does not readily cross the blood-brain barrier (6) it significantly increases systemic and central pro-inflammatory cytokines including interleukin-1b (IL-1b), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-a) (1,7,8) and can alter resting state networks (9) and local field potential (10, 11). Therefore information about the inflammatory status of the periphery is communicated to the brain and this occurs by multiple routes: i) direct neural activation of the brainstem and hypothalamus via sensory afferents such as the vagus nerve; ii) activation of macrophages of the circumventricular organs that lack a patent BBB, leading to sec...

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