Development of a Mouse Model of Sepsis Associated Encephalopathy and Delirium Using Electroencephalography and Neurobehavior

Abstract

Sepsis is a life-threatening illness characterized by acute organ dysfunction including encephalopathy that clinically manifests as delirium. Survivors experience persistent cognitive deficits that indicate lasting neurological damage from the acute inflammatory and oxidative insult. The underlying cerebral pathology of delirium and its contributions to development of cognitive deficits are not well understood due to limited preclinical tools. Using neurobehavioral testing and electrophysiology in a cecal slurry mouse model of sepsis, we characterized cerebral inflammatory and oxidative profiles, assessed lasting behavioral changes amidst varying antioxidant supplementation, and established prominent electroencephalogram metrics contributing to delirium severity and long-term cognitive decline. Following cecal slurry treatment, antioxidant reserves in the brain were challenged amidst a robust neuroinflammatory response, and surviving mice experienced persistent deficits in spatial memory, grip strength, and executive function that were not exacerbated by prior antioxidant deficiency. Generalized slowing in the electroencephalogram and hypersensitivity to acoustic stimulus implicated an observable delirium-like status in critically ill mice. Poorer executive function correlated with decreased hippocampal long-term potentiation up to 7 days following illness. Together, these studies outline a comprehensive mouse model of sepsis associated encephalopathy for preclinical investigation to improve delirium and long-term cognitive outcomes in patients.