Endocrine Abstracts

Critically ill patients are exposed to high levels of corticosteroids during their illness. While corticosteroid treatment has a modest effect on illness severity and survival dependent on the underlying diagnosis, observational and randomized data suggests that it also influences long-term neuropsychiatric outcomes. The mechanisms by which corticosteroid exposure during acute illness alters long-term brain function and neuropsychiatric risk are unknown. Because of the importance of the hippocampus for memory and mood and its known glucocorticoid sensitivity, we hypothesized that corticosteroid treatment during illness has long-term effects on hippocampal function in survivors. We tested this hypothesis in male and female mice using a widely used sepsis model, cecal ligation and puncture. Long-term CLP survivors exhibited anxiety-like behavior, increased central hypothalamic-pituitary-adrenal (HPA) axis activity, and persistent systemic and neuro-inflammation. Corticosterone treatment during illness primarily modified cognitive outcomes, improving non-fear memories from the time of the illness but impairing the formation of new memories. Corticosteroid-treated mice showed persistent downregulation of activity-dependent hippocampal genes suggesting a sustained decrease in hippocampal neural activity. The results suggest that corticosteroid treatment during sepsis influences hippocampal function in survivors via long-lasting changes to hippocampal activity. The relationships between gene expression, behavior, and neuroendocrine activity pointed to the importance of neural activity as well as inflammation and oxidative metabolism in functional outcomes.