Corticosterone Enhances Formation of Neutral but Not Fear Memory During Infectious Illness

Survivors of critical illness often report traumatic memories of their illness period, and these memories are thought to contribute to development of neuropsychiatric disorders, such as PTSD. Many patients are treated with high doses of glucocorticoids for their vasoactive and anti-inflammatory properties, and glucocorticoids have also been shown to prevent the development of PTSD after trauma. Due to their activity in the hippocampus and amygdala, the putative protective effect of glucocorticoids may occur via memory formation during illness. To examine the effect of glucocorticoids on memory formation during acute infectious illness, male and female C57BL/6 mice (N=80, 40 male/40 female) underwent cecal ligation and puncture and were treated with either corticosterone (16 mg/kg) or vehicle in the early afternoon daily for five days beginning on the day of surgery. All mice were habituated to a neutral object in their home cage for five days and underwent one 30-minute footshock/no shock training session during the illness period. After physiologic recovery (2 weeks), the mice underwent behavioral testing including open field exploration, object recognition testing in which they were presented with both the familiar (habituated) object and a novel object, and testing in the shock context. The results showed that drug treatment had no effect on behavior in the open field, including time spent in the center (VEH: 20.19±10.81 vs CORT: 22.32±12.87 sec; P=0.476). Drug treatment increased overall object exploration (12.28±10.79 vs 19.17±15.88 sec; P=0.049). Corticosterone-treated mice showed a preference for the familiar object (60.9±23.0% of total exploration time with familiar object; P=0.015), while vehicle-treated mice did not (54.1±23.3%; P=0.378). The increase in overall object exploration seen in corticosterone-treated mice could be accounted for by an increase in exploration of the familiar object. History of footshock increased freezing in the training context (3.96±2.54% vs 36.08±15.42%; P<0.0001) and corticosterone treatment had no effect (18.06±17.65% vs 22.16±21.19%; P=0.557). In conclusion, administration of corticosterone during infectious illness facilitated memory of a neutral object from the illness period, and recovered mice exhibited a preference for this object over a novel one. Corticosterone treatment had no impact on fear memory formed during illness. This is consistent with human literature suggesting that hydrocortisone decreases PTSD symptoms without impacting traumatic memories. These findings suggest that glucocorticoids selectively enhance the formation, consolidation, and/or recall of neutral but not fear memories during illness, which may rely on hippocampal circuitry. We further suggest that accurate memories of the illness period may influence patients’ perception of this experience and alter their risk for psychiatric sequelae.