LAUSR

Significance Circadian oscillations of glucocorticoids are a fundamental characteristic of adrenal hormone secretion in all mammals. These rhythms can be disrupted by chronic stress or synthetic glucocorticoid therapy, resulting in side effects including impaired memory, mood, and sleep. Here, we show that 5-d treatment with methylprednisolone induces prolonged activation of glucocorticoid receptors and consequent binding at glucocorticoid regulatory elements in the core clock gene Period 1, in the hippocampus. Furthermore, disruption of circadian hippocampal gene regulation was evident, along with loss of circadian variation in hippocampal long-term potentiation (LTP) and impaired hippocampal memory. Together, these data demonstrate dysregulated hippocampal function during long-acting glucocorticoid treatment and further support the importance of devising improved regimens of glucocorticoid therapy that recapitulate endogenous glucocorticoid rhythmicity.