Circadian regulation of hippocampal function is disrupted with corticosteroid treatment
Matthew T. Birnie, Matthew D. B. Claydon, Oliver R Troy, Benjamin P. Flynn, Mitsuhiro Yoshimura, Yvonne M. Kershaw, Zidong Zhao, Rebecca C. R. Demski-Allen, G.R. Barker, Elizabeth C. Warburton, Zuner A. Bortolotto, Stafford L. Lightman, Becky Conway-Campbell
Abstract
Disrupted circadian activity is associated with many neuropsychiatric disorders. A major coordinator of circadian biological systems is adrenal glucocorticoid secretion which exhibits a pronounced preawakening peak that regulates metabolic, immune, and cardiovascular processes, as well as mood and cognitive function. Loss of this circadian rhythm during corticosteroid therapy is often associated with memory impairment. Surprisingly, the mechanisms that underlie this deficit are not understood. In this study, in rats, we report that circadian regulation of the hippocampal transcriptome integrates crucial functional networks that link corticosteroid-inducible gene regulation to synaptic plasticity processes via an intrahippocampal circadian transcriptional clock. Further, these circadian hippocampal functions were significantly impacted by corticosteroid treatment delivered in a 5-d oral dosing treatment protocol. Rhythmic expression of the hippocampal transcriptome, as well as the circadian regulation of synaptic plasticity, was misaligned with the natural light/dark circadian-entraining cues, resulting in memory impairment in hippocampal-dependent behavior. These findings provide mechanistic insights into how the transcriptional clock machinery within the hippocampus is influenced by corticosteroid exposure, leading to adverse effects on critical hippocampal functions, as well as identifying a molecular basis for memory deficits in patients treated with long-acting synthetic corticosteroids.