INTRODUCTION: In the hippocampus, clock gene expression is important for memory and mood; however, the signaling mechanism controlling clock gene expression in the hippocampus is unknown. Recent findings suggest that circadian glucocorticoid rhythms driven by the suprachiasmatic nucleus (SCN) control rhythmic clock gene expression in neurons; in addition, dexamethasone modulates hippocampal clock gene expression. We therefore hypothesized that oscillations of clock genes in the hippocampus could be driven by SCN-controlled circadian rhythms in glucocorticoids.

METHODS: Temporal profiles of hippocampal clock gene expression were established by qRT-PCR on rat hippocampi, while cellular distribution was established by in situ hybridization. To determine the effect of rhythmic glucocorticoids on hippocampal clock gene expression, the SCN was lesioned, adrenal glands removed and a 24h exogenous corticosterone rhythm at physiological levels was reestablished by use of a programmable infusion pump.

RESULTS: Daily rhythms were detected for Per1, Per2, Bmal1, Nr1d1, and Dbp, while clock gene products were confirmed in both the hippocampus proper and the dentate gyrus. In sham controls, differential hippocampal expression of Per1 and Dbp between ZT3 and ZT15 was detectable. This rhythm was abolished by SCN-lesion; however, reestablishing the natural rhythm in corticosterone restored differential rhythmic expression of both Per1 and Dbp. Further, a 6h phase-delay in the corticosterone profile caused a predictable shift in expression of Nr1d1.

CONCLUSION: Our data show that rhythmic corticosterone can drive hippocampal clock gene rhythms suggesting that the SCN regulates the circadian oscillator of the hippocampus by controlling the circadian rhythm in circulating glucocorticoids.