Glucocorticoid ultradian rhythmicity directs cyclical gene pulsing of the Clock gene Period 1 in rat hippocampus

Publication Type:

Journal Article

Source:

J Neuroendocrinol, Volume 22, Number 10, p.1093–1100 (2010)

ISBN:

1365-2826 (Electronic)09

DOI Name (links to online publication)

10.1111/j.1365-2826.2010.02051.x

Abstract:

Abstract In vivo glucocorticoid (GC) secretion exhibits a distinctive ultradian rhythmicity. The lipophilic hormone can rapidly diffuse into cells, but only the pulse peak is of sufficient amplitude to activate the low affinity glucocorticoid receptor (GR). Discrete pulses readily access brain regions such as the hippocampus where GR expression is enriched and known to regulate neuronal function, including memory and learning processes. In the present study, we have tested the hypothesis that GR brain targets are responsive to ultradian GC rhythmicity. We have used adrenalectomised rats replaced with pulses of corticosterone to determine the transcriptional effects of ultradian pulses in the hippocampus. Confocal microscopy confirmed that each GC pulse results in transient GR nuclear localization in hippocampal CA1 neurons. Concomitant GR activation and DNA binding was demonstrated by synthetic GRE oligonucleotide binding, and verified for the Clock gene Period 1 promoter region by chromatin immunoprecipitation assays. Strikingly each GC pulse induced a "burst" of transcription of Period 1 measured by hnRNA qPCR. The net effect of pulsatile GC exposure on accumulation of the mature transcript was also assessed, revealing a plateau of mRNA levels throughout the time course of pulsatile exposure, indicating the pulse timing works optimally for steady state Per1 expression. The plateau dropped to baseline within 120min of the final pulse, indicating a relatively short half-life for hippocampal Per1. The significance of this strict temporal control is that any perturbation to the pulse frequency or duration would have rapid quantitative effects on the levels of Per1. This in turn could affect hippocampal function, especially circadian related memory and learning processes.

18/01/2013