Abstract
In mammals, the temporal order of physiology and behavior is primarily regulated by the circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). Rhythms are generated in cells by an auto-regulatory transcription/translation feedback loop, composed of several clock genes and their protein products. Taking advantage of bioluminescence reporters, we have succeeded in continuously monitoring the expression of clock gene reporters Per1-luc, PER2::LUC and Bmal1-ELuc in the SCN of freely moving mice for up to 3 weeks in constant darkness. Bioluminescence emitted from the SCN was collected with an implanted plastic optical fiber which was connected to a cooled photomultiplier tube. We found robust circadian rhythms in the clock gene expression, the phase-relation of which were the same as those observed ex vivo. The circadian rhythms were superimposed by episodic bursts which had ultradian periods of approximately 3.0 h. Episodic bursts often accompanied activity bouts, but stoichiometric as well as temporal analyses revealed no causality between them. Clock gene expression in the SCN in vivo is regulated by the circadian pacemaker and ultradian rhythms of unknown origin.
Highlights
In mammals, the temporal order of physiology and behavior is primarily regulated by the circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN)
Despite one pioneering study in which circadian rhythms in clock gene expression were monitored in vivo using a bioluminescence gene reporter[7], we are still ignorant of the clock gene dynamics in the intact SCN of freely moving
Circadian rhythms in Per1-luc, PER2::LUC and Bmal1-ELuc in the SCN of freely moving mice were measured continuously for up to 3 weeks using an in vivo monitoring system
Summary
The temporal order of physiology and behavior is primarily regulated by the circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). Clock gene expression in the SCN in vivo is regulated by the circadian pacemaker and ultradian rhythms of unknown origin. Heterodimers of Clock and Bmal[1] proteins (CLOCK/BMAL1) activate the transcription of the Per and Cry genes, the protein products of which in turn suppressed the transactivation of CLOCK/BMAL1, closing this feedback loop[2] One turn of this auto-feedback loop takes approximately 24 hr. Substantial knowledge on the pacemaker dynamics in the SCN has been obtained by real time monitoring of clock gene expression in cultured slices or dispersed cells[5,6]. Despite one pioneering study in which circadian rhythms in clock gene expression were monitored in vivo using a bioluminescence gene reporter[7], we are still ignorant of the clock gene dynamics in the intact SCN of freely moving. By employing a highly sensitive bioluminescence recorder, we have overcome technical barriers that have slowed progress in the SCN in vivo
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