In Vivo Monitoring of Peripheral Circadian Clocks in the Mouse

Abstract

The mammalian circadian system is comprised of a central clock in the suprachiasmatic nucleus (SCN) and a network of peripheral oscillators located in all of the major organ systems. The SCN is traditionally thought to be positioned at the top of the hierarchy, with SCN lesions resulting in an arrhythmic organism. However, recent work has demonstrated that the SCN and peripheral tissues generate independent circadian oscillations in Per1 clock gene expression in vitro. In the present study, we sought to clarify the role of the SCN in the intact system by recording rhythms in clock gene expression in vivo. A practical imaging protocol was developed that enables us to measure circadian rhythms easily, noninvasively, and longitudinally in individual mice. Circadian oscillations were detected in the kidney, liver, and submandibular gland studied in about half of the SCN-lesioned, behaviorally arrhythmic mice. However, their amplitude was decreased in these organs. Free-running periods of peripheral clocks were identical to those of activity rhythms recorded before the SCN lesion. Thus, we can report for the first time that many of the fundamental properties of circadian oscillations in peripheral clocks in vivo are maintained in the absence of SCN control.

The aging clock: circadian rhythms and later life

“…In support of this idea, manipulations intended to align peripheral oscillators with the master clock, such as imposing an environmental temperature rhythm that is synchronized with the light/dark cycle, have yielded improvements in sleep and activity rhythms in aged Drosophila (83). Similarly, in rodents lacking a functional master clock, restricted feeding schedules are sufficient to synchronize rhythmic clock gene expression across several peripheral oscillators (121,152).…”

Circadian regulation of lipid metabolism

“…Whereas light is the primary synchroniser of SCN neural activity and melatonin secretion, diurnal cycles of feeding and fasting can entrain circadian gene expression patterns in peripheral tissues (24) . Normally, circadian rhythms of sleep-wake and food intake are synchronised, but peripheral clocks can entrain to time-restricted feeding schedules, even when the SCN clock is rendered dysfunctional (25) . Recently, it has been established that the molecular circadian clock in peripheral tissues is sensitive to nutrient sensing pathways, suggesting that the content and timing of meals can influence the phase of peripheral clocks (26)(27)(28) .…”

The flexible clock: predictive and reactive homeostasis, energy balance and the circadian regulation of sleep–wake timing

“…Under standardized housing conditions, most peripheral clocks are considered to have a similar phase and bear a stable phase relation to the rhythms produced by the SCN, as shown in vivo (Tahara et al, 2012). Lesioning of the SCN results in severely dampened organ-level oscillations, showing the importance of the SCN in maintaining synchrony within peripheral tissues (Tahara et al, 2012), although this was only established for laboratory-housed animals, devoid of natural timing cues.…”

“…Under standardized housing conditions, most peripheral clocks are considered to have a similar phase and bear a stable phase relation to the rhythms produced by the SCN, as shown in vivo (Tahara et al, 2012). Lesioning of the SCN results in severely dampened organ-level oscillations, showing the importance of the SCN in maintaining synchrony within peripheral tissues (Tahara et al, 2012), although this was only established for laboratory-housed animals, devoid of natural timing cues. Furthermore, the phase of cellular clocks has been linked to tissue-specific rhythms in gene expression (Storch et al, 2002), giving rise to circadian rhythms in cell function and sensitivity, and leading to rhythmic activation of tissue-specific pathways (Oster et al, 2006;Zhang et al, 2014).…”