Singularity behaviour in circadian clocks--the loss of robust circadian rhythms following exposure to a stimulus such as a pulse of bright light--is one of the fundamental but mysterious properties of clocks. To quantitatively perturb and accurately measure the dynamics of cellular clocks, we synthetically produced photo-responsiveness within mammalian cells by exogenously introducing the photoreceptor melanopsin and continuously monitoring the effect of photo-perturbation on the state of cellular clocks. Here we report that a critical light pulse drives cellular clocks into singularity behaviour. Our theoretical analysis consistently predicts and subsequent single-cell level observation directly proves that desynchronization of individual cellular clocks underlies singularity behaviour. Our theoretical framework also explains why singularity behaviours have been experimentally observed in various organisms, and it suggests that desynchronization is a plausible mechanism for the observable singularity of circadian clocks. Importantly, these in vitro and in silico findings are further supported by in vivo observations that desynchronization underlies the multicell-level amplitude decrease in the rat suprachiasmatic nucleus induced by critical light pulses.
The mammalian master clock driving circadian rhythmicity in physiology and behavior resides within the suprachiasmatic nuclei (SCN) of the hypothalamus. SCN neurons contain a molecular oscillator composed of a set of clock genes that acts in intertwined negative and positive feedback loops [1]. In addition, all peripheral tissues analyzed thus far have been shown to contain circadian oscillators [2]. This raises the question of whether the central circadian pacemaker in the SCN is sufficient to evoke behavioral rhythms or whether peripheral circadian clockworks are also required. Mice with a mutated CLOCK protein (a transcriptional activator of E box-containing clock and clock output genes) or lacking both CRYPTOCHROMES, mCRY1 and mCRY2 proteins (inhibitors of E box-mediated transcription), lack circadian rhythmicity in behavior [3,4]. Here, we show that transplantation of mouse fetal SCN tissue into the hypothalamus restores free-running circadian behavioral rhythmicity in Clock mutant or mCry1/mCry2 double knockout mice. The periodicity of the emerged rhythms is determined by the genetic constitution (i.e., wild-type or mCry2 knockout) of the grafted SCN. Since transplanted mCry1/mCry2-deficient mice do not have functional circadian oscillators [5] other than those present in the grafted hypothalamus region, these findings suggest that the SCN can generate circadian behavioral rhythms in the absence of distant peripheral oscillators in the brain or elsewhere.
The suprachiasmatic nucleus is the master circadian clock and resets the peripheral clocks via various pathways. Glucocorticoids and daily feeding are major time cues for entraining most peripheral clocks. However, recent studies have suggested that the dominant timing factor differs among organs and tissues. In our current study, we reveal differences in the entrainment properties of the peripheral clocks in the liver, kidney, and lung through restricted feeding (RF) and antiphasic corticosterone (CORT) injections in adrenalectomized rats. The peripheral clocks in the kidney and lung were found to be entrained by a daily stimulus from CORT administration, irrespective of the meal time. In contrast, the liver clock was observed to be entrained by an RF regimen, even if daily CORT injections were given at antiphase. These results indicate that glucocorticoids are a strong zeitgeber that overcomes other entrainment factors regulating the peripheral oscillators in the kidney and lung and that RF is a dominant mediator of the entrainment ability of the circadian clock in the liver. (Endocrinology 153: 2277-2286, 2012) M ost living organisms have developed internal clock mechanisms that generate precise rhythms around a 24-h cycle. One such system, termed the circadian clock, governs daily variations in physiology and behavior. In mammals, the suprachiasmatic nucleus (SCN) is the center of the circadian clock and resides in the hypothalamus (1). The molecular oscillator in the SCN consists of interacting positive and negative transcription/translation feedback loops (2-4). The transcriptional activators CLOCK and BMAL1 form heterodimers and stimulate the transcription of other clock genes, such as the Period (Per) genes (Per1, Per2, and Per3), the Cryptochromes (Cry) (Cry1 and Cry2), retinoid-related orphan receptors (ROR) (ROR␣, ROR, and ROR␥) and Rev-erbes (Rev-erb␣ and Rev-erb) that bind to the E-box response elements in the promoter regions of these genes. Accumulated PER and CRY proteins form a complex that represses the transcriptional activity of the CLOCK/BMAL1 heterodimer. The ROR transcriptional activators and REV-ERB repressors control the transcriptional regulation of Clock and Bmal1 through their binding to the REV response element (RRE). This autoregulatory loop generates gene expression oscillations of approximately 24 h. In addition, the mammalian SCN can adapt to environmental changes in day/night cycles. Light information from the retinas is delivered to the SCN via the retino-hypothalamic tract and is the most effective time cue for the central clock. Nocturnal light induces the Per1 and Per2 genes, which leads to a resetting of the circadian clock in the SCN (5).The molecular circadian clock operates not only in the SCN but also in peripheral organs and tissues (6, 7). The peripheral clocks are entrained by the central circadian clock in the SCN and express overt circadian rhythms during physiological events (8, 9). Hence, it is commonly assumed that the mammalian circadian system is a complex h...
Three mammalian Period (Per) genes, termed Per1, Per2, and Per3, have been identified as structural homologues of the Drosophila circadian clock gene, period (per). The three Per genes are rhythmically expressed in the suprachiasmatic nucleus (SCN), the central circadian pacemaker in mammals. The phases of peak mRNA levels for the three Per genes in the SCN are slightly different. Light sequentially induces the transcripts of Per1 and Per2 but not of Per3 in mice. These data and others suggest that each Per gene has a different but partially redundant function in mammals. To elucidate the function of Per1 in the circadian system in vivo, we generated two transgenic rat lines in which the mouse Per1 (mPer1) transcript was constitutively expressed under the control of either the human elongation factor-1␣ (EF-1␣) or the rat neuronspecific enolase (NSE) promoter. The transgenic rats exhibited an Ϸ0.6 -1.0-h longer circadian period than their wild-type siblings in both activity and body temperature rhythms. Entrainment in response to light cycles was dramatically impaired in the transgenic rats. Molecular analysis revealed that the amplitudes of oscillation in the rat Per1 (rPer1) and rat Per2 (rPer2) mRNAs were significantly attenuated in the SCN and eyes of the transgenic rats. These results indicate that either the level of Per1, which is raised by overexpression, or its rhythmic expression, which is damped or abolished in over expressing animals, is critical for normal entrainment of behavior and molecular oscillation of other clock genes.transgenic rats ͉ entrainment
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