• Molecules and Cells
• /
• v.40 no.7
• /
• pp.450-456
• /
• 2017

Mammalian physiology and behavior are regulated by an internal time-keeping system, referred to as circadian rhythm. The circadian timing system has a hierarchical organization composed of the master clock in the suprachiasmatic nucleus (SCN) and local clocks in extra-SCN brain regions and peripheral organs. The circadian clock molecular mechanism involves a network of transcription-translation feedback loops. In addition to the clinical association between circadian rhythm disruption and mood disorders, recent studies have suggested a molecular link between mood regulation and circadian rhythm. Specifically, genetic deletion of the circadian nuclear receptor Rev-$erb{\alpha}$ induces mania-like behavior caused by increased midbrain dopaminergic (DAergic) tone at dusk. The association between circadian rhythm and emotion-related behaviors can be applied to pathological conditions, including neurodegenerative diseases. In Parkinson's disease (PD), DAergic neurons in the substantia nigra pars compacta progressively degenerate leading to motor dysfunction. Patients with PD also exhibit non-motor symptoms, including sleep disorder and neuropsychiatric disorders. Thus, it is important to understand the mechanisms that link the molecular circadian clock and brain machinery in the regulation of emotional behaviors and related midbrain DAergic neuronal circuits in healthy and pathological states. This review summarizes the current literature regarding the association between circadian rhythm and mood regulation from a chronobiological perspective, and may provide insight into therapeutic approaches to target psychiatric symptoms in neurodegenerative diseases involving circadian rhythm dysfunction.

• Sleep Medicine and Psychophysiology
• /
• v.21 no.2
• /
• pp.51-60
• /
• 2014

A 'circadian rhythm' is a self-sustained biological rhythm (cycle) that repeats itself approximately every 24 hours. Circadian rhythms are generated by an internal clock, or pacemaker, and persist even in the absence of environmental time cues, collectively termed 'zeitgebers.' Although organisms generate circadian rhythms internally, they are entrained by environmental stimuli, particularly the light-dark cycle. Measurement of the endogenous melatonin rhythm provides relatively reliable surrogate way of assessing the timing of the internal circadian clock. Also, core body temperature and cortisol can be used as markers of circadian rhythms. The sleep-wake cycle, body temperature, and melatonin rhythm have a stable internal phase relationship in humans and other diurnal species. They play an important role in controlling daily behavioral rhythms including task performance, blood pressure, and synthesis and secretion of several hormones. In this review, we address not only the properties, methods of measurement, and markers of circadian rhythms, but also the physiological and psychological importance of human circadian rhythms.

• Journal of Photoscience
• /
• v.9 no.2
• /
• pp.246-248
• /
• 2002

Light is a major environmental signal for entrainment of the circadian clock, but little is known about the phototransduction pathway triggered by light-activation of photoreceptive molecule(s) responsible for the phase shift of the clock in vertebrates. The chicken pineal gland and retina contain the autonomous circadian oscillators together with the photic entrainment pathway, and hence they provide useful experimental model for the clock system. We previously demonstrated the expression and light-dependent activation of rod-type transducin $\alpha$-subunit (Gtl$\alpha$) in the chicken pineal gland. It is unlikely, however, that the pineal Gt$_1$$\alpha$ plays a major role in the photic entrainment, because the light-induced phase shift is unaffected by bloking the signaling function of Gt$_1$$\alpha$. Here, we show the expression of G 11 $\alpha$, an $\alpha$-subunit of another heterotrimeric G-protein, in the chicken pineal gland and retina by cDNA cloning, Northern blot and Western blot analyses. GIl$\alpha$-immunoreactivity was colocalized with pinopsin in the chicken pineal cells and it was found predominantly at the outer segments of photoreceptor cells in the retinal sections, suggesting functional coupling of G11 $\alpha$ with opsins in the both the tissues. By coimmunoprecipitation experiments using the retina, we showed the light- and GTP-dependent interaction between rhodopsin and G11 $\alpha$. Upon ectopic expression of a Gq/ 11-coupled receptor in cultured pineal cells, pharmacological (non-photic) activation of endogenous G11 induced phase-dependent phase shifts of the melatonin rhythm in a manner very similar to the effect of light. These results suggested opsin-G11 pathway contributing to the photic entrainment of the circadian clock.

• Journal of Oral Medicine and Pain
• /
• v.40 no.3
• /
• pp.89-95
• /
• 2015

All living organisms have a biological clock that orchestrates every biological process and function, and this internal clock operates following a circadian rhythm. This biological clock is known to influence various clinical indicators such as blood pressure and body temperature. Also, the fluctuation of signs and symptoms of diseases including pain disorders are affected by circadian rhythm. It has been reported that the pain intensity of various somatic and neuropathic pain disorders show unique pain patterns that depend on the passage of time. The generation of pain patterns could be explained by extrinsic (e.g., physical activity, tactile stimulation, ambient temperature) and also intrinsic factors (neural and neuroendocrine modulation) that are related to the circadian rhythm. It is important to recognize and identify the individual pain pattern in pain therapy to approve treatment outcome. Moreover, chronotherapeutics which considers pain patterns and pharmacokinetics in context of the circadian rhythm could produce greater analgesia in response to medication. However, only a limited number of studies handle the issue of pain patterns according to circadian rhythm and chronotherapeutics in the orofacial region. The present review intends to reflect on the most recent and relevant data concerning the bidirectional relation between pain disorders of the orofacial region and circadian patterns.

• Animal cells and systems
• /
• v.13 no.2
• /
• pp.119-125
• /
• 2009

Mammalian hibernation is a type of natural adaptation that allows organisms to avoid harsh environment and to increase the possibility of survival. To investigate the molecular link between circadian and hibernating rhythms in the greater tube-nosed bats, Murina leucogaster, we set out to identify circadian genes that are expressed in bats, with specific focus on the PAS domain by using PCR-based screens. We could isolate a eDNA clone, designated as LPAS1, that encodes a protein of 521 amino acid residues. LPAS1 is closely related with CLOCK family with the highest homology to human CLOCK. Based on RT-PCR analyses, LPAS1 transcripts are ubiquitously present in tissues from both summer active and winter dormant periods. Given that LPAS1 is a member of the bHLH-PAS protein superfamily but lacks polyglutamine transactivation domains, it is likely to function as a repressor for endogenous CLOCK to hinder its roles in promoting transcription. Our result will open a new avenue to further examine the functional interconnection between the circadian clock and the circannual clock such as mammalian hibernation.

• Animal cells and systems
• /
• v.16 no.1
• /
• pp.27-33
• /
• 2012

The suprachiasmatic nucleus (SCN) of the teleost hypothalamus contains a central circadian pacemaker, which adjusts circadian rhythms within the body to environmental light-dark cycles. It has been shown that exposure to darkness during the day causes phase shifts in circadian rhythms. In this study, we examined the effect of exposure to darkness on the mRNA expression levels of two circadian clock genes, namely, $Period2$ ($Per2$) and $Cryptochrome1$ ($Cry1$), and the rate-limiting enzyme in melatonin synthesis, arylalkylamine $N$-acetyltransferase-2 (Aanat2), in the pineal gland of olive flounder, $Paralichthys$ $olivaceus$. The expression of these genes showed circadian variations and was significantly higher during the dark phase. These changes may be involved in the mechanism of dark-induced phase shifts. Furthermore, this study suggests that olive flounder may be a teleost model to investigate the localization and function of circadian oscillators.

• BMB Reports
• /
• v.50 no.5
• /
• pp.235-236
• /
• 2017

The circadian clock is an internal system that is synchronized by external stimuli, such as light and temperature, and influences various physiological and developmental processes in living organisms. In the model plant Arabidopsis, transcriptional, translational and post-translational processes are interlocked by feedback loops among morning- and evening-phased genes. In a post-translational loop, plant-specific single-gene encoded GIGANTEA (GI) stabilize the F-box protein ZEITLUPE (ZTL), driving the targeted-proteasomal degradation of TIMING OF CAB EXPRESSION 1 (TOC1) and PSEUDO-RESPONSE REGULATOR 5 (PRR5). Inherent to this, we demonstrate the novel biochemical function of GI as a chaperone and/or co-chaperone of Heat-Shock Protein 90 (HSP90). GI prevents ZTL degradation as a chaperone and facilitates ZTL maturation together with HSP90/HSP70, enhancing ZTL activity in vitro and in planta. GI is known to be involved in a wide range of physiology and development as well as abiotic stress responses in plants, but it could also interact with diverse client proteins to increase protein maturation. Our results provide evidence that GI helps proteostasis of ZTL by acting as a chaperone and a co-chaperone of HSP90 for proper functioning of the Arabidopsis circadian clock.

• Reproductive and Developmental Biology
• /
• v.33 no.3
• /
• pp.163-169
• /
• 2009

Many biological systems are regulated by an intricate set of feedback loops that oscillate with a circadian rhythm of roughly 24 h. This circadian clock mediates an increase in body temperature, heart rate, blood pressure, and cortisol secretion early in the day. Recent studies have shown changes in the amplitude of the circadian clock in the hearts and livers of streptozotocin (STZ)-treated rats. It is therefore important to examine the relationships between circadian clock genes and growth factors and their effects on diabetic phenomena in animal models as well as in human patients. In this study, we sought to determine whether diurnal variation in organ development and the regulation of metabolism, including growth and development during the juvenile period in rats, exists as a mechanism for anticipating and responding to the environment. Also, we examined the relationship between changes in growth factor expression in the liver and clock-controlled protein synthesis and turnover, which are important in cellular growth. Specifically, we assessed the expression patterns of several clock genes, including Per1, Per2, Clock, Bmal1, Cry1 and Cry2 and growth factors such as insulin-like growth factor (IGF)-1 and -2 and transforming growth factor (TGF)-${\beta}1$ in rats with STZ-induced diabetes. Growth factor and clock gene expression in the liver at 1 week post-induction was clearly increased compared to the level in control rats. In contrast, the expression patterns of the genes were similar to those observed after 5 weeks in the STZ-treated rats. The increase in gene expression is likely a compensatory change in response to the obstruction of insulin function during the initial phase of induction. However, as the period of induction was extended, the expression of the compensatory genes decreased to the control level. This is likely the result of decreased insulin secretion due to the destruction of beta cells in the pancreas by STZ.

• Journal of Photoscience
• /
• v.9 no.2
• /
• pp.240-242
• /
• 2002

In Drosophila melanogaster, it is known that the circadian clock consists of an autoregulatory feedback loop, which includes so-called clock genes, such as per, tim, dClk and cyc and produces periodical expression of per. It is recently suggested, however, that the circadian oscillation without the rhythmical expression of per is involved in the regulation of circadian locomotor rhythms. In the present study, we examined the existence and the property of the possible per-less oscillation using arrhythmic clock mutant flies carrying per$^{01}$, tim$^{01}$, dClk$^{Jrk}$ or cyc$^{01}$. When temperature cycles consisting of 25$^{\circ}$Ｃ and 30$^{\circ}$Ｃ with varying periods (T = 8~32 hr) were given, they showed rhythms synchronizing with the given cycle under constant darkness (DD). per$^{01}$ and tim$^{01}$ flies always showed a peak around 7 hr after the onset of thermophase irrespective of Ts of temperature cycles, while dClk$^{Jrk}$ and cyc$^{01}$ flies did not. In addition, several days were necessary to establish a clear temperature entrainment in per$^{01}$ and tim$^{01}$ flies, when they were transferred from a constant temperature to a temperature cycle under DD. These results suggest that per$^{01}$ and tim$^{01}$ flies have a temperature-entrainable weak oscillatory mechanism. The fact that dClk$^{Jrk}$ and cyc$^{01}$ flies did not show any sign of the endogenous oscillation suggests that the per-less oscillatory mechanism may require CLK and CYC.

• Molecules and Cells
• /
• v.22 no.3
• /
• pp.275-284
• /
• 2006

The molecular components that generate and maintain circadian rhythms of physiology and behavior in mammals are present both in the brain (suprachiasmatic nucleus; SCN) and in peripheral tissues. Examination of mice with targeted disruptions of either mPer1 or mPer2 has shown that these two genes have key roles in the SCN circadian clock. Here we show that loss of the clock gene mPer2 affects forced locomotor performance in mice without altering muscle contractility. A proteomic analysis revealed that the anterior tibialis muscles of the mPer2 knockout mice had higher levels of glycolytic enzymes such as triose phosphate isomerase and enolase than those of either the wild type or mPer1 knockout mice. In addition, the level of expression of HSP90 in the mPer2 mutant mice was also significantly higher than in wildtype mice. These results suggest that the reduced locomotor endurance of the mPer2 knockout mice reflects a greater dependence on anaerobic metabolism under stress conditions, and that the two canonical clock genes, mPer1 and mPer2, play distinct roles in the physiology of skeletal muscle.