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Publications (68)
In mammals, the central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, which transmits circadian information to other brain regions and regulates the timing of sleep and wakefulness. Neurons in the lateral hypothalamus (LH), particularly those producing melanin-concentrating hormone (MCH)- and orexin are key re...
It has been 50 years since the suprachiasmatic nucleus (SCN) was first identified as the central circadian clock and 25 years since the last overview of developments in the field was published in the Journal of Biological Rhythms. Here, we explore new mechanisms and concepts that have emerged in the subsequent 25 years. Since 1997, methodological d...
Narcolepsy is a sleep disorder caused by deficiency of orexin signaling. However, the neural mechanisms by which deficient orexin signaling causes the abnormal rapid eye movement (REM) sleep characteristics of narcolepsy, such as cataplexy and frequent transitions to REM states, are not fully understood. Here, we determined the activity dynamics of...
Many patients with psychiatric conditions, such as bipolar disorder and major depressive disorder, frequently experience disruptions in their sleep–wake cycles. Several case studies and clinical trials have shown that the administration of aripiprazole, a commonly prescribed antipsychotic drug, alleviates the symptoms of circadian sleep disorders i...
The central serotonergic system has multiple roles in animal physiology and behavior, including sleep-wake control. However, its function in controlling brain energy metabolism according to the state of animals remains undetermined. Through in vivo monitoring of energy metabolites and signaling, we demonstrated that optogenetic activation of raphe...
The mammalian central circadian clock, located in the suprachiasmatic nucleus (SCN), coordinates the timing of physiology and behavior to local time cues. In the SCN, second messengers, such as cAMP and Ca ²⁺ , are suggested to be involved in the input and/or output of the molecular circadian clock. However, the functional roles of second messenger...
The circadian rhythm is a biological oscillation of physiological activities with a period of approximately 24 h, that is driven by a cell-autonomous oscillator called the circadian clock. The current model of the mammalian circadian clock is based on a transcriptional-translational negative feedback loop in which the protein products of clock gene...
GABAergic neurons in the ventral tegmental area (VTA) have brain-wide projections and are involved in multiple behavioral and physiological functions. Here, we revealed the responsiveness of Gad67+ neurons in VTA (VTAGad67+) to various neurotransmitters involved in the regulation of sleep/wakefulness by slice patch clamp recording. Among the substa...
Circadian rhythms are defined as approximately 24-hour oscillations in physiology and behavior. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus is known as the central circadian clock. Based on current understanding, circadian rhythms are believed to be generated by transcription-translation feedback loops (TTFL) involving several...
Sleep and wakefulness are regulated by both the homeostatic mechanism and circadian clock. In mammals, the central circadian clock, the suprachiasmatic nucleus, in the hypothalamus plays a crucial role in the timing of physiology and behavior. Recently, we found that the circadian regulation of wakefulness was transmitted via corticotropin-releasin...
[This corrects the article DOI: 10.3389/fnins.2021.650154.].
The food-entrainable oscillator, which underlies the prefeeding activity peak developed by restricted daily feeding (RF) in rodents, does not depend on the circadian pacemaker in the suprachiasmatic nucleus (SCN) or on the known clock genes. In the present study, to clarify the roles of SCN circadian pacemaker and nutrient conditions on the develop...
Clock genes Cry1 and Cry2, inhibitory components of core molecular feedback loop, are regarded as critical molecules for the circadian rhythm generation in mammals. A double knockout of Cry1 and Cry2 abolishes the circadian behavioral rhythm in adult mice under constant darkness. However, robust circadian rhythms in PER2::LUC expression are detecte...
The circadian clock controls daily rhythms of physiological processes. The presence of the clock mechanism throughout the body is hampering its local regulation by small molecules. A photoresponsive clock modulator would enable precise and reversible regulation of circadian rhythms using light as a bio-orthogonal external stimulus. Here we show, th...
In mammals, the central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Individual SCN cells exhibit intrinsic oscillations, and their circadian period and robustness are different cell by cell in the absence of cellular coupling, indicating that cellular coupling is important for coherent circadian rhythms in t...
In mammals, the daily rhythms of physiological functions are timed by the central circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Although the importance of the SCN for the regulation of sleep/wakefulness has been suggested, little is known about the neuronal projections from the SCN, which regulate sleep/wakefulne...
The mammalian central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN contains multiple circadian oscillators which synchronize with each other via several neurotransmitters. Importantly, an inhibitory neurotransmitter, γ‐amino butyric acid (GABA), is expressed in almost all SCN neurons. In this review,...
Orexin/hypocretin-producing and melanin-concentrating hormone-producing (MCH) neurons are co-extensive in the hypothalamus and project throughout the brain to regulate sleep/wakefulness. Ablation of orexin neurons decreases wakefulness and results in a narcolepsy-like phenotype, whereas ablation of MCH neurons increases wakefulness. Since it is unc...
Orexin/hypocretin-producing and melanin-concentrating hormone-producing (MCH) neurons are co-extensive in the hypothalamus and project throughout the brain to regulate sleep/wakefulness. Ablation of orexin neurons decreases wakefulness and results in a narcolepsy-like phenotype, whereas ablation of MCH neurons increases wakefulness. Since it is unc...
Orexin/hypocretin-producing and melanin-concentrating hormone-producing (MCH) neurons are co-extensive in the hypothalamus and project throughout the brain to regulate sleep/wakefulness. Ablation of orexin neurons decreases wakefulness and results in a narcolepsy-like phenotype, whereas ablation of MCH neurons increases wakefulness. Since it is unc...
Orexin/hypocretin-producing and melanin-concentrating hormone-producing (MCH) neurons are co-extensive in the hypothalamus and project throughout the brain to regulate sleep/wakefulness. Ablation of orexin neurons decreases wakefulness and results in a narcolepsy-like phenotype, whereas ablation of MCH neurons increases wakefulness. Since it is unc...
A brain pathway for active forgetting
Sleep affects memories via several mechanisms. Izawa et al. identified a possible new pathway in the brain: REM sleep–active hypothalamic melanin-concentrating hormone (MCH)–producing neurons, which, among others, project to the hippocampus. Surprisingly, genetic ablation of MCH neurons increased memory perform...
Circadian rhythms are generated by interlocked transcriptional-translational negative feedback loops (TTFLs), the molecular process implemented within a cell. The contributions, weighting and balancing between the multiple feedback loops remain debated. Dissociated, free-running dynamics in the expression of distinct clock genes has been described...
Circadian clocks, biological timekeepers that are present in almost every cell of our body, are complex systems whose disruption is connected to various diseases. Controlling cellular clock function with high temporal resolution in an inducible manner would yield an innovative approach for the circadian rhythm regulation. In the present study, we p...
In mammals, the circadian rhythms are regulated by the central clock located in the hypothalamic suprachiasmatic nucleus (SCN), which is composed of heterogeneous neurons with various neurotransmitters. Among them an inhibitory neurotransmitter, γ-Amino-Butyric-Acid (GABA), is expressed in almost all SCN neurons, however, its role in the circadian...
Sleep/wakefulness cycle is regulated by coordinated interactions between sleep- and wakefulness-regulating neural circuitry. However, the detailed mechanism is far from understood. Here, we found that glutamic acid decarboxylase 67-positive GABAergic neurons in the ventral tegmental area (VTAGad67+) are a key regulator of non-rapid eye movement (NR...
Circadian rhythms are generated by interlocked transcriptional-translational negative feedback loops (TTFLs), the molecular process implemented within a cell. The contributions, weighting and balancing between the multiple feedback loops remain debated. Dissociated, free-running dynamics in the expression of distinct clock genes has been described...
Circadian rhythms are controlled by transcriptional feedback loops of clock genes and proteins. The stability of clock proteins is regulated by post-translational modification, such as phosphorylation by kinases. In particular, casein kinase I (CKI) phosphorylates PER protein to regulate proteasomal degradation and nuclear localization. Therefore,...
The daily sleep/wakefulness cycle is regulated by coordinated interactions between sleep- and wakefulness-regulating neural circuitry. However, the detailed neural circuitry mediating sleep is far from understood. Here, we found that glutamic acid decarboxylase 67 (Gad67)-positive GABAergic neurons in the ventral tegmental area (VTAGad67+) are a ke...
Circadian clocks are autonomous oscillators driving daily rhythms in physiology and behavior. In mammals, a network of coupled neurons in the suprachiasmatic nucleus (SCN) is entrained to environmental light-dark cycles and orchestrates the timing of peripheral organs. In each neuron, transcriptional feedbacks generate noisy oscillations. Coupling...
In mammals, circadian rhythms, such as sleep/wake cycles, are regulated by the central circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN consists of thousands of individual neurons, which exhibit circadian rhythms. They synchronize with each other and produce robust and stable oscillations. Although several n...
Sleep is one of the most important physiological functions in mammals. It is regulated by not only homeostatic regulation but also circadian clock. Several neuropeptide-producing neurons located in the hypothalamus are implicated in the regulation of sleep/wakefulness. Among them, orexin/hypocretin-producing neurons (orexin neurons) are a crucial c...
Significance
The circadian clock in the suprachiasmatic nucleus (SCN) regulates seasonality in physiology and behavior, which is best characterized by the change in the activity time of behavioral rhythms. In nocturnal rodents, the activity time was shortened in long summer days and lengthened in short winter days because of the change in the phase...
Significance
The mammalian master circadian clock, the suprachiasmatic nucleus (SCN), contains a network composed of various neuron types. The SCN network plays critical roles in expressing robust circadian rhythms in physiology and behavior, such as sleep–wake cycles. The molecular clock in individual SCN neurons controls membrane excitability, an...
In mammals, the master circadian clock is located in the suprachiasmatic nucleus (SCN), where most neurons show circadian rhythms of intracellular Ca2+ levels. However, the origin of these Ca2+ rhythms remains largely unknown. In this study, we successfully monitored the intracellular circadian Ca2+ rhythms together with the circadian PER2 and firi...
The suprachiasmatic nucleus (SCN) is the site of the master circadian clock in mammals. The SCN neural network plays a critical role in expressing the tissue-level circadian rhythm. Previously, we demonstrated postnatal changes in the SCN network in mice, in which the clock gene products CRYPTOCHROMES (CRYs) are involved. Here, we show that vasoact...
In mammals, a network of coupled neurons within the hypothalamus coordinates physiological rhythms with daily changes in the environment. In each neuron, delayed negative transcriptional feedbacks generate oscillations, albeit noisy and unreliable ones. Coupling mediated by diffusible neuropeptides lends precision and robustness to circadian rhythm...
The temporal order of physiology and behavior in mammals is regulated by the coordination of the master circadian clock in suprachiasmatic nucleus (SCN) and peripheral clocks in various tissues outside the SCN. Because the circadian oscillator(s) in the olfactory bulb (OB) is regarded as SCN independent, we examined the relationship between the SCN...
Methyl-CpG-binding protein 2 (Mecp2) is an X-linked gene encoding a methylated DNA-binding nuclear protein which regulates transcriptional activity. The mutation of MECP2 in humans is associated with Rett syndrome (RTT), a neurodevelopmental disorder. Patients with RTT frequently show abnormal sleep patterns and sleep-associated problems, in additi...
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 biolumine...
The suprachiasmatic nucleus (SCN), the primary circadian pacemaker in mammals, is a network structure composed of multiple types of neurons. Here, we report that mice with a Bmal1 deletion specific to arginine vasopressin (AVP)-producing neurons showed marked lengthening in the free-running period and activity time of behavior rhythms. When exposed...
Clock genes Cryptochrome (Cry1) and Cry2 are essential for expression of circadian rhythms in mice under constant darkness (DD). However, circadian rhythms in clock gene Per1 expression or clock protein PER2 are detected in the cultured suprachiasmatic nucleus (SCN) of neonatal Cry1 and Cry2 double deficient (Cry1-/-/Cry2-/-) mice. A lack of circad...
Cryptochrome (Cry) 1 and Cry2 are regarded as critical components for circadian rhythm generation in mammals. Nevertheless, cultured suprachiasmatic nucleus (SCN) of neonatal Cry double deficient (Cry1(-/-)/Cry2(-/-)) mice exhibit circadian rhythms that damp out in several cycles. Here, by combining bioluminescence imaging of Per1-luc and PER2::LUC...
The master circadian clock of the mammals locates in the hypothalamic suprachiasmatic nucleus (SCN) which is composed of multiple oscillator cells. Cellular oscillators mutually synchronize to form several regional pacemakers which further couple to make-up the master circadian clock for coherent rhythm expression in physiology and behavior. In the...
The circadian pacemaker in the hypothalamic suprachiasmatic nucleus (SCN) is a hierarchical multioscillator system in which neuronal networks play crucial roles in expressing coherent rhythms in physiology and behavior. However, our understanding of the neuronal network is still incomplete. Intracellular calcium mediates the input signals, such as...
The suprachiasmatic nucleus (SCN), the master circadian clock of mammals, is composed of multiple circadian oscillator neurons. Most of them exhibit significant circadian rhythms in their clock gene expression and spontaneous firing when cultured in dispersed cells, as well as in an organotypic slice. The distribution of periods depends on the SCN...
Single-point laser scanning confocal imaging produces signals with high spatial resolution in living organisms. However, photo-induced toxicity, bleaching, and focus drift remain challenges, especially when recording over several days for monitoring circadian rhythms. Bioluminescence imaging is a tool widely used for this purpose, and does not caus...
The posttranslational regulation of mammalian clock proteins has been assigned a time-keeping function, but seems to have more essential roles. Here we show that c-Jun N-terminal kinase (JNK), identified by inhibitor screening of BMAL1 phosphorylation at Ser 520/Thr 527/Ser 592, confers dynamic regulation on the clock. Knockdown of JNK1 and JNK2 ab...
The circadian oscillation is known to stop with prolonged inhibition of protein synthesis and to restart from a particular phase after the removal of inhibition. In order to know the underlying molecular mechanisms, the mouse suprachiasmatic nucleus was cultured and treated with a protein synthesis inhibitor, cycloheximide (CHX), for various durati...
The mammalian circadian system is composed of a master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus, and
peripheral clocks in organs and tissues. Light is the most dominant time cue which adjusts the intrinsic circadian period
to a 24-h day-night cycle. The master clock in the SCN is the only clock which acts as an interface betwe...
Abstract The circadian behavioral rhythms show seasonal changes not only in animals in the field but also in humans in urban environments. In nocturnal rodents the activity time is compressed or decompressed in response to day lengths. A two-oscillator model has been proposed to explain this photoperiodic response; an evening (E) oscillator is entr...
The roles of a local circuit of electrophysiological activity were examined in the expression of circadian rhythms in the suprachiasmatic nucleus (SCN) of the adult mouse. The neuronal activity of cultured SCN was suppressed with tetrodotoxin (TTX), an Na+ channel blocker, and the circadian rhythms in mRNA level were assessed for 13 genes by in sit...
The pattern of circadian behavioral rhythms is photoperiod-dependent, highlighted by the conservation of a phase relation between the behavioral rhythm and photoperiod. A model of two separate, but mutually coupled, circadian oscillators has been proposed to explain photoperiodic responses of behavioral rhythm in nocturnal rodents: an evening oscil...