Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

OBJECTIVES: Circadian rhythms in peripheral organs undergo dynamic reorganization during postnatal development. However, the mechanisms underlying the maturation of circadian clocks in the salivary glands, particularly in relation to feeding behavior, remain poorly understood. In this study, we aimed to characterize the developmental maturation of circadian rhythms in the mouse submandibular gland (SMG). METHODS: PERIOD2::LUCIFERASE bioluminescence rhythms were recorded from cultured suprachiasmatic nucleus (SCN) and SMG tissues isolated from mice at postnatal days 0, 1, 7, 14, 21, and 28, and 8 weeks. Maternal behavior and pup feeding activity were continuously monitored using infrared video recording. Peak phases and circadian periods were analyzed to evaluate developmental changes. RESULTS: Robust circadian oscillations were observed in the SCN tissue at all developmental stages, with stable periods and peak phases. In contrast, rhythms in the SMG were rapidly damped in culture, and exhibited a progressive phase shift from the light phase to the middle of the dark phase during postnatal development. Circadian periods in both tissues remained close to 24 h throughout development. Behavioral analyses revealed that developmental changes in maternal care and feeding activity were closely associated with the phase realignment of SMG rhythms. After weaning, SMG peak phases resembled those in adult mice. CONCLUSIONS: Postnatal maturation of circadian rhythms in the SMG is characterized by progressive phase realignment that parallels the transition from suckling to independent feeding. These findings suggest that developmental coordination between feeding behavior and peripheral clock machinery contributes to the establishment of circadian regulation of salivary function.

DOI： 10.1016/j.job.2026.100787

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Anxiety disorders are a growing public health concern in modern societies burdened with chronic stress and diminishing work motivation, imposing a substantial disease burden across all age groups. Lactoyl-phenylalanine (Lac-Phe), an endogenous metabolite produced during exercise and found in fermented foods, has recently gained attention for its metabolic regulatory functions, yet its potential anxiolytic effects remain unclear. In this study, we report that Lac-Phe administration elicits anxiolytic-like behavior in mice. Oral administration of Lac-Phe significantly increased open-arm exploration in the elevated plus maze (EPM), indicating anxiolytic-like activity. Similar behavioral effects were observed following intraperitoneal and intracerebroventricular administration in the EPM and the novelty-suppressed feeding test. Pharmacological blockade experiments indicated that dopamine D1 and serotonin 5-HT1A receptor signaling contribute to Lac-Phe-induced anxiolytic-like effects. Consistently, intraperitoneal administration of Lac-Phe increased dopamine tissue content in the hypothalamus and striatum and reduced hippocampal IL-1β and IL-6 mRNA expression. Together, these results suggest that Lac-Phe exerts anxiolytic-like effects, potentially involving monoaminergic signaling in the brain, and support further investigation of Lac-Phe as a food-derived metabolite in the context of stress- and anxiety-related outcomes.

DOI： 10.1038/s41398-026-04106-2

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Torpor is a state of hypometabolism accompanied by a reduction in body temperature, which serves as a survival strategy enabling animals to endure harsh environments. While the circadian clock is thought to regulate the timing of torpor, the underlying neural mechanisms remain unclear. Here, we show that inhibitory neurotransmission via gamma-aminobutyric acid (GABA) in the central circadian clock, suprachiasmatic nucleus (SCN), is crucial for encoding the timing of torpor induction in female mice. Optogenetic activation of GABAergic neurons in the SCN projecting to the preoptic area (POA) suppresses torpor. These SCN neurons form monosynaptic connections with two distinct types of POA neurons: excitatory neurons that promote torpor induction, and inhibitory neurons that suppress the activity of these excitatory neurons. Furthermore, the disconnection of neural output in the SCN abolishes the timing of torpor. Retrograde tracing revealed that arginine vasopressin (Avp) neurons in the SCN innervate the POA, and selective deletion of vesicular GABA transporter in Avp neurons of the SCN leads to impaired torpor induction. This hypothalamic neuronal circuit is crucial in ensuring the survival of animals during harsh environmental conditions.

DOI： 10.1038/s41467-026-73374-9

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The Period (Per) gene was first identified in Drosophila as a key regulator of circadian rhythms, with mutations that altered or abolished behavioral rhythmicity. Mammals possess 3 homologs, Per1, Per2, and Per3. Here, we systematically compared the circadian properties of mice deficient in each Per gene, singly and in combination, under constant darkness (DD). We analyzed their free-running periods (τ) and phase response curves (PRCs) to 6-h light pulses (6-h LPs). Each Per-deficient line exhibited distinct circadian characteristics. Per1-deficient mice (including Per1-/- Per3-/- double mutants) showed high-amplitude PRCs with large phase shifts near CT18, consistent with Type 0 resetting. Per2-deficient mice displayed shorter τ and Type 1 PRCs with crossover points near CT17. Remarkably, some Per2-deficient mice lost circadian rhythmicity after a single 6-h LP delivered near the crossover but regained rhythmicity following a second pulse 12 days later. In contrast, Per1-/- Per2-/- mice, which retain Per3, failed to maintain stable rhythms in DD yet transiently reestablished a short-period (~19.5 h) rhythm in response to a 6-h LP. These findings indicate that rhythm loss in Per2-deficient mice does not represent oscillation stop but rather light-induced desynchrony among multiple oscillators that constitute the circadian pacemaker. Collectively, our results demonstrate that Per1 sustains oscillator strength, Per2 maintains inter-oscillator coupling, and together they ensure the robustness of the mammalian circadian system against strong photic perturbation.

DOI： 10.1177/07487304261448768

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Mice are nocturnal and normally feed during the night; however, timed daily feeding can markedly alter behavioral and physiological rhythms. A well-known example is food-anticipatory activity (FAA), characterized by increased locomotor activity before feeding. In this study, we examined age-related effects on FAA under temporally restricted feeding (RF). Male C57BL/6 J mice aged 12 weeks and 54 weeks were maintained under a 12:12 light-dark cycle and subjected to a 4-h daily RF schedule. Wheel-running activity, feeding timing, intake, and body weight were monitored. Under ad libitum conditions, both age groups exhibited nocturnal activity and feeding. During RF, FAA emerged significantly earlier in young mice than in middle-aged mice. After returning to ad libitum feeding, daytime activity gradually merged into nocturnal rhythms, although some middle-aged mice showed unstable patterns. These results indicate that FAA reflects a circadian system distinct from the suprachiasmatic nucleus and that aging delays and destabilizes its expression.

DOI： 10.1016/j.jphyss.2026.100071

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DOI： 10.2139/ssrn.6515709

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Society for Neuroscience  

The human circadian rhythm is controlled by central and peripheral clocks, primarily by the central clock in the suprachiasmatic nucleus (SCN). We investigated the diurnal variation of basic metabolism in the human cerebrum by measuring human baseline cerebral activity at rest contrasted with the SCN baseline activity. To this end, we utilized magnetic resonance imaging perfusion data of cerebral blood flow (CBF) (N = 27, including both sexes), where each participant was scanned four times a day at six-hour intervals (18:00, 24:00, 6:00, and 12:00 local time). Similarly to the SCN exhibiting higher CBF activity at noon, we observed a consistent temporal activity pattern in the brain regions, including the limbic (cingulate, insular, and temporopolar) and sensorimotor (visual and somatosensory/motor) areas. In contrast, the hippocampus showed higher activity at midnight and lower activity at noon. To examine the functional interaction between the SCN and the cerebral regions showing diurnal variation, we calculated the resting-state functional connectivity using the database of the Human Connectome Project (N = 164, including both sexes). Notably, the hippocampus demonstrated greater functional connectivity with the SCN than the other regions. These results suggest that cerebral regions exhibit differential patterns of diurnal variation associated with their functional connectivity with the SCN.

Significance Statement The human circadian rhythm is regulated primarily by the suprachiasmatic nucleus (SCN) and peripheral clocks. This study examined diurnal variations in human cerebral activity by measuring baseline cerebral blood flow at rest using magnetic resonance imaging. Participants were scanned four times a day (18:00, 24:00, 6:00, and 12:00). Similar to the SCN, cerebral regions in the limbic and sensorimotor areas showed higher activity at noon. However, the hippocampus exhibited peak activity at midnight and lower activity at noon. Functional connectivity analysis revealed stronger SCN-hippocampus connectivity than the other cerebral regions. These findings suggest that brain areas (i.e., the hippocampus and the limbic and sensorimotor areas) show distinct diurnal activity patterns linked to their functional connectivity with the SCN.

DOI： 10.1523/jneurosci.0729-25.2026

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DOI： 10.1101/2024.10.29.620774

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Abstract

The ovarian steroid hormones, estrogen and progesterone, the levels of which fluctuate dynamically with the estrous cycle, alter circadian behavioral rhythms in mammals. However, it remains unclear whether the sleep–wake rhythm fluctuates with the menstrual cycle in humans. To ascertain the relationship between the menstrual cycle and sleep–wake rhythms, we evaluated the objective and long-term sleep–wake rhythms of ten healthy women using a recently developed wearable device. The results showed a strong negative correlation between the sleep midpoint and the quasi-peak value (an indicator of rhythm robustness), and a positive correlation between the length of the menstrual cycle (days) and social jetlag (hours). These results suggest that healthy women with late sleeping habits have a disturbed sleep–wake rhythm and that irregular habits prolong the menstrual cycle. The sleep midpoint and quasi-peak values showed variations during the menstrual cycle. The quasi-peak values in the follicular phase were significantly higher than those in the menstrual and luteal phases. In rodents, the phase of locomotor activity rhythm advances, and activity increases at night during proestrus. The increase in quasi-peak values during the follicular phase, when estrogen is relatively high, may be due to the increased activity caused by estrogen. These results suggest that ovarian steroid hormones influence sleep–wake rhythms in women. Verifying the results of this study under various conditions is necessary; however, accurately predicting the day of ovulation using only the acquisition of sleep–wake rhythms with wearable devices will be possible.

DOI： 10.1007/s41105-024-00543-y

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Other Link： https://link.springer.com/article/10.1007/s41105-024-00543-y/fulltext.html

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The suprachiasmatic nucleus (SCN) is the central clock for circadian rhythms. Animal studies have revealed daily rhythms in the neuronal activity in the SCN. However, the circadian activity of the human SCN has remained elusive. In this study, to reveal the diurnal variation of the SCN activity in humans, we localized the SCN by employing an areal boundary mapping technique to resting-state functional images and investigated the SCN activity using perfusion imaging. In the first experiment (n = 27, including both sexes), we scanned each participant four times a day, every 6 h. Higher activity was observed at noon, while lower activity was recorded in the early morning. In the second experiment (n = 20, including both sexes), the SCN activity was measured every 30 min for 6 h from midnight to dawn. The results showed that the SCN activity gradually decreased and was not associated with the electroencephalography. Furthermore, the SCN activity was compatible with the rodent SCN activity after switching off the lights. These results suggest that the diurnal variation of the human SCN follows the zeitgeber cycles of nocturnal and diurnal mammals and is modulated by physical lights rather than the local time.

DOI： 10.1523/JNEUROSCI.1730-23.2024

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DOI： 10.3389/fnins.2024.1453328

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Green tea (GT) catechins exhibit antiviral effects in experimental studies. However, we lack clinical evidence on the preventive effects of catechin concentrations in gargling against acute upper respiratory tract infections (URTIs). Therefore, we aimed to investigate the concentration-dependence of GT catechins in gargling on the incidence of URTIs. We conducted an open-label randomized study. The target population consisted of 209 students from the University of Shizuoka and Meiji University, who were randomly assigned to high-catechin (approximate catechin concentration: 76.4 mg/dL), low-catechin (approximate catechin concentration: 30.8 mg/dL), and a control water gargling (catechin concentration: 0 mg/dL) group. All participants gargled water or GT daily for 12 weeks. The symptoms of URTIs were recorded on a daily survey form by participants. The incidences of URTIs occurred in 6 (9.1%), 7 (10.8%), and 11 (15.7%) participants in the high-catechin, low-catechin, and water groups, respectively. Cox proportional hazards analysis, using background factors and prevention status as covariates, revealed a hazard ratio of 0.57 (95% Confidence Interval (CI): 0.21-1.55, p = 0.261) for the high-catechin vs. water group and 0.54 (95% CI: 0.20-1.50, p = 0.341) for the low-catechin vs. water group. Our findings showed the incidence of URTIs in a concentration-dependent GT gargling was not significantly different, partly owing to the low event rates caused by intense precautions against the coronavirus disease 2019 pandemic. Our study would serve as a foundation for the development of an advanced protocol with optimal concentrations and a larger number of participants.

DOI： 10.1248/bpb.b24-00113

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Public Library of Science ({PLoS})  

<jats:p>The central circadian clock of the suprachiasmatic nucleus (SCN) is a network consisting of various types of neurons and glial cells. Individual cells have the autonomous molecular machinery of a cellular clock, but their intrinsic periods vary considerably. Here, we show that arginine vasopressin (AVP) neurons set the ensemble period of the SCN network in vivo to control the circadian behavior rhythm. Artificial lengthening of cellular periods by deleting <jats:italic>casein kinase 1 delta</jats:italic> (<jats:italic>CK1δ</jats:italic>) in the whole SCN lengthened the free-running period of behavior rhythm to an extent similar to <jats:italic>CK1δ</jats:italic> deletion specific to AVP neurons. However, in SCN slices, PER2::LUC reporter rhythms of these mice only partially and transiently recapitulated the period lengthening, showing a dissociation between the SCN shell and core with a period instability in the shell. In contrast, in vivo calcium rhythms of both AVP and vasoactive intestinal peptide (VIP) neurons in the SCN of freely moving mice demonstrated stably lengthened periods similar to the behavioral rhythm upon AVP neuron-specific <jats:italic>CK1δ</jats:italic> deletion, without changing the phase relationships between each other. Furthermore, optogenetic activation of AVP neurons acutely induced calcium increase in VIP neurons in vivo. These results indicate that AVP neurons regulate other SCN neurons, such as VIP neurons, in vivo and thus act as a primary determinant of the SCN ensemble period.</jats:p>

DOI： 10.1371/journal.pbio.3002281

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Many female mammals have recurring cycles of ovulation and sexual behaviors that are regulated by reproductive hormones and confer reproductive success. In addition to sexual behaviors, circadian behavioral rhythms of locomotor activity also fluctuate across the estrous cycle in rodents. Moreover, there is a bidirectional relationship between circadian rhythms and estrous cyclicity since mice with disrupted circadian rhythms also have compromised estrous cycles resulting in fewer pregnancies. In the present study, we assessed whether extending day length, which alters circadian rhythms, normalizes estrous cyclicity in mice. We found that Period (Per) 1/2/3 triple knockout (KO) mice, that have disabled canonical molecular circadian clocks, have markedly disrupted estrous cycles. Surprisingly, extending the day length by only 2 h per day restored regular 4- or 5-day estrous cycles to Per1/2/3 KO mice. Longer days also induced consistent 4-day, rather than 5-day, estrous cycles in wild-type C57BL/6J mice. These data demonstrate that extending daytime light exposure could be used for enhancing reproductive success.

DOI： 10.1016/j.heliyon.2023.e16970

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Introduction

The trigeminal nerve conveys delicate sensations such as warmth, pain, and tactile pressure in the oral and facial regions, and most trigeminal afferent cell bodies are located in the trigeminal ganglion. Our previous study has shown that sensations in trigeminal nerve innervated areas, specifically in the maxillofacial region, exhibit diurnal variation and that sensitivity changes time-dependently. In this study, we aimed to clarify the rhythm of expression of clock gene in the trigeminal ganglion of mice to elucidate the mechanism of circadian regulation in the same area.

Methods

Immunohistochemistry examined the expression of the PER2 protein in the suprachiasmatic nucleus and trigeminal ganglion of wild-type mice. To measure gene expression as bioluminescence, PERIOD2::LUCIFERASE knock-in (PER2::LUC) mice were used. Unilateral trigeminal ganglion and brain sections including the suprachiasmatic nucleus were incubated ex vivo. Bioluminescence levels were then measured using a highly sensitive photodetector. The same experiments were then conducted with Cry1 gene-deficient (Cry1^−/−) or Cry2 gene-deficient (Cry2^−/−) mice.

Results

In the trigeminal ganglion, immunohistochemistry localized PER2 protein expression within the neuronal cell body. Mouse trigeminal ganglion ex vivo tissues showed distinct circadian oscillations in PER2::LUC levels in all genotypes, wild-type, Cry1^−/−, and Cry2^−/−. The period was shorter in the trigeminal ganglion than in the suprachiasmatic nucleus; it was shorter in Cry1^−/− and longer in Cry2^−/− mice than in the wild-type mice.

Conclusion

The expression of Per2 in neurons of the trigeminal ganglion in ex vivo culture and the oscillation in a distinct circadian rhythm suggests that the trigeminal ganglion is responsible for the relay of sensory inputs and temporal gating through autonomous circadian oscillations.

DOI： 10.3389/fnins.2023.1142785

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DOI： 10.1101/2022.08.04.502742

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media {LLC}  

INTRODUCTION: In mammals, the central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, which coordinates the circadian rhythm and controls locomotor activity rhythms. In addition to SCN cells, the peripheral tissues and embryonic fibroblasts also have clock genes, such as Per1/2 and Bmal1, which generate the transcriptional-translational feedback loop to produce an approximately 24-h cycle. Aging adversely affects the circadian clock system and locomotor functions. Oak extract has been reported to improve age-related physiological changes. However, no study has examined the effect of oak extract on the circadian clock system. METHODS: We examined the effects of oak extract and its metabolites (urolithin A [ULT] and ellagic acid [EA]) on clock gene expression rhythms in mouse embryonic fibroblasts (MEFs) and SCN. Furthermore, locomotor activity rhythm was assessed in young and aged mice. RESULTS: Chronic treatment with EA and ULT delayed the phase of PER2::LUC rhythms in SCN explants, and ULT prolonged the period of PER2::LUC rhythms in MEFs in a dose-dependent manner and increased the amplitude of PER2::LUC rhythms in MEFs, though only at low concentrations. Acute treatment with ULT affected the phase of PER2::LUC rhythms in MEFs depending on the concentration and timing of the treatment. In addition, oak extract prolonged the activity time of behavioral rhythms in old mice and tended to increase daily wheel-running revolutions in both young and old mice. CONCLUSIONS: These results suggest that oak extract is a novel modulator of the circadian clock in vitro and in vivo. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s41105-021-00365-2.

DOI： 10.1007/s41105-021-00365-2

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In mammals, the suprachiasmatic nucleus (SCN) is a principal circadian pacemaker that optimizes the timing of behavioral rhythms and physiological events. Normally, circadian behavioral rhythms are entrained by the environmental light-dark (LD) cycle via the SCN. However, daily rhythms of other synchronizing signals, such as food availability, also emerge. When food availability is restricted to a single recurring daytime meal in nocturnal rodents, they exhibit increased activity during the hours immediately preceding feeding time; this is called food anticipatory activity (FAA). Many reports suggest that FAA is mediated by the food-entrainable oscillator (FEO) with circadian properties, but not the SCN. However, the neural locus and timekeeping mechanisms of the FEO, including its relationship with gastrointestinal hormone signaling, remain unclear. Herein, to examine whether secretin receptor signaling is necessary for the FEO, the effect of daily food restriction was studied in secretin receptor-deficient (Sctr-/-) mice. Adult wild-type (WT) and Sctr-/- mice were housed in separate cages containing a running wheel, with ad libitum food access and in a LD cycle (12 hours:12 hours) for at least 2 weeks. After acclimation to the condition, food access times were gradually restricted and 4-hour restricted feeding lasted over 10 days. Subsequently, mice had ad libitum food access for 2 days and then fasted for 2 days. Thereafter, robust FAAs were observed in both WT and Sctr-/- mice during restricted feeding and subsequent fasting. These results indicate that secretin receptor signaling is not essential for the timekeeping mechanism of FEO.

DOI： 10.1016/j.neulet.2022.136462

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The circadian rhythms of physiology and behavior are based on molecular systems at the cellular level, which are regulated by clock genes, including cryptochrome genes, Cry1 and Cry2. In mammals, the circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus maintains the circadian rhythms throughout the body. Cry1 and Cry2 play distinct roles in regulating the circadian rhythm. However, the different effects of manipulating clock genes in heterozygous and homozygous alleles, Cry1 and Cry2, remain unclear. Therefore, this study aimed to understand the haplosufficiency of cryptochrome genes in regulating the circadian system. We examined wheel-running activity rhythms and PER2::LUC expression rhythms in SCN slices and pituitary explants in mice. Compared with wild-type mice, Cry1-/- or Cry2-/- mice had shortened or lengthened periods in free-running behavioral rhythms and PER2::LUC expression in the SCN and pituitary gland. Cry1+/- mice had similar circadian rhythms as wild-type mice, although Cry2+/- mice had lengthened periods. The amplitude of PER2::LUC expression exhibited faster damping in Cry1-/- mice. Therefore, Cry1 deficiency affects the circadian period length and stability of the circadian system. A single allele of Cry2 deficiency affects the circadian rhythm, whereas that of Cry1 deficit is compensated.

DOI： 10.1016/j.neulet.2021.136415

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Several studies have suggested a strong interaction between the circadian clock and lipid metabolism in mammals. The circadian clock is driven by endogenous cyclic gene expression patterns, commonly referred to as clock genes, and transcription-translation negative feedback loops. Clock genes regulate the transcription of some lipid metabolism-related genes; however, the relationship between the circadian clock and triglyceride (TG) accumulation at the cellular level remains unclear. Here, we evaluated rhythms of intracellular TG accumulation levels as well as the expression of clock genes and lipid metabolism-related genes for 54 h in mouse and bovine adipose-derived cell cultures. To the best of our knowledge, this study represents the first report demonstrating that TG accumulation exhibits diurnal variations, with the pattern differing among cell types. Furthermore, we found that expression of clock genes and corresponding lipid metabolism-related genes exhibited circadian rhythms. Our results suggest that the cellular clock regulates lipid metabolism-related genes to relate circadian rhythms of TG accumulation in each cell type. We anticipate that the amount of fat stored depends on the timing of the supply of glucose-the precursor of fat. The findings of this study will contribute to the advancement of chrono-nutrition.

DOI： 10.1111/asj.13802

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

The dorsal striatum forms part of the basal ganglia circuit that is a major regulator of voluntary motor behavior. Dysfunction in this circuit is a critical factor in the pathology of neurological (Parkinson's and Huntington's disease) as well as psychiatric disorders. In this study, we employed in vivo real-time monitoring of multiple unit neural activity (MUA) in the dorsal striatum of freely moving mice. We demonstrate that the striatum exhibits robust diurnal and circadian rhythms in MUA that peak in the night. These rhythms are dependent upon the central circadian clock located in the suprachiasmatic nucleus (SCN) as lesions of this structure caused the loss of rhythmicity measured in the striatum. Nonetheless, chronic treatment of methamphetamine (METH) makes circadian rhythms appear in MUA recorded from the striatum of SCN-lesioned mice. These data demonstrate that the physiological properties of neurons in the dorsal striatum are regulated by the circadian system and that METH drives circadian rhythms in striatal physiology in the absence of the SCN. The finding of SCN-driven circadian rhythms in striatal physiology has important implications for an understanding of the temporal regulation of motor control as well as revealing how disease processes may disrupt this regulation.

DOI： 10.1016/j.nbscr.2021.100070

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

Although diurnal variations have been observed in tear film parameters in various species, the molecular mechanisms that control circadian tear secretion remain unclear. The aim of our study was to evaluate the role of clock genes in the lacrimal gland (LG) in regulation of tear secretion. Tear volume was measured by cotton thread test in core clock genes deficient (Cry1-/-Cry2-/--) mice which are behaviorally arrhythmic. Real-time quantitative RT-PCR was used to examine expression profiles of core clock genes in the LG including Per1, Per2, Per3, Clock, Bmal1. All experiments were performed under a 12 h of light and 12 h of darkness (LD) and constant dark (DD) conditions. Under both LD and DD conditions, diurnal and circadian rhythms were observed in tear secretion of wild-type mice with tear volume increased in the objective and subjective night while disruption in diurnal and circadian variations of tear secretion were found in Cry1-/-Cry2-/--mice. In wild-type mice, the expression level of major clock genes in the LG showed oscillatory patterns under both LD and DD conditions. In contrast, expression clock genes in the lacrimal gland of Cry1-/-Cry2-/-- mice showed complete loss of oscillation regardless of environmental light conditions. These findings confirmed the presence of diurnal and circadian rhythms of tear secretion and provided evidences supporting a critical role for the clock in the control of tear secretion.

DOI： 10.1016/j.exer.2021.108524

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The suprachiasmatic nucleus (SCN), the central circadian pacemaker in mammals, is a network structure composed of multiple types of γ-aminobutyric acid (GABA)-ergic neurons and glial cells. However, the roles of GABA-mediated signaling in the SCN network remain controversial. Here, we report noticeable impairment of the circadian rhythm in mice with a specific deletion of the vesicular GABA transporter in arginine vasopressin (AVP)-producing neurons. These mice showed disturbed diurnal rhythms of GABAA receptor-mediated synaptic transmission in SCN neurons and marked lengthening of the activity time in circadian behavioral rhythms due to the extended interval between morning and evening locomotor activities. Synchrony of molecular circadian oscillations among SCN neurons did not significantly change, whereas the phase relationships between SCN molecular clocks and circadian morning/evening locomotor activities were altered significantly, as revealed by PER2::LUC imaging of SCN explants and in vivo recording of intracellular Ca2+ in SCN AVP neurons. In contrast, daily neuronal activity in SCN neurons in vivo clearly showed a bimodal pattern that correlated with dissociated morning/evening locomotor activities. Therefore, GABAergic transmission from AVP neurons regulates the timing of SCN neuronal firing to temporally restrict circadian behavior to appropriate time windows in SCN molecular clocks.

DOI： 10.1073/pnas.2010168118

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Management of time and circadian disruption is an extremely important factor in basic research on pain and analgesia. Although pain is known to vary throughout the day, the mechanism underlying this circadian variation remains largely unknown. In this study, we hypothesized that the process of pain transmission to the central nervous system (after receiving nociceptive stimuli from outside the body) would show day-night differences. Ten-week-old male mice were kept under a strict 12/12-h light/dark cycle for at least 10 days. Formalin was then injected into the second branch region of the trigeminal nerve and the duration of pain-related behaviors (PRBs) was assessed. Immunohistochemical staining was then performed, and the c-Fos-immunopositive cells in the trigeminal spinal tract subnucleus caudalis (Sp5C) were counted. The results showed that the duration of PRBs was longer and the number of c-Fos immunopositive cells in the Sp5C was higher at nighttime than during the day. In addition, the trigeminal ganglia (TG) were extracted from the mice and examined by quantitative real-time PCR to evaluate the daytime and nighttime expression of nociceptive receptors. The results showed that the mRNA expression of transient receptor potential ankyrin 1 in the TG was significantly higher at night than during the day. These results suggest that pain in the trigeminal nerve region is more intense at nighttime, when rodents are active, than during the daytime, partly due to differences in nociceptor expression.

DOI： 10.3389/fnins.2021.703440

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In mammals, the part of the nervous system responsible for most circadian behavior can be localized to a bilaterally paired structure in the hypothalamus known as the suprachiasmatic nucleus (SCN). Understanding the mammalian circadian system will require a detailed multilevel analysis of neural SCN circuits ex vivo and in vivo. Many of the techniques and approaches that are used for the analysis of the circuitry driving circadian oscillations in the SCN are similar to those employed in other brain regions. There is, however, one fundamental difference that needs to be taken into consideration, that is, the physiological, cell, and molecular properties of SCN neurons vary with the time of day. In this chapter, we will consider the preparations and electrophysiological techniques that we have used to analyze the SCN circuit focusing on the acute brain slice and intact, freely moving animal.

DOI： 10.1007/978-1-0716-0381-9_23

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DOI： 10.3389/fnins.2021.735007

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The circadian clocks within the hypothalamic-pituitary-gonadal axis control estrous cycles in female rodents. The suprachiasmatic nucleus (SCN), where the central clock is located, generates daily signals to trigger surge release of luteinizing hormone (LH), which in turn induces ovulation. It has been observed in aged rodents that output from the SCN such as neuronal firing activity is declined, and estrous cycles become irregular and finally stop. Circadian clock mutants display accelerated reproductive aging, suggesting the complicated interplay between the circadian system and the endocrine system. To investigate such circadian regulation of estrous cycles, we construct a mathematical model that describes dynamics of key hormones such as LH and of circadian clocks in the SCN and in the ovary, and simulate estrous cycles for various parameter values. Our simulation results demonstrate that reduction of the amplitude of the SCN signal, which is a symptom of aging, makes estrous cycles irregular. We also show that variation in the phase of the SCN signal and changes in the period of ovarian circadian clocks exacerbates the aging effect on estrous cyclicity. Our study suggests that misalignment between the SCN and ovarian circadian oscillations is one of the primary causes of the irregular estrous cycles.

DOI： 10.1038/s41598-020-73669-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

In mammals, the timing of behavior and physiological activity is controlled by the suprachiasmatic nucleus (SCN) in the hypothalamus. Incidentally, secretin is a peptide hormone that promotes digestive activities and regulates water reabsorption. In recent studies, exogenous administration of secretin has been reported to induce secretion of oxytocin in the supraoptic nucleus of the hypothalamus and modulate social behavior. These results indicate that secretin is involved in the neural network that controls social behavior and plays important roles in the central nervous system. In the present study, we investigated the effects of secretin on circadian rhythms, by assessing circadian rhythms during wheel-running behavior in secretin receptor-deficient (Sctr-/-) mice. Male adult wild-type (WT) and Sctr-/- mice were housed in separate cages containing a wheel. Every minute of the wheel-running activity was monitored during the normal light-dark (LD) cycle (12:12 h) and in constant darkness (DD). Significant differences were observed in the free-running period between the WT and Sctr-/- mice. However, no significant differences were observed in the daily wheel-running revolutions between WT and Sctr-/- mice, in the LD and DD conditions. Moreover, the ratio of the daily activity phase to the rest phase (α/ρ) was significantly smaller in Sctr-/- than that in WT mice in the DD condition. Secretin receptors were expressed in the SCN cells. These findings suggest that secretin receptors are involved in the central circadian clock in the SCN and the circadian system in general.

DOI： 10.1016/j.neulet.2020.134814

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Language：English   Publishing type：Research paper (scientific journal)  

Salt is an essential nutrient; however, excessive salt intake is a prominent public health concern worldwide. Various physiological functions are associated with circadian rhythms, and disruption of circadian rhythms is a prominent risk factor for cardiovascular diseases, cancer, and immune disease. Certain nutrients are vital regulators of peripheral circadian clocks. However, the role of a high-fat and high-salt (HFS) diet in the regulation of circadian gene expression is unclear. This study aimed to investigate the effect of an HFS diet on rhythms of locomotor activity, caecum glucocorticoid secretion, and clock gene expression in mice. Mice administered an HFS diet displayed reduced locomotor activity under normal light/dark and constant dark conditions in comparison with those administered a normal diet. The diurnal rhythm of caecum glucocorticoid secretion and the expression levels of glucocorticoid-related genes and clock genes in the adrenal gland were disrupted with an HFS diet. These results suggest that an HFS diet alters locomotor activity, disrupts circadian rhythms of glucocorticoid secretion, and downregulates peripheral adrenal gland circadian clock genes.

DOI： 10.1371/journal.pone.0233386

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Placental leucine aminopeptidase/insulin-regulated aminopeptidase (P-LAP/IRAP) regulates vasopressin and oxytocin levels in the brain and peripheral tissues by controlled degradation of these peptides. In this study, we determined the relationship between P-LAP/IRAP and vasopressin levels in subregions of the murine brain. P-LAP/IRAP expression was observed in almost all brain regions. The expression patterns of P-LAP/IRAP and vasopressin indicated that cells expressing one of these protein/peptide were distinct from those expressing the other, although there was significant overlap between the expression regions. In addition, we found reciprocal diurnal rhythm patterns in P-LAP/IRAP and arginine vasopressin (AVP) expression in the hippocampus and pituitary gland. Further, synchronously cultured PC12 cells on treatment with nerve growth factor (NGF) showed circadian expression patterns of P-LAP/IRAP and enzymatic activity during 24 h of incubation. Considering that vasopressin is one of the most efficient peptide substrates of P-LAP/IRAP, these results suggest a possible feedback loop between P-LAP/IRAP and vasopressin expression, that regulates the function of these substrate peptides of the enzyme via translocation of P-LAP/IRAP from intracellular vesicles to the plasma membrane in brain cells. These findings provide novel insights into the functions of P-LAP/IRAP in the brain and suggest the involvement of these peptides in modulation of brain AVP functions in hyperosmolality, memory, learning, and circadian rhythm.

DOI： 10.3389/fmolb.2020.00168

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Language：English   Publishing type：Research paper (scientific journal)  

Purpose: Light-emitting diodes that emit high-intensity blue light are associated with blue-light hazard. Here, we report that blue light disturbs circadian rhythms by interfering with the clock gene in the suprachiasmatic nucleus (SCN) and that suppression of blue light at night ameliorates metabolic abnormalities by controlling circadian rhythms. Methods: C57BL/6J mice were exposed to 10-lux light for 30 minutes at Zeitgeber time 14 for light pulse with blue light or blue-light cut light to induce phase shift of circadian rhythms. Phase shift, clock gene expression in SCN, and metabolic parameters were analyzed. In the clinical study, healthy participants wore blue-light shield eyewear for 2 to 3 hours before bed. Anthropometric data analyses, laboratory tests, and sleep quality questionnaires were performed before and after the study. Results: In mice, phase shift induced with a blue-light cut light pulse was significantly shorter than that induced with a white light pulse. The phase of Per2 expression in the SCN was also delayed after a white light pulse. Moreover, blood glucose levels 48 hours after the white light pulse were higher than those after the blue-cut light pulse. Irs2 expression in the liver was decreased with white light but significantly recovered with the blue-cut light pulse. In a clinical study, after 1 month of wearing blue-light shield eyeglasses, there were improvements in fasting plasma glucose levels, insulin resistance, and sleep quality. Conclusions: Our results suggest that suppression of blue light at night effectively maintains circadian rhythms and metabolism.

DOI： 10.1167/iovs.19-27195

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media {LLC}  

Serum testosterone concentration decreases with age in humans and rodents. Accordingly, old male mice show changes in locomotor activity rhythms: a lengthened free-running period and decreased activity levels among others. To investigate whether testosterone replacement improves the age-related decline in circadian rhythmicity, we examined the effects of testosterone on the circadian rhythms of wheel running activity in old male mice. Intact male C57BL/6J mice (18-22 months old) were subcutaneously implanted with silicone tubes packed with testosterone propionate (TP) or cholesterol. TP treatment significantly decreased the daily wheel running revolutions in a normal light/dark (LD) cycle and in constant darkness (DD), but did not affect the free-running period. The same experiment performed on young male gonadectomized mice (3-5 months old) demonstrated that TP treatment significantly increased activity levels in both LD and DD. These results suggest that testosterone replacement exacerbates the age-related decline in circadian rhythmicity.

DOI： 10.1007/s12576-019-00695-4

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Language：English   Publishing type：Research paper (scientific journal)  

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is a multi-functional enzyme. In this study, we analysed its role in lipopolysaccharide-induced inflammatory response in wild-type and ERAP1-knockout mice. Following lipopolysaccharide injection, ERAP1 was secreted into the blood, increasing leucine aminopeptidase activity and NO synthesis therein. Among the amino acids tested, arginine concentration was significantly increased in wild-type mice compared to ERAP1-knockout mice. These results suggest that ERAP1 behaves similar to acute-phase proteins, which are secreted into the blood in response to infectious/inflammatory stimuli and are involved in enhancing NO synthesis as a host defense mechanism.

DOI： 10.1093/jb/mvy090

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Language：Japanese   Publisher：(株)羊土社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier  

The photic entrainment system is critical for the internal circadian clock to be synchronized by external time cues. In nocturnal rodents, exposure to light during the early subjective night causes a phase delay, whereas it causes a phase advance during the late subjective night. This is represented by a phase-response curve (PRC). The PRC of females has not been well studied due to their estrous cycles. Our aim in this study was to understand the characteristics of photic entrainment in female cycling rodents and identify differences in photic entrainment among the stages of the estrous cycle. To establish two types of PRC, immediate PRC (iPRC) and steady state PRC (ssPRC), in each stage of the estrous cycle, we recorded circadian rhythms of wheel running activity, applying a 15-min light pulse to cycling female mice in constant darkness. In the iPRC, which was evaluated on the next day of the light pulse, the amount of phase shift in the diestrus was larger than that in the metestrus stage at circadian time (CT) 2. Similarly, the amount of phase shift in metestrus was larger than that in proestrus at CT 10. In the ssPRC, which was evaluated after completion of a new steady state, no significant estrous variations in the amount of photic phase shifts were detected for any CTs. Although these results indicate that the intrinsic photic entrainment system is not influenced by the estrous cycle, it may affect photoreception and cause sudden behavioral changes.

DOI： 10.1016/j.yhbeh.2018.07.008

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Language：Japanese   Publisher：メディカルレビュー社  

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Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I029270913

Language：English   Publishing type：Research paper (scientific journal)  

Salivary secretion displays day-night variations that are controlled by the circadian clock. The central clock in the suprachiasmatic nucleus (SCN) regulates daily physiological rhythms by prompting peripheral oscillators to adjust to changing environments. Aquaporin 5 (Aqp5) is known to play a key role in salivary secretion, but the association between Aqp5 and the circadian rhythm is poorly understood. The aim of our study was to evaluate whether Aqp5 expression in submandibular glands (SMGs) is driven by the central clock in the SCN or by autonomous oscillations. We observed circadian oscillations in the activity of period circadian protein homolog 2 and luciferase fusion protein (PER2::LUC) in cultured SMGs with periodicity depending on core clock genes. A daily rhythm was detected in the expression profiles of Aqp5 in SMGs in vivo. In cultured SMGs ex vivo, clock genes showed distinct circadian rhythms, whereas Aqp5 expression did not. These data indicate that daily Aqp5 expression in the mouse SMG is driven by the central clock in the SCN.

DOI： 10.1007/s12576-017-0540-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

DOI： 10.1016/j.bbamcr.2018.03.009

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The ability of the circadian clock to adapt to environmental changes is critical for maintaining homeostasis, preventing disease, and limiting the detrimental effects of aging. To date, little is known about age-related changes in the entrainment of peripheral clocks to external cues. We therefore evaluated the ability of the peripheral clocks of the kidney, liver, and submandibular gland to be entrained by external stimuli including light, food, stress, and exercise in young versus aged mice using in vivo bioluminescence monitoring. Despite a decline in locomotor activity, peripheral clocks in aged mice exhibited normal oscillation amplitudes under light-dark, constant darkness, and simulated jet lag conditions, with some abnormal phase alterations. However, age-related impairments were observed in peripheral clock entrainment to stress and exercise stimuli. Conversely, age-related enhancements were observed in peripheral clock entrainment to food stimuli and in the display of food anticipatory behaviors. Finally, we evaluated the hypothesis that deficits in sympathetic input from the central clock located in the suprachiasmatic nucleus of the hypothalamus were in part responsible for age-related differences in the entrainment. Aged animals showed an attenuated entrainment response to noradrenergic stimulation as well as decreased adrenergic receptor mRNA expression in target peripheral organs. Taken together, the present findings indicate that age-related circadian disorganization in entrainment to light, stress, and exercise is due to sympathetic dysfunctions in peripheral organs, while meal timing produces effective entrainment of aged peripheral circadian clocks.

DOI： 10.1038/npjamd.2016.30

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DOI： 10.1007/s12576-016-0439-2

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DOI： 10.1016/j.neulet.2015.10.071

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DOI： 10.1371/journal.pone.0146136

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DOI： 10.1016/j.celrep.2015.07.049

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DOI： 10.1093/jb/mvv001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Society for Neuroscience  

DOI： 10.1523/ENEURO.0064-15.2015

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DOI： 10.4049/jimmunol.1300935

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：東京 : メディカル葵出版  

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Language：Japanese   Publisher：日本内分泌撹乱物質学会  

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DOI： 10.1371/journal.pone.0058884

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DOI： 10.1016/j.neures.2012.09.005

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Publishing type：Research paper (scientific journal)   Publisher：化学同人  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Humana Press Inc.  

DOI： 10.1007/978-1-62703-020-5_5

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DOI： 10.1371/journal.pone.0028726

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DOI： 10.1523/JNEUROSCI.0451-11.2011

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DOI： 10.1177/0748730411401740

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DOI： 10.1111/j.1460-9568.2010.07119.x

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DOI： 10.1016/j.steroids.2010.01.007

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DOI： 10.1152/ajpendo.90392.2008

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DOI： 10.1371/journal.pone.0002050

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DOI： 10.1016/j.cub.2008.02.024

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DOI： 10.1152/ajpregu.00396.2006

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DOI： 10.1016/j.neures.2005.12.009

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DOI： 10.1159/000096093

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DOI： 10.1002/jnr.20677

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DOI： 10.1074/jbc.M413236200

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：じほう  

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DOI： 10.1016/j.neulet.2004.09.005

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DOI： 10.1111/j.0953-8194.2004.01136.x

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DOI： 10.1016/S0079-6123(02)41091-6

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DOI： 10.1016/S0306-4522(01)00479-1

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DOI： 10.1016/S0168-0102(01)00285-1

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DOI： 10.1016/S0168-0102(01)00255-3

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DOI： 10.1016/S0304-3940(01)02022-5

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Total pages：231   Language：Japanese  

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Total pages：xx, 407p   Language：Japanese  

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Language：Japanese   Publisher：日本睡眠学会・日本時間生物学会  

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Language：Japanese   Publisher：(公社)日本実験動物協会  

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Language：Japanese   Publisher：明治大学農学部  

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Other Link： http://id.ndl.go.jp/bib/031346330

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Language：Japanese   Publisher：[東京] : 三島海雲記念財団  

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Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I031934400

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Language：Japanese   Publisher：(一社)日本抗加齢医学会  

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DOI： 10.1016/j.neures.2004.06.002

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Language：Japanese   Publisher：(公社)日本生化学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：日本神経化学会  

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Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：高松  

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Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：浜松アクトシティコングレスセンター、浜松  

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Language：Japanese   Presentation type：Poster presentation  

Venue：Palm Harbor, FL,USA  

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Venue：Palm Harbor, FL, USA  

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Venue：Okazaki, Japan  

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Venue：札幌コンベンションセンター、札幌  

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Language：English   Presentation type：Poster presentation  

Venue：Sapporo, Japan  

The central circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus generates daily oscillations responsible for organizing the timing of most behaviors and physiological events in mammals, including the luteinizing hormone (LH) surge during the estrous cycle that triggers ovulation. In cycling female rodents, LH surge occurs on the day of proestrus at a specific critical period in the late afternoon, approximately 2-4 h before lights off. SCN lesioning abolishes this LH surge and prevents estrous cycles. Thus, timing-regulatory signals from the SCN are required for normal reproductive functions. It is known that these signals travel to specific sites in the brain and peripheral organs via neural connections and diffusible factors. However, which pathway is critical for reproductive functions, including the estrous cycle, remains unclear. In the present study, we employed a micro-knife originally designed by Prof. Halasz to sever nerves originating from the SCN. To determine the effect of the knife-cut on estrous cyclicity, we recorded wheel-running activity and examined vaginal smears of female C57BL/6J mice (n = 24) showing normal 4 or 5 days-estrous cycle before and after the knife-cut. Both assessments were continued for at least 15 days after the knife-cut, and then, the mice were killed with deep anesthesia, and their brains were removed and fixed with 4% paraformaldehyde. Coronal brain sections were obtained and stained with neutral red and anti-GFAP (Glial fibrillary acidic protein) antibody to determine the success of the knife-cut. In eight out of the 24 animals, the efferent connection from the SCN was completely cut, and seven out of these eight mice showed disappearance of the estrous cycle. In six mice, this neural connection was incompletely cut, and only one of them had a normal estrous cycle. Little or no cutting was achieved in the remaining 10 animals, and these mice showed a normal estrous cycle. In addition, mice experienced the knife-cut showed diurnal rhythms entrained with LD cycle and circadian rhythms in constant darkness, indicating that their SCN are intact. Our results strongly suggest that the timing-regulatory signaling via neural connections from the SCN is critical for estrous cyclicity.

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Venue：埼玉  

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Venue：東京  

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Venue：札幌  

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Language：Japanese   Presentation type：Symposium, workshop panel (public)  

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Language：English   Presentation type：Poster presentation  

Venue：Destin, Florida, USA  

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Venue：Chicago, USA  

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Venue：Hong Kong S.A.R., China  

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Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：大阪  

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Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：Kuala Lumpur, Malaysia  

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