|-2013年||早稲田大学 先進理工学研究科 電気・情報生命専攻|
博士（理学） 課程 早稲田大学
医歯薬学 / 基礎医学 / 環境生理学（含体力医学・栄養生理学）
Haraguchi, Atsushi; Fukuzawa, Miyabi; Iwami, Shiho; Nishimura, Yutaro; Motohashi, Hiroaki; Tahara, Yu; Shibata, Shigenobu
概要：© 2018 The Author(s). The circadian clock system is associated with feeding and mood. Patients with night eating syndrome (NES) delay their eating rhythm and their mood declines during the evening and night, manifesting as time-specific depression. Therefore, we hypothesized that the NES feeding pattern might cause time-specific depression. We established new NES model by restricted feeding with high-fat diet during the inactive period under normal-fat diet ad libitum. The FST (forced swimming test) immobility time in the NES model group was prolonged only after lights-on, corresponding to evening and early night for humans. We examined the effect of the NES feeding pattern on peripheral clocks using PER2::LUCIFERASE knock-in mice and an in vivo monitoring system. Caloric intake during the inactive period would shift the peripheral clock, and might be an important factor in causing the time-specific depression-like behavior. In the NES model group, synthesis of serotonin and norepinephrine were increased, but utilization and metabolism of these monoamines were decreased under stress. Desipramine shortened some mice's FST immobility time in the NES model group. The present study suggests that the NES feeding pattern causes phase shift of peripheral clocks and malfunction of the monoamine system, which may contribute to the development of time-specific depression.
Tahara, Yu; Tahara, Yu; Yamazaki, Mayu; Sukigara, Haruna; Motohashi, Hiroaki; Sasaki, Hiroyuki; Miyakawa, Hiroki; Haraguchi, Atsushi; Ikeda, Yuko; Fukuda, Shinji; Fukuda, Shinji; Shibata, Shigenobu
概要：© 2018 The Author(s). Microbiota-derived short-chain fatty acids (SCFAs) and organic acids produced by the fermentation of non-digestible fibre can communicate from the microbiome to host tissues and modulate homeostasis in mammals. The microbiome has circadian rhythmicity and helps the host circadian clock function. We investigated the effect of SCFA or fibre-containing diets on circadian clock phase adjustment in mouse peripheral tissues (liver, kidney, and submandibular gland). Initially, caecal SCFA concentrations, particularly acetate and butyrate, induced significant day-night differences at high concentrations during the active period, which were correlated with lower caecal pH. By monitoring luciferase activity correlated with the clock gene Period2 in vivo, we found that oral administration of mixed SCFA (acetate, butyrate, and propionate) and an organic acid (lactate), or single administration of each SCFA or lactate for three days, caused phase changes in the peripheral clocks with stimulation timing dependency. However, this effect was not detected in cultured fibroblasts or cultured liver slices with SCFA applied to the culture medium, suggesting SCFA-induced indirect modulation of circadian clocks in vivo. Finally, cellobiose-containing diets facilitated SCFA production and refeeding-induced peripheral clock entrainment. SCFA oral gavage and prebiotic supplementation can facilitate peripheral clock adjustment, suggesting prebiotics as novel therapeutic candidates for misalignment.
Tahara, Yu; Shibata, Shigenobu
Free Radical Biology and Medicine2018年01月-2018年01月
概要：© 2017 Elsevier Inc. The circadian clock system in mammals plays a fundamental role in maintaining homeostasis. Entrainment is an important characteristic of the internal clock, by which appropriate timing is maintained according to external daily stimuli, such as light, stress, exercise, and/or food. Disorganized entrainment or a misaligned clock time, such as jet lag, increases health disturbances. The central clock in the suprachiasmatic nuclei, located in the hypothalamus, receives information about arousal stimuli, such as physical stress or exercise, and changes the clock time by modifying neural activity or the expression of circadian clock genes. Although feeding stimuli cannot entrain the central clock in a normal light-dark cycle, the central clock can partially detect the metabolic status. Local clocks in the peripheral tissues, including liver and kidney, have a strong direct response to the external stimuli of stress, exercise, and/or food that is independent of the central clock. The mechanism underlying entrainment by stress/exercise is mediated by glucocorticoids, sympathetic nerves, oxidative stress, hypoxia, pH, cytokines, and temperature. Food/nutrition-induced entrainment is mediated by fasting-induced hormonal or metabolic changes and re-feeding-induced insulin or oxyntomodulin secretion. Chrono-nutrition is a clinical application based on chronobiology research. Future studies are required to elucidate the effects of eating and nutrient composition on the human circadian clock. Here, we focus on the central and peripheral clocks mostly in rodents' studies and review the findings of recent investigations of the effects of stress, exercise, and food on the entrainment system.
Kamagata, Mayo; Ikeda, Yuko; Sasaki, Hiroyuki; Hattori, Yuta; Yasuda, Shinnosuke; Iwami, Shiho; Tsubosaka, Miku; Ishikawa, Ryosuke; Todoh, Ai; Tamura, Konomi; Tahara, Yu; Shibata, Shigenobu
Chronobiology International34(8)p.1067 - 10822017年09月-2017年09月
概要：© 2017 Taylor & Francis Group, LLC. In mammals, the central clock (the suprachiasmatic nuclei, SCN) is entrained mainly by the light-dark cycle, whereas peripheral clocks in the peripheral tissues are entrained/synchronized by multiple factors, including feeding patterns and endocrine hormones such as glucocorticoids. Clock-mutant mice (Clock/Clock), which have a mutation in a core clock gene, show potent phase resetting in response to light pulses compared with wild-type (WT) mice, owing to the damped and flexible oscillator in the SCN. However, the phase resetting of the peripheral clocks in Clock/Clock mice has not been elucidated. Here, we characterized the peripheral clock gene synchronization in Clock/Clock mice by daily injections of a synthetic glucocorticoid (dexamethasone, DEX) by monitoring in vivo PER2::LUCIFERASE bioluminescence. Compared with WT mice, the Clock/Clock mice showed significantly decreased bioluminescence and peripheral clock rhythms with decreased amplitudes and delayed phases. In addition, the DEX injections increased the amplitudes and advanced the phases. In order to examine the robustness of the internal oscillator, T-cycle experiments involving DEX stimulations with 24- or 30-h intervals were performed. The Clock/Clock mice synchronized to the 30-h T-cycle stimulation, which suggested that the peripheral clocks in the Clock/Clock mice had increased synchronizing ability upon DEX stimulation, to that of circadian and hour-glass type oscillations, because of weak internal clock oscillators.
Motohashi, Hiroaki; Sukigara, Haruna; Tahara, Yu; Tahara, Yu; Saito, Keisuke; Yamazaki, Mayu; Shiraishi, Takuya; Kikuchi, Yosuke; Haraguchi, Atsushi; Shibata, Shigenobu
Nutrition Research43p.16 - 242017年07月-2017年07月
概要：© 2017 Elsevier Inc. In mammals, daily physiological events are precisely regulated by an internal circadian clock system. An important function of this system is to readjust the phase of the clock daily. In Japan, traditional herb medicines, so-called crude drugs (Shoyaku), are widely used for many diseases, and some are reported to affect circadian clock impairment, suggesting that some of them might have an ability to modify clock gene expression rhythms. Therefore, from selected 40 crude drugs, finding candidates that control the circadian clock phases was the first purpose of this study. As there are several crude drugs used for liver- and/or kidney-related diseases, the second aim of the present study was to find some crude drugs affecting liver/kidney circadian clock in vivo. To assess phase changes in the daily circadian rhythm, bioluminescence from the core clock gene product Period 2 was continuously monitored in mouse embryonic fibroblasts in vitro and in some peripheral tissues (kidney, liver, and submandibular gland) of PERIOD2::LUCIFERASE knock-in mice in vivo. In our screening, Polyporus and Bupleuri radix were found to be good candidates to effectively manipulate the peripheral circadian clock phase acutely, with stimulation time-of-day dependency in vitro as well as in vivo. Interestingly, Polyporus and Bupleuri radix are traditional herb medicines use for treating edema and promoting diuresis, and for chronic hepatitis, respectively. These crude drugs may be therefore good modulators of the circadian peripheral clocks including liver and kidney, and circadian clock genes become new molecular targets for these crude drugs.
Tahara, Yu; Tahara, Yu; Shibata, Shigenobu
Hepatology65(3)p.1061 - 10642017年03月-2017年03月
Shinozaki, Ayako; Misawa, Kenichiro; Ikeda, Yuko; Haraguchi, Atsushi; Kamagata, Mayo; Tahara, Yu; Shibata, Shigenobu
概要：© 2017 Shinozaki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Flavonoids are natural polyphenols that are widely found in plants. The effects of flavonoids on obesity and numerous diseases such as cancer, diabetes, and Alzheimer's have been well studied. However, little is known about the relationships between flavonoids and the circadian clock. In this study, we show that continuous or transient application of flavonoids to the culture medium of embryonic fibroblasts from PER2::LUCIFERASE (PER2::LUC) mice induced various modifications in the circadian clock amplitude, period, and phase. Transient application of some of the tested flavonoids to cultured cells induced a phase delay of the PER2::LUC rhythm at the down slope phase. In addition, continuous application of the polymethoxy flavonoids nobiletin and tangeretin increased the amplitude and lengthened the period of the PER2::LUC rhythm. The nobiletin-induced phase delay was blocked by cotreatment with U0126, an ERK inhibitor. In summary, among the tested flavonoids, polymethoxy flavones increased the amplitude, lengthened the period, and delayed the phase of the PER2::LUC circadian rhythm. Therefore, foods that contain polymethoxy flavones may have beneficial effects on circadian rhythm disorders and jet lag.
Tahara, Yu; Tahara, Yu; Aoyama, Shinya; Shibata, Shigenobu
Journal of Physiological Sciences67(1)2017年01月-2017年01月
概要：© 2016, The Physiological Society of Japan and Springer Japan.The mammalian circadian clock regulates day–night fluctuations in various physiological processes. The circadian clock consists of the central clock in the suprachiasmatic nucleus of the hypothalamus and peripheral clocks in peripheral tissues. External environmental cues, including light/dark cycles, food intake, stress, and exercise, provide important information for adjusting clock phases. This review focuses on stress and exercise as potent entrainment signals for both central and peripheral clocks, especially in regard to the timing of stimuli, types of stressors/exercises, and differences in the responses of rodents and humans. We suggest that the common signaling pathways of clock entrainment by stress and exercise involve sympathetic nervous activation and glucocorticoid release. Furthermore, we demonstrate that physiological responses to stress and exercise depend on time of day. Therefore, using exercise to maintain the circadian clock at an appropriate phase and amplitude might be effective for preventing obesity, diabetes, and cardiovascular disease.
Takahashi, Masaki; Haraguchi, Atsushi; Tahara, Yu; Aoki, Natsumi; Fukazawa, Mayuko; Tanisawa, Kumpei; Ito, Tomoko; Nakaoka, Takashi; Higuchi, Mitsuru; Higuchi, Mitsuru; Shibata, Shigenobu; Shibata, Shigenobu
概要：© Author(s) 2017.The circadian clock regulates many physiological functions including physical activity and feeding patterns. In addition, scheduled exercise and feeding themselves can affect the circadian clock. The purpose of the present study was to investigate the relationship between physical/feeding activity and expression of clock genes in hair follicle cells in older adults. Twenty adult men (age, 68 ± 7 years, mean ± SE) were examined in this cross-sectional study. Prior to hair follicle cell collection, the participants were asked to wear a uniaxial accelerometer for one week. The timings of breakfast, lunch, and dinner were also recorded. Hair follicle cells were then collected over a 24 h period at 4 h intervals. The amplitude of PER3 expression was positively correlated with moderate and vigorous physical activity (r = 0.582, p = 0.007) and peak oxygen uptake (r = 0.481, p = 0.032), but these correlations were not observed for NR1D1 or NR1D2. No association was noted between meal times and the amplitude or the acrophase for any of these three clock genes. These findings suggest that rhythmic expression of the circadian clock gene PER3 is associated with the amount of daily physical activity and physical fitness in older adults.
Tahara, Yu;Aoyama, Shinya;Shibata, Shigenobu
JOURNAL OF PHYSIOLOGICAL SCIENCES67(1)p.1 - 102017年-2017年
Takahashi, Masaki;Haraguchi, Atsushi;Tahara, Yu;Aoki, Natsumi;Fukazawa, Mayuko;Tanisawa, Kumpei;Ito, Tomoko;Nakaoka, Takashi;Higuchi, Mitsuru;Shibata, Shigenobu
Sasaki, Hiroyuki; Hattori, Yuta; Ikeda, Yuko; Kamagata, Mayo; Iwami, Shiho; Yasuda, Shinnosuke; Tahara, Yu; Shibata, Shigenobu
概要：Exercise during the inactive period can entrain locomotor activity and peripheral circadian clock rhythm in mice; however, mechanisms underlying this entrainment are yet to be elucidated. Here, we showed that the bioluminescence rhythm of peripheral clocks in PER2::LUC mice was strongly entrained by forced treadmill and forced wheel-running exercise rather than by voluntary wheel-running exercise at middle time during the inactivity period. Exercise-induced entrainment was accompanied by increased levels of serum corticosterone and norepinephrine in peripheral tissues, similar to the physical stress-induced response. Adrenalectomy with norepinephrine receptor blockers completely blocked the treadmill exercise-induced entrainment. The entrainment of the peripheral clock by exercise is independent of the suprachiasmatic nucleus clock, the main oscillator in mammals. The present results suggest that the response of forced exercise, but not voluntary exercise, may be similar to that of stress, and possesses the entrainment ability of peripheral clocks through the activation of the adrenal gland and the sympathetic nervous system.
Tahara, Yu; Shibata, Shigenobu
Nature Reviews Gastroenterology and Hepatology13(4)p.217 - 2262016年04月-2016年04月
概要：The circadian clock system consists of a central clock located in the suprachiasmatic nucleus in the hypothalamus and peripheral clocks in peripheral tissues. Peripheral clocks in the liver have fundamental roles in maintaining liver homeostasis, including the regulation of energy metabolism and the expression of enzymes controlling the absorption and metabolism of xenobiotics. Over the past two decades, research has investigated the molecular mechanisms linking circadian clock genes with the regulation of hepatic physiological functions, using global clock-gene-knockout mice, or mice with liver-specific knockout of clock genes or clock-controlled genes. Clock dysfunction accelerates the development of liver diseases such as fatty liver diseases, cirrhosis, hepatitis and liver cancer, and these disorders also disrupt clock function. Food is an important regulator of circadian clocks in peripheral tissues. Thus, controlling the timing of food consumption and food composition, a concept known as chrononutrition, is one area of active research to aid recovery from many physiological dysfunctions. In this Review, we focus on the molecular mechanisms of hepatic circadian gene regulation and the relationships between hepatic circadian clock systems and liver physiology and disease. We concentrate on experimental data obtained from cell or mice and rat models and discuss how these findings translate into clinical research, and we highlight the latest developments in chrononutritional studies.
Li, Heng; Ohta, Hidenobu; Tahara, Yu; Nakamura, Sakiko; Taguchi, Kazuaki; Nakagawa, Machiko; Nakagawa, Machiko; Oishi, Yoshihisa; Oishi, Yoshihisa; Goto, Yu Ichi; Wada, Keiji; Kaga, Makiko; Inagaki, Masumi; Otagiri, Masaki; Yokota, Hideo; Shibata, Shigenobu; Sakai, Hiromi; Okamura, Kunihiro; Yaegashi, Nobuo
概要：Pre-eclampsia affects approximately 5% of all pregnant women and remains a major cause of maternal and fetal morbidity and mortality. The hypertension associated with pre-eclampsia develops during pregnancy and remits after delivery, suggesting that the placenta is the most likely origin of this disease. The pathophysiology involves insufficient trophoblast invasion, resulting in incomplete narrow placental spiral artery remodeling. Placental insufficiency, which limits the maternal-fetal exchange of gas and nutrients, leads to fetal intrauterine growth restriction. In this study, in our attempt to develop a new therapy for pre-eclampsia, we directly rescued placental and fetal hypoxia with nano-scale size artificial oxygen carriers (hemoglobin vesicles). The present study is the first to demonstrate that artificial oxygen carriers successfully treat placental hypoxia, decrease maternal plasma levels of anti-angiogenic proteins and ameliorate fetal growth restriction in the pre-eclampsia rat model.
Hamaguchi, Yutaro; Tahara, Yu; Kuroda, Hiroaki; Haraguchi, Atsushi; Shibata, Shigenobu
概要：The circadian clock system in peripheral tissues can endogenously oscillate and is entrained by the light-dark and fasting-feeding cycles in mammals. Although the systems range of entrainment to light-dark cycles with a non-24 h (<24 h) interval has been studied, the range of entrainment to fasting-feeding cycles with shorter periods (<24 h) has not been investigated in peripheral molecular clocks. In the present study, we measured this range by monitoring the mouse peripheral PER2::LUCIFERASE rhythm in vivo at different periods under each feeding cycle (Tau (T) = 15-24 h) under normal light-dark conditions. Peripheral clocks could be entrained to the feeding cycle with T = 22-24 h, but not to that with T = 15-21 h. Under the feeding cycle with T = 15-18 h, the peripheral clocks oscillated at near the 24-h period, suggesting that they were entrained to the light-dark cycle. Thus, for the first time, we demonstrated the range of entrainment to the non-24 h feeding cycle, and that the circadian range (T = 22-24 h) of feeding stimulus is necessary for peripheral molecular clock entrainment under light-dark cycles.
Tanabe, Kana; Kitagawa, Eri; Wada, Misaki; Haraguchi, Atsushi; Orihara, Kanami; Tahara, Yu; Tahara, Yu; Nakao, Atsuhito; Shibata, Shigenobu
概要：© 2015 Scientific Reports. The mammalian circadian clock controls many physiological processes that include immune responses and allergic reactions. Several studies have investigated the circadian regulation of intestinal permeability and tight junctions known to be affected by cytokines. However, the contribution of circadian clock to food allergy symptoms remains unclear. Therefore, we investigated the role of the circadian clock in determining the severity of food allergies. We prepared an ovalbumin food allergy mouse model, and orally administered ovalbumin either late in the light or late in the dark period under light-dark cycle. The light period group showed higher allergic diarrhea and weight loss than the dark period group. The production of type 2 cytokines, IL-13 and IL-5, from the mesenteric lymph nodes and ovalbumin absorption was higher in the light period group than in the dark period group. Compared to the dark period group, the mRNA expression levels of the tight junction proteins were lower in the light period group. We have demonstrated that increased production of type 2 cytokines and intestinal permeability in the light period induced severe food allergy symptoms. Our results suggest that the time of food antigen intake might affect the determination of the severity of food allergy symptoms.
Furutani, Akiko; Ikeda, Yuko; Itokawa, Misa; Nagahama, Hiroki; Ohtsu, Teiji; Furutani, Naoki; Kamagata, Mayo; Yang, Zhi Hong; Hirasawa, Akira; Hirasawa, Akira; Tahara, Yu; Shibata, Shigenobu
概要：© 2015 Furutani et al. The circadian peripheral clock is entrained by restricted feeding (RF) at a fixed time of day, and insulin secretion regulates RF-induced entrainment of the peripheral clock in mice. Thus, carbohydrate-rich food may be ideal for facilitating RF-induced entrainment, although the role of dietary oils in insulin secretion and RF-induced entrainment has not been described. The soybean oil component of standard mouse chow was substituted with fish or soybean oil containing docosahexaenoic acid (DHA) and/or eicosapentaenoic acid (EPA). Tuna oil (high DHA/EPA), menhaden oil (standard), and DHA/EPA dissolved in soybean oil increased insulin secretion and facilitated RF-induced phase shifts of the liver clock as represented by the bioluminescence rhythms of PER2::LUCIFERASE knock-in mice. In this model, insulin depletion blocked the effect of tuna oil and fish oil had no effect on mice deficient for GPR120, a polyunsaturated fatty acid receptor. These results suggest food containing fish oil or DHA/EPA is ideal for adjusting the peripheral clock. Copyright:
Tahara, Yu; Shiraishi, Takuya; Kikuchi, Yosuke; Haraguchi, Atsushi; Kuriki, Daisuke; Sasaki, Hiroyuki; Motohashi, Hiroaki; Sakai, Tomoko; Shibata, Shigenobu
概要：The effects of acute stress on the peripheral circadian system are not well understood in vivo. Here, we show that sub-acute stress caused by restraint or social defeat potently altered clock gene expression in the peripheral tissues of mice. In these peripheral tissues, as well as the hippocampus and cortex, stressful stimuli induced time-of-day-dependent phase-advances or -delays in rhythmic clock gene expression patterns; however, such changes were not observed in the suprachiasmatic nucleus, i.e. the central circadian clock. Moreover, several days of stress exposure at the beginning of the light period abolished circadian oscillations and caused internal desynchronisation of peripheral clocks. Stress-induced changes in circadian rhythmicity showed habituation and disappeared with long-term exposure to repeated stress. These findings suggest that sub-acute physical/psychological stress potently entrains peripheral clocks and causes transient dysregulation of circadian clocks in vivo.
Ikeda Y, Sasaki H, Ohtsu T, Shiraishi T, Tahara Y, Shibata S
Chronobiology International32p.195 - 2102015年-
Tahara, Yu-Ki;Matsubara, Riku;Shibata, Takanori
HETEROCYCLES90(2)p.1094 - 11102015年-2015年
Ikeda, Yuko;Sasaki, Hiroyuki;Ohtsu, Teiji;Shiraishi, Takuya;Tahara, Yu;Shibata, Shigenobu
CHRONOBIOLOGY INTERNATIONAL32(2)p.195 - 2102015年-2015年
Tahara, Yu;Shiraishi, Takuya;Kikuchi, Yosuke;Haraguchi, Atsushi;Kuriki, Daisuke;Sasaki, Hiroyuki;Motohashi, Hiroaki;Sakai, Tomoko;Shibata, Shigenobu
Furutani, Akiko;Ikeda, Yuko;Itokawa, Misa;Nagahama, Hiroki;Ohtsu, Teiji;Furutani, Naoki;Kamagata, Mayo;Yang, Zhi-Hong;Hirasawa, Akira;Tahara, Yu;Shibata, Shigenobu
Tahara, Yu-ki;Ito, Mamoru;Kanyiva, Kyalo Stephen;Shibata, Takanori
CHEMISTRY-A EUROPEAN JOURNAL21(32)p.11340 - 113432015年-2015年
Moriya, Shunpei;Tahara, Yu;Sasaki, Hiroyuki;Ishigooka, Jun;Shibata, Shigenobu
NEUROSCIENCE RESEARCH99p.16 - 212015年-2015年
Hamaguchi, Yutaro;Tahara, Yu;Kuroda, Hiroaki;Haraguchi, Atsushi;Shibata, Shigenobu
Moriya, Shunpei;Tahara, Yu;Sasaki, Hiroyuki;Ishigooka, Jun;Shibata, Shigenobu
SLEEP MEDICINE16(11)p.1352 - 13592015年-2015年
Ikeda Yuko;Sasaki Hiroyuki;Ohtsu Teiji;Shiraishi Takuya;Tahara Yu;Shibata Shigenobu
概要：:The mammalian circadian rhythm is entrained by multiple factors, including the light-dark cycle, the organism's feeding pattern and endocrine hormones such as glucocorticoids. Both a central clock (the suprachiasmatic nucleus, or SCN) and peripheral clocks (i.e. in the liver and lungs) in mice are entrained by photoperiod. However, the factors underlying entrainment signals from the SCN to peripheral clocks are not well known. To elucidate the role of entrainment factors such as corticosterone and feeding, we examined whether peripheral clock rhythms were impaired by adrenalectomy (ADX) and/or feeding of 6 meals per day at equal intervals under short-day, medium-day and long-day photoperiods (SP, MP and LP, respectively). We evaluated the waveform and phase of circadian rhythms in the liver, kidney and salivary gland by in vivo imaging of PER2::LUCIFERASE knock-in mice. In intact mice, the waveforms of the peripheral clocks were similar among all photoperiods. The phases of peripheral clocks were well adjusted by the timing of the "lights-off"-operated evening (E) oscillator but not the "lights-on"-operated morning (M) oscillator. ADX had almost no effect on the rhythmicity and phase of peripheral clocks, regardless of photoperiod. To reduce the feeding-induced signal, we placed mice on a restricted feeding regimen with 6 meals per day (6 meals RF). This caused advances of the peripheral clock phase in LP-housed mice (2-5 h) and MP-housed mice (1-2 h) but not SP-housed mice. Thus, feeding pattern may affect the phase of peripheral clocks, depending on photoperiod. More specifically, ADX + 6 meals RF mice showed impairment of circadian rhythms in the kidney and liver but not in the salivary gland, regardless of photoperiod. However, the impairment of peripheral clocks observed in ADX + 6 meals RF mice was reversed by administration of dexamethasone for 3 days. The phase differences in the salivary gland clock among SP-, MP- and LP-housed mice became very small following treatment with ADX + 6 meals RF, suggesting that the effect of photoperiod was reduced by ADX and 6 meals RF. Because the SCN rhythm (as evaluated by PER2 immunohistochemistry) was not disrupted by ADX + 6 meals RF, impairment of peripheral clocks in these mice was not because of impaired SCN clock function. In addition, locomotor activity rhythm and modifications of the feeding pattern may not be completely responsible for determining the phase of peripheral clocks. Thus, this study demonstrates that the phase of peripheral clocks responds to a photoperiodic lights-off signal, and suggests that signals from normal feeding patterns and the adrenal gland are necessary to maintain the oscillation and phase of peripheral clocks under various photoperiods.
Moriya Shunpei;Tahara Yu;Sasaki Hiroyuki;Ishigooka Jun;Shibata Shigenobu
概要：:Although the results of previous studies have suggested that disruptions in circadian rhythms are involved in the pathogenesis of depression, no studies have examined the interaction of clock gene expression deficit and depression state. In this study, we examined clock gene expression levels and depressive-like behavior in mice housed under 3.5h light, 3.5h dark (T = 7) conditions to investigate the association between clock gene expression and depressive state. C57BL/6J mice were housed under a T = 24 cycle (12h light, 12h dark) or a T = 7 cycle and clock gene expression levels in the hippocampus and the amygdala were measured by real-time RT-PCR. Depressive state was evaluated by the forced swim test (FST). Although circadian rhythms of Per1 and Per2 clock gene expression in the hippocampus and amygdala were still detected under T = 7 conditions, rhythmicity and expression levels of both significantly decreased. Mice housed with a T = 7 cycle showed increased immobile time in the FST than those with a T = 24 cycle. The present results suggest that the presence of a depressive state around the early active phase of activity may be related to impairment of rhythmicity and expression levels of Per1 and Per2 genes under abnormal light-dark conditions.
Tahara Yu;Shiraishi Takuya;Kikuchi Yosuke;Haraguchi Atsushi;Kuriki Daisuke;Sasaki Hiroyuki;Motohashi Hiroaki;Sakai Tomoko;Shibata Shigenobu
概要：:The effects of acute stress on the peripheral circadian system are not well understood in vivo. Here, we show that sub-acute stress caused by restraint or social defeat potently altered clock gene expression in the peripheral tissues of mice. In these peripheral tissues, as well as the hippocampus and cortex, stressful stimuli induced time-of-day-dependent phase-advances or -delays in rhythmic clock gene expression patterns; however, such changes were not observed in the suprachiasmatic nucleus, i.e. the central circadian clock. Moreover, several days of stress exposure at the beginning of the light period abolished circadian oscillations and caused internal desynchronisation of peripheral clocks. Stress-induced changes in circadian rhythmicity showed habituation and disappeared with long-term exposure to repeated stress. These findings suggest that sub-acute physical/psychological stress potently entrains peripheral clocks and causes transient dysregulation of circadian clocks in vivo.
Furutani Akiko;Ikeda Yuko;Itokawa Misa;Nagahama Hiroki;Ohtsu Teiji;Furutani Naoki;Kamagata Mayo;Yang Zhi-Hong;Hirasawa Akira;Tahara Yu;Shibata Shigenobu
概要：:The circadian peripheral clock is entrained by restricted feeding (RF) at a fixed time of day, and insulin secretion regulates RF-induced entrainment of the peripheral clock in mice. Thus, carbohydrate-rich food may be ideal for facilitating RF-induced entrainment, although the role of dietary oils in insulin secretion and RF-induced entrainment has not been described. The soybean oil component of standard mouse chow was substituted with fish or soybean oil containing docosahexaenoic acid (DHA) and/or eicosapentaenoic acid (EPA). Tuna oil (high DHA/EPA), menhaden oil (standard), and DHA/EPA dissolved in soybean oil increased insulin secretion and facilitated RF-induced phase shifts of the liver clock as represented by the bioluminescence rhythms of PER2::LUCIFERASE knock-in mice. In this model, insulin depletion blocked the effect of tuna oil and fish oil had no effect on mice deficient for GPR120, a polyunsaturated fatty acid receptor. These results suggest food containing fish oil or DHA/EPA is ideal for adjusting the peripheral clock.
Narishige S, Kuwahara M, Shinozaki A, Okada S, Ikeda Y, Kamagata M, Tahara Y, Shibata S.
British Journal of Pharmacology171p.5858 - 58692014年-
Aoki N, Yoshida D, Ishikawa R, Ando M, Nakamura K, Tahara Y, and Shibata S
Nutr Res34p.613 - 6222014年-
Moriya S, Tahara Y, Sasaki H, Hamaguchi Y, Kuriki D, Ishikawa R, Ishigooka J, Shibata S
J Pharmacol Sci125p.329 - 3322014年-
Haraguchi A, Aoki N, Ohtsu T, Ikeda Y, Tahara Y, and Shibata S
Chronobiology International31p.935 - 9442014年-
Ohnishi N*, Tahara Y*, Kuriki D, Haraguchi A, and Shibata S
Nakamura Y*, Ishimaru K*, Tahara Y*, Shibata S, Nakao A
J Immunological Research2014p.ID4742172014年-
Nakamura Y, Nakano N, Ishimaru K, Hara M, Ikegami T, Tahara Y, Katoh R, Ogawa H, Okumura K, Shibata S, Nishiyama C, Nakao A
J Allergy Clin Immunol133p.568 - 5752014年-
Kudo T, Loh DH, Tahara Y, Truong D, Hern_ndez-Echeagaray E, Colwell CS
Tahara, Yu;Shiraishi, Takuya;Kikuchi, Yosuke;Onishi, Nobuaki;Yamada, Shun-ya;Haraguchi, Atsushi;Kuriki, Daisuke;Shibata, Shigenobu
JOURNAL OF PHARMACOLOGICAL SCIENCES124p.206P - 206P2014年-2014年
Kudo, Takashi;Loh, Dawn H.;Tahara, Yu;Danny Truong;Hernandez-Echeagaray, Elizabeth;Colwell, Christopher S.
ASN NEURO6(1)p.7 - U722014年-2014年
Nakamura, Yuki;Nakano, Nobuhiro;Ishimaru, Kayoko;Hara, Mutsuko;Ikegami, Takako;Tahara, Yu;Katoh, Ryohei;Ogawa, Hideoki;Okumura, Ko;Shibata, Shigenobu;Nishiyama, Chiharu;Nakao, Atsuhito
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY133(2)p.568 - +2014年-2014年
Kikuchi, Yosuke;Tahara, Yu;Shiraishi, Takuya;Shibata, Shigenobu
JOURNAL OF PHARMACOLOGICAL SCIENCES124p.206P - 206P2014年-2014年
Kikuchi, Yosuke;Tahara, Yu;Shiraishi, Takuya;Shibata, Shigenobu
JOURNAL OF PHARMACOLOGICAL SCIENCES124p.206P - 206P2014年-2014年
Tahara, Yu;Shibata, Shigenobu
JOURNAL OF PHARMACOLOGICAL SCIENCES124(3)p.320 - 3352014年-2014年
Nakamura, Yuki;Ishimaru, Kayoko;Tahara, Yu;Shibata, Shigenobu;Nakao, Atsuhito
JOURNAL OF IMMUNOLOGY RESEARCH2014年-2014年
Ohnishi, Nobuaki;Tahara, Yu;Kuriki, Daisuke;Haraguchi, Atsushi;Shibata, Shigenobu
Moriya, Shunpei;Tahara, Yu;Sasaki, Hiroyuki;Hamaguchi, Yutaro;Kuriki, Daisuke;Ishikawa, Ryosuke;Ishigooka, Jun;Shibata, Shigenobu
JOURNAL OF PHARMACOLOGICAL SCIENCES125(3)p.329 - 3322014年-2014年
Aoki, Natsumi;Yoshida, Daisuke;Ishikawa, Ryosuke;Ando, Midori;Nakamura, Kaai;Tahara, Yu;Shibata, Shigenobu
NUTRITION RESEARCH34(7)p.613 - 6222014年-2014年
Haraguchi, Atsushi;Aoki, Natsumi;Ohtsu, Teiji;Ikeda, Yuko;Tahara, Yu;Shibata, Shigenobu
CHRONOBIOLOGY INTERNATIONAL31(8)p.935 - 9442014年-2014年
Tahara, Yu-ki;Gake, Manami;Matsubara, Riku;Shibata, Takanori
ORGANIC LETTERS16(22)p.5980 - 59832014年-2014年
Narishige, Seira;Kuwahara, Mari;Shinozaki, Ayako;Okada, Satoshi;Ikeda, Yuko;Kamagata, Mayo;Tahara, Yu;Shibata, Shigenobu
BRITISH JOURNAL OF PHARMACOLOGY171(24)p.5858 - 58692014年-2014年
Tahara Yu;Shibata Shigenobu
Journal of Pharmacological Sciences124(3)p.320 - 3352014年-2014年
概要：The circadian clock system in mammals drives many physiological processes including the daily rhythms of sleep–wake behavior, hormonal secretion, and metabolism. This system responds to daily environmental changes, such as the light–dark cycle, food intake, and drug administration. In this review, we focus on the central and peripheral circadian clock systems in response to drugs, food, and nutrition. We also discuss the adaptation and anticipation mechanisms of our body with regard to clock system regulation of various kinetic and dynamic pathways, including absorption, distribution, metabolism, and excretion of drugs and nutrients. "Chrono-pharmacology" and "chrono-nutrition" are likely to become important research fields in chrono-biological studies.
Shibata Shigenobu;Tahara Yu
The Journal of Physical Fitness and Sports Medicine3(1)p.65 - 722014年-2014年
概要：In mammals, the circadian clock organizes physiological processes, including sleep/wake patterns, hormonal secretion, and metabolism, and regulates athletic performance. The circadian system is responsive to environmental changes such as light/dark cycles, food intake, and exercise. In this review, we will focus on the central and peripheral circadian molecular clock system, discussing how circadian rhythm affects athletic performance and muscle metabolism, and how exercise entrains the circadian rhythm. Importance of exercise training in rescuing circadian deficit–induced metabolic disorder is also discussed. The interaction of the circadian clock and exercise, called "chrono-exercise," is poised to become an important research field of chronobiology.
Moriya Shunpei;Tahara Yu;Sasaki Hiroyuki;Hamaguchi Yutaro;Kuriki Daisuke;Ishikawa Ryosuke;Ishigooka Jun;Shibata Shigenobu
Journal of Pharmacological Sciences125(3)p.329 - 3322014年-2014年
概要：Circadian rhythms are related to various psychiatric disorders. Recently, antipsychotics, including quetiapine (QTP), have been accepted as potential therapeutic agents for the treatment of depression, but its mechanism remains poorly understood. In this study, we examined clock gene fluctuation patterns in QTP-treated mice. QTP significantly increased Per2 mRNA at ZT12 and Per1 and Per2 expression at ZT18 in the amygdala. There were significant differences between the control and QTP groups in the cross-time effects of Per2 mRNA expression in the amygdala. Our findings suggest that QTP possibly acts on the circadian system, which then induces changes in mood symptoms.
Nakamura Yuki;Nakano Nobuhiro;Ishimaru Kayoko;Hara Mutsuko;Ikegami Takako;Tahara Yu;Katoh Ryohei;Ogawa Hideoki;Okumura Ko;Shibata Shigenobu;Nishiyama Chiharu;Nakao Atsuhito
Circadian regulation of allergic reactions by the mast cell clock in mice.133(2)2014年-2014年
概要：BACKGROUND:It remains elusive how allergic symptoms exhibit prominent 24-hour variations. In mammals the circadian clocks present in nearly all cells, including mast cells, drive the daily rhythms of physiology. Recently, we have shown that the circadian clocks drive the daily rhythms in IgE/mast cell-mediated allergic reactions. However, the precise mechanisms, particularly the specific roles of the mast cell-intrinsic clockwork in temporal regulation, remain unclear.;OBJECTIVE:We determined whether the mast cell clockwork contributes to the temporal regulation of IgE/mast cell-mediated allergic reaction.;METHODS:The kinetics of a time of day-dependent variation in passive cutaneous anaphylactic reactions were compared between mast cell-deficient mice reconstituted with bone marrow-derived cultured mast cells generated from mice with a wild-type allele and a dominant negative type mutation of the key clock gene Clock. We also examined the temporal responses of wild-type and Clock-mutated bone marrow-derived cultured mast cells to IgE stimulation in vitro. Furthermore, factors influencing the mast cell clockwork were determined by using in vivo imaging.;RESULTS:The Clock mutation in mast cells resulted in the absence of temporal variations in IgE-mediated degranulation in mast cells both in vivo and in vitro associated with the loss of temporal regulation of FcεRI expression and signaling. Additionally, adrenalectomy abolished the mast cell clockwork in vivo.;CONCLUSION:The mast cell-intrinsic clockwork, entrained by humoral factors from the adrenal gland, primarily contributes to the temporal regulation of IgE/mast cell-mediated allergic reactions. Our results reveal a novel regulatory mechanism for IgE-mediated mast cell responses that might underlie the circadian pathophysiology in patients with allergic diseases.
Tahara Yu;Shibata Shigenobu
Chrono-biology, chrono-pharmacology, and chrono-nutrition.124(3)2014年-2014年
概要：:The circadian clock system in mammals drives many physiological processes including the daily rhythms of sleep-wake behavior, hormonal secretion, and metabolism. This system responds to daily environmental changes, such as the light-dark cycle, food intake, and drug administration. In this review, we focus on the central and peripheral circadian clock systems in response to drugs, food, and nutrition. We also discuss the adaptation and anticipation mechanisms of our body with regard to clock system regulation of various kinetic and dynamic pathways, including absorption, distribution, metabolism, and excretion of drugs and nutrients. "Chrono-pharmacology" and "chrono-nutrition" are likely to become important research fields in chrono-biological studies.
Nakamura Yuki;Ishimaru Kayoko;Tahara Yu;Shibata Shigenobu;Nakao Atsuhito
Disruption of the suprachiasmatic nucleus blunts a time of day-dependent variation in systemic anaphylactic reaction in mice.20142014年-2014年
概要：:Anaphylaxis is a severe systemic allergic reaction which is rapid in onset and potentially fatal, caused by excessive release of mediators including histamine and cytokines/chemokines from mast cells and basophils upon allergen/IgE stimulation. Increased prevalence of anaphylaxis in industrialized countries requires urgent needs for better understanding of anaphylaxis. However, the pathophysiology of the disease is not fully understood. Here we report that the circadian clock may be an important regulator of anaphylaxis. In mammals, the central clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus synchronizes and entrains peripheral circadian clock present in virtually all cell types via neural and endocrine pathways, thereby driving the daily rhythms in behavior and physiology. We found that mechanical disruption of the SCN resulted in the absence of a time of day-dependent variation in passive systemic anaphylactic (PSA) reaction in mice, associated with loss of daily variations in serum histamine, MCP-1 (CCL2), and IL-6 levels. These results suggest that the central SCN clock controls the time of day-dependent variation in IgE-mediated systemic anaphylactic reaction, which may provide a novel insight into the pathophysiology of anaphylaxis.
Ohnishi Nobuaki;Tahara Yu;Kuriki Daisuke;Haraguchi Atsushi;Shibata Shigenobu
Warm water bath stimulates phase-shifts of the peripheral circadian clocks in PER2::LUCIFERASE mouse.9(6)2014年-2014年
概要：:Circadian clocks in the peripheral tissues of mice are known to be entrained by pulse stimuli such as restricted feeding, novel wheel running, and several other agents. However, there are no reports on high temperature pulse-mediated entrainment on the phase-shift of peripheral clocks in vivo. Here we show that temperature treatment of mice for two days at 41°C, instead of 37°C, for 1-2 h during the inactive period, using a temperature controlled water bath stimulated phase-advance of peripheral clocks in the kidney, liver, and submandibular gland of PER2::LUCIFERASE mice. On the other hand, treatment for 2 days at 35°C ambient room temperature for 2 h did not cause a phase-advance. Maintenance of mice at 41°C in a water bath, sustained the core body temperature at 40-41°C. However, the use of 37°C water bath or the 35°C ambient room temperature elevated the core body temperature to 38.5°C, suggesting that at least a core body temperature of 40-41°C is necessary to cause phase-advance under light-dark cycle conditions. The temperature pulse stimulation at 41°C, instead of 37°C water bath for 2 h led to the elevated expression of Per1 and Hsp70 in the peripheral tissue of mice. In summary, the present study demonstrates that transient high temperature pulse using water bath during daytime causes phase-advance in mouse peripheral clocks in vivo. The present results suggest that hot water bath may affect the phase of peripheral clocks.
Moriya Shunpei;Tahara Yu;Sasaki Hiroyuki;Hamaguchi Yutaro;Kuriki Daisuke;Ishikawa Ryosuke;Ishigooka Jun;Shibata Shigenobu
Effect of quetiapine on Per1, Per2, and Bmal1 clock gene expression in the mouse amygdala and hippocampus.125(3)2014年-2014年
概要：:Circadian rhythms are related to various psychiatric disorders. Recently, antipsychotics, including quetiapine (QTP), have been accepted as potential therapeutic agents for the treatment of depression, but its mechanism remains poorly understood. In this study, we examined clock gene fluctuation patterns in QTP-treated mice. QTP significantly increased Per2 mRNA at ZT12 and Per1 and Per2 expression at ZT18 in the amygdala. There were significant differences between the control and QTP groups in the cross-time effects of Per2 mRNA expression in the amygdala. Our findings suggest that QTP possibly acts on the circadian system, which then induces changes in mood symptoms.
Haraguchi Atsushi;Aoki Natsumi;Ohtsu Teiji;Ikeda Yuko;Tahara Yu;Shibata Shigenobu
Controlling access time to a high-fat diet during the inactive period protects against obesity in mice.31(8)2014年-2014年
概要：:Free feeding (FF) with a high fat diet (HFD) causes excessive body weight gain, whereas restricted feeding (RF) with a HFD attenuates body weight gain. The effects of timing of feeding with a HFD (day vs. night) and feeding duration on energy homeostasis have not yet been investigated. In this study, we fed mice a HFD or a normal diet (ND) twice a day, during their active and inactive periods, on a schedule. The amount of food was regulated by feeding duration (2, 4 or 8 h). First, we investigated the effects of 4-h RF during active-inactive periods (ND-ND, HFD-HFD, ND-HFD or HFD-ND). Among all the 4-h RF groups, mice consumed almost the same amount of calories as those in the FF[ND] group, even those fed a HFD. Body weight and visceral fat in these three groups were lower than that in the FF[HFD] group. Second, we investigated the effects of RF duration. Body weight and visceral fat were higher in the 8-h groups than in the 4-h groups. Body weight and visceral fat were higher in the 2-h groups than in the 4-h groups even though the 2-h groups had less food. Third, we investigated the effects of eating a HFD during the inactive period, when RF duration was extended (2, 6 or 12 h). Mice were fed with a HFD during the inactive period for 2 h and fed with a ND during the active period for 2, 6 or 12 h. Body weight and visceral fat in these mice were comparable to those in the FF[ND] mice. The results of our first set of experiments suggest that 4-h RF was an adequate feeding duration to control the effect of a HFD on obesity. The results of our second set of experiments suggest 2-h RF (such as speed-eating) and 8-h RF, representative of eating disorders, are unhealthy feeding patterns related to obesity. The results of our third set of experiments suggest that eating a HFD for a short period during the night does not affect body weight and visceral fat. Taken together, these results indicate that consideration to feeding with a HFD during the inactive period and restricting eating habits relieve the risks of body weight gain and visceral fat accumulation.
Aoki Natsumi;Yoshida Daisuke;Ishikawa Ryosuke;Ando Midori;Nakamura Kaai;Tahara Yu;Shibata Shigenobu
A single daily meal at the beginning of the active or inactive period inhibits food deprivation-induced fatty liver in mice.34(7)2014年-2014年
概要：:Food deprivation (FD) induces hepatic steatosis in both rodents and humans. Although body composition, age, and sex influence hepatic triglyceride (TG) levels after FD, whether feeding patterns affect FD-induced liver TG increases is unknown. We hypothesized that restricted feeding (RF) of 1 meal per day during the active or inactive period (especially the inactive period) augments FD-induced elevation of liver TGs because RF in the inactive period impairs the circadian rhythm. Triglyceride levels and the expression of genes related to TG metabolism in the liver were examined by a bioassay and real-time reverse transcription-polymerase chain reaction, respectively. In the first experiment, when compared to nonfasted mice, mice that fasted for 24 hours showed a 1.5-fold (FD starting during the inactive period) to 3-fold (FD started during the active period) increase in liver TG levels. This experiment showed that TG levels depend upon the starting time of FD. In the second experiment, mice were given free access to food for 3 hours at the beginning of either the inactive ("supper-only") or the active ("breakfast-only") period for 2 weeks. Restricted feeding inhibited the FD-induced increases in liver and serum TG levels, serum free fatty acids, and the expression of genes related to fatty acid uptake in the liver, including fatty acid transport protein 1 (Fatp1) and 4 (Fatp4). Unexpectedly, compared to free feeding, RF during the active or inactive period resulted in resistance to FD-induced fatty liver. This is the first study to demonstrate that feeding patterns affect FD-induced TG accumulation in the mouse liver.
Narishige Seira;Kuwahara Mari;Shinozaki Ayako;Okada Satoshi;Ikeda Yuko;Kamagata Mayo;Tahara Yu;Shibata Shigenobu
Effects of caffeine on circadian phase, amplitude and period evaluated in cells in vitro and peripheral organs in vivo in PER2::LUCIFERASE mice.171(24)2014年-2014年
概要：BACKGROUND AND PURPOSE:Caffeine is one of the most commonly used psychoactive substances. Circadian rhythms consist of the main suprachiasmatic nucleus (SCN) clocks and peripheral clocks. Although caffeine lengthens circadian rhythms and modifies phase changes in SCN-operated rhythms, the effects on caffeine on the phase, period and amplitude of peripheral organ clocks are not known. In addition, the role of cAMP/Ca(2+) signalling in effects of caffeine on rhythm has not been fully elucidated.;EXPERIMENTAL APPROACH:We examined whether chronic or transient application of caffeine affects circadian period/amplitude and phase by evaluating bioluminescence rhythm in PER2::LUCIFERASE knock-in mice. Circadian rhythms were monitored in vitro using fibroblasts and ex vivo and in vivo for monitoring of peripheral clocks.;KEY RESULTS:Chronic application of caffeine (0.1-10 mM) increased period and amplitude in vitro. Transient application of caffeine (10 mM) near the bottom of the decreasing phase of bioluminescence rhythm caused phase advance in vitro. Caffeine (0.1%) intake caused a phase delay under light-dark or constant dark conditions, suggesting a period-lengthening effect in vivo. Caffeine (20 mg·kg(-1) ) at daytime or at late night-time caused phase advance or delay in bioluminescence rhythm in the liver and kidney respectively. The complicated roles of cAMP/Ca(2+) signalling may be involved in the caffeine-induced increase of period and amplitude in vitro.;CONCLUSIONS AND IMPLICATIONS:Caffeine affects circadian rhythm in mice by lengthening the period and causing a phase shift of peripheral clocks. These results suggest that caffeine intake with food/drink may help with food-induced resetting of peripheral circadian clocks.
KudoT, Tahara Y, Gamble KL, McMahon DG, Block GD, Colwell CS
J of Neurophysiol110p.1097 - 11062013年-
Ishii, Hiroyuki;Shi, Qing;Fumino, Shogo;Konno, Shinichiro;Kinoshita, Shinichi;Okabayashi, Satoshi;Iida, Naritoshi;Kimura, Hiroshi;Tahara, Yu;Shibata, Shigenobu;Takanishi, Atsuo
ADVANCED ROBOTICS27(1)p.61 - 692013年-2013年
Tahara, Yu;Shibata, Shigenobu
JOURNAL OF PHARMACOLOGICAL SCIENCES121p.13P - 13P2013年-2013年
Kuroda H*, Tahara Y*, Saito K, Ohnishi N, Kubo Y, Seo Y, Otsuka M, Fuse Y, Ohura Y, Hirao A, Shibata S
Takita E, Yokota S, Tahara Y, Hirao A, Aoki N, Nakamura Y, Nakao A, Shibata S
Br J Dermatol168p.39 - 462012年-
Fuse Y, Hirao A, Kuroda H, Otsuka M, Tahara Y, Shibata S
J Circadian Rhythms10p.42012年-
Tahara Y, Kuroda H, Saito K, Nakajima Y, Kubo Y, Ohnishi N, Seo Y, Otsuka M, Fuse Y, Ohura Y, Komatsu T, Moriya Y, Okada S, Furutani N, Hirao A, Horikawa K, Kudo T, Shibata S
Curr Biol22p.1029 - 10342012年-
Kubo Y, Tahara Y, Hirao A, Shibata S
J Pharmacol Exp Ther340p.698 - 7052012年-
Kubo, Yuji;Tahara, Yu;Hirao, Akiko;Shibata, Shigenobu
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS340(3)p.698 - 7052012年-2012年
Tahara, Yu;Kuroda, Hiroaki;Saito, Keisuke;Nakajima, Yoshihiro;Kubo, Yuji;Ohnishi, Nobuaki;Seo, Yasuhiro;Otsuka, Makiko;Fuse, Yuta;Ohura, Yuki;Komatsu, Takuya;Moriya, Youhei;Okada, Satoshi;Furutani, Naoki;Hirao, Akiko;Horikawa, Kazumasa;Kudo, Takashi;Shibata, Shigenobu
CURRENT BIOLOGY22(11)p.1029 - 10342012年-2012年
Kuroda, Hiroaki;Tahara, Yu;Saito, Keisuke;Ohnishi, Nobuaki;Kubo, Yuji;Seo, Yasuhiro;Otsuka, Makiko;Fuse, Yuta;Ohura, Yuki;Hirao, Akiko;Shibata, Shigenobu
Kubo Yuji;Tahara Yu;Hirao Akiko;Shibata Shigenobu
2,2,2-Tribromoethanol phase-shifts the circadian rhythm of the liver clock in Per2::Luciferase knockin mice: lack of dependence on anesthetic activity.340(3)2012年-2012年
概要：:Comprehensive gene expression profiling in mice in response to the inhalation of sevoflurane has revealed that circadian clock gene expression is affected strongly in the liver, heart, lung, and kidney, in this order, but moderately in the spleen and slightly in the brain. Therefore, we examined whether the administration of general anesthetics at different times of the day induces phase shifts of the liver clock in Per2::Luciferase knockin mice. One to 4 days of intraperitoneal injection of 2,2,2-tribromoethanol (240 mg/kg, anesthetic time 60 min) or 2,2,2-trichloroethanol (240 mg/kg, 60 min), common anesthetics in veterinary surgery, caused phase delays when injected during the daytime and phase advances when injected during the nighttime. Inhalation administration of isoflurane for 30 or 60 min during the daytime did not induce a phase delay. Injection of propofol (300 mg/kg, 17 min) during the daytime induced an insignificant phase delay of the Per2 bioluminescence rhythm. Injection of 2,2,2-tribromoethanol did not induce a phase shift in the suprachiasmatic nucleus, the main oscillator, or in behavioral locomotor rhythms, suggesting that 2,2,2-tribromoethanol induced phase shifts of the liver clock independent of the main suprachiasmatic clock. The expression of clock genes, such as Bmal1 and Clock, in mouse liver was decreased strongly 1 and 4 h after a single injection of 2,2,2-tribromoethanol. These results demonstrate that 2,2,2-tribromoethanol or 2,2,2-trichloroethanol produce phase shifts of the peripheral clock, independent of anesthetic activity. These anesthetics may cause circadian rhythm disorders in peripheral organs when administered as general anesthetics several times during the day.
Tahara Yu;Kuroda Hiroaki;Saito Keisuke;Nakajima Yoshihiro;Kubo Yuji;Ohnishi Nobuaki;Seo Yasuhiro;Otsuka Makiko;Fuse Yuta;Ohura Yuki;Komatsu Takuya;Moriya Youhei;Okada Satoshi;Furutani Naoki;Hirao Akiko;Horikawa Kazumasa;Kudo Takashi;Shibata Shigenobu
In vivo monitoring of peripheral circadian clocks in the mouse.22(11)2012年-2012年
概要：:The mammalian circadian system is comprised of a central clock in the suprachiasmatic nucleus (SCN) and a network of peripheral oscillators located in all of the major organ systems. The SCN is traditionally thought to be positioned at the top of the hierarchy, with SCN lesions resulting in an arrhythmic organism. However, recent work has demonstrated that the SCN and peripheral tissues generate independent circadian oscillations in Per1 clock gene expression in vitro. In the present study, we sought to clarify the role of the SCN in the intact system by recording rhythms in clock gene expression in vivo. A practical imaging protocol was developed that enables us to measure circadian rhythms easily, noninvasively, and longitudinally in individual mice. Circadian oscillations were detected in the kidney, liver, and submandibular gland studied in about half of the SCN-lesioned, behaviorally arrhythmic mice. However, their amplitude was decreased in these organs. Free-running periods of peripheral clocks were identical to those of activity rhythms recorded before the SCN lesion. Thus, we can report for the first time that many of the fundamental properties of circadian oscillations in peripheral clocks in vivo are maintained in the absence of SCN control.
Fuse Yuta;Hirao Akiko;Kuroda Hiroaki;Otsuka Makiko;Tahara Yu;Shibata Shigenobu
Differential roles of breakfast only (one meal per day) and a bigger breakfast with a small dinner (two meals per day) in mice fed a high-fat diet with regard to induced obesity and lipid metabolism.10(1)2012年-2012年
概要：BACKGROUND:Recent studies on humans and rodents have suggested that the timing of food intake plays an important role in circadian regulation and metabolic health. Consumption of high-fat foods during the inactive period or at the end of the awake period results in weight gain and metabolic syndrome in rodents. However, the distinct effects of breakfast size and the breakfast/dinner size ratio on metabolic health have not yet been fully examined in mice.;METHODS:We examined whether the parameters of metabolic syndrome were differentially affected in mice that consumed a large meal at the beginning of the awake period (breakfast; one meal group) and a relatively smaller meal at end of the awake period (dinner; two meals group). The mice of each group were provided equal food volume per day.;RESULTS:Mice on one meal exhibited an increase in body weight gain, hyperinsulinemia, hyperleptinemia, and a decrease of gene expression associated with β-oxidation in adipose tissue and liver compared with those on two meals. The circadian expression pattern of the Clock gene in mice on one meal was disturbed compared with those on two meals.;CONCLUSIONS:In conclusion, a bigger breakfast with a smaller dinner (two meals per day) but not breakfast only (one meal per day) helps control body weight and fat accumulation in mice on a high-fat meals schedule. The findings of this study suggest that dietary recommendations for weight reduction and/or maintenance should include information on the timing and quantity of dietary intake.
Kuroda Hiroaki;Tahara Yu;Saito Keisuke;Ohnishi Nobuaki;Kubo Yuji;Seo Yasuhiro;Otsuka Makiko;Fuse Yuta;Ohura Yuki;Hirao Akiko;Shibata Shigenobu
Meal frequency patterns determine the phase of mouse peripheral circadian clocks.22012年-2012年
概要：:Peripheral circadian clocks in mammals are strongly entrained by light-dark and eating cycles. Their physiological functions are maintained by the synchronization of the phase of organs via clock gene expression patterns. However, little is known about the adaptation of peripheral clocks to the timing of multiple daily meals. Here, we investigated the effect of irregular eating patterns, in terms of timing and volume, on their peripheral clocks in vivo. We found that the phase of the peripheral clocks was altered by the amount of food and the interval between feeding time points but was unaffected by the frequency of feeding, as long as the interval remained fixed. Moreover, our results suggest that a late dinner should be separated into 2 half-dinners in order to alleviate the effect of irregular phases of peripheral clocks.
Okamoto M, Irii H, Tahara Y, Ishii H, Hirao A, Udagawa H, Hiramoto M, Yasuda K, Takanishi A, Shibata S, Shimizu I
J Med Chem54p.6295 - 63042011年-
Tahara Y, Otsuka M, Fuse Y,Hirao A, and Shibata S
J Biol Rhythms26p.230 - 2402011年-
Nakamura Y, Harama D, Shimokawa N, Hara M, Suzuki R, Tahara Y, Ishimaru K, Katoh R, Okumura K, Ogawa H, Shibata S, Nakao A
J Allergy Clin Immunol127p.1038 - 10452011年-
Okamoto, Mayumi;Kamikihara, Keigo;Irii, Hiroyuki;Tahara, Yu;Hirao, Akiko;Shibata, Shigenobu;Shimizu, Isao
JOURNAL OF PHARMACOLOGICAL SCIENCES115p.74P - 74P2011年-2011年
Nakamura, Yuki;Harama, Daisuke;Shimokawa, Naomi;Hara, Mutsuko;Suzuki, Ryuyo;Tahara, Yu;Ishimaru, Kayoko;Katoh, Ryohei;Okumura, Ko;Ogawa, Hideoki;Shibata, Shigenobu;Nakao, Atsuhito
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY127(4)p.1038 - U3012011年-2011年
Tahara, Yu;Otsuka, Makiko;Fuse, Yuta;Hirao, Akiko;Shibata, Shigenobu
JOURNAL OF BIOLOGICAL RHYTHMS26(3)p.230 - 2402011年-2011年
Okamoto, Mayumi;Irii, Hiroyuki;Tahara, Yu;Ishii, Hiroyuki;Hirao, Akiko;Udagawa, Haruhide;Hiramoto, Masaki;Yasuda, Kazuki;Takanishi, Atsuo;Shibata, Shigenobu;Shimizu, Isao
JOURNAL OF MEDICINAL CHEMISTRY54(18)p.6295 - 63042011年-2011年
Tahara Yu;Otsuka Makiko;Fuse Yuta;Hirao Akiko;Shibata Shigenobu
Refeeding after fasting elicits insulin-dependent regulation of Per2 and Rev-erbα with shifts in the liver clock.26(3)2011年-2011年
概要：:The mammalian circadian clock is known to be entrained by both a daily light-dark cycle and daily feeding cycle. However, the mechanisms of feeding-induced entrainment are not as fully understood as those of light entrainment. To elucidate the first step of entrainment of the liver clock, we identified the circadian clock gene(s) that show both phase advance and acute change of gene expression during the early term of the daytime refeeding schedule in mice. The expressions of liver Per2 and Rev-erbα genes were phase-advanced within 1 day of refeeding. Additionally, the upregulation of Per2 mRNA and down-regulation of Rev-erbα mRNA were induced within 2 hours, not only by food intake but also by insulin injection in intact mice. These expression changes by food intake were not revealed in streptozotocin-treated insulin-deficient mice, but insulin injection was able to recover the impairment of Per2 and Rev-erbα gene expression. Furthermore, we demonstrated using an ex vivo luciferase monitoring system that insulin injection during the daytime causes a phase advance of liver Per2 expression rhythm in Per2::luciferase knock-in mice. In embryonic fibroblasts from Per2::luciferase knock-in mice, insulin infusion caused an acute increase of Per2 gene expression and a similar phase advance of Per2 expression rhythm. Our results indicate that an acute change of Per2 and Rev-erbα gene expression mediated by refeeding-induced insulin secretion is a critical step mediating the early phase of feeding-induced entrainment of the liver clock.
Okamoto Mayumi;Irii Hiroyuki;Tahara Yu;Ishii Hiroyuki;Hirao Akiko;Udagawa Haruhide;Hiramoto Masaki;Yasuda Kazuki;Takanishi Atsuo;Shibata Shigenobu;Shimizu Isao
Synthesis of a new -gingerol analogue and its protective effect with respect to the development of metabolic syndrome in mice fed a high-fat diet.54(18)2011年-2011年
概要：:To determine the effects of a -gingerol analogue (6G), a major chemical component of the ginger rhizome, and its stable analogue after digestion in simulated gastric fluid, aza--gingerol (A6G), on diet-induced body fat accumulation, we synthesized 6G and A6G. Mice were fed either a control regular rodent chow, a high-fat diet (HFD), or a HFD supplemented with 6G and A6G. Magnetic resonance imaging adiposity parameters of the 6G- and A6G-treated mice were compared with those of control mice. Supplementation with 6G and A6G significantly reduced body weight gain, fat accumulation, and circulating levels of insulin and leptin. The mRNA levels of sterol regulatory element-binding protein 1c (SREBP-1c) and acetyl-CoA carboxylase 1 in the liver were significantly lower in mice fed A6G than in HFD control mice. Our findings indicate that A6G, rather than 6G, enhances energy metabolism and reduces the extent of lipogenesis by downregulating SREBP-1c and its related molecules, which leads to the suppression of body fat accumulation.
Hirao A, Nagahama H, Tsuboi T, Hirao M, Tahara Y, Shibata S
Am J Physiol Gastrointest Liver Physiol299p.G1045 - 10532010年-
Tahara Y, Hirao A, Moriya T, Kudo T, Shibata S
J Biol Rhythms25p.9 - 182010年-
Tahara, Yu;Hirao, Akiko;Moriya, Takahiro;Kudo, Takashi;Shibata, Shigenobu
JOURNAL OF BIOLOGICAL RHYTHMS25(1)p.9 - 182010年-2010年
Shibata, Shigenobu;Hirao, Akiko;Tahara, Yu
SLEEP AND BIOLOGICAL RHYTHMS8(1)p.18 - 272010年-2010年
Furutani, Naoki;Tahara, Yu;Hirao, Akiko;Shibata, Shigenobu
JOURNAL OF PHARMACOLOGICAL SCIENCES112p.154P - 154P2010年-2010年
Koiwa, Goki;Tahara, Yu;Hirao, Akiko;Morishima, Takeshi;Shibata, Shigenobu
JOURNAL OF PHARMACOLOGICAL SCIENCES112p.167P - 167P2010年-2010年
Takita, Eriko;Kubo, Yuji;Tahara, Yu;Nakao, Atsuhito;Shibata, Shigenobu
JOURNAL OF PHYSIOLOGICAL SCIENCES60p.S198 - S1982010年-2010年
Shibata, Shigenobu;Tahara, Yu;Hirao, Akiko
ADVANCED DRUG DELIVERY REVIEWS62(9-10)p.918 - 9272010年-2010年
Hirao, Akiko;Nagahama, Hiroki;Tsuboi, Takuma;Hirao, Mizuho;Tahara, Yu;Shibata, Shigenobu
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY299(5)p.G1045 - G10532010年-2010年
Tahara Yu;Hirao Akiko;Moriya Takahiro;Kudo Takashi;Shibata Shigenobu
Effects of medial hypothalamic lesions on feeding-induced entrainment of locomotor activity and liver Per2 expression in Per2::luc mice.25(1)2010年-2010年
概要：:Restricted feeding induces anticipatory activity rhythm and also entrains the peripheral circadian clocks, although the underlying brain mechanisms have not been fully elucidated. The dorsomedial hypothalamus (DMH) has been implicated in the regulation of restricted feeding-induced anticipatory activity rhythms (FAA), but the role of the DMH in restricted feeding- induced entrainment of peripheral circadian clocks is still unknown. In the present study, the role of the DMH in entrainment of the peripheral circadian clock was examined using Per2::luciferase knock-in mice. The results indicate that lesions that destroy the large mediobasal hypothalamic (MBH) lesions destroying the DMH, ventrolateral hypothalamus (VMH), and arcuate nucleus (ARC) significantly reduce daily locomotor activity rhythms and FAA formation. In addition, these lesions phase advanced the peak of liver Per2 expression by 2 h when compared to sham-operated mice. Following the administration of MBH lesions, the animals run less and start later in the restricted feeding- induced FAA rhythm but do not have any alterations in the restricted feeding- induced phase shift of the liver Per2 rhythm. These results demonstrate that the hypothalamus, including the MBH, is an important brain area for maintaining the locomotor rhythm and FAA formation. However, it is not necessary for restricted feeding-induced entrainment of the liver clock.
Shibata Shigenobu;Tahara Yu;Hirao Akiko
The adjustment and manipulation of biological rhythms by light, nutrition, and abused drugs.62(9-10)2010年-2010年
概要：:Daily restricted feeding entrains the circadian rhythm of mouse clock gene expression in the central nervous system, excluding the suprachiasmatic nucleus (SCN), as well as in the peripheral tissues such as the liver, lung, and heart. In addition to entrainment of the clock genes, daily restricted feeding induces a locomotor activity increase 2-3h before the restricted feeding time initiates. The increase in activity is called the food-anticipatory activity (FAA). In addition to FAA, daily restricted feeding can also entrain peripheral circadian clocks in other organs such as liver, lung, and heart. This type of oscillator is called the food-entrainable peripheral oscillator (FEPO). At present, the mechanisms for restricted feeding-induced entrainment of locomotor activity (FAA) and/or peripheral clock (FEPO) are still unknown. In this review, we describe the role of the central nervous system and peripheral tissues in FAA performance and also in the entrainment of clock gene expression. In addition, the mechanism for entrainment of circadian oscillators by the abuse of drugs, such as methamphetamine, is discussed.
Hirao Akiko;Nagahama Hiroki;Tsuboi Takuma;Hirao Mizuho;Tahara Yu;Shibata Shigenobu
Combination of starvation interval and food volume determines the phase of liver circadian rhythm in Per2::Luc knock-in mice under two meals per day feeding.299(5)2010年-2010年
概要：:Although the circadian liver clock is entrained by the feeding cycle, factors such as food volume and starvation interval are poorly understood. Per2::Luc knock-in mice were given two meals per day with different food volume sizes and/or with different intervals of starvation between two mealtimes with the total food volume per day fixed at 3.6 g (80 food pellets, ∼75% of free feeding) per mouse. The bioluminescence rhythm in the liver produced a unimodal peak but not bimodal peak under the regimen of two meals per day over 14-15 days. Peak Per2 expression occurred concurrently with the mealtime of the larger food volume, when the first and second meal were given as different food volume ratios under a 12 h feeding interval. When an equal volume of food was given under different starvation interval (8 h:16 h), the peak of the Per2 rhythm was close to peak by mealtime after long starvation (16 h). When food volumes for each mealtime were changed under 8 h:16 h, the peak rhythm was influenced by combined factors of food volume and starvation interval. Food intake after the 16-h starvation caused a significant increase in liver Per2, Dec1, and Bmal1 gene expression compared with food intake after the 8-h starvation with 8 h:16 h feeding intervals. In conclusion, the present results clearly demonstrate that food-induced entrainment of the liver clock is dependent on both food volume and the starvation interval between two meals. Therefore, normal feeding habits may help to maintain normal clock function in the liver organ.
Hirao A, Tahara Y, Kimura I, Shibata S
Tahara Y, Shibata S
Shibata S, Tahara Y
J Phys Fitness Sports Med2014年-
Tahara Y, Shibata S
J pharm Sci2014年-
Tahara Y, Shibata S
Tahara Y, Shibata S
田原 優、柴田 重信
田原 優、柴田 重信
田原 優、柴田 重信
田原 優、 柴田 重信
Shibata S, Tahara Y, Hirao A
Advanced Drug Delivery Reviews2010年-
田原 優、柴田 重信
Shibata S, Hirao A, Tahara Y
Sleep & Biological Rhythms2010年-
研究成果概要：哺乳類の概日時計機構は、主要なエネルギー代謝関連遺伝子の発現調節を行なっている。肥満状態における概日時計機構の減弱化の報告（Kohsaka et al., Cell Metab., 2007）がある一方で、概日時計の破綻は肥満・糖...哺乳類の概日時計機構は、主要なエネルギー代謝関連遺伝子の発現調節を行なっている。肥満状態における概日時計機構の減弱化の報告（Kohsaka et al., Cell Metab., 2007）がある一方で、概日時計の破綻は肥満・糖尿病のリスクを増大する(Turek et al., Science, 2005)。しかし、肥満が進行していく過程において、いつ概日時計が破綻するのかは分かっていない。申請者は現在までに、マウスの概日時計振動を生きた状態で測定する事に成功している(Tahara et al., Curr Biol., 2012)。本研究では、まず概日時計と代謝関連遺伝子の両方を同時にin vivoでモニター出来る実験系の確立を目指した。その後、高脂肪食負荷による肥満誘導時に、概日時計とエネルギー代謝経路の破綻の過程を経時的に観測する事で、肥満発症における概日時計の意義を探る。また、慢性時差ボケマウスにおいても、肥満と体内時計の相互作用を検討する。概日時計と代謝関連遺伝子をin vivoで同時モニターするために、波長の異なる２種類のルシフェラーゼ遺伝子（SLG緑, SLR赤）と目的遺伝子のプロモーター領域を組み込んだアデノ随伴（AAV）ウイルスベクターを構築する。目的遺伝子は、概日時計遺伝子（Bmal1）と主要な代謝関連遺伝子（Pparα, Pgc1α, Srebp-1c等）とする。現在までに、強制発現プロモーターを挿入したSLG, SLRを作成し終えた。また、Bmal1-SLGのベクターも完成した。また、細胞へのトランスフェクションにより、二色のルシフェラーゼの発光波長域が分かれていること、またその細胞をマウス皮下に移植し、in vivo imaging systemを用いて撮影した結果も、同様に二色の発光を確認できた。今後の予定として、ウイルスを作成し、マウスへの感染を試みる。特に尾静脈から投与し肝臓や筋肉組織への感染を行う。また、脳室内や小脳、大脳皮質への直接投与も検討してみる。また、ウイルス作成完了後に感染実験を予定している、慢性時差ボケモデルについても実験を行った。時差ボケモデルマウスは、明暗サイクルを８時間シフトさせると共に、ケージの浸透による断眠を暗期に行った。マウスの活動は、ケージの浸透により上がり、その結果浸透無しの群に比べ有意に、新しい位相へ同調した。現在、それらのマウスの末梢時計について、PER2::LUCノックインマウスを用いて検討している。
研究成果概要： 哺乳類の概日時計はあらゆる細胞に発現する時計遺伝子群により制御されており、生体の恒常性維持に寄与している。概日時計の乱れの例として時差ボケや夜間交代勤務が挙げられ、睡眠障害、うつ病、肥満・糖尿病などが報告されているが、概日時計の... 哺乳類の概日時計はあらゆる細胞に発現する時計遺伝子群により制御されており、生体の恒常性維持に寄与している。概日時計の乱れの例として時差ボケや夜間交代勤務が挙げられ、睡眠障害、うつ病、肥満・糖尿病などが報告されているが、概日時計の乱れが疾患発症に繋がる過程には未だ不明な点が多い。本研究では、拘束ストレスや社会的恐怖ストレスが、マウス末梢臓器の概日時計を強く変調させる事を明らかにした。その作用はストレス負荷の時刻依存的であり、視床下部-下垂体-副腎軸、及び視床下部-交感神経-副腎髄質軸を介して起こる現象であることが分かった。
研究成果概要：本研究では、1日を感じるメカニズムである概日時計に着目し、アルツハイマー病などの神経変性疾患、またはうつ病における時間の感じ方の変化、またその変化のメカニズム解明を行う。アルツハイマー病モデルマウス（APPswe, PS1M146...本研究では、1日を感じるメカニズムである概日時計に着目し、アルツハイマー病などの神経変性疾患、またはうつ病における時間の感じ方の変化、またその変化のメカニズム解明を行う。アルツハイマー病モデルマウス（APPswe, PS1M146V, tauP301L; 3xTg mouse）を用いて、生後3, 10ヶ月における恒暗条件下における睡眠-覚醒リズムを測定した。睡眠ー覚醒リズムは、赤外線センサーとCLOCK LABを用いて、単独飼育下で測定した。結果、アルツハイマー病の症状が現れる10ヶ月齢のマウスにおいて、行動周期の有意な短縮が認められた。さらに、まだアルツハイマー症状の見られない3ヶ月齢のマウスでも、行動周期の短縮が認められた。よって、認知症において概日時計の感じ方が早まっている可能性があることが分かった。さらに、若齢でも同様の結果が見られたことから、概日時計の変化は、神経変性による結果ではなく、遺伝的な変化によるものと考えられた。
研究成果概要：これまでに、ハンチントン病モデルマウスを用いて、食事時刻の制限が疾患の進行予防に効果的であることを示した。特に、睡眠・覚醒リズムの改善、中途覚醒の改善、心機能の改善、運動機能の低下予防を示すことができた（Whittaker&nbs...これまでに、ハンチントン病モデルマウスを用いて、食事時刻の制限が疾患の進行予防に効果的であることを示した。特に、睡眠・覚醒リズムの改善、中途覚醒の改善、心機能の改善、運動機能の低下予防を示すことができた（Whittaker and Tahara et al., JBR, 2018）。本研究課題では、老化促進モデルマウスを用いて、食事時刻の制限（マウスの活動期である暗期のみに食事時刻を制限）の効果を検討した。６ヶ月齢付近のミュータントマウスで、運動機能の低下、睡眠・覚醒リズムの乱れ、活動量の低下を確認できた。現在最初に得られたコホートにて食事時刻制限を継続し、３ヶ月おきに睡眠・覚醒リズム、運動機能の評価を行っている。
|Science and Engineering Laboratory||基幹理工学部||2020||秋学期|
|Science and Engineering Laboratory 1B||基幹理工学部||2020||秋学期|
|Science and Engineering Laboratory||創造理工学部||2020||秋学期|
|Science and Engineering Laboratory 1B||創造理工学部||2020||秋学期|
|Science and Engineering Laboratory||先進理工学部||2020||秋学期|
|Science and Engineering Laboratory 1B||先進理工学部||2020||秋学期|
|Current Topics in Biosciences||先進理工学部||2020||秋学期|
|Current Topics in Biosciences [S Grade]||先進理工学部||2020||秋学期|
|Research on Pharmacology||大学院先進理工学研究科||2020||通年|
|Master's Thesis (Department of Electrical Engineering and Bioscience)||大学院先進理工学研究科||2020||通年|