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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Zoological science  

Yawning is a stereotyped behavior widely observed in vertebrates, serving as an adaptation to the environment. Previous research has highlighted the correlations between yawning and physiological arousal or temperature regulation. However, the majority of those studies have primarily focused on endothermic animals. Thus far, the function of yawning in ectothermic animals remains unclear. In this study, we observed the behavior of leopard geckos, Eublepharis macularius, ectothermic reptiles, over a period of 3 days under constant ambient temperatures of 25°C, 30°C, or 35°C. By investigating the relationship between temperature, spontaneous yawning, and activity levels, we found that yawning frequency is affected by ambient temperature, and also observed a significant increase in post-yawning activity particularly under the 30°C and 35°C conditions. Furthermore, a near 24-hour periodicity in yawning was detected under all temperature conditions. These results align with previous studies conducted on endothermic animals, suggesting the conservation of primitive functions of yawning across vertebrate species.

DOI： 10.2108/zs230123

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記述言語：英語   出版者・発行元：Journal of Biological Rhythms  

Animals frequently experience temperature fluctuations in their natural life cycle, including periods of low temperatures below their activity range. For example, poikilothermic animals are known to enter a hibernation-like state called brumation during transient cooling. However, the knowledge regarding the physiological responses of brumation is limited. Specifically, the impact of exposure to low-temperature conditions outside the range of temperature compensation on the subsequent circadian behavioral rhythms remains unclear. In this study, we investigated the effects of transient cooling on the behavioral circadian rhythm in the non-avian reptile, the bearded dragon (Pogona vitticeps). Under constant light (LL) conditions at 30 °C, the animals exhibited a free-running rhythm, and exposure to low temperatures (4 °C) caused a complete cessation of locomotion. Furthermore, we revealed that the behavioral rhythm after rewarming is determined not by the circadian phase at the onset or the duration of cooling, but by the timing of cooling cessation.

DOI： 10.1177/07487304241273190

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記述言語：英語   出版者・発行元：The journal of physiological sciences : JPS  

An increase in ambient temperature leads to an increase in sleep. However, the mechanisms behind this phenomenon remain unknown. This study aimed to investigate the role of microglia in the increase of sleep caused by high ambient temperature. We confirmed that at 35 °C, slow-wave sleep was significantly increased relative to those observed at 25 °C. Notably, this effect was abolished upon treatment with PLX3397, a CSF1R inhibitor that can deplete microglia, while sleep amount at 25 °C was unaffected. These observations suggest that microglia play a pivotal role in modulating the homeostatic regulation of sleep in response to the fluctuations in ambient temperature.

DOI： 10.1186/s12576-024-00929-0

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.jphs.2024.03.003

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DOI： 10.1101/2024.03.19.585680

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PNAS Nexus  

Although diurnal animals displaying monophasic sleep patterns exhibit periodic cycles of alternating slow-wave sleep (SWS) and rapid eye movement sleep (REMS), the regulatory mechanisms underlying these regular sleep cycles remain unclear. Here, we report that in the Australian dragon Pogona vitticeps exposed to constant darkness (DD), sleep behavior and sleep-related neuronal activity emerged over a 24-h cycle. However, the regularity of the REMS/SWS alternation was disrupted under these conditions. Notably, when the lizards were then exposed to 12 h of light after DD, the regularity of the sleep stages was restored. These results suggest that sleep-related neuronal activity in lizards is regulated by circadian rhythms and that the regularity of REMS and SWS cycling is influenced by daytime light exposure.

DOI： 10.1093/pnasnexus/pgad481

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PLoS ONE  

Memory is a fundamental brain function that can be affected by a variety of external factors including environmental pollutants. One of these pollutants is methyl vinyl ketone (MVK), a hazardous substance found in cigarettes, industrial wastes, and car exhaust. Humans can be exposed to MVK under many circumstances; however, it is unclear whether MVK affects higher-order brain functions such as memory. Here, we examined the memory performances of mice receiving systemic MVK administration. We found that 1 mg/kg of MVK impaired spatial memory. We also showed that 1 mg/kg MVK activated glial cells and altered glial functions in several subregions of the hippocampus, a brain region involved in learning and memory. These results suggest that MVK induces memory deficits and activates glial cells in hippocampal subregions.

DOI： 10.1371/journal.pone.0289714

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Molecular Brain  

Microglia, as macrophages in the brain, are responsible for immune responses and synaptic remodeling. Although the function of microglia is regulated by circadian rhythms, it is still unclear whether microglia are involved in the generation and light entrainment of circadian rhythms of behavior. Here, we report that microglial depletion does not alter behavioral circadian rhythms. We depleted ~ 95% of microglia in the mouse brain by PLX3397, a CSF1R inhibitor, and analyzed the effect on the spontaneous behaviors of mice. We found that neither the free-running period under constant darkness nor light entrainment under jet-lag circumstances were influenced by the ablation of microglia. Our results demonstrate that the circadian rhythms of locomotor activity, an important output of the circadian clock in the brain, are likely a phenomenon not produced by microglia.

DOI： 10.1186/s13041-023-01021-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Neuroscience Research  

Memory is one of the fundamental cognitive functions of brain. The formation and consolidation of memory depend on the hippocampus and sleep. Sharp wave ripple (SWR) is an electrophysiological event which is most frequently observed in the hippocampus during sleep. It represents a highly synchronized neuronal activity pattern which modulates numerous brain regions including the neocortex, subcortical areas, and the hippocampus itself. In this review, we discuss how SWRs link experiences to memories and what happens in the hippocampus and other brain regions during sleep by focusing on synaptic plasticity.

DOI： 10.1016/j.neures.2023.01.011

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：一般社団法人　日本毒性学会  

Methyl vinyl ketone (MVK) is an environmental hazardous substrate which is main-ly present in cigarette smoke, industrial waste, and exhaust gas. Despite many chances to be exposed to MVK, the cellular toxicity of MVK is largely unknown. Neurons are the main component of the brain, which is one the most vital organs to human beings. Nevertheless, the influence of MVK to neurons has not been investigated. Here, we determined whether MVK treatment negatively affects neuronal survival and axonal morphogenesis using primary hippocampal neuronal cultures. We treated hippocampal neurons with 0.1 μM to 3.0 μM MVK and observed a concentration-dependent increase of neuronal death rate. We also demonstrated that the treatment with a low concentration of MVK 0.1 μM or 0.3 μM inhibit-ed axonal branching specifically without affecting axon outgrowth. Our results suggest that MVK is highly toxic to neurons.

DOI： 10.2131/jts.47.375

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記述言語：日本語   出版者・発行元：公益社団法人 日本薬理学会  

<p>Most animal species sleep, from invertebrates to primates. We describe the electrophysiological hallmarks of sleep in reptiles. Recordings from the brains of Australian dragon <i>Pogona vitticeps</i> revealed the typical features of slow-wave sleep and rapid eye movement (REM) sleep, suggesting that dragons can be a useful model for studying these sleep stages. In this presentation, I will focus on the claustrum. The mammalian claustrum, owing to its widespread connectivity with other forebrain structures, has been hypothesized to mediate functions ranging from decision making to consciousness. We report that a homolog of the claustrum, identified by single-cell transcriptomics and viral tracing of connectivity, exists also in reptiles. There, it underlies the generation of sharp-waves during slow-wave sleep. The sharp-waves, together with superimposed high-frequency ripples, propagate to the entire forebrain. It is also characterized by converging input from mid- and hind-brain areas involved in wake/sleep control. Periodic modulation of serotonin concentration in claustrum, for example, imposes a matching modulation of sharp-wave production. The claustrum is therefore an ancient brain structure, with a potentially important role in the widespread control of brain states due to its divergent projections to the forebrain and its role in sharp-wave generation during slow-wave sleep.</p>

DOI： 10.1254/jpssuppl.94.0_1-p1-42

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Pharmacological Sciences  

Hippocampal neurons play a crucial role in memory formation. Accumulating evidence raises the possibility that hippocampal sharp-wave ripples (SW-Rs) are involved in memory consolidation. Here, we examined in an animal model of diabetes and found the amplitude of SW-Rs in diabetic mice were smaller than control group and were rescued by acute application of L-lactate, a major neural energy source. The cognitive impairment in diabetic mice was alleviated by intracerebroventricular L-lactate treatment. Our results suggested that L-lactate is important for hippocampal dysfunction in diabetes.

DOI： 10.1016/j.jphs.2019.09.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Biological Psychiatry  

Background: A method that promotes the retrieval of lost long-term memories has not been well established. Histamine in the central nervous system is implicated in learning and memory, and treatment with antihistamines impairs learning and memory. Because histamine H3 receptor inverse agonists upregulate histamine release, the inverse agonists may enhance learning and memory. However, whether the inverse agonists promote the retrieval of forgotten long-term memory has not yet been determined. Methods: Here, we employed multidisciplinary methods, including mouse behavior, calcium imaging, and chemogenetic manipulation, to examine whether and how the histamine H3 receptor inverse agonists, thioperamide and betahistine, promote the retrieval of a forgotten long-term object memory in mice. In addition, we conducted a randomized double-blind, placebo-controlled crossover trial in healthy adult participants to investigate whether betahistine treatment promotes memory retrieval in humans. Results: The treatment of H3 receptor inverse agonists induced the recall of forgotten memories even 1 week and 1 month after training in mice. The memory recovery was mediated by the disinhibition of histamine release in the perirhinal cortex, which activated the histamine H2 receptor. Histamine depolarized perirhinal cortex neurons, enhanced their spontaneous activity, and facilitated the reactivation of behaviorally activated neuronal ensembles. A human clinical trial revealed that treatment of H3 receptor inverse agonists is specifically more effective for items that are more difficult to remember and subjects with poorer performance. Conclusions: These results highlight a novel interaction between the central histamine signaling and memory engrams.

DOI： 10.1016/j.biopsych.2018.11.009

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記述言語：英語   出版者・発行元：Japanese Pharmacological Society  

<p>Even after memories fade over long time, the lost memories may persist latently in the brain. Reinforcement of positive modulators for retrieval of long-term memory may recover the ostensibly forgotten items. However, how the retrieval of long-term memory is modulated is less understood than short-term memory. Thus, a method that promotes the retrieval of forgotten long-term memories has not been well established. Central histamine is implicated in learning and memory. Histamine H3 receptors inhibit the presynaptic release of histamine and other neurotransmitters and negatively regulate histamine synthesis. Because histamine H3 receptors are constitutively active, their inverse agonists upregulate histamine release. Therefore, histamine H3 receptor inverse agonists may enhance learning and memory. In this study, we examined whether histamine H3 receptor inverse agonists enhance retrieval of long-term memory and recover the forgotten long-term memory in mice and humans.</p><p>We employed the novel object recognition task, wherein the test session mice were presented with a novel and a familiar object that was presented during the training session. A single treatment of histamine H3 receptor inverse agonists (thioperamide and betahistine) followed by memory retrieval tests restored forgotten object recognition memories in mice. The treatment induced the recall of forgotten memories even 1 week and 1 month after training. Activation of histamine receptor signaling in the perirhinal cortex (PRh) was critical for thioperamide-induced memory recovery because intraperitoneal thioperamide treatment increased PRh histamine release, and intra-PRh injection of ranitidine (H2 receptor antagonist) blocked the thioperamide-induced memory recovery. In neuronal and neuronal circuit levels, histamine depolarized PRh neurons, enhanced their spontaneous activity, and facilitated the reactivation of behaviorally activated neurons. Chemogenetically increased spontaneous activity in the PRh was sufficient for the memory recovery. Moreover, in a human clinical trial, betahistine treatment enhanced retrieval of object recognition memory. The enhancement of memory retrieval was more evident for items that are more difficult to remember and subjects with poorer performance. Betahistine treatment did not alter working memory or attention.</p><p>In conclusion, our findings indicate that activation of histamine receptor signaling in the PRh boosts reactivation of weak memory engrams and restores the apparently forgotten memories.</p>

DOI： 10.1254/jpssuppl.wcp2018.0_po1-1-11

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Molecular Medicine Reports  

Our group has recently reported that in the immortal human HepG2 liver cell line, sphingosine 1-phosphate (S1P) increases transcription of plasminogen activator inhibitor type-1 (PAI-1), the major physiological inhibitor of fibrinolysis, within 4 h. The present study aimed to elucidate the molecular mechanisms underlying this effect. PAI-1 expression was measured by reverse transcription-quantitative polymerase chain reaction and immunoblotting. It was demonstrated that S1P increased PAI-1 promoter activity but did not increase the activity of promoters lacking the hypoxia responsive element (HRE) 2. In addition, S1P transiently increased the concentration of hypoxia inducible factor (HIF)-1α, a transcription factor capable of binding to HRE. When HIF-1α was knocked down, the induction of transcription of PAI-1 by S1P was no longer observed. Sphingosine kinase (SPHK) activity is increased by hypoxia. It was demonstrated that increases in the concentration of the HIF-1α protein induced by hypoxia were prevented by treatment with SPHK inhibitor or S1P receptor antagonists. Thus, modification of the induction of HIF-1α by S1P, leading to increased transcription of PAI-1, may be an attractive therapeutic target for thrombosis and consequent inhibition of fibrinolysis associated with hypoxia.

DOI： 10.3892/mmr.2016.5451

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jneumeth.2015.10.014

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12576-014-0337-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：8  

DOI： 10.1371/journal.pone.0104438

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：3  

DOI： 10.1523/JNEUROSCI.2522-12.2013

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/srep02696

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.brainres.2012.04.037

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：2  

DOI： 10.1254/jphs.11199FP

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