Publications by authors named "Masashi Yanagisawa"

221 Publications

Two novel mouse models mimicking minor deletions in 22q11.2 deletion syndrome revealed the contribution of each deleted region to psychiatric disorders.

Mol Brain 2021 04 12;14(1):68. Epub 2021 Apr 12.

Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

22q11.2 deletion syndrome (22q11.2DS) is a disorder caused by the segmental deletion of human chromosome 22. This chromosomal deletion is known as high genetic risk factors for various psychiatric disorders. The different deletion types are identified in 22q11.2DS patients, including the most common 3.0-Mb deletion, and the less-frequent 1.5-Mb and 1.4-Mb deletions. In previous animal studies of psychiatric disorders associated with 22q11.2DS mainly focused on the 1.5-Mb deletion and model mice mimicking the human 1.5-Mb deletion have been established with diverse genetic backgrounds, which resulted in the contradictory phenotypes. On the other hand, the contribution of the genes in 1.4-Mb region to psychiatric disorders is poorly understood. In this study, we generated two mouse lines that reproduced the 1.4-Mb and 1.5-Mb deletions of 22q11.2DS [Del(1.4 Mb)/+ and Del(1.5 Mb)/+] on the pure C57BL/6N genetic background. These mutant mice were analyzed comprehensively by behavioral tests, such as measurement of locomotor activity, sociability, prepulse inhibition and fear-conditioning memory. Del(1.4 Mb)/+ mice displayed decreased locomotor activity, but no abnormalities were observed in all other behavioral tests. Del(1.5 Mb)/+ mice showed reduction of prepulse inhibition and impairment of contextual- and cued-dependent fear memory, which is consistent with previous reports. Furthermore, apparently intact social recognition in Del(1.4 Mb)/+ and Del(1.5 Mb)/+ mice suggests that the impaired social recognition observed in Del(3.0 Mb)/+ mice mimicking the human 3.0-Mb deletion requires mutations both in 1.4-Mb and 1.5 Mb regions. Our previous study has shown that Del(3.0 Mb)/+ mice presented disturbance of behavioral circadian rhythm. Therefore, we further evaluated sleep/wakefulness cycles in Del(3.0 Mb)/+ mice by electroencephalogram (EEG) and electromyogram (EMG) recording. EEG/EMG analysis revealed the disturbed wakefulness and non-rapid eye moving sleep (NREMS) cycles in Del(3.0 Mb)/+ mice, suggesting that Del(3.0 Mb)/+ mice may be unable to maintain their wakefulness. Together, our mouse models deepen our understanding of genetic contributions to schizophrenic phenotypes related to 22q11.2DS.
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http://dx.doi.org/10.1186/s13041-021-00778-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042712PMC
April 2021

An endothelial activin A-bone morphogenetic protein receptor type 2 link is overdriven in pulmonary hypertension.

Nat Commun 2021 03 19;12(1):1720. Epub 2021 Mar 19.

Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, Higashinada, Kobe, Japan.

Pulmonary arterial hypertension is a progressive fatal disease that is characterized by pathological pulmonary artery remodeling, in which endothelial cell dysfunction is critically involved. We herein describe a previously unknown role of endothelial angiocrine in pulmonary hypertension. By searching for genes highly expressed in lung microvascular endothelial cells, we identify inhibin-β-A as an angiocrine factor produced by pulmonary capillaries. We find that excess production of inhibin-β-A by endothelial cells impairs the endothelial function in an autocrine manner by functioning as activin-A. Mechanistically, activin-A induces bone morphogenetic protein receptor type 2 internalization and targeting to lysosomes for degradation, resulting in the signal deficiency in endothelial cells. Of note, endothelial cells isolated from the lung of patients with idiopathic pulmonary arterial hypertension show higher inhibin-β-A expression and produce more activin-A compared to endothelial cells isolated from the lung of normal control subjects. When endothelial activin-A-bone morphogenetic protein receptor type 2 link is overdriven in mice, hypoxia-induced pulmonary hypertension was exacerbated, whereas conditional knockout of inhibin-β-A in endothelial cells prevents the progression of pulmonary hypertension. These data collectively indicate a critical role for the dysregulated endothelial activin-A-bone morphogenetic protein receptor type 2 link in the progression of pulmonary hypertension, and thus endothelial inhibin-β-A/activin-A might be a potential pharmacotherapeutic target for the treatment of pulmonary arterial hypertension.
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http://dx.doi.org/10.1038/s41467-021-21961-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979873PMC
March 2021

Protein intake in inhabitants with regular exercise is associated with sleep quality: Results of the Shika study.

PLoS One 2021 26;16(2):e0247926. Epub 2021 Feb 26.

Department of Environmental and Preventive Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan.

Study Objectives: Although associations between sleep quality and environmental factors and nutrient intake have been reported, interactions between these factors have not been elucidated in detail. Therefore, this cross-sectional study examined the effects of regular exercise and nutrient intake on sleep quality using the Pittsburgh Sleep Quality Index (PSQI), which is the most frequently used index for sleep evaluation.

Methods: The participants included 378 individuals aged 40 years or older living in Shika Town, Ishikawa Prefecture. Of these individuals, 185 met the inclusion criteria. The participants completed a self-administered questionnaire assessing lifestyle habits and frequency and duration of exercise, the PSQI, and the brief-type self-administered diet history questionnaire (BDHQ) on nutrient intake.

Results: A two-way analysis of covariance on regular exercise and PSQI scores indicated that protein intake (17.13% of energy) was significantly higher in the regular exercise and PSQI ≤10 groups than in the non-regular exercise or PSQI ≥11 groups (p = 0.002). In a multiple logistic regression analysis with PSQI scores (≤10 and ≥11), protein intake was a significant independent variable in any of the models adjusted for confounding factors such as age, sex, body mass index, current smoker, and current drinker (OR: 1.357, 95% CI: 1.081, 1.704, p = 0.009) in the regular exercise group but not in the non-regular exercise group.Conclusions We identified a positive relationship between sleep quality and protein intake in the regular exercise group. These findings suggest that regular exercise at least twice a week for 30 minutes or longer combined with high protein intake contributes to good sleep quality.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247926PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909647PMC
February 2021

Induction of narcolepsy-like symptoms by orexin receptor antagonists in mice.

Sleep 2021 Feb 20. Epub 2021 Feb 20.

International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki Japan.

Orexins/hypocretins are hypothalamic neuropeptides that promote and stabilize wakefulness by binding to the orexin receptor type-1 (OX1R) and type-2 (OX2R). Disruption of orexinergic signaling results in the sleep disorder narcolepsy in mice, rats, dogs, and humans. The orexin receptor antagonist suvorexant promotes sleep by blocking both OX1R and OX2R. Whereas suvorexant has been clinically approved for the treatment of insomnia because it is well tolerated in experimental animals as well as in human patients, a logical question remains as to why orexin receptor antagonists do not induce overt narcolepsy-like symptoms. Here we show that acute and chronic suvorexant promotes both rapid eye movement (REM) and non-REM (NREM) sleep without inducing cataplexy in mice. Interestingly, chronic suvorexant increases OX2R mRNA and decreases orexin mRNA and peptide levels, which remain low long after termination of suvorexant administration. When mice are chronically treated with suvorexant and then re-challenged with the antagonist after a 1-week washout, however, cataplexy and sleep-onset REM (SOREM) are observed, which are exacerbated by chocolate administration. Heterozygous orexin knockout mice, with lower brain orexin levels, show cataplexy and SOREM after acute suvorexant administration. Furthermore, we find that acute suvorexant can induce cataplexy and SOREM in wild-type mice when co-administered with chocolate under stress-free (temporally anesthetized) conditions. Taken together, these results suggest that suvorexant can inhibit orexin synthesis resulting in susceptibility to narcolepsy-like symptoms in mice under certain conditions.
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http://dx.doi.org/10.1093/sleep/zsab043DOI Listing
February 2021

Induction of Mutant Allele in Neurons in Late Infancy Increases Sleep Need.

J Neurosci 2021 Mar 8;41(12):2733-2746. Epub 2021 Feb 8.

International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan

Sleep is regulated in a homeostatic manner. Sleep deprivation increases sleep need, which is compensated mainly by increased EEG δ power during non-rapid eye movement sleep (NREMS) and, to a lesser extent, by increased sleep amount. Although genetic factors determine the constitutive level of sleep need and sleep amount in mice and humans, the molecular entity behind sleep need remains unknown. Recently, we found that a gain-of-function () mutation in the () gene, which produces the mutant SIK3(SLP) protein, leads to an increase in NREMS EEG δ power and sleep amount. Since mice express SIK3(SLP) in various types of cells in the brain as well as multiple peripheral tissues from the embryonic stage, the cell type and developmental stage responsible for the sleep phenotype in mice remain to be elucidated. Here, we generated two mouse lines, and mice, which enable inducible Cre-mediated, conditional expression of SIK3(SLP) in neurons on tamoxifen administration. Administration of tamoxifen to mice during late infancy resulted in higher recombination efficiency than administration during adolescence. SIK3(SLP) expression after late infancy increased NREMS and NREMS δ power in male mice. The expression of SIK3(SLP) after adolescence led to a higher NREMS δ power without a significant change in NREMS amounts. Thus, neuron-specific expression of SIK3(SLP) after late infancy is sufficient to increase sleep. The propensity to accumulate sleep need during wakefulness and to dissipate it during sleep underlies the homeostatic regulation of sleep. However, little is known about the developmental stage and cell types involved in determining the homeostatic regulation of sleep. Here, we show that allele induction in mature neurons in late infancy is sufficient to increase non-rapid eye movement sleep amount and non-rapid eye movement sleep δ power. SIK3 signaling in neurons constitutes an intracellular mechanism to increase sleep.
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http://dx.doi.org/10.1523/JNEUROSCI.1004-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018738PMC
March 2021

Subacute Ingestion of Caffeine and Oolong Tea Increases Fat Oxidation without Affecting Energy Expenditure and Sleep Architecture: A Randomized, Placebo-Controlled, Double-Blinded Cross-Over Trial.

Nutrients 2020 Nov 28;12(12). Epub 2020 Nov 28.

International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.

Ingesting oolong tea or caffeine acutely increases energy expenditure, and oolong tea, but not caffeine, stimulates fat oxidation. The acute effects of caffeine, such as increased heart rate and interference with sleep, diminish over 1-4 days, known as caffeine tolerance. During each 14-day session of the present study, 12 non-obese males consumed oolong tea (100 mg caffeine, 21.4 mg gallic acid, 97 mg catechins and 125 mg polymerized polyphenol), caffeine (100 mg), or placebo at breakfast and lunch. On day 14 of each session, 24-h indirect calorimetry and polysomnographic sleep recording were performed. Caffeine and oolong tea increased fat oxidation by ~20% without affecting energy expenditure over 24-h. The decrease in the respiratory quotient by oolong tea was greater than that by caffeine during sleep. The effect of oolong tea on fat oxidation was salient in the post-absorptive state. These findings suggest a role of unidentified ingredients in oolong tea to stimulate fat oxidation, and this effect is partially suppressed in a postprandial state. Two weeks of caffeine or oolong tea ingestion increased fat oxidation without interfering with sleep. The effects of subacute ingestion of caffeine and oolong tea differed from the acute effects, which is a particularly important consideration regarding habitual tea consumption.
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http://dx.doi.org/10.3390/nu12123671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760339PMC
November 2020

Gut microbiota depletion by chronic antibiotic treatment alters the sleep/wake architecture and sleep EEG power spectra in mice.

Sci Rep 2020 11 11;10(1):19554. Epub 2020 Nov 11.

International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.

Dysbiosis of the gut microbiota affects physiological processes, including brain functions, by altering the intestinal metabolism. Here we examined the effects of the gut microbiota on sleep/wake regulation. C57BL/6 male mice were treated with broad-spectrum antibiotics for 4 weeks to deplete their gut microbiota. Metabolome profiling of cecal contents in antibiotic-induced microbiota-depleted (AIMD) and control mice showed significant variations in the metabolism of amino acids and vitamins related to neurotransmission, including depletion of serotonin and vitamin B6, in the AIMD mice. Sleep analysis based on electroencephalogram and electromyogram recordings revealed that AIMD mice spent significantly less time in non-rapid eye movement sleep (NREMS) during the light phase while spending more time in NREMS and rapid eye movement sleep (REMS) during the dark phase. The number of REMS episodes seen in AIMD mice increased during both light and dark phases, and this was accompanied by frequent transitions from NREMS to REMS. In addition, the theta power density during REMS was lower in AIMD mice during the light phase compared with that in the controls. Consequently, the gut microbiota is suggested to affect the sleep/wake architecture by altering the intestinal balance of neurotransmitters.
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http://dx.doi.org/10.1038/s41598-020-76562-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659342PMC
November 2020

Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16 Cells In Vivo.

Cell Metab 2020 11 18;32(5):814-828.e6. Epub 2020 Sep 18.

Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute of Biomedical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-0022, Japan.

Cell senescence plays a key role in age-associated organ dysfunction, but the in vivo pathogenesis is largely unclear. Here, we generated a p16-Cre-tdTomato mouse model to analyze the in vivo characteristics of p16 cells at a single-cell level. We found tdTomato-positive p16 cells detectable in all organs, which were enriched with age. We also found that these cells failed to proliferate and had half-lives ranging from 2.6 to 4.2 months, depending on the tissue examined. Single-cell transcriptomics in the liver and kidneys revealed that p16 cells were present in various cell types, though most dominant in hepatic endothelium and in renal proximal and distal tubule epithelia, and that these cells exhibited heterogeneous senescence-associated phenotypes. Further, elimination of p16 cells ameliorated nonalcoholic steatohepatitis-related hepatic lipidosis and immune cell infiltration. Our new mouse model and single-cell analysis provide a powerful resource to enable the discovery of previously unidentified senescence functions in vivo.
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http://dx.doi.org/10.1016/j.cmet.2020.09.006DOI Listing
November 2020

Sleep Architecture in Mice Is Shaped by the Transcription Factor AP-2β.

Genetics 2020 11 2;216(3):753-764. Epub 2020 Sep 2.

International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 305-8575, Japan

The molecular mechanism regulating sleep largely remains to be elucidated. In humans, families that carry mutations in , which encodes the transcription factor AP-2β, self-reported sleep abnormalities such as short-sleep and parasomnia. Notably, AP-2 transcription factors play essential roles in sleep regulation in the nematode and the fruit fly Thus, AP-2 transcription factors might have a conserved role in sleep regulation across the animal phyla. However, direct evidence supporting the involvement of TFAP2B in mammalian sleep was lacking. In this study, by using the CRISPR/Cas9 technology, we generated two mutant mouse strains, and , each harboring a single-nucleotide mutation within the introns of mimicking the mutations in two human kindreds that self-reported sleep abnormalities. The effects of these mutations were compared with those of a knockout allele (). The protein expression level of TFAP2B in the embryonic brain was reduced to about half in mice and was further reduced in mice. By contrast, the protein expression level was normal in mice but was reduced in mice to a similar extent as mice. and showed normal protein expression levels. female mice showed increased wakefulness time and decreased nonrapid eye movement sleep (NREMS) time. By contrast, female mice showed an apparently normal amount of sleep but instead exhibited fragmented NREMS, whereas male mice showed reduced NREMS time specifically in the dark phase. Finally, in the adult brain, expression was detected in the superior colliculus, locus coeruleus, cerebellum, and the nucleus of solitary tract. These findings provide direct evidence that TFAP2B influences NREMS amounts in mice and also show that different mutations in can lead to diverse effects on sleep architecture.
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http://dx.doi.org/10.1534/genetics.120.303435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648583PMC
November 2020

Hypnotic effect of thalidomide is independent of teratogenic ubiquitin/proteasome pathway.

Proc Natl Acad Sci U S A 2020 09 26;117(37):23106-23112. Epub 2020 Aug 26.

International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan;

Thalidomide exerts its teratogenic and immunomodulatory effects by binding to cereblon (CRBN) and thereby inhibiting/modifying the CRBN-mediated ubiquitination pathway consisting of the Cullin4-DDB1-ROC1 E3 ligase complex. The mechanism of thalidomide's classical hypnotic effect remains largely unexplored, however. Here we examined whether CRBN is involved in the hypnotic effect of thalidomide by generating mice harboring a thalidomide-resistant mutant allele of ( knock-in mice). Thalidomide increased non-REM sleep time in knock-in homozygotes and heterozygotes to a similar degree as seen in wild-type littermates. Thalidomide similarly depressed excitatory synaptic transmission in the cortical slices obtained from wild-type and homozygous knock-in mice without affecting GABAergic inhibition. Thalidomide induced Fos expression in vasopressin-containing neurons of the supraoptic nucleus and reduced Fos expression in the tuberomammillary nuclei. Thus, thalidomide's hypnotic effect seems to share some downstream mechanisms with general anesthetics and GABA-activating sedatives but does not involve the teratogenic CRBN-mediated ubiquitin/proteasome pathway.
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http://dx.doi.org/10.1073/pnas.1917701117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502749PMC
September 2020

Discovery of attenuation effect of orexin 1 receptor to aversion of nalfurafine: Synthesis and evaluation of D-nor-nalfurafine derivatives and analyses of the three active conformations of nalfurafine.

Bioorg Med Chem Lett 2020 09 19;30(17):127360. Epub 2020 Jun 19.

International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305 8575, Japan; Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305 8571, Japan. Electronic address:

The D-nor-nalfurafine derivatives, which were synthesized by contraction of the six-membered D-ring in nalfurafine (1), had no affinity for orexin 1 receptors (OXRs). The 17N-lone electron pair in 1 oriented toward the axial direction, while that of D-nor-derivatives was directed in the equatorial configuration. The axial lone electron pair can form a hydrogen bond with the 14-hydroxy group, which could push the 6-amide side chain toward the downward direction with respect to the C-ring. The resulting conformation would be an active conformation for binding with OXR. The dual affinities of 1 for OXR and κ opioid receptor (KOR) led us to elucidate the mechanism by which only 1 showed no aversion but U-50488H. Actually, 1 selectively induced severe aversion in OXR knockout mice, but not in wild-type mice. These results well support that OXR suppresses the aversion of 1. This is the elucidation of long period puzzle which 1 showed no aversion in KOR.
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http://dx.doi.org/10.1016/j.bmcl.2020.127360DOI Listing
September 2020

Ablation of Ventral Midbrain/Pons GABA Neurons Induces Mania-like Behaviors with Altered Sleep Homeostasis and Dopamine DR-mediated Sleep Reduction.

iScience 2020 Jun 4;23(6):101240. Epub 2020 Jun 4.

International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. Electronic address:

Individuals with the neuropsychiatric disorder mania exhibit hyperactivity, elevated mood, and a decreased need for sleep. The brain areas and neuronal populations involved in mania-like behaviors, however, have not been elucidated. In this study, we found that ablating the ventral medial midbrain/pons (VMP) GABAergic neurons induced mania-like behaviors in mice, including hyperactivity, anti-depressive behaviors, reduced anxiety, increased risk-taking behaviors, distractibility, and an extremely shortened sleep time. Strikingly, these mice also showed no rebound sleep after sleep deprivation, suggesting abnormal sleep homeostatic regulation. Dopamine D receptor deficiency largely abolished the sleep reduction induced by ablating the VMP GABAergic neurons without affecting the hyperactivity and anti-depressive behaviors. Our data demonstrate that VMP GABAergic neurons are involved in the expression of mania-like behaviors, which can be segregated to the short-sleep and other phenotypes on the basis of the dopamine D receptors.
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http://dx.doi.org/10.1016/j.isci.2020.101240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305386PMC
June 2020

A discrete neuronal circuit induces a hibernation-like state in rodents.

Nature 2020 07 11;583(7814):109-114. Epub 2020 Jun 11.

Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

Hibernating mammals actively lower their body temperature to reduce energy expenditure when facing food scarcity. This ability to induce a hypometabolic state has evoked great interest owing to its potential medical benefits. Here we show that a hypothalamic neuronal circuit in rodents induces a long-lasting hypothermic and hypometabolic state similar to hibernation. In this state, although body temperature and levels of oxygen consumption are kept very low, the ability to regulate metabolism still remains functional, as in hibernation. There was no obvious damage to tissues and organs or abnormalities in behaviour after recovery from this state. Our findings could enable the development of a method to induce a hibernation-like state, which would have potential applications in non-hibernating mammalian species including humans.
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http://dx.doi.org/10.1038/s41586-020-2163-6DOI Listing
July 2020

Sparse Activity of Hippocampal Adult-Born Neurons during REM Sleep Is Necessary for Memory Consolidation.

Neuron 2020 08 4;107(3):552-565.e10. Epub 2020 Jun 4.

International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-0006, Japan. Electronic address:

The occurrence of dreaming during rapid eye movement (REM) sleep prompts interest in the role of REM sleep in hippocampal-dependent episodic memory. Within the mammalian hippocampus, the dentate gyrus (DG) has the unique characteristic of exhibiting neurogenesis persisting into adulthood. Despite their small numbers and sparse activity, adult-born neurons (ABNs) in the DG play critical roles in memory; however, their memory function during sleep is unknown. Here, we investigate whether young ABN activity contributes to memory consolidation during sleep using Ca imaging in freely moving mice. We found that contextual fear learning recruits a population of young ABNs that are reactivated during subsequent REM sleep against a backdrop of overall reduced ABN activity. Optogenetic silencing of this sparse ABN activity during REM sleep alters the structural remodeling of spines on ABN dendrites and impairs memory consolidation. These findings provide a causal link between ABN activity during REM sleep and memory consolidation.
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http://dx.doi.org/10.1016/j.neuron.2020.05.008DOI Listing
August 2020

Structure of cortical network activity across natural wake and sleep states in mice.

PLoS One 2020 29;15(5):e0233561. Epub 2020 May 29.

WPI-IIIS, International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan.

Cortical neurons fire intermittently and synchronously during non-rapid eye movement sleep (NREMS), in which active and silent periods are referred to as ON and OFF periods, respectively. Neuronal firing rates during ON periods (NREMS-ON-activity) are similar to those of wakefulness (W-activity), raising the possibility that NREMS-ON neuronal-activity is fragmented W-activity. To test this, we investigated the patterning and organization of cortical spike trains and of spike ensembles in neuronal networks using extracellular recordings in mice. Firing rates of neurons during NREMS-ON and W were similar, but showed enhanced bursting in NREMS with no apparent preference in occurrence, relative to the beginning or end of the on-state. Additionally, there was an overall increase in the randomness of occurrence of sequences comprised of multi-neuron ensembles in NREMS recorded from tetrodes. In association with increased burst firing, somatic calcium transients were increased in NREMS. The increased calcium transients associated with bursting during NREM may activate calcium-dependent, cell-signaling pathways for sleep related cellular processes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233561PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259746PMC
August 2020

Loss of the conserved PKA sites of SIK1 and SIK2 increases sleep need.

Sci Rep 2020 05 26;10(1):8676. Epub 2020 May 26.

International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, 305-8575, Japan.

Although sleep is one of the most conserved behaviors, the intracellular mechanism regulating sleep/wakefulness remains unknown. We recently identified a protein kinase, SIK3, as a sleep-regulating molecule. Mice that lack a well-conserved protein kinase A (PKA) phosphorylation site, S551, showed longer non-rapid eye movement (NREM) sleep and increased NREMS delta density. S551 of SIK3 is conserved in other members of the SIK family, such as SIK1 (S577) and SIK2 (S587). Here, we examined whether the PKA phosphorylation sites of SIK1 and SIK2 are involved in sleep regulation by generating Sik1 and Sik2 mice. The homozygous Sik1 mice showed a shorter wake time, longer NREMS time, and higher NREMS delta density than the wild-type mice. The heterozygous and homozygous Sik2 mice showed increased NREMS delta density. Both the Sik1 and Sik2 mice exhibited proper homeostatic regulation of sleep need after sleep deprivation. Despite abundant expression of Sik1 in the suprachiasmatic nucleus, the Sik1 mice showed normal circadian behavior. Although Sik2 is highly expressed in brown adipose tissue, the male and female Sik2 mice that were fed either a chow or high-fat diet showed similar weight gain as the wild-type littermates. These results suggest that PKA-SIK signaling is involved in the regulation of sleep need.
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http://dx.doi.org/10.1038/s41598-020-65647-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250853PMC
May 2020

Loss of attenuates the behavioral and molecular responses for sleep homeostasis in mice.

Proc Natl Acad Sci U S A 2020 05 29;117(19):10547-10553. Epub 2020 Apr 29.

Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390;

The activity-regulated cytoskeleton-associated protein () gene is a neural immediate early gene that is involved in synaptic downscaling and is robustly induced by prolonged wakefulness in rodent brains. Converging evidence has led to the hypothesis that wakefulness potentiates, and sleep reduces, synaptic strengthening. This suggests a potential role for in these and other sleep-related processes. However, the role of in sleep remains unknown. Here, we demonstrated that is important for the induction of multiple behavioral and molecular responses associated with sleep homeostasis. knockout (KO) mice displayed increased time spent in rapid eye movement (REM) sleep under baseline conditions and marked attenuation of sleep rebound to both 4 h of total sleep deprivation (SD) and selective REM deprivation. At the molecular level, the following homeostatic sleep responses to 4-h SD were all blunted in KO mice: increase of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 and its phosphorylation in synaptoneurosomes; induction of a subset of SD-response genes; and suppression of the messenger RNA in the cortex. In wild-type brains, SD increased Arc protein expression in multiple subcellular locations, including the nucleus, cytoplasm, and synapse, which is reversed in part by recovery sleep. is critical for these behavioral and multiple molecular responses to SD, thus providing a multifunctional role for in the maintenance of sleep homeostasis, which may be attributed by the sleep/wake-associated changes in subcellular location of Arc.
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http://dx.doi.org/10.1073/pnas.1906840117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229651PMC
May 2020

Copine-7 is required for REM sleep regulation following cage change or water immersion and restraint stress in mice.

Neurosci Res 2021 Apr 11;165:14-25. Epub 2020 Apr 11.

International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. Electronic address:

Sleep is affected by the environment. In rodents, changes in the amount of rapid eye movement sleep (REMS) can precede those of other sleep/wake stages. The molecular mechanism underlying the dynamic regulation of REMS remains poorly understood. Here, we focused on the sublaterodorsal nucleus (SLD), located in the pontine tegmental area, which plays a crucial role in the regulation of REMS. We searched for genes selectively expressed in the SLD and identified copine-7 (Cpne7), whose involvement in sleep was totally unknown. We generated Cpne7-Cre knock-in mice, which enabled both the knockout (KO) of Cpne7 and the genetic labeling of Cpne7-expressing cells. While Cpne7-KO mice exhibited normal sleep under basal conditions, the amount of REMS in Cpne7-KO mice was larger compared to wildtype mice following cage change or water immersion and restraint stress, both of which are conditions that acutely reduce REMS. Thus, it was suggested that copine-7 is involved in negatively regulating REMS under certain conditions. In addition, chemogenetically activating Cpne7-expressing neurons in the SLD reduced the amount of REMS, suggesting that these neurons negatively regulate REMS. These results identify copine-7 and Cpne7-expressing neurons in the SLD as candidate molecular or neuronal components of the regulatory system that controls REMS.
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http://dx.doi.org/10.1016/j.neures.2020.04.002DOI Listing
April 2021

Enhanced cortical responsiveness during natural sleep in freely behaving mice.

Sci Rep 2020 02 10;10(1):2278. Epub 2020 Feb 10.

International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan.

Cortical networks exhibit large shifts in spontaneous dynamics depending on the vigilance state. Waking and rapid eye movement (REM) sleep are characterized by ongoing irregular activity of cortical neurons while during slow wave sleep (SWS) these neurons show synchronous alterations between silent (OFF) and active (ON) periods. The network dynamics underlying these phenomena are not fully understood. Additional information about the state of cortical networks can be obtained by evaluating evoked cortical responses during the sleep-wake cycle. We measured local field potentials (LFP) and multi-unit activity (MUA) in the cortex in response to repeated brief optogenetic stimulation of thalamocortical afferents. Both LFP and MUA responses were considerably increased in sleep compared to waking, with larger responses during SWS than during REM sleep. The strongly increased cortical response in SWS is discussed within the context of SWS-associated neuro-modulatory tone that may reduce feedforward inhibition. Responses to stimuli were larger during SWS-OFF periods than during SWS-ON periods. SWS responses showed clear daily fluctuation correlated to light-dark cycle, but no reaction to increased sleep need following sleep deprivation. Potential homeostatic synaptic plasticity was either absent or masked by large vigilance-state effects.
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http://dx.doi.org/10.1038/s41598-020-59151-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010820PMC
February 2020

Dynamics of Cortical Local Connectivity during Sleep-Wake States and the Homeostatic Process.

Cereb Cortex 2020 06;30(7):3977-3990

International Institute for Integrative Sleep Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.

Sleep exerts modulatory effects on the cerebral cortex. Whether sleep modulates local connectivity in the cortex or only individual neural activity, however, is poorly understood. Here we investigated functional connectivity, that is, covarying activity between neurons, during spontaneous sleep-wake states and during and after sleep deprivation using calcium imaging of identified excitatory/inhibitory neurons in the motor cortex. Functional connectivity was estimated with a statistical learning approach glasso and quantified by "the probability of establishing connectivity (sparse/dense)" and "the strength of the established connectivity (weak/strong)." Local cortical connectivity was sparse in non-rapid eye movement (NREM) sleep and dense in REM sleep, which was similar in both excitatory and inhibitory neurons. The overall mean strength of the connectivity did not differ largely across spontaneous sleep-wake states. Sleep deprivation induced strong excitatory/inhibitory and dense inhibitory, but not excitatory, connectivity. Subsequent NREM sleep after sleep deprivation exhibited weak excitatory/inhibitory, sparse excitatory, and dense inhibitory connectivity. These findings indicate that sleep-wake states modulate local cortical connectivity, and the modulation is large and compensatory for stability of local circuits during the homeostatic control of sleep, which contributes to plastic changes in neural information flow.
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http://dx.doi.org/10.1093/cercor/bhaa012DOI Listing
June 2020

Widely Distributed Neurotensinergic Neurons in the Brainstem Regulate NREM Sleep in Mice.

Curr Biol 2020 03 6;30(6):1002-1010.e4. Epub 2020 Feb 6.

International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. Electronic address:

Classical transection studies suggest that, in addition to the hypothalamus, the brainstem is essential for non-rapid eye movement (NREM) sleep. The circuits underlying this function, however, have remained largely unknown. We identified a circuit distributed in the midbrain, pons, and medulla that promotes NREM sleep in mice. We focused on the sublaterodorsal tegmentum, an area implicated in dual regulation of REM and NREM sleep. Transcriptomic and genetic analyses revealed that neurons positive for the neuropeptide neurotensin promote NREM sleep. Further analyses identified downstream NREM sleep-promoting neurons in the dorsal deep mesencephalic nucleus, the lateral part of the periaqueductal gray, and the medial vestibular nucleus that were also neurotensinergic. Infusion of neurotensin into the fourth ventricle induced NREM sleep-like cortical activity, whereas mice deficient for neurotensin exhibited increased REM sleep, implicating the involvement of the neuropeptide itself. These findings identify a widely distributed NREM sleep-regulating circuit in the brainstem with a common molecular property.
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http://dx.doi.org/10.1016/j.cub.2020.01.047DOI Listing
March 2020

Essential structure of orexin 1 receptor antagonist YNT-707, part V: Structure-activity relationship study of the substituents on the 17-amino group.

Bioorg Med Chem Lett 2020 02 17;30(3):126893. Epub 2019 Dec 17.

International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan. Electronic address:

The morphinan-type orexin 1 receptor (OXR) antagonists such as YNT-707 (2) and YNT-1310 (3) show potent and extremely high selective antagonistic activity against OXR. In the course of our studies of the essential structure of 2, we identified new scaffolds by simplification of the morphinan skeleton. However, the new chemical entities carrying the D-ring removed scaffold showed insufficient activity. To improve the activity of these derivatives, we investigated the effect of substituents mainly focused on the 17-nitrogen group. The 17-N-substituted derivatives, as well as the cyclic derivatives, were synthesized and examined the OXR antagonistic activity. The assay results showed the interesting relationship between the OXR antagonistic activity and the substituents on the 17-nitrogen: the antagonistic activity was increased as the bulkiness of 17-substituents increased. Finally, the 17-N-Boc derivative 14a showed the most potent OXR antagonistic activity (K = 14.8 nM).
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http://dx.doi.org/10.1016/j.bmcl.2019.126893DOI Listing
February 2020

α-Synuclein BAC transgenic mice exhibit RBD-like behaviour and hyposmia: a prodromal Parkinson's disease model.

Brain 2020 01;143(1):249-265

Department of Neurology Kyoto University Graduate School of Medicine, Kyoto, Japan.

Parkinson's disease is one of the most common movement disorders and is characterized by dopaminergic cell loss and the accumulation of pathological α-synuclein, but its precise pathogenetic mechanisms remain elusive. To develop disease-modifying therapies for Parkinson's disease, an animal model that recapitulates the pathology and symptoms of the disease, especially in the prodromal stage, is indispensable. As subjects with α-synuclein gene (SNCA) multiplication as well as point mutations develop familial Parkinson's disease and a genome-wide association study in Parkinson's disease has identified SNCA as a risk gene for Parkinson's disease, the increased expression of α-synuclein is closely associated with the aetiology of Parkinson's disease. In this study we generated bacterial artificial chromosome transgenic mice harbouring SNCA and its gene expression regulatory regions in order to maintain the native expression pattern of α-synuclein. Furthermore, to enhance the pathological properties of α-synuclein, we inserted into SNCA an A53T mutation, two single-nucleotide polymorphisms identified in a genome-wide association study in Parkinson's disease and a Rep1 polymorphism, all of which are causal of familial Parkinson's disease or increase the risk of sporadic Parkinson's disease. These A53T SNCA bacterial artificial chromosome transgenic mice showed an expression pattern of human α-synuclein very similar to that of endogenous mouse α-synuclein. They expressed truncated, oligomeric and proteinase K-resistant phosphorylated forms of α-synuclein in the regions that are specifically affected in Parkinson's disease and/or dementia with Lewy bodies, including the olfactory bulb, cerebral cortex, striatum and substantia nigra. Surprisingly, these mice exhibited rapid eye movement (REM) sleep without atonia, which is a key feature of REM sleep behaviour disorder, at as early as 5 months of age. Consistent with this observation, the REM sleep-regulating neuronal populations in the lower brainstem, including the sublaterodorsal tegmental nucleus, nuclei in the ventromedial medullary reticular formation and the pedunculopontine nuclei, expressed phosphorylated α-synuclein. In addition, they also showed hyposmia at 9 months of age, which is consistent with the significant accumulation of phosphorylated α-synuclein in the olfactory bulb. The dopaminergic neurons in the substantia nigra pars compacta degenerated, and their number was decreased in an age-dependent manner by up to 17.1% at 18 months of age compared to wild-type, although the mice did not show any related locomotor dysfunction. In conclusion, we created a novel mouse model of prodromal Parkinson's disease that showed RBD-like behaviour and hyposmia without motor symptoms.
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http://dx.doi.org/10.1093/brain/awz380DOI Listing
January 2020

Distinct effects of orexin receptor antagonist and GABA agonist on sleep and physical/cognitive functions after forced awakening.

Proc Natl Acad Sci U S A 2019 11 11;116(48):24353-24358. Epub 2019 Nov 11.

International Institute for Integrative Sleep Medicine, University of Tsukuba, 305-8575 Tsukuba, Ibaraki, Japan;

The majority of patients with insomnia are treated with hypnotic agents. In the present study, we evaluated the side-effect profile of an orexin receptor antagonist and γ-aminobutyric acid A (GABA) receptor agonist on physical/cognitive functions upon forced awakening. This double-blind, randomized, placebo-controlled, cross-over study was conducted on 30 healthy male subjects. Fifteen minutes before bedtime, the subjects took a pill of suvorexant (20 mg), brotizolam (0.25 mg), or placebo and were forced awake 90 min thereafter. Physical- and cognitive-function tests were performed before taking the pill, after forced awakening, and the next morning. Polysomnographic recordings revealed that the efficacies of the hypnotic agents in prolonging total sleep time (∼30 min) and increasing sleep efficiency (∼6%) were comparable. When the subjects were allowed to go back to sleep after the forced awakening, the sleep latency was shorter under the influence of hypnotic agents (∼2 min) compared to the placebo trial (24 min), and the rapid eye movement latency was significantly shorter under suvorexant (98.8, 81.7, and 48.8 min for placebo, brotizolam, and suvorexant, respectively). Although brotizolam significantly impaired the overall physical/cognitive performance (sum of score) compared with placebo upon forced awakening, there was no significant difference in the total score of performance between suvorexant and placebo. Notably, the score for static balance with the eyes open was higher under suvorexant compared to brotizolam administration. The energy expenditure was lower under suvorexant and brotizolam compared with the placebo. The effect size of brotizolam ( = 0.24) to reduce the energy expenditure was larger than that of suvorexant ( < 0.01).
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http://dx.doi.org/10.1073/pnas.1907354116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883838PMC
November 2019

Effects of 3 Weeks of Water Immersion and Restraint Stress on Sleep in Mice.

Front Neurosci 2019 14;13:1072. Epub 2019 Oct 14.

International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan.

Repeated stress is a risk factor for mental disorders and can also lead to sleep disturbances. Although the effects of stress on sleep architecture have been investigated in rodents, the length of the stress exposure period in most studies has been limited to about 10 days, and few studies have analyzed the effects of chronic stress over a longer period. Here we investigated how sleep is affected in a mouse model of depression induced by 3 weeks of daily water immersion and restraint stress (WIRS). Sleep was recorded after 1, 2, and 3 weeks of stress exposure. Some stress-induced changes in several sleep measures were maintained across the 3 weeks, whereas other changes were most prominent during the 1st week. The total amount of non-rapid eye movement sleep (NREMS) was increased and the total amount of time spent awake was decreased across all 3 weeks. On the other hand, the amount of REMS during the dark phase was significantly increased in the 1st week compared with that at baseline or the 2nd and 3rd weeks. Electroencephalogram (EEG) power in the delta range was decreased during NREMS, although the total amount of NREMS was increased. These findings indicate that repeated WIRS, which eventually leads to a depression-like phenotype, differentially affects sleep between the early and subsequent periods. The increase in the amount of REMS during the dark phase in the 1st week significantly correlated with changes in body weight. Our results show how sleep changes throughout a long period of chronic stress in a mouse model of depression.
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http://dx.doi.org/10.3389/fnins.2019.01072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813282PMC
October 2019

Endothelin: 30 Years From Discovery to Therapy.

Hypertension 2019 12 4;74(6):1232-1265. Epub 2019 Nov 4.

International Institute for Integrative Sleep Medicine (WPI-IIIS) and Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, Japan (M.Y.).

Discovered in 1987 as a potent endothelial cell-derived vasoconstrictor peptide, endothelin-1 (ET-1), the predominant member of the endothelin peptide family, is now recognized as a multifunctional peptide with cytokine-like activity contributing to almost all aspects of physiology and cell function. More than 30 000 scientific articles on endothelin were published over the past 3 decades, leading to the development and subsequent regulatory approval of a new class of therapeutics-the endothelin receptor antagonists (ERAs). This article reviews the history of the discovery of endothelin and its role in genetics, physiology, and disease. Here, we summarize the main clinical trials using ERAs and discuss the role of endothelin in cardiovascular diseases such as arterial hypertension, preecclampsia, coronary atherosclerosis, myocardial infarction in the absence of obstructive coronary artery disease (MINOCA) caused by spontaneous coronary artery dissection (SCAD), Takotsubo syndrome, and heart failure. We also discuss how endothelins contributes to diabetic kidney disease and focal segmental glomerulosclerosis, pulmonary arterial hypertension, as well as cancer, immune disorders, and allograft rejection (which all involve ET autoantibodies), and neurological diseases. The application of ERAs, dual endothelin receptor/angiotensin receptor antagonists (DARAs), selective ET agonists, novel biologics such as receptor-targeting antibodies, or immunization against ET receptors holds the potential to slow the progression or even reverse chronic noncommunicable diseases. Future clinical studies will show whether targeting endothelin receptors can prevent or reduce disability from disease and improve clinical outcome, quality of life, and survival in patients.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.12105DOI Listing
December 2019

MC-SleepNet: Large-scale Sleep Stage Scoring in Mice by Deep Neural Networks.

Sci Rep 2019 10 31;9(1):15793. Epub 2019 Oct 31.

Center for Computational Sciences, University of Tsukuba, Tsukuba, Japan.

Automated sleep stage scoring for mice is in high demand for sleep research, since manual scoring requires considerable human expertise and efforts. The existing automated scoring methods do not provide the scoring accuracy required for practical use. In addition, the performance of such methods has generally been evaluated using rather small-scale datasets, and their robustness against individual differences and noise has not been adequately verified. This research proposes a novel automated scoring method named "MC-SleepNet", which combines two types of deep neural networks. Then, we evaluate its performance using a large-scale dataset that contains 4,200 biological signal records of mice. The experimental results show that MC-SleepNet can automatically score sleep stages with an accuracy of 96.6% and kappa statistic of 0.94. In addition, we confirm that the scoring accuracy does not significantly decrease even if the target biological signals are noisy. These results suggest that MC-SleepNet is very robust against individual differences and noise. To the best of our knowledge, evaluations using such a large-scale dataset (containing 4,200 records) and high scoring accuracy (96.6%) have not been reported in previous related studies.
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http://dx.doi.org/10.1038/s41598-019-51269-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823352PMC
October 2019

Differential Roles of Each Orexin Receptor Signaling in Obesity.

iScience 2019 Oct 9;20:1-13. Epub 2019 Sep 9.

International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Department of Anatomy, Faculty of Medicine, Toho University, Ota-ku, Tokyo 143-8540, Japan. Electronic address:

Orexins are hypothalamic neuropeptides that regulate feeding, energy expenditure, and sleep. Although orexin-deficient mice are susceptible to obesity, little is known about the roles of the orexin receptors in long-term energy metabolism. Here, we performed the metabolic characterization of orexin receptor-deficient mice. Ox1r-deficient mice were resistant to diet-induced obesity, and their food intake was similar between chow and high-fat food. Ox2r-deficient mice exhibited less energy expenditure than wild-type mice when fed a high-fat diet. Neither Ox1r-deficient nor Ox2r-deficient mice showed body weight gain similar to orexin-deficient mice. Although the presence of a running wheel suppressed diet-induced obesity in wild-type mice, the effect was weaker in orexin neuron-ablated mice. Finally, we did not detect abnormalities in brown adipose tissues of orexin-deficient mice. Thus, each orexin receptor signaling has a unique role in energy metabolism, and orexin neurons are involved in the interactive effect of diet and exercise on body weight gain.
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http://dx.doi.org/10.1016/j.isci.2019.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817686PMC
October 2019

Neuronal Myocyte-Specific Enhancer Factor 2D (MEF2D) Is Required for Normal Circadian and Sleep Behavior in Mice.

J Neurosci 2019 10 16;39(40):7958-7967. Epub 2019 Aug 16.

Department of Neuroscience, Peter O'Donnell Jr. Brain Insitute,

The transcription factor, myocyte enhancer factor-2 (MEF2), is required for normal circadian behavior in ; however, its role in the mammalian circadian system has not been established. Of the four mammalian genes, is highly expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus, a region critical for coordinating peripheral circadian clocks. Using both conventional and brain-specific KO () mouse lines, we demonstrate that MEF2D is essential for maintaining the length of the circadian free-running period of locomotor activity and normal sleep patterns in male mice. Crossing with reporter mice, we show that these behavioral changes are achieved without altering the endogenous period of the master circadian oscillator in the SCN. Together, our data suggest that alterations in behavior in mice may be the result of an effect on SCN output, rather than an effect on timekeeping within the SCN itself. These findings add to the growing body of evidence that MEF2 proteins play important roles in the brain. These studies are the first to show a role for MEF2 proteins in the brain outside of the hippocampus, and our findings suggest that these proteins may play diverse roles in the CNS. It is important to continue to build on our understanding of the roles of proteins acting in the SCN because SCN dysfunction underlies jet lag in humans and influences the response to shift work schedules, which are now known as risk factors for the development of cancer. Our work on MEF2D could be the basis for opening new lines of research in the development and regulation of circadian rhythms.
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http://dx.doi.org/10.1523/JNEUROSCI.0411-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774416PMC
October 2019

A new mouse model of GLUT1 deficiency syndrome exhibits abnormal sleep-wake patterns and alterations of glucose kinetics in the brain.

Dis Model Mech 2019 09 12;12(9). Epub 2019 Sep 12.

Japan Mouse Clinic, RIKEN BioResource Research Center, Tsukuba, Ibaraki 305-0074, Japan.

Dysfunction of glucose transporter 1 (GLUT1) proteins causes infantile epilepsy, which is designated as a GLUT1 deficiency syndrome (GLUT1DS; OMIM #606777). Patients with GLUT1DS display varied clinical phenotypes, such as infantile seizures, ataxia, severe mental retardation with learning disabilities, delayed development, hypoglycorrhachia, and other varied symptoms. mutant mice mutagenized with N-ethyl-N-nitrosourea (ENU) carry a missense mutation in the gene that results in amino acid substitution at the 324th residue of the GLUT1 protein. In this study, these mutants exhibited various phenotypes, including embryonic lethality of homozygotes, a decreased cerebrospinal-fluid glucose value, deficits in contextual learning, a reduction in body size, seizure-like behavior and abnormal electroencephalogram (EEG) patterns. During EEG recording, the abnormality occurred spontaneously, whereas the seizure-like phenotypes were not observed at the same time. In sleep-wake analysis using EEG recording, heterozygotes exhibited a longer duration of wake times and shorter duration of non-rapid eye movement (NREM) sleep time. The shortened period of NREM sleep and prolonged duration of the wake period may resemble the sleep disturbances commonly observed in patients with GLUT1DS and other epilepsy disorders. Interestingly, an kinetic analysis of glucose utilization by positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose imaging revealed that glucose transportation was reduced, whereas hexokinase activity and glucose metabolism were enhanced. These results indicate that a mutant is a useful tool for elucidating the molecular mechanisms of GLUT1DS.This article has an associated First Person interview with the joint first authors of the paper.
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http://dx.doi.org/10.1242/dmm.038828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765196PMC
September 2019