Publications by authors named "Hiromasa Funato"

49 Publications

Cellular Composition of the Preoptic Area Regulating Sleep, Parental, and Sexual Behavior.

Front Neurosci 2021 31;15:649159. Epub 2021 Mar 31.

Department of Anatomy, Faculty of Medicine, Toho University, Tokyo, Japan.

The preoptic area (POA) has long been recognized as a sleep center, first proposed by von Economo. The POA, especially the medial POA (MPOA), is also involved in the regulation of various innate functions such as sexual and parental behaviors. Consistent with its many roles, the MPOA is composed of subregions that are identified by different gene and protein expressions. This review addresses the current understanding of the molecular and cellular architecture of POA neurons in relation to sleep and reproductive behavior. Optogenetic and pharmacogenetic studies have revealed a diverse group of neurons within the POA that exhibit different neural activity patterns depending on vigilance states and whose activity can enhance or suppress wake, non-rapid eye movement (NREM) sleep, or rapid eye movement (REM) sleep. These sleep-regulating neurons are not restricted to the ventrolateral POA (VLPO) region but are widespread in the lateral MPOA and LPOA as well. Neurons expressing galanin also express gonadal steroid receptors and regulate motivational aspects of reproductive behaviors. Moxd1, a novel marker of sexually dimorphic nuclei (SDN), visualizes the SDN of the POA (SDN-POA). The role of the POA in sleep and other innate behaviors has been addressed separately; more integrated observation will be necessary to obtain physiologically relevant insight that penetrates the different dimensions of animal behavior.
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http://dx.doi.org/10.3389/fnins.2021.649159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044373PMC
March 2021

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

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

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

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

Modified Hybridization Chain Reaction Using Short Hairpin DNAs.

Front Mol Neurosci 2020 12;13:75. Epub 2020 May 12.

Department of Anatomy, Faculty of Medicine, Toho University, Tokyo, Japan.

The visualization of multiple gene expressions in well-preserved tissues is crucial for the elucidation of physiological and pathological processes. hybridization chain reaction (HCR) is a method to visualize specific mRNAs in diverse organisms by applying a HCR that is an isothermal enzyme-free nucleotide polymerization method using hairpin DNAs. Although HCR is a versatile method, this method is not widely used by researchers because of their higher cost than conventional hybridization (ISH). Here, we redesigned hairpin DNAs so that their lengths were half the length of commonly used hairpin DNAs. We also optimized the conjugated fluorophores and linkers. Modified HCR showed sufficient fluorescent signals to detect various mRNAs such as , , , , , and in mouse neural tissues with a high signal-to-noise ratio. The sensitivity of modified HCR in detecting the mRNA was better than that of fluorescent ISH using tyramide signal amplification. Notably, the modified HCR does not require proteinase K treatment so that it enables the preservation of morphological structures and antigenicity. The modified HCR simultaneously detected the distributions of c-Fos immunoreactivity and mRNA, and detected multiple mRNAs with a high signal-noise ratio at subcellular resolution in mouse brains. These results suggest that the modified HCR using short hairpin DNAs is cost-effective and useful for the visualization of multiple mRNAs and proteins.
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http://dx.doi.org/10.3389/fnmol.2020.00075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235299PMC
May 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

Infants Show Physiological Responses Specific to Parental Hugs.

iScience 2020 Apr 6;23(4):100996. Epub 2020 Apr 6.

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

Caregivers hug their infants to express affection and joy. However, it remains unknown how infants react to being hugged. Here we examined heart rate responses in first-year infants during a hug, hold, and tight hug from parents. Infants older than four months showed an increased R-R interval (RRI) during a hug, indicating reduced heart rates and pronounced parasympathetic activity. Few head movements predicted a higher RRI increase in infants during a parental hug compared with that during a hold and tight hug. Infants did not show an increased RRI during a hug from a female stranger. Infants younger than four months did not show RRI increase during parental hug but exhibited a decreased RRI correlated with contact pressure. Parents showed an increased RRI during hugging their infants. These results suggest the parent-infant hug underlies the parent-infant bonding and psychophysiological development of infants.
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http://dx.doi.org/10.1016/j.isci.2020.100996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360522PMC
April 2020

Forward genetic approach for behavioral neuroscience using animal models.

Authors:
Hiromasa Funato

Proc Jpn Acad Ser B Phys Biol Sci 2020 ;96(1):10-31

Department of Anatomy, Faculty of Medicine, Toho University.

Forward genetics is a powerful approach to understand the molecular basis of animal behaviors. Fruit flies were the first animal to which this genetic approach was applied systematically and have provided major discoveries on behaviors including sexual, learning, circadian, and sleep-like behaviors. The development of different classes of model organism such as nematodes, zebrafish, and mice has enabled genetic research to be conducted using more-suitable organisms. The unprecedented success of forward genetic approaches was the identification of the transcription-translation negative feedback loop composed of clock genes as a fundamental and conserved mechanism of circadian rhythm. This approach has now expanded to sleep/wakefulness in mice. A conventional strategy such as dominant and recessive screenings can be modified with advances in DNA sequencing and genome editing technologies.
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http://dx.doi.org/10.2183/pjab.96.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974404PMC
April 2020

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

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

Methodology and theoretical basis of forward genetic screening for sleep/wakefulness in mice.

Proc Natl Acad Sci U S A 2019 08 23;116(32):16062-16067. Epub 2019 Jul 23.

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

The regulatory network of genes and molecules in sleep/wakefulness remains to be elucidated. Here we describe the methodology and workflow of the dominant screening of randomly mutagenized mice and discuss theoretical basis of forward genetics research for sleep in mice. Our high-throughput screening employs electroencephalogram (EEG) and electromyogram (EMG) to stage vigilance states into a wake, rapid eye movement sleep (REMS) and non-REM sleep (NREMS). Based on their near-identical sleep/wake behavior, C57BL/6J (B6J) and C57BL/6N (B6N) are chosen as mutagenized and counter strains, respectively. The total time spent in the wake and NREMS, as well as the REMS episode duration, shows sufficient reproducibility with small coefficients of variance, indicating that these parameters are most suitable for quantitative phenotype-driven screening. Coarse linkage analysis of the quantitative trait, combined with whole-exome sequencing, can identify the gene mutation associated with sleep abnormality. Our simulations calculate the achievable LOD score as a function of the phenotype strength and the numbers of mice examined. A pedigree showing a mild decrease in total wake time resulting from a heterozygous point mutation in the gene is described as an example.
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http://dx.doi.org/10.1073/pnas.1906774116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689935PMC
August 2019

A single phosphorylation site of SIK3 regulates daily sleep amounts and sleep need in mice.

Proc Natl Acad Sci U S A 2018 10 25;115(41):10458-10463. Epub 2018 Sep 25.

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

Sleep is an evolutionally conserved behavior from vertebrates to invertebrates. The molecular mechanisms that determine daily sleep amounts and the neuronal substrates for homeostatic sleep need remain unknown. Through a large-scale forward genetic screen of sleep behaviors in mice, we previously demonstrated that the mutant allele of the protein kinase gene markedly increases daily nonrapid-eye movement sleep (NREMS) amounts and sleep need. The mutation deletes the in-frame exon 13 encoding a peptide stretch encompassing S551, a known PKA recognition site in SIK3. Here, we demonstrate that single amino acid changes at SIK3 S551 ( and ) reproduce the hypersomnia phenotype of the mutant mice. These mice exhibit increased NREMS amounts and inherently increased sleep need, the latter demonstrated by increased duration of individual NREMS episodes and higher EEG slow-wave activity during NREMS. At the molecular level, deletion or mutation at SIK3 S551 reduces PKA recognition and abolishes 14-3-3 binding. Our results suggest that the evolutionally conserved S551 of SIK3 mediates, together with PKA and 14-3-3, the intracellular signaling crucial for the regulation of daily sleep amounts and sleep need at the organismal level.
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http://dx.doi.org/10.1073/pnas.1810823115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187192PMC
October 2018

Ablation of Central Serotonergic Neurons Decreased REM Sleep and Attenuated Arousal Response.

Front Neurosci 2018 7;12:535. Epub 2018 Aug 7.

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

Sleep/wake behavior is regulated by distinct groups of neurons, such as dopaminergic, noradrenergic, and orexinergic neurons. Although monoaminergic neurons are usually considered to be wake-promoting, the role of serotonergic neurons in sleep/wake behavior remains inconclusive because of the effect of serotonin (5-HT)-deficiency on brain development and the compensation for inborn 5-HT deficiency by other sleep/wake-regulating neurons. Here, we performed selective ablation of central 5-HT neurons in the newly developed mouse line that was crossed with mice to examine the role of 5-HT neurons in the sleep/wake behavior of adult mice. Intracerebroventricular administration of diphtheria toxin completely ablated tdTomato-positive cells in mice. Electroencephalogram/electromyogram-based sleep/wake analysis demonstrated that central 5-HT neuron ablation in adult mice decreased the time spent in rapid eye movement (REM) sleep, which was associated with fewer transitions from non-REM (NREM) sleep to REM sleep than in control mice. Central 5-HT neuron-ablated mice showed attenuated wake response to a novel environment and increased theta power during wakefulness compared to control mice. The current findings indicated that adult 5-HT neurons work to support wakefulness and regulate REM sleep time through a biased transition from NREM sleep to REM sleep.
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http://dx.doi.org/10.3389/fnins.2018.00535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090062PMC
August 2018

Corticotropin-Releasing Factor Receptor 1 in the Anterior Cingulate Cortex Mediates Maternal Absence-Induced Attenuation of Transport Response in Mouse Pups.

Front Cell Neurosci 2018 13;12:204. Epub 2018 Jul 13.

Laboratory for Affiliative Social Behavior, Center for Brain Science, RIKEN, Saitama, Japan.

A human infant initially shows non-selective sociality, and gradually develops selective attachment toward its caregiver, manifested as "separation anxiety." It was unclear whether such sophistication of attachment system occurs in non-human mammals. To seek a mouse model of separation anxiety, we utilized a primitive attachment behavior, the Transport Response, in that both human and mouse newborns immediately stop crying and stay immobile to cooperate with maternal carrying. We examined the mouse Transport Response in three social contexts: 30-min isolation in a novel environment, 30-min maternal absence experienced with littermates in the home cage, and the control home-cage condition with the mother and littermates. The pups after postnatal day (PND) 13 attenuated their Transport Response not only in complete isolation but also by maternal absence, and activated several brain areas including the periventricular nucleus of the hypothalamus, suggesting that 30-min maternal absence was perceived as a social stress by mouse pups after PND13. This attenuation of Transport Response by maternal absence was independent with plasma corticosterone, but was diminished by prior administration of a corticotropin-releasing factor receptor 1 (CRFR1) antagonist. Among 18 brain areas examined, only neurons in the anterior cingulate cortex (ACC) co-express mRNA and CRFR1 after maternal absence. Consistently, excitotoxic ACC lesions inhibited the maternal absence-induced attenuation of Transport Response. These data indicate that the expression of mouse Transport Response is influenced not only by social isolation but also by maternal absence even in their home cage with littermates after PND13, at least partly via CRF-CRFR1 signaling in the ACC.
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http://dx.doi.org/10.3389/fncel.2018.00204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053499PMC
July 2018

Mechanisms of sleep deprivation-induced hepatic steatosis and insulin resistance in mice.

Am J Physiol Endocrinol Metab 2018 11 10;315(5):E848-E858. Epub 2018 Jul 10.

Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine , Tokyo , Japan.

Sleep deprivation is associated with increased risk for type 2 diabetes mellitus. However, the underlying mechanisms of sleep deprivation-induced glucose intolerance remain elusive. The aim of this study was to investigate the mechanisms of sleep deprivation-induced glucose intolerance in mice with a special focus on the liver. We established a mouse model of sleep deprivation-induced glucose intolerance using C57BL/6J male mice. A single 6-h sleep deprivation by the gentle handling method under fasting condition induced glucose intolerance. Hepatic glucose production assessed by a pyruvate challenge test was significantly increased, as was hepatic triglyceride content (by 67.9%) in the sleep deprivation group, compared with freely sleeping control mice. Metabolome and microarray analyses were used to evaluate hepatic metabolites and gene expression levels and to determine the molecular mechanisms of sleep deprivation-induced hepatic steatosis. Hepatic metabolites, such as acetyl coenzyme A, 3β-hydroxybutyric acid, and certain acylcarnitines, were significantly increased in the sleep deprivation group, suggesting increased lipid oxidation in the liver. In contrast, fasted sleep-deprived mice showed that hepatic gene expression levels of elongation of very long chain fatty acids-like 3, lipin 1, perilipin 4, perilipin 5, and acyl-CoA thioesterase 1, which are known to play lipogenic roles, were 2.7, 4.5, 3.7, 2.9, and 2.8 times, respectively, those of the fasted sleeping control group, as assessed by quantitative RT-PCR. Sleep deprivation-induced hepatic steatosis and hepatic insulin resistance seem to be mediated through upregulation of hepatic lipogenic enzymes.
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http://dx.doi.org/10.1152/ajpendo.00072.2018DOI Listing
November 2018

Forebrain Ptf1a Is Required for Sexual Differentiation of the Brain.

Cell Rep 2018 07;24(1):79-94

Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Kodaira, Tokyo 187-8502, Japan. Electronic address:

The mammalian brain undergoes sexual differentiation by gonadal hormones during the perinatal critical period. However, the machinery at earlier stages has not been well studied. We found that Ptf1a is expressed in certain neuroepithelial cells and immature neurons around the third ventricle that give rise to various neurons in several hypothalamic nuclei. We show that conditional Ptf1a-deficient mice (Ptf1a cKO) exhibit abnormalities in sex-biased behaviors and reproductive organs in both sexes. Gonadal hormone administration to gonadectomized animals revealed that the abnormal behavior is caused by disorganized sexual development of the knockout brain. Accordingly, expression of sex-biased genes was severely altered in the cKO hypothalamus. In particular, Kiss1, important for sexual differentiation of the brain, was drastically reduced in the cKO hypothalamus, which may contribute to the observed phenotypes in the Ptf1a cKO. These findings suggest that forebrain Ptf1a is one of the earliest regulators for sexual differentiation of the brain.
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http://dx.doi.org/10.1016/j.celrep.2018.06.010DOI Listing
July 2018

Quantitative phosphoproteomic analysis of the molecular substrates of sleep need.

Nature 2018 06 13;558(7710):435-439. Epub 2018 Jun 13.

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

Sleep and wake have global effects on brain physiology, from molecular changes and neuronal activities to synaptic plasticity. Sleep-wake homeostasis is maintained by the generation of a sleep need that accumulates during waking and dissipates during sleep. Here we investigate the molecular basis of sleep need using quantitative phosphoproteomic analysis of the sleep-deprived and Sleepy mouse models of increased sleep need. Sleep deprivation induces cumulative phosphorylation of the brain proteome, which dissipates during sleep. Sleepy mice, owing to a gain-of-function mutation in the Sik3 gene , have a constitutively high sleep need despite increased sleep amount. The brain proteome of these mice exhibits hyperphosphorylation, similar to that seen in the brain of sleep-deprived mice. Comparison of the two models identifies 80 mostly synaptic sleep-need-index phosphoproteins (SNIPPs), in which phosphorylation states closely parallel changes of sleep need. SLEEPY, the mutant SIK3 protein, preferentially associates with and phosphorylates SNIPPs. Inhibition of SIK3 activity reduces phosphorylation of SNIPPs and slow wave activity during non-rapid-eye-movement sleep, the best known measurable index of sleep need, in both Sleepy mice and sleep-deprived wild-type mice. Our results suggest that phosphorylation of SNIPPs accumulates and dissipates in relation to sleep need, and therefore SNIPP phosphorylation is a molecular signature of sleep need. Whereas waking encodes memories by potentiating synapses, sleep consolidates memories and restores synaptic homeostasis by globally downscaling excitatory synapses. Thus, the phosphorylation-dephosphorylation cycle of SNIPPs may represent a major regulatory mechanism that underlies both synaptic homeostasis and sleep-wake homeostasis.
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http://dx.doi.org/10.1038/s41586-018-0218-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350790PMC
June 2018

Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors.

Nat Commun 2018 05 23;9(1):2041. Epub 2018 May 23.

Functional Neuroscience Lab, Kansai Medical University, Hirakata, Osaka, 573-1010, Japan.

Innate behaviors are genetically encoded, but their underlying molecular mechanisms remain largely unknown. Predator odor 2,4,5-trimethyl-3-thiazoline (TMT) and its potent analog 2-methyl-2-thiazoline (2MT) are believed to activate specific odorant receptors to elicit innate fear/defensive behaviors in naive mice. Here, we conduct a large-scale recessive genetics screen of ethylnitrosourea (ENU)-mutagenized mice. We find that loss of Trpa1, a pungency/irritancy receptor, diminishes TMT/2MT and snake skin-evoked innate fear/defensive responses. Accordingly, Trpa1 mice fail to effectively activate known fear/stress brain centers upon 2MT exposure, despite their apparent ability to smell and learn to fear 2MT. Moreover, Trpa1 acts as a chemosensor for 2MT/TMT and Trpa1-expressing trigeminal ganglion neurons contribute critically to 2MT-evoked freezing. Our results indicate that Trpa1-mediated nociception plays a crucial role in predator odor-evoked innate fear/defensive behaviors. The work establishes the first forward genetics screen to uncover the molecular mechanism of innate fear, a basic emotion and evolutionarily conserved survival mechanism.
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http://dx.doi.org/10.1038/s41467-018-04324-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966455PMC
May 2018

Immunolocalization of muscarinic M1 receptor in the rat medial prefrontal cortex.

J Comp Neurol 2018 06 28;526(8):1329-1350. Epub 2018 Feb 28.

Department of Anatomy, Faculty of Medicine, Toho University, Tokyo, 143-8540, Japan.

The medial prefrontal cortex (mPFC) has been considered to participate in many higher cognitive functions, such as memory formation and spatial navigation. These cognitive functions are modulated by cholinergic afferents via muscarinic acetylcholine receptors. Previous pharmacological studies have strongly suggested that the M1 receptor (M1R) is the most important subtype among muscarinic receptors to perform these cognitive functions. Actually, M1R is abundant in mPFC. However, the proportion of somata containing M1R among cortical cellular types, and the precise intracellular localization of M1R remain unclear. In this study, to clarify the precise immunolocalization of M1R in rat mPFC, we examined three major cellular types, pyramidal neurons, inhibitory neurons, and astrocytes. M1R immunopositivity signals were found in the majority of the somata of both pyramidal neurons and inhibitory neurons. In pyramidal neurons, strong M1R immunopositivity signals were usually found throughout their somata and dendrites including spines. On the other hand, the signal strength of M1R immunopositivity in the somata of inhibitory neurons significantly varied. Some neurons showed strong signals. Whereas about 40% of GAD67-immunopositive neurons and 30% of parvalbumin-immunopositive neurons (PV neurons) showed only weak signals. In PV neurons, M1R immunopositivity signals were preferentially distributed in somata. Furthermore, we found that many astrocytes showed substantial M1R immunopositivity signals. These signals were also mainly distributed in their somata. Thus, the distribution pattern of M1R markedly differs between cellular types. This difference might underlie the cholinergic modulation of higher cognitive functions subserved by mPFC.
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http://dx.doi.org/10.1002/cne.24409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900831PMC
June 2018

Sleep/Wake Behaviors in Mice During Pregnancy and Pregnancy-Associated Hypertensive Mice.

Sleep 2018 03;41(3)

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

Study Objectives: In humans and other mammals, sleep is altered during pregnancy. However, no studies have been conducted on sleep/wakefulness during pregnancy in mice. In this study, we examined sleep/wakefulness in female C57BL/6 mice during pregnancy. We also examined sleep/wake behaviors in an animal model of preeclampsia, pregnancy-associated hypertensive (PAH) mice, in which increased angiotensin causes hypertension.

Methods: Sleep/wake behaviors of female C57BL/6 and PAH mice were examined based on electroencephalogram (EEG) or electromyogram recordings before, during, and after pregnancy. To examine whether high blood pressure disrupts the integrity of the blood-brain barrier in PAH mice, Evans blue dye was injected intravenously. Angiotensin II receptor blocker (olmesartan)-administered PAH mice and female Tsukuba hypertensive mice were also examined.

Results: C57BL/6 mice showed a decreased total wake time and increased nonrapid eye movement (NREM) sleep time during late pregnancy. Rapid eye movement (REM) sleep time did not change during the course of pregnancy. PAH mice exhibited a general slowing of EEG during late pregnancy and subsequently returned to apparently normal sleep/wakefulness after delivery. All PAH mice exhibited multiple focal leakages of Evans blue dye in the brain. Spike-and-wave discharges were observed in 50% of PAH mice. Olmesartan-administered PAH mice did not show general slowing of EEG. Tsukuba hypertensive mice showed a normal time spent in wakefulness and NREM sleep and a decreased total REM sleep time.

Conclusions: This study showed pregnant-stage-specific changes in sleep/wakefulness in C57BL/6 mice. Furthermore, PAH mice may be useful as an animal model for eclampsia.
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http://dx.doi.org/10.1093/sleep/zsx209DOI Listing
March 2018

Neurotransmitters and neuropeptides in gonadal steroid receptor-expressing cells in medial preoptic area subregions of the male mouse.

Sci Rep 2017 08 29;7(1):9809. Epub 2017 Aug 29.

Department of Anatomy, Faculty of Medicine, Toho University, Tokyo, 143-8540, Japan.

Testosterone is involved in male sexual, parental and aggressive behaviors through the androgen receptor (AR) and estrogen receptor (ER) α expressed in the brain. Although several studies have demonstrated that ERα and AR in the medial preoptic area (MPOA) are required for exhibiting sexual and aggressive behaviors of male mice, the molecular characteristics of ERα- and AR-expressing cells in the mouse MPOA are largely unknown. Here, we performed in situ hybridization for neurotransmitters and neuropeptides, combined with immunohistochemistry for ERα and AR to quantitate and characterize gonadal steroid receptor-expressing cells in the MPOA subregions of male mice. Prodynorphin, preproenkephalin (Penk), cocaine- and amphetamine-related transcript, neurotensin, galanin, tachykinin (Tac)1, Tac2 and thyrotropin releasing hormone (Trh) have distinct expression patterns in the MPOA subregions. Gad67-expressing cells were the most dominant neuronal subtype among the ERα- and AR-expressing cells throughout the MPOA. The percentage of ERα- and AR-immunoreactivities varied depending on the neuronal subtype. A substantial proportion of the neurotensin-, galanin-, Tac2- and Penk-expressing cells in the MPOA were positive for ERα and AR, whereas the vast majority of the Trh-expressing cells were negative. These results suggest that testosterone exerts differential effects depending on both the neuronal subtypes and MPOA subregions.
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http://dx.doi.org/10.1038/s41598-017-10213-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575033PMC
August 2017

Moxd1 Is a Marker for Sexual Dimorphism in the Medial Preoptic Area, Bed Nucleus of the Stria Terminalis and Medial Amygdala.

Front Neuroanat 2017 27;11:26. Epub 2017 Mar 27.

Department of Anatomy, Faculty of Medicine, Toho UniversityTokyo, Japan; International Institutes for Integrative Sleep Medicine (WPI-IIIS), University of TsukubaIbaraki, Japan.

The brain shows various sex differences in its structures. Various mammalian species exhibit sex differences in the sexually dimorphic nucleus of the preoptic area (SDN-POA) and parts of the extended amygdala such as the principal nucleus of the bed nucleus of the stria terminalis (BNSTpr) and posterodorsal part of the medial amygdala (MePD). The SDN-POA and BNSTpr are male-biased sexually dimorphic nuclei, and characterized by the expression of calbindin D-28K (calbindin 1). However, calbindin-immunoreactive cells are not restricted to the SDN-POA, but widely distributed outside of the SDN-POA. To find genes that are more specific to sexually dimorphic nuclei, we selected candidate genes by searching the Allen brain atlas and examined the detailed expressions of the candidate genes using hybridization. We found that the strong expression of () was restricted to the SDN-POA, BNSTpr and MePD. The numbers of -positive cells in the SDN-POA, BNSTpr and MePD in male mice were larger than those in female mice. Most of the -positive cells in the SDN-POA and BNSTpr expressed calbindin. Neonatal castration of male mice reduced the number of -positive cells in the SDN-POA, whereas gonadectomy in adulthood did not change the expression of the gene in the SDN-POA in both sexes. These results suggest that the gene is a suitable marker for sexual dimorphic nuclei in the POA, BNST and amygdala, which enables us to manipulate sexually dimorphic neurons to examine their roles in sex-biased physiology and behaviors.
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http://dx.doi.org/10.3389/fnana.2017.00026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366752PMC
March 2017

Forward-genetics analysis of sleep in randomly mutagenized mice.

Nature 2016 11 2;539(7629):378-383. Epub 2016 Nov 2.

Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.

Sleep is conserved from invertebrates to vertebrates, and is tightly regulated in a homeostatic manner. The molecular and cellular mechanisms that determine the amount of rapid eye movement sleep (REMS) and non-REMS (NREMS) remain unknown. Here we identify two dominant mutations that affect sleep and wakefulness by using an electroencephalogram/electromyogram-based screen of randomly mutagenized mice. A splicing mutation in the Sik3 protein kinase gene causes a profound decrease in total wake time, owing to an increase in inherent sleep need. Sleep deprivation affects phosphorylation of regulatory sites on the kinase, suggesting a role for SIK3 in the homeostatic regulation of sleep amount. Sik3 orthologues also regulate sleep in fruitflies and roundworms. A missense, gain-of-function mutation in the sodium leak channel NALCN reduces the total amount and episode duration of REMS, apparently by increasing the excitability of REMS-inhibiting neurons. Our results substantiate the use of a forward-genetics approach for studying sleep behaviours in mice, and demonstrate the role of SIK3 and NALCN in regulating the amount of NREMS and REMS, respectively.
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http://dx.doi.org/10.1038/nature20142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076225PMC
November 2016

Identification of mutations through dominant screening for obesity using C57BL/6 substrains.

Sci Rep 2016 09 2;6:32453. Epub 2016 Sep 2.

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

The discovery of leptin substantiated the usefulness of a forward genetic approach in elucidating the molecular network regulating energy metabolism. However, no successful dominant screening for obesity has been reported, which may be due to the influence of quantitative trait loci between the screening and counter strains and the low fertility of obese mice. Here, we performed a dominant screening for obesity using C57BL/6 substrains, C57BL/6J and C57BL/6N, with the routine use of in vitro fertilization. The screening of more than 5000 mutagenized mice established two obese pedigrees in which single nucleotide substitutions in Mc4r and Sim1 genes were identified through whole-exome sequencing. The mutation in the Mc4r gene produces a premature stop codon, and the mutant SIM1 protein lacks transcriptional activity, showing that the haploinsufficiency of SIM1 and MC4R results in obesity. We further examined the hypothalamic neuropeptide expressions in the mutant pedigrees and mice with diet-induced obesity, which showed that each obesity mouse model has distinct neuropeptide expression profiles. This forward genetic screening scheme is useful and applicable to any research field in which mouse models work.
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http://dx.doi.org/10.1038/srep32453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009433PMC
September 2016

High-fat diet feeding alters olfactory-, social-, and reward-related behaviors of mice independent of obesity.

Obesity (Silver Spring) 2016 Apr 18;24(4):886-94. Epub 2016 Feb 18.

Department of Anatomy, Toho University School of Medicine, Ota-Ku, Tokyo, Japan.

Objective: High-fat diet (HFD) consumption causes obesity, which is associated with well-known increased health risks. Moreover, obesity has been associated with altered sensorimotor and emotional behaviors of humans and mice. This study attempted to dissociate the influence of HFD-induced obesity on behaviors from the influence of HFD consumption itself.

Methods: C57BL male mice were randomly allocated to a low-fat diet (LFD) group, an HFD-induced obesity (DIO) group, or a pair-fed HFD-feeding nonobese (HFD) group. A comprehensive behavioral test battery was performed on all three groups to assess sensorimotor functions, anxiety- and depression-like behaviors, reward-related behaviors, social behaviors, and learning/memory functions.

Results: Both the DIO and HFD groups exhibited disturbed olfaction, blunted ethanol preference, and enhanced social interactions. The DIO group exhibited blunted sucrose preference, shorter latency before falling off during the rotarod test, and a lower response to mechanical stimuli.

Conclusions: The HFD-fed nonobese mice showed altered behaviors related to olfaction, social interactions, and rewards that were similar to those of the DIO mice. This finding suggests that HFD consumption alters a variety of behaviors independent of obesity.
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http://dx.doi.org/10.1002/oby.21441DOI Listing
April 2016

Sleep as a biological problem: an overview of frontiers in sleep research.

J Physiol Sci 2016 Jan 5;66(1):1-13. Epub 2015 Nov 5.

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

Sleep is a physiological process not only for the rest of the body but also for several brain functions such as mood, memory, and consciousness. Nevertheless, the nature and functions of sleep remain largely unknown due to its extremely complicated nature and lack of optimized technology for the experiments. Here we review the recent progress in the biology of the mammalian sleep, which covers a wide range of research areas: the basic knowledge about sleep, the physiology of cerebral cortex in sleeping animals, the detailed morphological features of thalamocortical networks, the mechanisms underlying fluctuating activity of autonomic nervous systems during rapid eye movement sleep, the cutting-edge technology of tissue clearing for visualization of the whole brain, the ketogenesis-mediated homeostatic regulation of sleep, and the forward genetic approach for identification of novel genes involved in sleep. We hope this multifaceted review will be helpful for researchers who are interested in the biology of sleep.
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http://dx.doi.org/10.1007/s12576-015-0414-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742504PMC
January 2016