Integrated Molecular Mechanisms of Sleep/Wakefulness and Metabolic Regulation in a Novel Hypersomnia and Obese Mouse Model

• Project/Area Number: 18K06024
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 42040:Laboratory animal science-related
• Research Institution: University of Tsukuba
• Principal Investigator: Miyoshi Chika 筑波大学, 国際統合睡眠医科学研究機構, 助教 (60613437)
• Co-Investigator(Kenkyū-buntansha): 船戸 弘正 筑波大学, 国際統合睡眠医科学研究機構, 客員教授 (90363118)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: 過眠 / 肥満 / 睡眠

Outline of Final Research Achievements

In sleepy mutant SIK3 mice, obesity is observed from young age with hypersomnia. In this study, to elucidate the mechanisms underlying the appearance and regulation of hypersomnia and obesity, we investigated the molecular network involved in their regulation by cell type-specific sleepy expression in a spatiotemporal manner.
In brain neuron-specific and peripheral tissue-specific cre mice, the hypersomnia phenotype of systemic type of sleepy mice was reproduced only by the expression of a type of cranial neuron-specific sleepy, while peripheral expression did not alter sleep duration or EEG spectrum components. The obesity phenotype was also not a peripheral function, suggesting that the hypersomnolence and obesity phenotypes in Sleepy mice are neuronal control of the brain.

Academic Significance and Societal Importance of the Research Achievements

睡眠は心身の健康を保ち、質の高い社会生活を送ることに不可欠である。不眠等の睡眠障害は、わが国でも広く認められており、うつ病などの気分障害、メタボリック症候群との関連も深い。睡眠覚醒行動の異常と摂食行動の障害とは密接に関係すると考えられるが、その分子機構は明らかではない。よいモデル動物が得られれば、睡眠覚醒行動や摂食行動など、異なる行動モダリティーを制御する統合的な研究が可能になると考えられた。

Research Products

• [Journal Article] Metabolomic and pharmacologic analyses of brain substances associated with sleep pressure in mice (2022)
  • Author(s): Suzuki-Abe Haruka、Sonomura Kazuhiro、Nakata Shinya、Miyanishi Kazuya、Mahmoud Asmaa、Hotta-Hirashima Noriko、Miyoshi Chika、Sato Taka-Aki、Funato Hiromasa、Yanagisawa Masashi
  • Journal Title: Neuroscience Research Volume: 177 Pages: 16-24
  • DOI: 10.1016/j.neures.2021.11.008
  • Peer Reviewed / Open Access
• [Journal Article] Induction of Mutant Sik3Sleepy Allele in Neurons in Late Infancy Increases Sleep Need (2021)
  • Author(s): Iwasaki Kanako, Fujiyama Tomoyuki, Nakata Shinya, Park Minjeong, Miyoshi Chika, Hotta-Hirashima Noriko, Ikkyu Aya, Kakizaki Miyo, Sugiyama Fumihiro, Mizuno Seiya, Abe Manabu, Sakimura Kenji, Takahashi Satoru, Funato Hiromasa, Yanagisawa Masashi
  • Journal Title: The Journal of Neuroscience Volume: 41 Pages: 2733-2746
  • DOI: 10.1523/jneurosci.1004-20.2020
  • Peer Reviewed / Open Access
• [Journal Article] The Role of Reproductive Hormones in Sex Differences in Sleep Homeostasis and Arousal Response in Mice (2021)
  • Author(s): Choi Jinhwan、Kim Staci J.、Fujiyama Tomoyuki、Miyoshi Chika、Park Minjeong、Suzuki-Abe Haruka、Yanagisawa Masashi、Funato Hiromasa
  • Journal Title: Frontiers in Neuroscience Volume: 15 Pages: 1-14
  • DOI: 10.3389/fnins.2021.739236
  • Peer Reviewed / Open Access
• [Journal Article] Two novel mouse models mimicking minor deletions in 22q11.2 deletion syndrome revealed the contribution of each deleted region to psychiatric disorders (2021)
  • Author(s): Saito Ryo、Miyoshi Chika、Koebis Michinori、Kushima Itaru、Nakao Kazuki、Mori Daisuke、Ozaki Norio、Funato Hiromasa、Yanagisawa Masashi、Aiba Atsu
  • Journal Title: Mlecular Brain Volume: 14 Pages: 1-15
  • DOI: 10.1186/s13041-021-00778-7
  • Peer Reviewed / Open Access
• [Journal Article] Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16 high Cells In Vivo (2020)
  • Author(s): 3, Omori S, Wang TW, Johmura Y, Makoto Nakanishi, et al
  • Journal Title: Cell Metabolism Volume: 32 Pages: 814-828
  • DOI: 10.1016/j.cmet.2020.09.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss of the conserved PKA sites of SIK1 and SIK2 increases sleep need (2020)
  • Author(s): Minjeong Park, Chika Miyoshi, Tomoyuki Fujiyama, Miyo Kakizaki, Aya Ikkyu, Takato Honda, Jinhwan Choi, Fuyuki Asano, Seiya Mizuno, Satoru Takahashi, Masashi Yanagisawa, Hiromasa Funato
  • Journal Title: Scientific Reports Volume: 10 Pages: 8676-8676
  • DOI: 10.1038/s41598-020-65647-0
  • NAID: 120007163335
  • Peer Reviewed / Open Access
• [Journal Article] Gut microbiota depletion by chronic antibiotic treatment alters the sleep/wake architecture and sleep EEG power spectra in mice (2020)
  • Author(s): Yukino Ogawa, Chika Miyoshi, Nozomu Obana, Kaho Yajima, Noriko Hotta-Hirashima, Aya Ikkyu, Satomi Kanno, Tomoyoshi Soga, Shinji Fukuda & Masashi Yanagisawa
  • Journal Title: Scientific Reports Volume: 10 Pages: 19554-19554
  • DOI: 10.1038/s41598-020-76562-9
  • Peer Reviewed / Open Access
• [Journal Article] Methodology and theoretical basis of forward genetic screening for sleep/wakefulness in mice. (2019)
  • Author(s): Miyoshi C, Kim SJ, Ezaki T, Ikkyu A, Hotta-Hirashima N, Kanno S, Kakizaki M, Yamada M, Wakana S, Yanagisawa M, Funato H
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 116 Pages: 16062-16067
  • DOI: 10.1073/pnas.1906774116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A single phosphorylation site of SIK3 regulates daily sleep amounts and sleep need in mice (2018)
  • Author(s): Takato Honda, Tomoyuki Fujiyama, Chika Miyoshi, Aya Ikkyu, Noriko Hotta-Hirashima, Satomi Kanno, Seiya Mizuno, Fumihiro Sugiyama, Satoru Takahashi, Hiromasa Funato and Masashi Yanagisawa
  • Journal Title: Proceedings of the National Academy of Sciences of the United States of America (PNAS) Volume: 115 Pages: 10458-10463
  • DOI: 10.1073/pnas.1810823115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ablation of Central Serotonergic Neurons Decreased REM Sleep and Attenuated Arousal Response (2018)
  • Author(s): Iwasaki Kanako、Komiya Haruna、Kakizaki Miyo、Miyoshi Chika、Abe Manabu、Sakimura Kenji、Funato Hiromasa、Yanagisawa Masashi
  • Journal Title: Frontiers in Neuroscience Volume: 12 Pages: 1-13
  • DOI: 10.3389/fnins.2018.00535
  • NAID: 120007133025
  • Peer Reviewed / Open Access
• [Journal Article] Quantitative phosphoproteomic analysis of the molecular substrates of sleep need (2018)
  • Author(s): Z. Wang, J. Ma, C. Miyoshi, Y. Li, M Sato, Y. Ogawa, T. Lou, C. Ma, X. Gao, C. Lee, T. Fujiyama, X. Yang, S. Zhou, N. Hotta-Hirashima, D. Klewe-Nebenus, A. Ikkyu, M. Kakizaki, S. Kanno, L. Cao, S. Takahashi, J. Peng, Y. Yu, H. Funato, M. Yanagisawa, Q. Liu
  • Journal Title: Nature Volume: 558 Pages: 435-439
  • DOI: 10.1038/s41586-018-0218-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors (2018)
  • Author(s): Wang, Y., Cao, L., Lee, C-Y., Matsuo, M., Wu, K., Asher, G., Saitoh, T., Klewe-Nebenius, D., Wang, L., Soya, S., Hasegawa, E., Cherasse, Y., Miyoshi,C., Irukayama, Y., Wang, Z., Sakurai, K., Funato, H., Sakurai, T., Yanagisawa, M., Nagase, H., Kobayakawa, R., Kobayakawa, K., Beutler, B., Liu, Q
  • Journal Title: Nat Comm Volume: 9 Pages: 1-15
  • DOI: 10.1038/s41467-018-04324-3
  • NAID: 120007134033
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] フォワードジェネティクスの手法を用いた睡眠スクリーニングによる過眠・肥満マウスモデル 家系の確立 (2022)
  • Author(s): Chika Miyoshi, Noriko Hotta-Hirashim, Aya Ikkyu, Miyo Kakizaki, Satomi Kanno, Masashi Yanagisawa and Hiromasa Funato
  • Organizer: 第99回日本生理学会大会
  • Int'l Joint Research
• [Presentation] Establishment of a Model Mouse Pedigree with Hypersomnia, Sleepy, by Large-Scale Forward Genetic Screening (2019)
  • Author(s): Miyoshi C, Hotta-Hirashima N, Ikkyu A,Kanno S, Kakizaki M,Yamada M, Kim SJ, Ezaki T,Wakana S, Funato H,Yanagisawa M
  • Organizer: 8th Japan-Sino-Korea Mouse Resource Workshop
  • Int'l Joint Research
• [Presentation] Establishment of Screening Method for Sleep/Wakefullness in Mice Through Forward Genetics. (2019)
  • Author(s): Miyoshi C, Hotta-Hirashima N, Kanno S, Ikkyu A,Kakizaki M,Yamada M,Kim SJ, Wakana S, Yanagisawa M, Funato H
  • Organizer: 97th Annual Meeting of the Physiological Society of Japan
• [Presentation] Effect of central serotonergic ablation on sleep/wake behavior in mice (2018)
  • Author(s): Kanako Iwasaki, Haruna Komiya, Miyo Kakizaki, Chika Miyoshi, Manabu Abe, Kenji Sakimura, Hiromasa Funato, and Masashi Yanagisawa
  • Organizer: The 41st Annual Meeting of Japan Neuroscience Society
• [Presentation] Identification of a novel gene family in sleep and wake regulation (2018)
  • Author(s): Staci J. Kim, Tomoyuki Fujiyama, Chika Miyoshi, Noriko Hotta-Hirashima, Satomi Kanno, Aya Ikkyu, Miyo Kakizaki, Seiya Mizuno, Satoru Takahashi, Hiromasa Funato, and Masashi Yanagisawa
  • Organizer: The 41st Annual Meeting of the Japan Neuroscience Society
• [Presentation] Forward genes study identifies novel gene in sleep/wake regulation (2018)
  • Author(s): Staci J. Kim, Tomoyuki Fujiyama, Chika Miyoshi, Noriko Hotta-Hirashima, Satomi Kanno, Aya Ikkyu, Miyo Kakizaki, Seiya Mizuno, Satoru Takahashi, Hiromasa Funato, and Masashi Yanagisawa
  • Organizer: 2018 Korean Society for Molecular and Cellular Biology
  • Int'l Joint Research
• [Presentation] Establishment of the neuron-type specific SIK3-deficient mice (2018)
  • Author(s): Fuyuki Asano, Tomoyuki Fujiyama, Chika Miyoshi, Miyo Kakizaki, Noriko Hotta-Hirashima, Aya Ikkyu, Satomi Kanno, Seiya Mizuno, Fumihiro Sugiyama, Satoru Takahashi, Hiromasa Funato, Masashi Yanagisawa
  • Organizer: Tsukuba Global Science Week(TGSW) 2018
• [Presentation] Sik1, Sik2, point mutation mice -Paralog analysis of Sik3 gene in Sleepy Mutant pedigree (2018)
  • Author(s): Minjeong Park, Chika Miyoshi, Tomoyuki Fujiyama, Miyo Kakizaki, Aya Ikkyu, Takato Honda, Jinhwan Choi,Seiya Mizuno, Kanako Kato, Yoko Taimoto, Hiromasa Funato, and Masashi Yanagisawa
  • Organizer: Tsukuba Global Science Week(TGSW) 2018
• [Presentation] Production of brain-specific SIK3-deficient mice (2018)
  • Author(s): Fuyuki Asano, Tomoyuki Fujiyama, Chika Miyoshi, Miyo Kakizaki, Noriko Hotta-Hirashima, Aya Ikkyu, Satomi Kanno, Seiya Mizuno, Fumihiro Sugiyama, Satoru Takahashi, Hiromasa Funato, Masashi Yanagisawa
  • Organizer: The 41st Annual Meeting of the Molecular Biology Society of Japan
• [Presentation] Sleep arousal behavior of SIK1 and SIK2 PKA phosphorylation site mutated mice (2018)
  • Author(s): Staci J. Kim, Tomoyuki Fujiyama, Chika Miyoshi, Noriko Hotta-Hirashima, Satomi Kanno, Aya Ikkyu, Miyo Kakizaki, Hiromasa Funato, and Masashi Yanagisawa&
  • Organizer: The 41st Annual Meeting of the Molecular Biology Society of Japan
• [Presentation] Title: Where does the Dreamless mutation take effect? (2018)
  • Author(s): Tomoyuki Fujiyama, Seiya Mizuno, Manabu Abe, Satomi Kanno, Miyo Kakizaki, Kanako Iwasaki, Aya Ikkyu, Noriko Hotta-Hirashima, Mana Yamada, Chika Miyoshi, Makito Sato, Takeshi Kanda, Kenji Sakimura, Satoru Takahashi, Hiromasa Funato, Masashi Yanagisawa
  • Organizer: The 7th IIIS Symposium
  • Int'l Joint Research
• [Presentation] Investigation of Sleep/Wake Regulatory Mechanisms by Analysis of the Sik3 Gene Identified Through Forward Genetics (2018)
  • Author(s): Takato Honda, Tomoyuki Fujiyama, Chika Miyoshi, Aya Ikkyu, Noriko Hotta, Satomi Kanno, Hiromasa Funato and Masashi Yanagisawa
  • Organizer: The 41st Annual Meeting of the Japan Neuroscience Society
• [Presentation] Investigation of Sleep/Wake Regulatory Mechanisms by Analysis of the Sik3 Gene Identified Through Forward Genetics (2018)
  • Author(s): Takato Honda, Tomoyuki Fujiyama, Chika Miyoshi, Aya Ikkyu, Noriko Hotta, Satomi Kanno, Hiromasa Funato and Masashi Yanagisawa
  • Organizer: The 43rd Japanese Society of Sleep Research jointly held with The 9th Asian Sleep Research Society Asian Forum on Chronobiology
  • Int'l Joint Research
• [Presentation] Ablation of central serotonergic neurons decreased REM sleep and attenuated arousal response (2018)
  • Author(s): Kanako Iwasaki, Haruna Komiya, Miyo Kakizaki, Chika Miyoshi, Manabu Abe, Kenji Sakimura, Hiromasa Funato, and Masashi Yanagisawa
  • Organizer: Tsukuba Global Science Week(TGSW) 2018