Role of SIK family in the regulation of sleep/wakefulness

• Project/Area Number: 17H04023
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Environmental physiology(including physical medicine and nutritional physiology)
• Research Institution: University of Tsukuba
• Principal Investigator: Funato Hiromasa 筑波大学, 国際統合睡眠医科学研究機構, 客員教授 (90363118)
• Co-Investigator(Kenkyū-buntansha): 三好 千香 筑波大学, 国際統合睡眠医科学研究機構, 助教 (60613437)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2019: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2018: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2017: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
• Keywords: 睡眠覚醒 / キナーゼ / 細胞内シグナル / 遺伝子改変マウス / リン酸化酵素 / CRISPR / ゲノム編集

Outline of Final Research Achievements

We investigated the role of SIK1(S577) and SIK2(S587), PKA-phosphorylated serines of SIK1 and SIK2, in sleep regulation. Sik1(S577A) mice had shorter wake time, longer NREMS time, and higher NREMS delta density than wild-type mice. Sik2( S587A) mice showed increased NREMS delta power. Sik1(S577A) mice showed normal circadian behavior. Sik2(S587A) mice showed weight gain comparable to wild-type mice, although Sik2 is expressed predominantly in brown adipose tissue. These results indicate that PKA-SIK signaling is involved in the regulation of the need for sleep.

Academic Significance and Societal Importance of the Research Achievements

睡眠制御がSIKファミリーに共通した役割であることは、SIKファミリーに共通した上流及び下流シグナルが睡眠必要量の決定を担うことを示している。SIK1は概日リズム行動に、SIK2は褐色脂肪組織を場とするエネルギー代謝に関与するという報告があるもの、今回の検討では変化が見られなかった。SIKファミリーのキナーゼ活性はLKB1が制御していることから、PKAによる制御は特定の機能や行動に限定されると考えられる。
睡眠制御機構の理解が深まれば睡眠障害、気分障害等の疾患の介入方法開発を可能にする。

Research Products

• [Journal Article] Forward genetic approach for behavioral neuroscience using animal models (2020)
  • Author(s): Hiromasa Funato
  • Journal Title: Proceedings of the Japan Academy, Series B Volume: 96 Issue: 1 Pages: 10-31
  • DOI: 10.2183/pjab.96.002
  • NAID: 130007783761
  • ISSN: 0386-2208, 1349-2896
  • Year and Date: 2020-01-10
  • Peer Reviewed / Open Access
• [Journal Article] Effect of using smartphone during breast-feeding (2019)
  • Author(s): Nakagawa Haruka、Yoshida Sachine、Ohnishi Ayumi、Terada Tsutomu、Funato Hiromasa、Tsukamoto Masahiko
  • Journal Title: UbiComp/ISWC '19 Adjunct: Adjunct Proc 2019 ACM Int Joint Conf Pervasive and Ubiquit Comput and Proc 2019 ACM Int Symp Wearable Comput Volume: - Pages: 1190-1193
  • DOI: 10.1145/3341162.3344840
  • Peer Reviewed / Open Access
• [Journal Article] MC-SleepNet: Large-scale Sleep Stage Scoring in Mice by Deep Neural Networks. (2019)
  • Author(s): Yamabe M, Horie K, Shiokawa H, Funato H, Yanagisawa M, Kitagawa H.
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 15793-15793
  • DOI: 10.1038/s41598-019-51269-8
  • NAID: 120007127675
  • Peer Reviewed / Open Access
• [Journal Article] Differential Roles of Each Orexin Receptor Signaling in Obesity (2019)
  • Author(s): Kakizaki Miyo、Tsuneoka Yousuke、Takase Kenkichi、Kim Staci J.、Choi Jinhwan、Ikkyu Aya、Abe Manabu、Sakimura Kenji、Yanagisawa Masashi、Funato Hiromasa
  • Journal Title: iScience Volume: 20 Pages: 1-13
  • DOI: 10.1016/j.isci.2019.09.003
  • NAID: 120007132695
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A new mouse model of GLUT1 deficiency syndrome exhibits abnormal sleep-wake patterns and alterations of glucose kinetics in the brain. (2019)
  • Author(s): Furuse T, Mizuma H, Hirose Y, Kushida T, Yamada I, Miura I, Masuya H, Funato H, Yanagisawa M, Onoe H, Wakana S.
  • Journal Title: Dis Model Mech. Volume: 12 Issue: 9 Pages: 38828-38828
  • DOI: 10.1242/dmm.038828
  • NAID: 120007161317
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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: Proceedings of the National Academy of Sciences Volume: 116 Issue: 32 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): Honda Takato、Fujiyama Tomoyuki、Miyoshi Chika、Ikkyu Aya、Hotta-Hirashima Noriko、Kanno Satomi、Mizuno Seiya、Sugiyama Fumihiro、Takahashi Satoru、Funato Hiromasa、Yanagisawa Masashi
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 115 Issue: 41 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: 535-535
  • DOI: 10.3389/fnins.2018.00535
  • NAID: 120007133025
  • Peer Reviewed / Open Access
• [Journal Article] Mechanisms of sleep deprivation-induced hepatic steatosis and insulin resistance in mice (2018)
  • Author(s): Shigiyama F, Kumashiro N, Tsuneoka Y, Igarashi H, Yoshikawa F, Kakehi S, Funato H, Hirose T
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 315 Issue: 5 Pages: E848-E858
  • DOI: 10.1152/ajpendo.00072.2018
  • Peer Reviewed / Open Access
• [Journal Article] Corticotropin-Releasing Factor Receptor 1 in the Anterior Cingulate Cortex Mediates Maternal Absence-Induced Attenuation of Transport Response in Mouse Pups (2018)
  • Author(s): Yoshida Sachine、Ohnishi Ryuko、Tsuneoka Yousuke、Yamamoto-Mimura Yuka、Muramatsu Reiko、Kato Tadafumi、Funato Hiromasa、Kuroda Kumi O.
  • Journal Title: Frontiers in Cellular Neuroscience Volume: 12 Pages: 1-14
  • DOI: 10.3389/fncel.2018.00204
  • Peer Reviewed / Open Access
• [Journal Article] Forebrain Ptf1a Is Required for Sexual Differentiation of the Brain (2018)
  • Author(s): Fujiyama Tomoyuki、Miyashita Satoshi、Tsuneoka Yousuke、Kanemaru Kazumasa、Kakizaki Miyo、Kanno Satomi、Ishikawa Yukiko、Yamashita Mariko、Owa Tomoo、Nagaoka Mai、Kawaguchi Yoshiya、Yanagawa Yuchio、Magnuson Mark A.、Muratani Masafumi、Shibuya Akira、Nabeshima Yo-ichi、Yanagisawa Masashi、Funato Hiromasa、Hoshino Mikio
  • Journal Title: Cell Reports Volume: 24 Issue: 1 Pages: 79-94
  • DOI: 10.1016/j.celrep.2018.06.010
  • NAID: 120006491717
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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 Issue: 7710 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: Nature Communications Volume: 9 Issue: 1 Pages: 2041-2041
  • DOI: 10.1038/s41467-018-04324-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immunolocalization of muscarinic M1 receptor in the rat medial prefrontal cortex (2018)
  • Author(s): Oda Satoko、Tsuneoka Yousuke、Yoshida Sachine、Adachi-Akahane Satomi、Ito Masanori、Kuroda Masaru、Funato Hiromasa
  • Journal Title: Journal of Comparative Neurology Volume: 526 Issue: 8 Pages: 1329-1350
  • DOI: 10.1002/cne.24409
  • Peer Reviewed / Open Access
• [Journal Article] Sleep/Wake Behaviors in Mice During Pregnancy and Pregnancy-Associated Hypertensive Mice (2017)
  • Author(s): Komiya Haruna、Miyoshi Chika、Iwasaki Kanako、Hotta-Hirashima Noriko、Ikkyu Aya、Kanno Satomi、Honda Takato、Gosho Masahiko、Hamada Hiromi、Satoh Toyomi、Fukamizu Akiyoshi、Funato Hiromasa、Yanagisawa Masashi
  • Journal Title: Sleep Volume: 41 Issue: 3 Pages: 1-1
  • DOI: 10.1093/sleep/zsx209
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neurotransmitters and neuropeptides in gonadal steroid receptor-expressing cells in medial preoptic area subregions of the male mouse (2017)
  • Author(s): Yousuke Tsuneoka, Sachine Yoshida, Kenkichi Takase, Satoko Oda, Masaru Kuroda, Hiromasa Funato
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 1-16
  • DOI: 10.1038/s41598-017-10213-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Moxd1 Is a Marker for Sexual Dimorphism in the Medial Preoptic Area, Bed Nucleus of the Stria Terminalis and Medial Amygdala (2017)
  • Author(s): Tsuneoka Y and Funato H et al.
  • Journal Title: Front Neuroanat Volume: 11 Pages: 26-26
  • DOI: 10.3389/fnana.2017.00026
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] SIK family regulates sleep/wakefulness in mice (2020)
  • Author(s): Hiromasa Funato
  • Organizer: 第９３回日本薬理学会年会
  • Invited
• [Presentation] 睡眠覚醒の謎に挑む (2019)
  • Author(s): 船戸弘正
  • Organizer: 第８回日本食品分析センター技術成果発表会
  • Invited
• [Presentation] SIKファミリーによる睡眠覚醒とエネルギー代謝制御 (2019)
  • Author(s): 船戸弘正
  • Organizer: 第９２回日本生化学学会大会
  • Invited
• [Presentation] Forward genetics in mice identified novel sleep-regulating genes (2019)
  • Author(s): Hiromasa Funato
  • Organizer: V World Congress of Chronobiology
  • Int'l Joint Research / Invited
• [Presentation] Sleep and energy metabolism regulation though mouse genetics (2019)
  • Author(s): Hiromasa Funato
  • Organizer: CIBR Beijing Conference on Brain & Behavior
  • Int'l Joint Research / Invited
• [Presentation] Altered sleep/wakefulness behavior and phosphoproteomics in Sik3 mutant mice (2018)
  • Author(s): Hiromasa Funato
  • Organizer: 第４１回日本分子生物学会年会 シンポジウム "個体行動制御の細胞内シグナル" \
  • Invited
• [Presentation] Forward genetic research on sleep using mice (2018)
  • Author(s): Hiromasa Funato
  • Organizer: 第４１回日本神経科学大会 シンポジウム "サーカディアンリズムと睡眠を制御する神経機構"
  • Invited
• [Presentation] マウスを用いたフォワード・ジェネティクス研究による新規睡眠制御分子同定 (2018)
  • Author(s): 船戸弘正
  • Organizer: 第91回日本内分泌学会学術総会
  • Invited
• [Presentation] 視索前野の性差とその発生 (2018)
  • Author(s): 船戸弘正
  • Organizer: 第123回日本解剖学会総会・全国学術集会
  • Invited
• [Presentation] Forward genetic analysis of sleep in mice (2018)
  • Author(s): Hiromasa Funato
  • Organizer: Gordon Research Conference "Sleep Regulation and Function"
  • Int'l Joint Research
• [Presentation] Forward genetic analysis of sleep in mice (2018)
  • Author(s): Hiromasa Funato, Masashi Yanagisawa
  • Organizer: Keystone symposia "State of the Brain"
  • Int'l Joint Research
• [Presentation] マウスを用いた睡眠のフォワード・ジェネティクス研究 (2017)
  • Author(s): 船戸弘正
  • Organizer: 第24回日本時間生物学会学術大会
  • Invited
• [Book] ブレインサイエンスレビュー2020 新規睡眠制御分子同定による睡眠覚醒機構の解明を目指して（269-288） (2020)
  • Author(s): 船戸弘正
  • Total Pages: 344
  • Publisher: クバプロ
  • ISBN: 9784878051609
• [Remarks] 国際統合睡眠医科学研究機構柳沢・船戸研究室
  • URL: http://sleepymouse.jp/
• [Remarks] 東邦大学医学部解剖学講座
  • URL: http://toho-funatolab.jp/
• [Remarks] 筑波大学IIIS Y-F lab
  • URL: http://sleepymouse.jp/
• [Remarks] http://sleepymouse.jp/
• [Remarks] http://toho-funatolab.jp/