Roles of orexin-producing neurons in awakening from anesthesia : Analyses using various genetically-modified mice

• Project/Area Number: 19390402
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Anesthesiology/Resuscitation studies
• Research Institution: University of Tsukuba
• Principal Investigator: TAKAHASHI Hiroshi University of Tsukuba, 大学院・人間総合科学研究科, 准教授 (70236313)
• Co-Investigator(Kenkyū-buntansha): SAKURAI Takeshi 金沢大学, 大学院・医学系研究科, 教授 (60251055) ; IRUKAYAMA Yoko 筑波大学, 大学院・人間総合科学研究科, 講師 (90312834)
• Project Period (FY): 2007 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2009: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2008: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2007: ¥11,830,000 (Direct Cost: ¥9,100,000、Indirect Cost: ¥2,730,000)
• Keywords: オレキシン / GABA / 睡眠 / 覚醒 / セロトニン / GAVA

Research Abstract

We analyze the in vivo and in vitro phenotype of mice lacking the GABA_<B1> gene specifically in orexin neurons (GABA_<B1>^<flox/flox> ; orexin-Cre mice), and demonstrate that GABA_B receptors on orexin neurons are essential in stabilizing and consolidating sleep/wake states. In GABA_<B1>^<flox/flox> ; orexin-Cre brain slices, we show that the absence of GABA_B receptors decreases the sensitivity of orexin neurons to both excitatory and inhibitory inputs, due to an augmented GABA_A-mediated inhibition that increases the membrane conductance and shunts postsynaptic currents in these neurons. This increase in GABA_A-mediated inhibitory tone is apparently due to an OX1 orexin receptor-mediated activation of local GABAergic interneurons that project back onto orexin neurons. GABA_<B1>^<flox/flox> ; orexin-Cre mice exhibit severe fragmentation of sleep/wake states during both the light and dark periods, without showing an abnormality in total sleep time or signs of cataplexy. Thus, GABA_B receptors on orexin neurons are crucial in the appropriate control of the orexinergic tone through sleep/wake states, thereby stabilizing the state switching mechanisms. We also made mice lacking the 5HT1a gene specifically in orexin neurons, and are anlyzing their phenotypes.

Research Products

• [Journal Article] Activation of Bombesin Receptor Subtype-3 influences Activity of Orexin Neurons by both direct and indirect Pathways. (2010)
  • Author(s): Furutani, N., et al.
  • Journal Title: J.Mol.Neurosci. (印刷中)
  • Peer Reviewed
• [Journal Article] Circadian characteristics of mice depleted with GPR7 (2009)
  • Author(s): Uchio, N, Doi, M, Matsuo, M, Yamazaki, F, Mizoro, Y, Hondo, M, Sakurai, T, Okamura, H.
  • Journal Title: Biomed Res. 30 Pages: 357-364
  • Peer Reviewed
• [Journal Article] Hypothalamic orexin stimulates feeding-associated glucose utilization in skeletal muscle via sympathetic nervous system (2009)
  • Author(s): Shiuchi, T., Haque, M. S., Okamoto, S., Inoue, T., Kageyama, H., Lee, S, Toda, C., Suzuki, A., Bachman, E. S., Kim, Y-B., Sakurai, T., Yanagisawa, M., Shioda, S., Imoto, K., Minokoshi, Y.
  • Journal Title: Cell Metab. 10 Pages: 466-480
  • Peer Reviewed
• [Journal Article] Orexin neurons in the hypothalamus mediate cardiorespiratory responses induced by disinhibition of the amygdala and bed nucleus of the stria terminalis (2009)
  • Author(s): Zhang, W., Zhang, N., Sakurai, T., Kuwaki, T.
  • Journal Title: Brain Res 1262 Pages: 25-37
  • Peer Reviewed
• [Journal Article] Thyrotropin-Releasing Hormone Increases Behavioral Arousal through Modulation of Hypocretin/Orexin Neurons (2009)
  • Author(s): Hara, J. Gerashchenko, D, Wisor, J. P., Sakurai, T., Xie, X., Kilduff, T. S.
  • Journal Title: J.Neurosci. 29 Pages: 3705-3714
  • Peer Reviewed
• [Journal Article] Aromatic D-amino acids act as chemoattractant factors for human leukocytes through a G protein-coupled receptor GPR109B (2009)
  • Author(s): Irukayama-Tomobe, Y, Tanaka, H., Yokomizo, T., Hashidate-Yoshida, T., Yanagisawa, M., Sakurai, T.
  • Journal Title: Proc.Natl.Acad.,Sci.,USA. 106 Pages: 3930-3934
  • Peer Reviewed
• [Journal Article] Selective loss of GABA_B receptors in orexin/hypocretin-producing neurons results in disrupted sleep/wakefulness architecture (2009)
  • Author(s): Matsuki, T., Nomiyama, M, Takahira, H., Hirashima, N., Kilduff, T. S., Kunita, S., Takahashi, S., Yagami, K., Bettler, B., Yanagisawa, M., Sakurai, T.
  • Journal Title: Proc.Natl.Acad.,Sci.,USA. 106 Pages: 4459-64
  • Peer Reviewed
• [Journal Article] IGFBP3 colocalizes with and regulates hypocretin (orexin) (2009)
  • Author(s): Honda, M., Eriksson, K. S., Zhang, S., Tanaka, S., Lin, L., Salehi, A., Hesla, P. E., Maehlen, J., Gaus, S. E., Yanagisawa, M., Sakurai, T., Taheri, S., Tsuchiya, K., Honda, Y., Mignot, E.
  • Journal Title: PLoS ONE. 4
  • Peer Reviewed
• [Journal Article] Enhanced Orexin Signaling Prevents Diet-Induced Obesity and Improves Leptin Sensitivity (2009)
  • Author(s): Funato, H., Tsai, A., Willie, J. T., Kisanuki, Y., Williams, S. C., Sakurai, T., Yanagisawa, M.
  • Journal Title: Cell Metab. 9 Pages: 64-76
  • Peer Reviewed
• [Journal Article] Hypothalamic orexin stimulates feeding-associated glucose utilization in skeletal muscle via sympathetic nervous system. (2009)
  • Author(s): Shiuchi, T., et al.
  • Journal Title: Cell Metab 10 Pages: 466-480
  • Peer Reviewed
• [Journal Article] Histamine-1 receptor is not required as a downstream effector of orexin-2 receptor in maintenance of basal sleep/wake states. (2009)
  • Author(s): Hondo, M
  • Journal Title: Acta Physiol(Oxf) (印刷中)
  • Peer Reviewed
• [Journal Article] Thyrotropin-Releasing Hormone Increases Behavioral Arousal through Modulation of Hypocretin/Orexin Neurons (2009)
  • Author(s): Hara, J. et a
  • Journal Title: J. Neurosci 29 Pages: 3705-3714
  • Peer Reviewed
• [Journal Article] Selective loss of GABABB receptors in orexin/hypocretin-producing neurons results in disrupted sleep/wakefulness architecture (2009)
  • Author(s): Matsuki, T. et al
  • Journal Title: Proc. Natl. Acad., Sci, USA 106 Pages: 4459-4464
  • Peer Reviewed
• [Journal Article] Enhanced Orexin Signaling Prevents Diet-Induced Obesity and Improves Leptin Sensitivity. (2009)
  • Author(s): Funato H. et al
  • Journal Title: Cell Metab 9 Pages: 64-76
  • Peer Reviewed
• [Journal Article] The NPB/NPW neuropeptide system and its role in regulating energy homeostasis, pain, and emotion (2008)
  • Author(s): Hondo, M., Ishii, M., Sakurai, T.
  • Journal Title: Results Probl Cell Differ 46 Pages: 239-256
  • Peer Reviewed
• [Journal Article] Effect of neuropeptide B on feeding behavior is influenced by endogenous corticotropin-releasing factor activities (2008)
  • Author(s): Aikawa, S., Ishii, M., Yanagisawa, M., Sakakibara, Y., Sakurai, T.
  • Journal Title: Regul Pept. 151 Pages: 147-152
  • Peer Reviewed
• [Journal Article] Identification of a population of sleep-active cerebral cortex neurons (2008)
  • Author(s): Gerashchenko, D., Wisor, J. P., Burns, D., Reh, R. K., Shiromani, P. J., Sakurai, T., de la Iglesia, H. O., Kilduff, T. S.
  • Journal Title: Proc.Natl.Acad.,Sci.,USA. 105 Pages: 10227-10232
  • Peer Reviewed
• [Journal Article] Hypocretin/orexin & nociceptin/orphanin FQ coordinately regulate analgesia in a mouse model of stress-induced analgesia (2008)
  • Author(s): Xie, X, Wisor, JP, Hara, J, Crowder, TL, Lewinter, R, Khroyan, T. V., Yamanaka, A., Diano, S., Horvath, T. L., Sakurai, T., Toll, L., Kilduff, T. S.
  • Journal Title: J Clin Invest. 118 Pages: 2471-81
  • Peer Reviewed
• [Journal Article] Vasopressin increases locomotion through a Vla receptor in orexin/hypocretin neurons : implications for water homeostasis (2008)
  • Author(s): Tsunematsu, T, Fu, L. Y., Yamanaka, A., Ichiki, K., Tanoue, A., Sakurai, T., van den Pol A. N.
  • Journal Title: J Neurosci. 28 Pages: 228-238
  • Peer Reviewed
• [Journal Article] Cholinergic Regulation of Orexin/Hypocretin Neurons through M3 Muscarinic Receptor in mice (2008)
  • Author(s): Ohno, K., Hondo, M., Sakurai, T.
  • Journal Title: J.Pharmacol.Sci. 106 Pages: 485-91
  • Peer Reviewed
• [Journal Article] Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice. (2008)
  • Author(s): Tsuneki H. Murata S, Anzawa Y. Soed Y, Tokai E, Wada T, Kimura I, Yanagisawa M, Sakurai T, Sasaoka T.
  • Journal Title: Diabetologia 51 Pages: 657-667
  • Peer Reviewed
• [Journal Article] Vasopressin increases locomotion through a V1a receptor in orexin/hypocretin neurons: implications for water homeostasis. (2008)
  • Author(s): Tsunematsu T, Fu LY, Yamanaka A, Ichiki K, Tanoue A, Sekurai T, van den Pol AN.
  • Journal Title: J Neurosci. 28 Pages: 228-238
  • Peer Reviewed
• [Journal Article] Cholinergic Regulation of Orexin/Hypocretin Neurons through M3 Muscarinic Receptor in mice (2008)
  • Author(s): Ohno, K., Hondo, M., and Sakurai, T.
  • Journal Title: J. Pharmacol. Sci. 106 Pages: 485-491
  • Peer Reviewed
• [Journal Article] Dexmedetomidine inhibits muscarinic type 3 receptors expressed in Xenopus oocytes and muscarine-induced intracellular Ca(2+) elevation in cultured rat dorsal root ganglia cells. (2007)
  • Author(s): Takizuka A, Minami K, Uezono Y, Horishita T, Yokoyama T, Shiraishi M, Sakurai T, Shigematsu A, Ueta Y.
  • Journal Title: Naunyn Schmiedebergs Arch Pharmacol. 375 Pages: 293-301
  • Peer Reviewed
• [Journal Article] Effects of Anesthetics on the Function of Orexin-1 Receptors Expressed in Xenopus (2007)
  • Author(s): Minami K, Uezono Y, Sakurai T, Horishita T, Shiraishi M, Ueta Y.
  • Journal Title: Oocytes. Pharmacology 79 Pages: 236-242
  • Peer Reviewed
• [Journal Article] Sleep/wake fragmentation disrupts metabolism in a mouse model of narcolepsy. (2007)
  • Author(s): Zhang S, Zeitzer JM, Sakurai T, Nishino S, Mignot E.
  • Journal Title: J Physiol. 581 Pages: 649-663
  • Peer Reviewed
• [Presentation] Genetic variation of NPBWR1 alters amygdala function. Neuroendocrine Function of GPCRs (GPCR2010) (2010)
  • Author(s): Sakurai, T.
  • Organizer: Official Satelite Symposium of the 14^<th> International Congress on Endocrinology
  • Place of Presentation: Kyoto
• [Presentation] Roles of orexins in regulation of energy homeostasis (2010)
  • Author(s): Sakurai, T.
  • Organizer: Symposium of the 14^<th> International Congress on Endocrinology
  • Place of Presentation: Kyoto
• [Presentation] 新規神経ペプチドとその生理機能の探求 (2009)
  • Author(s): 桜井武
  • Organizer: 第1回 Advans 研究会
  • Place of Presentation: 名古屋
  • Year and Date: 2009-12-26
• [Presentation] 睡眠・覚醒と情動における新規神経ペプチドの役割 (2009)
  • Author(s): 桜井武
  • Organizer: 第7回北海道大学脳科学研究教育センターシンポジウム「脳の個性を科学する : 遺伝子と環境がつくる脳の力」
  • Place of Presentation: 札幌
  • Year and Date: 2009-12-08
• [Presentation] 新規神経ペプチドと睡眠・覚醒・情動 (2009)
  • Author(s): 桜井武
  • Organizer: 第56回中部日本生理学会 教育講演
  • Place of Presentation: 金沢
  • Year and Date: 2009-12-04
• [Presentation] 新規神経ペプチドと精神機能 (2009)
  • Author(s): 桜井武
  • Organizer: 「社会性認識」学際脳科学シンポジウム
  • Place of Presentation: 金沢
  • Year and Date: 2009-11-06
• [Presentation] A decade of research on orexin (2009)
  • Author(s): Sakurai, T
  • Organizer: The 36^<th> Congress of the International Union of Physiological Sciences
  • Place of Presentation: Kyoto
  • Year and Date: 2009-07-29
• [Presentation] A decade of research on orexin. (2009)
  • Author(s): Sakurai、T
  • Organizer: The 36^<th> Congress of the International Union of Physiological Sciences
  • Place of Presentation: Kyoto
  • Year and Date: 2009-07-29
• [Presentation] オレキシン産生神経による睡眠・覚醒の安定化機構 (2009)
  • Author(s): 桜井武
  • Organizer: 日本実験動物学会総会 シンポジウム3
  • Place of Presentation: 大宮
  • Year and Date: 2009-05-15
• [Presentation] 芳香族D-アミノ酸によるGPR109Bを介したヒト好中球細胞活性化機構について (2009)
  • Author(s): 入鹿山容子
  • Organizer: 第6回GPCR研究会
  • Place of Presentation: 日本科学未来館
  • Year and Date: 2009-05-08
• [Presentation] オレキシンによる睡眠・覚醒の安定化機構と行動制御 (2009)
  • Author(s): 桜井武
  • Organizer: 日北陸実験動物研究会
  • Place of Presentation: 金沢
  • Year and Date: 2009-04-18
• [Presentation] 新規神経ペプチドの探索とその機能解析 (2009)
  • Author(s): 桜井武
  • Organizer: フォーラム富山第27回研究会
  • Place of Presentation: 富山
  • Year and Date: 2009-02-10
• [Presentation] Orexin : a neuropeptide at the interface of emotion, metabolism and sleep/wake states (2009)
  • Author(s): Sakurai, T.
  • Organizer: Satellite Symposium of the 9^<th> International Symposium on VIP, PACAP and Related Peptide
  • Place of Presentation: Yakushima, Kagoshima
• [Presentation] 新規神経ペプチドと覚醒・情動 (2009)
  • Author(s): 桜井武
  • Organizer: 第27回内分泌代謝学サマーセミナー
  • Place of Presentation: 福井
• [Presentation] (2009)
  • Author(s): Sakurai, T
  • Organizer: Speaker in the 3^<rd> annual symposium of Japanese-French Frontiers of Science
  • Place of Presentation: Kanagawa, Japan
• [Presentation] Orexin : a neuropeptide at the interface of emotion, metabolism and sleep/wake states. (2009)
  • Author(s): Sakurai, T
  • Organizer: Satellite Symposium of the 9^<th> International Symposium on VIP, PACAP and Related Peptide
  • Place of Presentation: Yakushima, Kagoshima
• [Presentation] Acute and Chronic Regulation of Sleep-Wakefulness States by Orexin/Hypocretin Neurons (2008)
  • Author(s): Sakurai,T
  • Organizer: SfN meeting
  • Place of Presentation: ワシントンD.C(米国)
  • Year and Date: 2008-11-14
• [Presentation] 視床下部におけるオレキシン産生神経の機能特異的な分布 (2008)
  • Author(s): 桜井 武
  • Organizer: 日本薬理学会第81回年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2008-03-17
• [Presentation] Acute and Chronic Regulation of Sleep-Wakefulness States by Orexin/Hypocretin Neurons (2008)
  • Author(s): Sakurai, T
  • Organizer: SfN meeting
  • Place of Presentation: Washington D. C., USA
• [Presentation] The Neural Circuit of Orexin : Mechanisms for Maintaining Sleep and Wakefulness (2008)
  • Author(s): Sakurai, T
  • Organizer: 2nd WFSBP Asia-Pacific Congress and 30th Annual Meeting of JSBP
  • Place of Presentation: Toyama, Japan
• [Presentation] Roles of orexin/hypocretin system in the regulation of sleep-waking cycle (2008)
  • Author(s): Sakurai, T
  • Organizer: Acta Physiologica International Symposium
  • Place of Presentation: Oulu, Finland
• [Presentation] Acute and Chronic Regulation of Sleep-Wakefulness States by Orexin/Hypocretin Symposium S02 at Sleep2008 (2008)
  • Author(s): Sakurai, T.
  • Organizer: 22^<nd> APSS annual meeting
  • Place of Presentation: Baltimore, MD, USA
• [Book] Orphan G. protein-coupled receptors and novel neuropeptides. Orexins and Orexin Receptors: From Molecules to Integrative Physiology (2008)
  • Author(s): Matsuki T and Sakurai T
  • Total Pages: 256
  • Publisher: Springer
• [Book] Input and Output of Orexin/Hypocretin Neurons: Link Between Arousal Pthways and Feeding Behavior. (2007)
  • Author(s): Sakurai, T
  • Total Pages: 697
  • Publisher: Informa Healthcare, USA, Inc.