Physiological roles of the regulatory system of orexin-producing neurons

2010 Fiscal Year Final Research Report

• Project/Area Number: 20390067
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Kanazawa University
• Principal Investigator: SAKURAI Takeshi Kanazawa University, 医学系, 教授 (60251055)
• Co-Investigator(Kenkyū-buntansha): YAMANAKA Akihiro 大学共同利用法人・自然科学研究機構, 生理学研究所・細胞生理研究部門, 准教授 (60323292)
• Project Period (FY): 2008 – 2010
• Keywords: オレキシン / 睡眠 / 覚醒 / GABA / TRH

Research Abstract

We studied the physiological roles of the regulatory system of orexin-producing neurons. We examined the involvement of GABA_B receptors in the regulation of orexin neurons, by utilizing mice with a conditional deletion of the GABA_<B1> subunit in these neurons. The frequency of spontaneous fast TPSCs mediated by GABA_A receptors was markedly increased to compensate for an increase in orexin receptor-1 mediated excitation of local GABAergic interneurons. Sleep state analysis of the conditional GABA_<B1> knockout mice revealed that these mice displayed a robust fragmentation of the sleep/waking states. These observations suggest that pre- and postsynaptic GABA_B receptors in orexin neurons are essential for the normal regulation of orexin neuronal activity, and regulation of sleep/wakefulness states in vivo. We also revealed the involvement of BRS-3 in the regulation of orexin neuron. We also found that orexin-overexpresisng mice exhibit fragmentation of NREM sleep, suggesting the importance of inhibitory mechanisms of orexin neurons in maintenance of normal sleep.

Research Products

• [Journal Article] Orexin neurons are indispensable for stress-induced thermogenesis in mice (2010)
  • Author(s): Zhang W, Sunanaga J, Takahashi Y, Mori T, Sakurai T, Kanmura Y, Kuwaki T.
  • Journal Title: J Physiol. 588(Pt21) Pages: 4117-4129
• [Journal Article] The orexin system : roles in sleep/wake regulation. (2010)
  • Author(s): Sakurai T, Mieda M, Tsujino N.
  • Journal Title: Ann N Y Acad Sci. 1200 Pages: 149-161
• [Journal Article] Ectopic Overexpression of Orexin Alters Sleep/Wakefulness States and Muscle Tone Regulation during REM Sleep in Mice. (2010)
  • Author(s): Willie JT, Takahira H, Shibahara M, Hara J, Nomiyama M, Yanagisawa M, Sakurai T.
  • Journal Title: J Mol Neurosci. 43(2) Pages: 155-161
• [Journal Article] Activation of Bombesin Receptor Subtype-3 Influences Activity of Orexin Neurons by Both Direct and Indirect Pathways. (2010)
  • Author(s): Furutani N, Hondo M, Tsujino N, Sakurai T.
  • Journal Title: J Mol Neurosci. 42(1)[Epub ahead of print] Pages: 106-111
• [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 Dec 10(6) Pages: 466-480
• [Journal Article] Attenuated phrenic long-term facilitation in orexin neuron-ablated mice. (2009)
  • Author(s): Toyama S, Sakurai T, Tatsumi K, Kuwaki T.
  • Journal Title: Respir Physiol Neurobiol. 168(3) Pages: 295-302
• [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. 25;1262 Pages: 25-37
• [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(12) Pages: 3705-3714
• [Journal Article] Integrative physiology of orexins and orexin receptors. (2009)
  • Author(s): Mieda M, Sakurai T.
  • Journal Title: CNS Neurol Disord Drug Targets. 8(4) Pages: 281-295
• [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(11) Pages: 4456-4464
• [Journal Article] IGFBP3 colocalizes with and regulates hypocretin (orexin). (2009)
  • Author(s): Honda M, Eriksson KS, Zhang S, Tanaka S, Lin L, Salehi A, Hesla PE, Maehlen J, Gaus SE, Yanagisawa M, Sakurai T, Taheri S, Tsuchiya K, Honda Y, Mignot E.
  • Journal Title: PLoS ONE. 4(1) Pages: e4254
• [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. 7;9(1) Pages: 64-76
• [Journal Article] Orexin/Hypocretin : a neuropeptide at the interface of sleep, energy homeostasis, and reward system. (2009)
  • Author(s): Tsujino N, Sakurai T.
  • Journal Title: Pharmacol Rev. 61(2) Pages: 162-176
• [Journal Article] Orexin (hypocretin) gene transfer diminishes narcoleptic sleep behavior in mice. (2008)
  • Author(s): Liu M, Thankachan S, Kaur S, Begum S, Blanco-Centurion C, Sakurai T, Yanagisawa M, Neve R, Shiromani PJ.
  • Journal Title: Eur J Neurosci. 28(7) Pages: 1382-1393
• [Journal Article] Hypocretin receptor expression in canine and murine narcolepsy models and in hypocretin-ligand deficient human narcolepsy. (2008)
  • Author(s): Mishima K, Fujiki N, Yoshida Y, Sakurai T, Honda M, Mignot E, Nishino S.
  • Journal Title: Sleep 31(8) Pages: 1119-1126
• [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., delaIglesia, H.O., Kilduff, T.S.
  • Journal Title: Proc.Natl.Acad., Sci., USA. 105 Pages: 10227-10232
• [Journal Article] Hypocretin/orexin and 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 TV, Yamanaka A, Diano S, Horvath TL, Sakurai T, Toll L, Kilduff TS.
  • Journal Title: J Clin Invest. 118(7) Pages: 2471-2481
• [Journal Article] Entrainment of temperature and activity rhythms to restricted feeding in orexin knock out mice. (2008)
  • Author(s): Kaur S, Thankachan S, Begum S, Blanco-Centurion C, Sakurai T, Yanagisawa M, Shiromani PJ.
  • Journal Title: Brain Res. 1205 Pages: 47-54
• [Journal Article] Enhanced BMP signaling results in supernumerary tooth formation in USAG-1 deficient mouse. (2008)
  • Author(s): Murashima-Suginami, A., Takahashi, K., Sakata, T., Tsukamoto, H., Sugai, M., Yanagita, M., Shimizu, A., Sakurai, T., Slavkin, H.C., Bessho, K.
  • Journal Title: Biochem Biophys Res Commun 369(4) Pages: 1012-1016
• [Journal Article] Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice. (2008)
  • Author(s): Tsuneki H, Murata S, Anzawa Y, Soeda Y, Tokai E, Wada T, Kimura I, Yanagisawa M, Sakurai T, Sasaoka T.
  • Journal Title: Diabetologia. 51(4) Pages: 657-667
• [Presentation] Orexin neurons at interface of energy homeostasis, emotion, and sleep/wakefulness states. (2010)
  • Author(s): 桜井武
  • Organizer: 5th International Peptide Symposium in conjunction with 47th Japanese Peptide Symposium.
  • Place of Presentation: Kyoto International Conference Center, Kyoto, Japan.
  • Year and Date: 20101204-20101209
• [Presentation] 睡眠・覚醒状態の制御機構におけるオレキシン産生ニューロンの役割 (2010)
  • Author(s): 桜井武
  • Organizer: 第35回日本睡眠学会定期学術集会
  • Place of Presentation: 名古屋国際会議場、愛知
  • Year and Date: 20100701-20100702
• [Presentation] 睡眠覚醒状態の維持機構におけるオレキシンニューロンの役割 (2010)
  • Author(s): 桜井武
  • Organizer: 第87回日本生理学会大会シンポジウム7
  • Place of Presentation: 盛岡市民文化ホール(マリオス)、いわて県民情報センター(アイーナ)、盛岡
  • Year and Date: 20100519-20100521
• [Presentation] 扁桃体におけるNPBWR1の役割 (2010)
  • Author(s): 桜井武
  • Organizer: 第7回GPCR研究会
  • Place of Presentation: 未来館ホール、東京
  • Year and Date: 20100507-20100508
• [Presentation] Orexin as a waking substance. (2010)
  • Author(s): 桜井武
  • Organizer: Turkish-Japanese Sleep Forum 2010
  • Place of Presentation: Crown Plaza, Izmir, Turky
  • Year and Date: 20100503-20100504
• [Presentation] Roles of orexins in regulation of energy homeostasis. (2010)
  • Author(s): 桜井武
  • Organizer: Symposium of the 1^<4th> International Congress on Endocrinology
  • Place of Presentation: Kyoto International Conference Center, Kyoto
  • Year and Date: 20100327-20100330
• [Presentation] オレキシンによる睡眠覚醒の制御機構 (2010)
  • Author(s): 桜井武
  • Organizer: 金沢大学薬学シンポジウム2010～生物時計の謎に挑む～
  • Place of Presentation: 金沢大学、石川
  • Year and Date: 2010-12-02
• [Presentation] オレキシンニューロンのコネクトミクス:各種モデルマウスによる解析 (2010)
  • Author(s): 桜井武
  • Organizer: 第20回日本臨床精神神経薬理学会・第40回日本神経精神薬理学会合同年会シンポジウム7
  • Place of Presentation: 仙台国際センター、宮城
  • Year and Date: 2010-09-16
• [Presentation] 睡眠・覚醒状態の制御機構におけるオレキシンによる睡眠・覚醒の制御機構およびエネルギー恒常性への関与特別講演 (2010)
  • Author(s): 桜井武
  • Organizer: 第8回メタボリックシンドロームカンファレンス
  • Place of Presentation: 芝蘭会館、京都
  • Year and Date: 2010-07-17
• [Presentation] Orexin : a neuropeptide at the interface of emotion, metabolism and sleep/wake states. (2009)
  • Author(s): 桜井武
  • Organizer: Satellite Symposium of the 9th International Symposium on VIP, PACAP and Related Peptide
  • Place of Presentation: Iwasaki Hotel, Yakushima, Kagoshima
  • Year and Date: 20091002-20091003
• [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: 三国観光ホテル、福井
  • Year and Date: 20090716-20090717
• [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: 石川県立音楽堂、石川
  • Year and Date: 2009-12-04
• [Presentation] A decade of research on orexin. (2009)
  • Author(s): 桜井武
  • Organizer: The 36^<th> Congress of the International Union of Physiological Sciences
  • Place of Presentation: Kyoto International Conference Center, 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: 第56回日本実験動物学会総会シンポジウム3
  • Place of Presentation: 大宮ソニックシティ、大宮
  • Year and Date: 2009-05-15
• [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: 北陸実験動物研究会
  • Place of Presentation: 金沢大学、石川
  • Year and Date: 2009-04-18
• [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: (金)北海道大学、北海道
  • Year and Date: 2009-02-08
• [Presentation] Acute and Chronic Regulation of Sleep-Wakefulness States by Orexin/Hypocretin Neurons. (2008)
  • Author(s): 桜井武
  • Organizer: SfN meeting, Walter E.
  • Place of Presentation: Washington Convention CenterWashington D.C., USA
  • Year and Date: 20081112-20081116
• [Presentation] The Neural Circuit of Orexin : Mechanisms for Maintaining Sleep and Wakefulness. (2008)
  • Author(s): 桜井武
  • Organizer: 2nd WFSBP Asia-Pacific Congress and 30th Annual Meeting of JSBP
  • Place of Presentation: Toyama International Conference Center, Toyama, Japan.
  • Year and Date: 20080911-20080913
• [Presentation] Roles of orexin/hypocretin system in the regulation of sleep-waking cycle. (2008)
  • Author(s): 桜井武
  • Organizer: Acta Physiologica International Symposium.
  • Place of Presentation: Kastelli Research Centre.University of Oulu, Oulu, Finland
  • Year and Date: 20080813-20080814
• [Presentation] Acute and Chronic Regulation of Sleep-Wakefulness States by Orexin/Hypocretin Symposium S02 at Sleep 2008 (2008)
  • Author(s): 桜井武
  • Organizer: 22^<nd> APSS annual meeting
  • Place of Presentation: Baltimore Convention Center, Baltimore, MD, USA
  • Year and Date: 20080607-20080612
• [Book] なぜ目覚めるのか(睡眠の科学-なぜ眠るのか)(ISBN-10: 4062577054、ISBN-13:978-4062577052) (2010)
  • Author(s): 櫻井武
  • Total Pages: 248
  • Publisher: 講談社ブルーバックス
• [Remarks] ホームページ等
  • URL: http://web.kanazawa-u.ac.jp/~med05/