Neural mechanisms underlying the circadian pacemakers

• Project/Area Number: 24390052
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: General physiology
• Research Institution: Kanazawa University
• Principal Investigator: Mieda Michihiro 金沢大学, 医学系, 准教授 (20296552)
• Co-Investigator(Renkei-kenkyūsha): SAKURAI TAKESHI 金沢大学, 医学系, 教授 (60251055)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000); Fiscal Year 2015: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2014: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2013: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2012: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
• Keywords: 概日リズム / 視交叉上核 / バソプレシン / 遺伝子操作マウス / 体内時計 / 神経ネットワーク / 時計遺伝子 / トランスジェニックマウス / Bmal1 / VIP / casein kinase 1d / Vgat / SCN / AVP / 食餌

Outline of Final Research Achievements

The suprachiasmatic nucleus (SCN), the primary circadian pacemaker in mammals, is a network structure composed of multiple types of neurons. However, the neural mechanisms underlying the generation of robust and stable circadian oscillation by the SCN network remains unknown. We generated mice with neuron type-specific genetic manipulations and performed analyses of their behavior, gene expression in vivo and ex vivo, and so on. We found that AVP producing neurons in the SCN play a critical role in the generation of stable circadian behavioral rhythms and the determination of the circadian period.

Research Products

• [Journal Article] Genetic dissection of neural mechanisms underlying the central circadian pacemaker (2016)
  • Author(s): Mieda M, Ono D, Hasegawa E, Okamoto H, Honma K, Honma S, Sakurai T.
  • Journal Title: The proceeding volume of Sapporo Symposium on Biological Rhythm in 2014 Volume: in press Pages: 139-148
• [Journal Article] 睡眠障害とオレキシン拮抗薬 (2016)
  • Author(s): 三枝理博，櫻井武
  • Journal Title: Annual Review 糖尿病・代謝・内分泌2016 Volume: NA Pages: 197-205
• [Journal Article] 概日時計による睡眠の調節 (2015)
  • Author(s): 三枝理博
  • Journal Title: 実験医学 Volume: 33 Pages: 2071-2076
• [Journal Article] Cellular Clocks in AVP Neurons of the SCN Are Critical for Interneuronal Coupling Regulating Circadian Behavior Rhythm. (2015)
  • Author(s): Mieda M, Ono D, Hasegawa E, Okamoto H, Honma K, Honma S, Sakurai T.
  • Journal Title: Neuron Volume: 85 Issue: 5 Pages: 1103-1116
  • DOI: 10.1016/j.neuron.2015.02.005
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Orexin neurons suppress narcolepsy via 2 distinct efferent pa thways. (2014)
  • Author(s): Hasegawa E, Yanagisawa M, Sakurai T, Mieda M.
  • Journal Title: J Clin Invest. Volume: 124 Issue: 2 Pages: 604-16
  • DOI: 10.1172/jci71017
  • Peer Reviewed
• [Journal Article] GABAergic neurons in the preoptic area send direct inhibitory projections to orexin neurons. (2013)
  • Author(s): Saito YC, Tsujino N, Hasegawa E, Akashi K, Abe M, Mieda M, Sakimura K, Sakurai T.
  • Journal Title: Front Neural Circuits. Volume: 7 Pages: 192-192
  • DOI: 10.3389/fncir.2013.00192
  • Peer Reviewed
• [Journal Article] Orexin receptor-1 in the locus coeruleus plays an important role in cue- dependent fear memory consolidation. (2013)
  • Author(s): Soya S, Shoji H, Hasegawa E, Hondo M, Miyakawa T, Yanagisawa M, Mieda M, Sakurai T.
  • Journal Title: J Neurosci. Volume: 33 Issue: 36 Pages: 14549-57
  • DOI: 10.1523/jneurosci.1130-13.2013
  • Peer Reviewed / Open Access
• [Journal Article] Neurotensin co-expressed in orexin-producing neurons in the lateral hypothalamus plays an important role in regulation of sleep/wakefulness States. (2013)
  • Author(s): Furutani N, Hondo M, Kageyama H, Tsujino N, Mieda M, Yanagisawa M, Shioda S, Sakurai T.
  • Journal Title: PLoS One Volume: 8 Issue: 4 Pages: e62391-e62391
  • DOI: 10.1371/journal.pone.0062391
  • Peer Reviewed
• [Journal Article] Differential roles of orexin receptors in the regulation of sleep/wakefulness (2013)
  • Author(s): Mieda M, Tsujino N, Sakurai T.
  • Journal Title: Front Endocrinol Volume: 4 Pages: 57-57
  • DOI: 10.3389/fendo.2013.00057
  • Peer Reviewed
• [Journal Article] Neurotensin co-expressed in orexin-producing neurons in the lateral hypothalamus plays an important role in regulation of sleep/wakefulness states (2013)
  • Author(s): Furutani. N
  • Journal Title: PLoS one Volume: (in press)
  • Peer Reviewed
• [Journal Article] Orexin (hypocretin) receptor agonists and antagonists for treatment of sleep disorders. Rationale for development and current status. (2013)
  • Author(s): Mieda. M
  • Journal Title: CNS Drugs Volume: 27 Issue: 2 Pages: 83-90
  • DOI: 10.1007/s40263-012-0036-8
  • NAID: 120005254048
  • Peer Reviewed
• [Journal Article] Clock genes influence gene expression in growth plate and endochondral ossification in mice. (2012)
  • Author(s): Takarada. T
  • Journal Title: J Biol Chem Volume: 287 Pages: 36081-36095
  • Peer Reviewed
• [Journal Article] Overview of orexin/hypocretin system. (2012)
  • Author(s): Mieda. M
  • Journal Title: Prog Brain Res Volume: 198 Pages: 5-14
  • DOI: 10.1016/b978-0-444-59489-1.00002-1
  • NAID: 120004419378
  • Peer Reviewed
• [Presentation] 中枢概日ペースメーカーにおけるバソプレシン産生ニューロンの役割 (2016)
  • Author(s): 三枝理博
  • Organizer: 日本解剖学会
  • Place of Presentation: ビッグパレットふくしま（福島県郡山市）
  • Year and Date: 2016-03-28
  • Invited
• [Presentation] ニューロンタイプ特異的遺伝子操作による中枢概日ペースメーカー神経機構の解析 (2016)
  • Author(s): 三枝理博
  • Organizer: 日本生理学会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2016-03-22
  • Invited
• [Presentation] 中枢概日時計におけるバソプレシン産生ニューロンの役割 (2015)
  • Author(s): 三枝理博
  • Organizer: 日本分子生物学会年会・日本生化学会大会 合同大会
  • Place of Presentation: 神戸コンベンションセンター（兵庫県神戸市）
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] Cellular clocks in AVP neurons of the SCN are critical for interneuronal coupling regulating circadian behavior rhythm (2015)
  • Author(s): Mieda M.
  • Organizer: Asian Forum on Chronobiology in 2015
  • Place of Presentation: 北海道大学（北海道札幌市）
  • Year and Date: 2015-09-07
  • Int'l Joint Research / Invited
• [Presentation] Cellular clocks in AVP neurons of the SCN are critical for interneuronal coupling regulating circadian behavior rhythm (2015)
  • Author(s): Mieda M.
  • Organizer: European Biological Rhythms Society
  • Place of Presentation: University of Manchester (Manchester, UK)
  • Year and Date: 2015-08-02
  • Int'l Joint Research / Invited
• [Presentation] Cellular Circadian Oscillators in Vasopressin Neurons of the Suprachiasmatic Nucleus Play a Critical Role in Coupling between Morning and Evening Behavioral Rhythms in Mice (2015)
  • Author(s): Mieda, M.
  • Organizer: 日本生理学会
  • Place of Presentation: 神戸コンベンションセンター（兵庫県神戸市）
  • Year and Date: 2015-03-22 – 2015-03-23
  • Invited
• [Presentation] Roles of AVP-producing neurons in the central circadian pacemaker of the suprachiasmatic nucleus. (2014)
  • Author(s): Mieda, M.
  • Organizer: 日本神経科学会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-09-11 – 2014-09-13
  • Invited
• [Presentation] Genetic dissection of neural mechanisms underlying the central circadian pacemaker (2014)
  • Author(s): Mieda, M.
  • Organizer: Sapporo Symposium on Biological Rhythm
  • Place of Presentation: 北海道大学（北海道札幌市）
  • Year and Date: 2014-07-25 – 2014-07-26
  • Invited
• [Presentation] Roles of AVP-producing neurons in the central circadian pacemaker of the suprachiasmatic nucleus (2014)
  • Author(s): Mieda M, Ono D, Hasegawa E, Okamoto H, Honma K, Honma S, Sakurai T.
  • Organizer: Society for Reseach on Biological Rhythms
  • Place of Presentation: Conference Center at Big Sky Resort (MT, USA)
  • Year and Date: 2014-06-14 – 2014-06-18
• [Presentation] Roles of AVP-producing neurons in the central circadian pacemaker of the suprachiasmatic nucleus (2014)
  • Author(s): Mieda, M. Ono, D. Hasegawa, E. Okamoto, H. Honma, S. Sakurai, T.
  • Organizer: Gordon Research Conferences, Sleep Regulation & Function,
  • Place of Presentation: Hotel Galvez (USA)
• [Presentation] Roles of AVP-producing neurons in the central circa dian pacemaker of the suprachiasmatic nucleus (2013)
  • Author(s): 三枝理博
  • Organizer: 第90回生理学会
  • Place of Presentation: タワーホール船堀(東京都)
  • Year and Date: 2013-03-29
• [Presentation] Roles of AVP-producing neurons in the central circadian pacemaker of the suprachiasmatic nucleus. (2013)
  • Author(s): 三枝理博
  • Organizer: 脳・肝インターフェースメディシン研究センターシンポジウム
  • Place of Presentation: 東京国際フォーラム(東京都)(招待講演)
  • Year and Date: 2013-03-26
• [Presentation] 視交叉上核AVP産生ニューロンは概日周期・活動時間の決定に重要な役割を果たす (2013)
  • Author(s): 三枝理博、小野大輔、長谷川恵美、岡本仁、本間さと、櫻井武
  • Organizer: 第20回日本時間生物学会学術大会
  • Place of Presentation: 近畿大学東大阪キャンパス（大阪府）
• [Presentation] Dissection of neural mechanisms underlying circadian pacemakers usingbrain region/cell-specific Bmall deficient mice. (2012)
  • Author(s): Mieda. M
  • Organizer: The 7th Asian Sleep Research Society Congress
  • Place of Presentation: Taipei International Convention Center (Taiwan)(招待講演)
  • Year and Date: 2012-12-02
• [Presentation] 脳領域・細胞特異的Bmall欠損マウスを用いた概日ペースメーカー機構の解析 (2012)
  • Author(s): 三枝理博
  • Organizer: 日本睡眠学会第37回定期学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県)(招待講演)
  • Year and Date: 2012-10-28
• [Presentation] Differential regulation of non-REM and REM sleep by orexinergic neurons (2012)
  • Author(s): Mieda. M
  • Organizer: Neuroscience 2012
  • Place of Presentation: Morial Convention Center (USA)(招待講演)
  • Year and Date: 2012-10-17
• [Presentation] Neural mechanisms underlying food-entrainable circadian rhythms (2012)
  • Author(s): Mieda. M
  • Organizer: 日本味と匂学会 第46回大会
  • Place of Presentation: 大阪大学(大阪府)(招待講演)
  • Year and Date: 2012-10-03
• [Presentation] 概日ペースメーカー・視交叉上核神経ネットワークにおけるAVP産生ニューロンの役割 (2012)
  • Author(s): 三枝理博
  • Organizer: 時間生物学会
  • Place of Presentation: 北海道大学(北海道)
  • Year and Date: 2012-09-16
• [Presentation] Search for neurons mediating functions of orexin as a wakefulness-stabilizer (2012)
  • Author(s): Hasegawa. E
  • Organizer: 21st Congress of the European Sleep Research Society
  • Place of Presentation: CNIT Paris La Defnse (フランス)
  • Year and Date: 2012-09-07
• [Presentation] Neural mechanisms underlying food-entrainable circadian rhythms (2012)
  • Author(s): Mieda. M
  • Organizer: 26th Annual Meeting of the Associated Professional Sleep Societies
  • Place of Presentation: John B. Hynes Veterans Memorial Convention Center (USA)(招待講演)
  • Year and Date: 2012-06-10
• [Presentation] 概日ペースメーカー・視交叉上核神経ネットワークにおけるAVP産生ニューロンの役割
  • Author(s): 三枝理博、長谷川恵美、岡本仁、櫻井武
  • Organizer: 第36回日本神経科学学会大会
  • Place of Presentation: 京都国際会議場（京都府）
• [Book] Orexin (Hypocretin) and Narcolepsy. In Narcolepsy, 2nd Edition: A Clinical Guide (2016)
  • Author(s): Mieda M, Sakurai T. (Goswami M, Thorpy MJ, Pandi-Perumal SR, eds)
  • Publisher: Springer
• [Book] Pharmacogenetic dissection of neural mechanisms underlying the regulation of sleep/wakefulness using DREADDs. In Designer Receptors Exclusively Activated by Designer Drugs (2015)
  • Author(s): Mieda M, Sakurai T. (Thiel G. eds)
  • Publisher: Humana Press
• [Book] Physiological roles of orexin receptors on sleep/wakefulness regulation. In Orexin and Sleep - Molecular, Functional and Clinical Aspects (2015)
  • Author(s): Mieda M, Sakurai T. (Sakurai T, Monti JM, Pandi-Perumal SR, eds)
  • Publisher: Springer