Molecular and neural mechanism of memory regulation during sleep

2019 Fiscal Year Annual Research Report

• Project/Area Number: 18H02523
• Research Institution: Nagoya University
• Principal Investigator: 山中 章弘 名古屋大学, 環境医学研究所, 教授 (60323292)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 睡眠 / 視床下部 / メラニン凝集ホルモン / オレキシン / 神経ペプチド / アデノ随伴ウイルスベクター / 光遺伝学 / 化学遺伝学

Outline of Annual Research Achievements

視床下部のメラニン凝集ホルモン産生神経(MCH)神経が、睡眠覚醒状態のどのタイミングで活性化されているのかについて、カルシウムインジケータであるGCaMP6とファイバーフォトメトリーを用いた記録を行った。その結果、MCH神経活動は、覚醒時に僅かに観察され、レム睡眠時に強い活動が見られるものの、ノンレム睡眠時にはほとんど活動が見られなかった。次に、超小型顕微鏡を用いた1細胞レベルでのMCH神経活動のイメージングによって、MCH神経には、覚醒時に活動するタイプ、レム睡眠時に活動するタイプ、覚醒時とレム睡眠時の両方で活動するタイプの3種類存在することが明らかになった。MCH神経活動を光遺伝学や化学遺伝学を用いて操作して、記憶を評価できる行動実験と組み合わせて、MCH神経活動と記憶の関係について検討を行った。その結果、MCH神経を活性化させると記憶が悪くなり、抑制すると記憶が良くなった。次に、3つのタイプのMCH神経のどのタイプが記憶の制御に関わっているのかを明らかにするために、脳波筋電図から睡眠覚醒状態をリアルタイムで判定しながら、MCH神経の活動を睡眠覚醒状態依存的に抑制した。その結果レム睡眠時だけでMCH神経活動を抑制した場合に記憶が良くなった。これらのことから、レム睡眠時に活動するMCH神経が記憶を悪くしていることが明らかになった(Izawa et al., Science 365(6459), pp.1308-1313, 2019)。

Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

光遺伝学、化学遺伝学などの神経活動操作を駆使してMCH神経活動がレム睡眠時に記憶の制御に関わっていることを明らかにし、これらの結果をまとめて、Science誌に報告することができた。

Strategy for Future Research Activity

今後はメラニン凝集ホルモン産生神経がレム睡眠時に記憶を制御する分子メカニズムについて、遺伝子改変マウスや、ウイルスベクターを用いて明らかにしていく。

Research Products

• [Int'l Joint Research] SRI International(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: SRI International
• [Int'l Joint Research] Flinders University(オーストラリア)
  • Country Name: AUSTRALIA
  • Counterpart Institution: Flinders University
• [Journal Article] Involvement of A13 dopaminergic neurons located in the zona incerta in nociceptive processing: a fiber photometry study. (2020)
  • Author(s): *Moriya S, Yamashita A, Masukawa D, Setoyama H, Hwang Y, Yamanaka A, Kuwaki T.
  • Journal Title: Mol Brain Volume: 13 Pages: 60
  • DOI: 10.1186/s13041-020-00600-w.
  • Peer Reviewed
• [Journal Article] Dual orexin and MCH neuron-ablated mice display severe sleep attacks and cataplexy. (2020)
  • Author(s): Hung CJ, Ono D, Kilduff TS, *Yamanaka A.
  • Journal Title: eLife Volume: - Pages: 9
  • DOI: 10.7554/eLife.54275.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Orexin signaling in GABAergic lateral habenula neurons modulates aggressive behavior in male mice. (2020)
  • Author(s): Flanigan ME, Aleyasin H, Li L, Burnett CJ, Chan KL, LeClair KB, Lucas EK, Matikainen-Ankney B, Durand-de Cuttoli R, Takahashi A, Menard C, Pfau ML, Golden SA, Bouchard S, Calipari ES, Nestler EJ, DiLeone RJ, Yamanaka A, Huntley GW, Clem RL, *Russo SJ.
  • Journal Title: Nat Neurosci Volume: 23 Pages: 638-650
  • DOI: 10.1038/s41593-020-0617-7.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Glutamatergic neurons in the medial prefrontal cortex mediate the formation and retrieval of cocaine-associated memories in mice. (2020)
  • Author(s): Zhang T, Yanagida J, Kamii H, Wada S, Domoto M, Sasase H, Deyama S, Takarada T, Hinoi E, Sakimura K, Yamanaka A, Maejima T, Mieda M, Sakurai T, Nishitani N, Nagayasu K, Kaneko S, Minami M, Kaneda K
  • Journal Title: Addict Biol Volume: 25(1) Pages: e12723
  • DOI: 10.1111/adb.12723.
  • Peer Reviewed
• [Journal Article] Acute restraint stress augments the rewarding memory of cocaine through activation of ホア1 adrenoceptors in the medial prefrontal cortex of mice. (2020)
  • Author(s): Wada S, Yanagida J, Sasase H, Zhang T, Li X, Kamii H, Domoto M, Deyama S, Hinoi E, Yamanaka A, Nishitani N, Nagayasu K, Kaneko S, Minami M, *Kaneda K.
  • Journal Title: Neuropharmacology Volume: 166 Pages: 107968
  • DOI: 10.1016/j.neuropharm.2020.107968.
  • Peer Reviewed
• [Journal Article] Involvement of supralemniscal nucleus (B9) 5-HT neuronal system in nociceptive processing: a fiber photometry study. (2020)
  • Author(s): Moriya S, Yamashita A, Masukawa D, Kambe Y, Sakaguchi J, Setoyama H, Yamanaka A, Kuwaki T
  • Journal Title: Mol Brain Volume: 13(1) Pages: 14
  • DOI: 10.1186/s13041-020-0553-1.
  • Peer Reviewed
• [Journal Article] Light-induced silencing of neural activity in Rosa26 knock-in and BAC transgenic mice conditionally expressing the microbial halorhodopsin eNpHR3. (2020)
  • Author(s): Imayoshi I, Tabuchi S, Matsumoto M, Kitano S, Miyachi H, Kageyama R, Yamanaka A
  • Journal Title: Sci Rep Volume: 10(1) Pages: 3191
  • DOI: 10.1038/s41598-020-59984-3.
  • Peer Reviewed / Open Access
• [Journal Article] Behavioral characteristics of 5-HT2C receptor knockout mice: Locomotor activity, anxiety-, and fear memory-related behaviors. (2020)
  • Author(s): Nebuka M, Ohmura Y, Izawa S, Bouchekioua Y, Nishitani N, Yoshida T, Yoshioka M.
  • Journal Title: Behav Brain Res Volume: 379 Pages: 112394
  • DOI: 10.1016/j.bbr.2019.112394.
  • Peer Reviewed
• [Journal Article] The Role of Dorsal Raphe Serotonin Neurons in the Balance between Reward and Aversion. (2020)
  • Author(s): Nagai Y, Takayama K, Nishitani N, Andoh C, Koda M, Shirakawa H, Nakagawa T, Nagayasu K* , Yamanaka A, Kaneko S*
  • Journal Title: Int J Mol Sci Volume: 21(6) Pages: E2160
  • DOI: 10.3390/ijms21062160
  • Peer Reviewed
• [Journal Article] GABA neurons in the ventral tegmental area regulate non-rapid eye movement sleep in mice. (2019)
  • Author(s): Chowdhury S, Matsubara T, Miyazaki T, Ono D, Fukatsu N, Abe M, Sakimura K, Sudo Y, Yamanaka A*
  • Journal Title: eLife Volume: 8 Pages: e44928
  • DOI: 10.7554/eLife.44928.
  • Peer Reviewed / Open Access
• [Journal Article] Dissociating orexin-dependent and -independent functions of orexin neurons using novel Orexin-Flp knock-in mice. (2019)
  • Author(s): Chowdhury S, Hung CJ, Izawa S, Inutsuka A, Kawamura M, Kawashima T, BitoH, Imayoshi I, AbeM, Sakimura K, Yamanaka A*
  • Journal Title: eLife Volume: 8 Pages: e44927
  • DOI: 10.7554/eLife.44927.
  • Peer Reviewed / Open Access
• [Journal Article] Acute nociceptive stimuli rapidly induce the activity of serotonin and noradrenalin neurons in the brain stem of awake mice. (2019)
  • Author(s): Moriya S, Yamashita A, Nishi R, Ikoma Y, Yamanaka A, Kuwaki T
  • Journal Title: IBRO Rep Volume: 7 Pages: 1~9
  • DOI: 10.1016/j.ibror.2019.05.005.
  • Peer Reviewed / Open Access
• [Journal Article] CRISPR/Cas9-mediated in vivo gene editing reveals that neuronal 5-HT1A receptors in the dorsal raphe nucleus contribute to body temperature regulation in mice. (2019)
  • Author(s): Nishitani N, Ohmura Y, Nagayasu K, Shibui N, Kaneko S, Ohashi A, Yoshida T, Yamanaka A, Yoshioka M
  • Journal Title: Brain Res Volume: 1719 Pages: 243~252
  • DOI: 10.1016/j.brainres.2019.06.009.
  • Peer Reviewed
• [Journal Article] Quantitation of the neural silencing activity of anion channelrhodopsins in Caenorhabditis elegans and their applicability for long-term illumination. (2019)
  • Author(s): Yamanashi T, Maki M, Kojima K, Shibukawa A, Tsukamoto T, Chowdhury S, Yamanaka A, Takagi S, Sudo Y
  • Journal Title: Sci Rep Volume: 9(1) Pages: 7863
  • DOI: 10.1038/s41598-019-44308-x.
  • Peer Reviewed / Open Access
• [Journal Article] GABA in the suprachiasmatic nucleus refines circadian output rhythms in mice. (2019)
  • Author(s): Ono D, Honma KI, Yanagawa Y, Yamanaka A, Honma S
  • Journal Title: Commun Biol Volume: 2(1) Pages: 232
  • DOI: 10.1038/s42003-019-0483-6.
  • Peer Reviewed / Open Access
• [Journal Article] Thin-fibre receptors expressing acid-sensing ion channel 3 contribute to muscular mechanical hypersensitivity after exercise. (2019)
  • Author(s): Matsubara T,Hayashi K,Wakatsuki K,Abe M,Ozaki N,Yamanaka A,Mizumura K,Taguchi T
  • Journal Title: Eur J Pain Volume: 23(10) Pages: 1801~1813
  • DOI: 10.1002/ejp.1454.
  • Peer Reviewed
• [Journal Article] Different roles of distinct serotonergic pathways in anxiety-like behavior, antidepressant-like, and anti-impulsive effects. (2019)
  • Author(s): Ohmura Y, Tsutsui-Kimura I, Sasamori H, Nebuka M, Nishitani N, Tanaka KF, Yamanaka A, Yoshioka M.
  • Journal Title: Neuropharmacology Volume: 9 Pages: 107703
  • DOI: 10.1016/j.neuropharm.2019.107703.
  • Peer Reviewed
• [Journal Article] REM sleep-active MCH neurons are involved in forgetting hippocampus-dependent memories. (2019)
  • Author(s): Izawa S, Chowdhury S, Miyazaki T, Mukai Y, Ono D, Inoue R, Ohmura Y, Mizoguchi H, Kimura K, Yoshioka M, Terao A, Kilduff TS, Yamanaka A*
  • Journal Title: Science Volume: 365(6459) Pages: 1308~1313
  • DOI: 10.1126/science.aax9238.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Transgenic Archaerhodopsin-3 Expression in Hypocretin/Orexin Neurons Engenders Cellular Dysfunction and Features of Type 2 Narcolepsy. (2019)
  • Author(s): Williams RH, Tsunematsu T, Thomas AM, Bogyo K, Yamanaka A*, Kilduff TS*.
  • Journal Title: J Neurosci Volume: 39(47) Pages: 9435~9452
  • DOI: 10.1523/JNEUROSCI.0311-19.2019.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mechanical allodynia induced by optogenetic sensory nerve excitation activates dopamine signaling and metabolism in medial nucleus accumbens. (2019)
  • Author(s): Sugiyama E, Kondo T, Kuzumaki N, Honda K, Yamanaka A, Narita M, Suematsu M, Sugiura Y.
  • Journal Title: Neurochem Int Volume: 129 Pages: 104494
  • DOI: 10.1016/j.neuint.2019.104494.
  • Peer Reviewed
• [Presentation] 視床下部神経による睡眠覚醒と記憶の制御 (2020)
  • Author(s): 山中章弘
  • Organizer: 第218回精神科医会及び第174回学術講演会
  • Invited
• [Presentation] オレキシンとは？睡眠覚醒調節における役割について (2020)
  • Author(s): 山中章弘
  • Organizer: 東区医師会学術講演会
  • Invited
• [Presentation] Functional interaction between the hypothalamus, septum and hippocampus to regulate sleep and memory (2019)
  • Author(s): Yamanaka A
  • Organizer: NUS Physiology Research Seminar
  • Int'l Joint Research / Invited
• [Presentation] Role of REM sleep on memory (2019)
  • Author(s): Yamanaka A
  • Organizer: Cold Spring Harbor Asia Neurobiology of Behavior & Neuropsychiatric Disorders
  • Int'l Joint Research / Invited
• [Presentation] REM sleep active MCH neurons are involved in forgetting hippocampus-dependent memories (2019)
  • Author(s): Yamanaka A, Izawa S
  • Organizer: IBRO 2019
  • Int'l Joint Research / Invited
• [Presentation] MCH neurons impaired memories during REM sleep (2019)
  • Author(s): Yamanaka A
  • Organizer: 2019 Chinese Sleep Research Society (CSRS) Annual Academic Conference
  • Int'l Joint Research / Invited
• [Presentation] REM sleep active MCH neurons are involved in forgetting hippocampus-dependent memories (2019)
  • Author(s): Yamanaka A
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology
  • Int'l Joint Research
• [Remarks] 浅い眠りで記憶が消去される仕組みを解明
  • URL: http://www.riem.nagoya-u.ac.jp/4/drof1/nr/files/Sci_190920.pdf