気分障害と概日リズムの分子相関理解のための統合的研究

2015 Fiscal Year Annual Research Report

• Project/Area Number: 25242077
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: 内匠 透 国立研究開発法人理化学研究所, 脳科学総合研究センター, シニアチームリーダー (00222092)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 気分障害 / 概日リズム / リン酸化 / モデルマウス

Outline of Annual Research Achievements

気分障害と概日リズムとの関連は従来から示唆されているところであるが、その分子相関研究は、時計遺伝子を含む様々なリズムの定量的アッセイ系が確立された現在でこそ可能になったプロジェクトである。研究代表者の研究室で最近明らかになった気分障害における概日リズム表現型をもとに、本研究では、気分障害の新規エンドフェノタイプを同定・確立するとともに、そのシグナルパスウェイを明らかにする。気分障害の分子病態理解を目指すとともに、本研究の成果として得られる新規抗体やモデルマウスは、これまでの概念とは一線を画す新規診断法や治療薬のスクリーニング系の開発基盤となることが期待される。
PER2リン酸化変異ノックインマウスの行動解析により、概日リズム周期が野生型に比べて短周期になりヒトでみられる睡眠相前進症候群の表現型を示した。また学習性無力テストでは野生型に比べてうつに抵抗性であることを明らかにした。またリチウム投与によって、短くなった概日周期がもとの周期に戻らないことから、本PER2変異体がGSK3betaによるリン酸化に必須の部位であることが個体レベルでの実験からも実証できた。
また、PER2リン酸化変異ノックインマウスでは、PER2のタンパク安定性及びPER2の核内移行に異常が見られることを明らかにした。これらが当該モデルマウスにおいてリズム異常が見られる原因であると示唆された。
本モデルマウス、睡眠覚醒障害モデルだけでなく、概日リズムと気分障害の関連を解析するに有用なモデルである。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Role for neonatal D-serine signaling: prevention of physiological and behavioral deficits in adult Pick knockout mice (2016)
  • Author(s): Nomura J, Jaaro-Peled H, Lewis E, Nunez-Abades P, Huppe-Gourgues F, Cash-Padgett T, Emiliani F, Kondo MA, Furuya A, Landek-Salgado MA, Ayhan Y, Kamiya A, Takumi T, Huganir R, Pletnikov M, O'Donnell P, Sawa A
  • Journal Title: Mol Psychiatry Volume: 21 Pages: 386-393
  • DOI: 10.1038/mp.2015.61
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Sequence features assciated with the cleavage efficiency of CRISPR/Cas9 system (2016)
  • Author(s): Liu X, Homma A, Sayadi J, Yang S, Ohashi J, Takumi T
  • Journal Title: Sci Rep Volume: 6 Pages: 19675
  • DOI: 10.1038/srep19675
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Translocated in liposarcoma regulates the distribution and function of mammalian enabled, a modulator of actin dynamics (2016)
  • Author(s): Sugiura T, Matsuda S, Kurosaka S, Nakai N, Fukumoto K, Takahashi T, Maruyama H, Imaizumi K, Matsumoto M, Takumi T
  • Journal Title: FEBS J Volume: 283 Pages: 1475-1487
  • DOI: 10.1111/febs.13685
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] GABA-mediated repulsive coupling between circadian clock neurons in the SCN encodes seasonal time (2015)
  • Author(s): Myung J, Hong S, DeWoskin D, De Schutter E, Forger DB, Takumi T
  • Journal Title: Proc Natl Acad Sci U S A Volume: 112 Pages: E3920-3929
  • DOI: 10.1073/pnas.1421200112
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Distinct roles for GABA across multiple timescales in mammalian circadian timekeeping (2015)
  • Author(s): DeWoskin D, Myung J, Belle MD, Piggins HD, Takumi T, Forger DB
  • Journal Title: Proc Natl Acad Sci U S A Volume: 112 Pages: E3911-3919
  • DOI: 10.1073/pnas.1420753112
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] DEC2-E4BP4 hereodimer represses the transcriptional enhancer activity of the EE element in the Per2 promoter (2015)
  • Author(s): Tanoue S, Fujimoto K, Myung J, Hatanaka F, Kato Y, Takumi T
  • Journal Title: Front Neurol Volume: 6 Pages: 166
  • DOI: 10.3389/fneur.2015.00166
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Constant light enhances synchrony among circadian clock cells and promotes beahvioral rhythms in VPAC2-signaling deficeint mice (2015)
  • Author(s): Hughes AT, Croft CL, Samuels RE, Myung J, Takumi T, Piggins HD
  • Journal Title: Sci Rep Volume: 5 Pages: 14044
  • DOI: 10.1038/srep14044
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Neuroanatomical phenotypes are consistent with autism-like behavioral phenotypes in the 15q11-13 duplication mouse model (2015)
  • Author(s): Ellegood J, Nakai N, Nakatani J, Henkelman M, Takumi T, Lerch J
  • Journal Title: Autism Res Volume: 8 Pages: 545-555
  • DOI: 10.1002/aur.1469
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] FUS/TLS deficiency causes beahvioral and pathological abnoramlities distinct from amyotrophic lateral sclerosis (2015)
  • Author(s): Kino Y, Washizu C, Kurosawa M, Yamada M, Miyazaki H, Akagi T, Hashikawa T, Doi H, Takumi T, Hicks GG, Hattori N, Shimogori T, Nukina N
  • Journal Title: Acta Neuropathol Commun Volume: 3 Pages: 24
  • DOI: 10.1186/s40478-015-0202-6
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Altered microglia in the amygdala are involved in anxiety-related beahviors of a copu number variation mouse model of autism (2015)
  • Author(s): Shigemori T, Sakai A, Takumi T, Itoh Y, Suzuki H
  • Journal Title: J Nippon Med Sch Volume: 82 Pages: 92-99
  • DOI: 10.1272/jnms.82.92
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] MOdel mice for 15q11-13 duplication syndrome exhibit late-onset obesity and altred lipid metabolism (2015)
  • Author(s): Kishimoto R, Tamada K, Liu X, Okubo H, Ise S, Ohta H, Ruf S, Nakatani J, Kohno N, Spitz F, Takumi T
  • Journal Title: Hum Mol Genet Volume: 24 Pages: 4559-4572
  • DOI: 10.1093/hmg/ddv187
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Cerebellar associative sensory learning defects in five mouse autism models (2015)
  • Author(s): Kloth AD, Badura A, Li A, Cherskov A, Connolly SG, Giovannucci A, Bangash MA, Grasselli G, Penagarikano O, Piochon C, Tsai PT, Geschwind DH, Hansel C, Sahin M, Takumi T, Worley PF, Wang SS
  • Journal Title: Elife Volume: 4 Pages: e06085
  • DOI: 10.7554/eLife.06085
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Autism spectrum disorder model mice: Focus on copy number variation and epigenetics (2015)
  • Author(s): Nakai N, Otsuka S, Myung J, Takumi T
  • Journal Title: Sci China Life Sci Volume: 58 Pages: 976-984
  • DOI: 10.1007/s11427-015-4891-7
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Transcriptome profiling of white adipose tissue in a mouse model for 15q duplication syndrome (2015)
  • Author(s): Liu X, Tamada K, Kishimoto R, Okubo H, Ise S, Ohta H, Ruf S, Nakatani J, Kohno N, Spitz F, Takumi T.
  • Journal Title: Genom Data Volume: 5 Pages: 394-396
  • DOI: 10.1016/j.gdata.2015.06.035
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Mammalian circadian clock: Its mechanism, physiology and pathophysiology (2016)
  • Author(s): Toru Takumi
  • Organizer: IBRO/APRC Neuroscience School
  • Place of Presentation: Nagarkot, Nepal
  • Year and Date: 2016-02-09 – 2016-02-13
  • Int'l Joint Research / Invited
• [Presentation] Seasonal encoding in the SCN: circuit principles and GABA (2015)
  • Author(s): Jihwan Myung, Toru Takumi
  • Organizer: 第２２回日本時間生物学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2015-11-21 – 2015-11-22
• [Presentation] Mood and Clock (2015)
  • Author(s): Toru Takumi
  • Organizer: 4th Swiss Chronobiology Meeting
  • Place of Presentation: Fribourg, Switzerland
  • Year and Date: 2015-09-03
  • Int'l Joint Research / Invited
• [Presentation] Phase organization of clock neurons and its implications for mood disorders (2015)
  • Author(s): Forger DB, Myung, J, Belle MDC, Cochran A, DeWoskin D, Joshi A, Stinchcombe A, Walch OJ, Takumi T, Piggins H
  • Organizer: XIV European Biological Rhythms Society (EBRS) and IV World Congress of Chronobiology (WCC)
  • Place of Presentation: Manchester, UK
  • Year and Date: 2015-08-02 – 2015-08-06
  • Int'l Joint Research / Invited
• [Presentation] Plasticity of the circadian clock network enables a seasonal clock (2015)
  • Author(s): Jihwan Myung, Toru Takumi
  • Organizer: 第３８回日本神経科学大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-07-28 – 2015-07-31