Integrative research on mood and clock

• Project/Area Number: 25242077
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Basic / Social brain science
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Takumi Toru 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
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥47,190,000 (Direct Cost: ¥36,300,000、Indirect Cost: ¥10,890,000); Fiscal Year 2015: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000); Fiscal Year 2014: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000); Fiscal Year 2013: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000)
• Keywords: 概日リズム / 気分障害 / 時計遺伝子 / リン酸化 / モデルマウス / 遺伝子 / 生理学 / 神経科学 / 脳神経疾患 / 行動学

Outline of Final Research Achievements

Dysfunction of mood and the circadian clock together represent a large proportion of mental illness with adverse economic impact. Clinical and genetic evidence indicates that the two disorders are co-regulated but direct molecular evidence is lacking. We showed that GSK3β phosphorylation of PER2 is essential for co-regulation of mood and the circadian clock. In rodent depression models, we observed defective circadian rhythms associated with the loss of synchronized phosphorylation of GSK3β. Both molecular and behavioral phenotypes were restored by lithium, a mood stabilizer. GSK3β phosphorylation in PER2 was essential for both mood and circadian behaviors. Strikingly, Per2 mutant mice were resistant to both lithium and learned helplessness, a depression model. Together, these findings show that mood and the circadian clock share a coherent molecular mechanism and reveal the potential for synchronized drug and behavioral therapy of mood and circadian disorders.

Research Products

• [Journal Article] Role for neonatal D-serine signaling: prevention of physiological and bahavioral deficits in adult Pick1 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 Issue: 3 Pages: 386-393
  • DOI: 10.1038/mp.2015.61
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Sequence features associated 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 Issue: 1 Pages: 19675-19675
  • DOI: 10.1038/srep19675
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Translocated in liposarcoma regulates the ditrubution and funciton 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 Issue: 8 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 Issue: 29
  • DOI: 10.1073/pnas.1421200112
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Distinct roles for GABA across multiple timesacels 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 Issue: 29
  • DOI: 10.1073/pnas.1420753112
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] DEC2-E4BP4 heterodimer represses the trancriptional 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: 166-166
  • DOI: 10.3389/fneur.2015.00166
  • Peer Reviewed / Open Access / Int'l Joint Research / 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 Issue: 1 Pages: 14044-14044
  • DOI: 10.1038/srep14044
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Consistency between the neuroanatomical and behavioural phenotype in the 15q11-13 duplication mouse model (2015)
  • Author(s): Ellegood, J. Nakai, N., Nakatani, J., Henkelman, R. M., Takumi, T. and Lerch, J.
  • Journal Title: Autism Res. Volume: in press Issue: 5 Pages: 545-555
  • DOI: 10.1002/aur.1469
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] FUS/TLS deficiency causes behavioral and pathological abnormalities 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 Issue: 1 Pages: 24-24
  • DOI: 10.1186/s40478-015-0202-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Altered Microglia in the Amygdala Are Involved in Anxiety-related Behaviors of a Copy Number Variation Mouse Model of Autism (2015)
  • Author(s): Shigemori, T., Sakai, A., Takumi, T., Itoh, Y. and Suzuki H.
  • Journal Title: Journal of Nippon Medical School Volume: 82 Issue: 2 Pages: 92-99
  • DOI: 10.1272/jnms.82.92
  • NAID: 130005068463
  • ISSN: 1345-4676, 1347-3409
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] MOdel mice for 15q11-13 duplication syndrome exhibit late-onset obesity and altered 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 Issue: 16 Pages: 4559-4572
  • DOI: 10.1093/hmg/ddv187
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Cerebllar 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: 9
  • 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 Issue: 10 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
• [Journal Article] FUS/TLS deficiency causes behavioral and pathological abnormalities 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, G.G., Hattori, N., Shimogori, T., Nukina, N.
  • Journal Title: Acta Neuropathol. Commun. Volume: 25 Pages: 24-24
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clustering autism-using neuroanatomincal differences in 30 mouse models related to autism and gain insight into the heterogeneity of the disorder. (2015)
  • Author(s): Ellegood, J. et al.
  • Journal Title: Mol. Psychiatry Volume: 20 Issue: 1 Pages: 118-125
  • DOI: 10.1038/mp.2014.98
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Role for neonatal D-serine signaling: prevention of physiological and behavioral deficits in adult Pick1 knockout mice (2015)
  • Author(s): Nomura, J., Jaaro-Peled, H., Lewis, E., Nunez-Abades, P., Huppe-Gourgues, F., Cash-Padgett, T., Emiliani, F., Kondo, M. A., Furuya, A., Landek-Salgado, M. A., Ayhan, Y., Kamiya, A., Takumi, T., Huganir, R., Pletnikov, M., O’Donnell, P. and Sawa, A.
  • Journal Title: Mol. Psychiatry Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A novel protein, CHRONO, functions as a core component of the mammalian circadian clock. (2014)
  • Author(s): Goriki, A., Hatanaka, F., Myung J., Kim, J., Yoritaka, T., Tanoue, S., Abe, T., Kiyonari, H., Fujimoto, K., Kato, Y., Todo, T., Matsubara, A., Forger, D. and Takumi, T.
  • Journal Title: PLoS Biol. Volume: 12 Issue: 4 Pages: e1001839-e1001839
  • DOI: 10.1371/journal.pbio.1001839
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genomic and Genetic Aspects of Autism Spectrum Disorder. (2014)
  • Author(s): Liu, X. and Takumi, T.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 452 Issue: 2 Pages: 244-253
  • DOI: 10.1016/j.bbrc.2014.08.108
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Enhanced synapse remodeling as a common phenotype in mouse models of autism. (2014)
  • Author(s): Isshiki, M., Tanaka, S., Kuriu, T., Tabuchi, K., Takumi, T. and Okabe, S.
  • Journal Title: Nat. Commun. Volume: 5 Issue: 1 Pages: 4742-4742
  • DOI: 10.1038/ncomms5742
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Deficits in cerebellar plasticity and motor learning in a copy number variation mouse model of autism spectrum disorder. (2014)
  • Author(s): Pichon, C., Kloth, A. D., Grasselli, G., Titley, H. K., Nakayama, H., Hashimoto, K., Wan, V., Simmons, D. H., Eissa, T., Nakatani, J., Cherskov, A., Miyazaki, T., Watanabe, M., Takumi T., Kano, M., Wang S. S-H. and Hansel, C.
  • Journal Title: Nat. Commun. Volume: 5 Issue: 1 Pages: 5586-5586
  • DOI: 10.1038/ncomms6586
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Helix-loop-helix protein Id2 stabilizes mammalian circadian oscillation under constant light conditions (2013)
  • Author(s): Adachi AA et al
  • Journal Title: Zoolog Sci Volume: 30 Issue: 12 Pages: 1011-8
  • DOI: 10.2108/zsj.30.1011
  • Peer Reviewed
• [Journal Article] Nuclear receptor-mediated cell-autonomous oscillatory expression of the circadian transcription factor, neuronal PAS domain protein 2. (2013)
  • Author(s): Matsumura R et al.
  • Journal Title: J Biol Chem Volume: 288 Issue: 51 Pages: 36548-53
  • DOI: 10.1074/jbc.m113.517235
  • Peer Reviewed
• [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
  • 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
• [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
  • 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
• [Presentation] A novel protein, CHRONO, functions as a core component of the mammalian circadian clock (2014)
  • Author(s): Fumiyuki Hatanaka, Akihiro Goriki, Jihwan Myung, Jae Kyoung Kim, Katusmi Fujimoto, Yukio Kato, Ako Matsubara, Daniel Forger, Toru Takumi
  • Organizer: Neuroscience 2014
  • Place of Presentation: Washington Conference Center, Washington DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Rhythm and blues in mammals (2014)
  • Author(s): Toru Takumi
  • Organizer: 1st IBRO/APRC Chandigarh Neuroscience School
  • Place of Presentation: Panjab University, Chandigarh, India
  • Year and Date: 2014-11-02 – 2014-11-08
  • Invited
• [Presentation] Plasticity in the suprachiasmatic nucleus lies in individual neurons (2014)
  • Author(s): Jihwan Myung, Toru Takumi
  • Organizer: 第３７回日本神経科学大会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Plasticity in spatial patterning of clock phases in the neuron of the mammalian circadian center (2014)
  • Author(s): Jihwan Myung and Toru Takumi
  • Organizer: Joint Annual Meeting of the Japanese Society for Mathematical Biology and the Society for Mathematical Biology
  • Place of Presentation: Osaka International Conference Center, Osaka
  • Year and Date: 2014-07-28 – 2014-08-01
  • Invited
• [Presentation] Rhythms and blues in mice and cells (2014)
  • Author(s): Toru Takumi
  • Organizer: Symposium on “Sleep, circadian rhythms and psychiatric disorders”
  • Place of Presentation: Institute Pasteur, Paris, France
  • Year and Date: 2014-05-13
  • Invited
• [Presentation] Stress and circadian clock (2014)
  • Author(s): Toru Takumi
  • Organizer: 第９１回日本生理学会大会
  • Place of Presentation: 鹿児島
  • Invited
• [Presentation] 概日リズムとうつ病の調節機構としてのPERIOD2-glycogen synthase kinase 3β経路 (2013)
  • Author(s): 山脇洋輔、高野敦子、仲西萌絵、玉田鉱太、畠中史幸、内匠透
  • Organizer: Neuro 2013第３６回日本神経科学大会、第５６回日本神経化学大会、第２３回日本神経回路学会大会
  • Place of Presentation: 京都
• [Presentation] Negative coupling as a mechanism of photoperiodic encoding (2013)
  • Author(s): Jihwan Myung, Sungho Hong, Erik De Schutter, Toru Takumi
  • Organizer: EBRS XIII Congress
  • Place of Presentation: Munich, Germany
• [Presentation] 新規時計遺伝子Chronoの統合的解析 (2013)
  • Author(s): 郷力昭宏、畠中史幸、Jihwan Myung、寄高崇志、田ノ上信太郎、阿部高也、清成寛、藤本勝巳、加藤幸夫、松原明郎、内匠透
  • Organizer: 第８６回日本生化学会大会
  • Place of Presentation: 横浜
• [Presentation] A novel protein, CHRONO, functions as a core component of the mammalian clock. (2013)
  • Author(s): Fumiyuki Hatanaka, Akihiro Goriki, Jihwan Myung, Toru Takumi
  • Organizer: 第３６回日本分子生物学会年会
  • Place of Presentation: 神戸
• [Presentation] The final core clock gene, Chrono
  • Author(s): Toru Takumi
  • Organizer: 2nd Swiss Chronobiology Meeting
  • Place of Presentation: Fribourg, Switzerland
  • Invited
• [Presentation] 新たなコア時計遺伝子Chrono
  • Author(s): 畠中史幸、内匠透
  • Organizer: 第２０回日本時間生物学会学術大会
  • Place of Presentation: 東大阪、大阪
• [Presentation] Rhythm and blues in mammals
  • Author(s): Toru Takumi
  • Organizer: The 2nd Annual IIIS Symposium
  • Place of Presentation: Tsukuba, Ibaragi
  • Invited