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Study of cerebral synapses and circuits using two-photon microscopy and novel optoprobes

Research Project

Project/Area Number 26221001
Research Category

Grant-in-Aid for Scientific Research (S)

Allocation TypeSingle-year Grants
Research Field Neurophysiology / General neuroscience
Research InstitutionThe University of Tokyo

Principal Investigator

Kasai Haruo  東京大学, 大学院医学系研究科(医学部), 教授 (60224375)

Co-Investigator(Kenkyū-buntansha) 林 朗子 (高木朗子)  東京大学, 医学(系)研究科(研究院), 講師 (60415271)
Research Collaborator TAKAHASHI Noriko  
NOGUCHI Jun  
YAGISHITA Sho  
Project Period (FY) 2014-05-30 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥195,000,000 (Direct Cost: ¥150,000,000、Indirect Cost: ¥45,000,000)
Fiscal Year 2018: ¥34,710,000 (Direct Cost: ¥26,700,000、Indirect Cost: ¥8,010,000)
Fiscal Year 2017: ¥34,710,000 (Direct Cost: ¥26,700,000、Indirect Cost: ¥8,010,000)
Fiscal Year 2016: ¥34,710,000 (Direct Cost: ¥26,700,000、Indirect Cost: ¥8,010,000)
Fiscal Year 2015: ¥36,660,000 (Direct Cost: ¥28,200,000、Indirect Cost: ¥8,460,000)
Fiscal Year 2014: ¥54,210,000 (Direct Cost: ¥41,700,000、Indirect Cost: ¥12,510,000)
Keywordsシナプス / 学習・記憶 / ドーパミン / 大脳皮質 / 大脳基底核 / グルタミン酸 / 蛋白質合成 / 条件学習 / 精神症状 / D2受容体 / 記憶 / 光刺激 / 光プローブ / 2光子顕微鏡 / 蛍光プローブ / スパイン / カルシウム / 樹状突起スパイン / 学習
Outline of Final Research Achievements

We have developed the synaptic probe (AS-probe) that can label and erase the labeled dendritic spines by blue laser irradiation. Using AS-probe, we have operationally shown the involvement of spines in motor learning in the motor cortex (Nature 2015) and anti-depressant effects of spine generations in the prefrontal cortex by s-ketamine (Science 2019). We are extending our technique to presynaptic boutons (in preparation). We also studied the cellular mechanisms of the reward classical conditioning, and found that the spine enlargement of D1 neurons can explain the reward timing found in earlier works (Science 2014). We have also clarified that discrimination learning involves spine enlargement of D2 neurons, and is impaired in psychotic symptoms which can be ameliorated by D2 antagonist (an antipsychotic drug), pointing to a new understanding of D2 receptors (in preparations).

Academic Significance and Societal Importance of the Research Achievements

心を育む脳の働きは神経回路の電気化学的活動で起きると信じられている。しかし、学習するときには、これに加えて神経を繋ぐシナプスが運動することを我々は見出し、これが運動学習、うつ症状など個体レベルで使われていることを証明した(Nature 2015, Science 2019)。また、条件付け学習の際には、脳内報酬信号であるドーパミンは適切なタイミングで神経から放出されれば記憶を強く促す作用があることを明らかにした(Science 2014)。この個性的に運動する脳の描像は我々の個性や病気を理解する新しい鍵となるであろう。

Assessment Rating
Verification Result (Rating)

A

Result (Rating)

A+: Progress in the research exceeds the initial goal. More than expected research results are expected.

Report

(10 results)
  • 2019 Research Progress Assessment (Verification Result) ( PDF )
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report   Abstract(Research Progress Assessment) ( PDF )   Research Progress Assessment (Result) ( PDF )
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • 2014 Abstract ( PDF )   Annual Research Report

Research Products

(43 results)

All 2019 2018 2017 2016 2015 Other

All Int'l Joint Research (4 results) Journal Article (13 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 13 results,  Open Access: 10 results,  Acknowledgement Compliant: 8 results) Presentation (23 results) (of which Int'l Joint Research: 17 results,  Invited: 22 results) Remarks (3 results)

  • [Int'l Joint Research] University of North Carolina(米国)

    • Related Report
      2015 Annual Research Report
  • [Int'l Joint Research] Cardiff University(英国)

    • Related Report
      2015 Annual Research Report
  • [Int'l Joint Research] University of North Carolina(米国)

    • Related Report
      2014 Annual Research Report
  • [Int'l Joint Research] Cardiff University(英国)

    • Related Report
      2014 Annual Research Report
  • [Journal Article] Calcineurin knockout mice show a selective loss of small spines2018

    • Author(s)
      Okazaki H, Hayashi-Takagi A, Nagaoka A, Negishi M, Ucar H, Yagishita S, Ishii K, Toyoizumi T, Kasai H
    • Journal Title

      Neurosci Lett

      Volume: 671 Pages: 99-102

    • DOI

      10.1016/j.neulet.2018.02.006

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Chemical Landscape for Tissue Clearing Based on Hydrophilic Reagents.2018

    • Author(s)
      Tainaka K. Murakami TC, Susaki EA, Shimizu C, Saito R, Takahashi K, Hayashi-Takagi A, Sekiya H, Arima Y, Nojima S, Ikemura M, Ushiku T, Shimizu Y, Murakami M, Tanaka KF, Iino M, Kasai H, Sasaoka T. Kobayashi K, Miyazono K, Morii E, Isa T, Fukayama M, Kakita A. Ueda HR.
    • Journal Title

      Cell Reports

      Volume: 24 Pages: 2196-2210

    • DOI

      10.1016/j.celrep.2018.07.056

    • NAID

      120006542018

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] In Vivo Volume Dynamics of Dendritic Spines in the Neocortex of Wild-Type and Fmr1 KO Mice.2018

    • Author(s)
      Ishii K, Nagaoka A, Kishida Y, Okazaki H, Yagishita S, Ucar H, Takahashi N, Saito N, Kasai H.
    • Journal Title

      eneuro

      Volume: 5 Pages: 1-13

    • DOI

      10.1523/eneuro.0282-18.2018

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Strong stimulation triggers full fusion exocytosis and very slow endocytosis of the small dense core granules in carotid glomus cells.2018

    • Author(s)
      Tse A, Lee AK, Takahashi N, Gong A, Kasai H, Tse FW.
    • Journal Title

      J. Neurogenetics

      Volume: 32 Pages: 267-278

    • DOI

      10.1080/01677063.2018.1497629

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Engineering Pak1 allosteric switches2017

    • Author(s)
      Dagliyan, O., Karginov, A., Yagishita, S., Gale, M., Wang, H., DerMardirossian, C., Wells, C., Dokholyan, N., Kasai, H. & Hahn, K.
    • Journal Title

      ACS Synthetic Biology

      Volume: 6 Pages: 1257-1262

    • DOI

      10.1021/acssynbio.6b00359

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Abnormal intrinsic dynamics of dendritic spines in a fragile X syndrome mouse model in vivo.2016

    • Author(s)
      Nagaoka A, Takehara H, _Hayashi-Takagi A_, Noguchi J, Ishii K, Shirai F, Yagishita S, Akagi T, Ichiki T, Kasai H.
    • Journal Title

      Scientific Reports.

      Volume: 6 Pages: 26651-26651

    • DOI

      10.1038/srep26651

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Implantable Microfluidic Device with Hydrogel Permeable Membrane for Delivering Chemical Compounds and Imaging Neural Cells in Living Mice2016

    • Author(s)
      Takehara, H., Nagaoka, A., Noguchi, J., Akagi, T., Kasai, H. & Ichiki, T.
    • Journal Title

      J. Photopol. Sci. Technol.

      Volume: 29 Issue: 4 Pages: 513-518

    • DOI

      10.2494/photopolymer.29.513

    • NAID

      130005261780

    • ISSN
      0914-9244, 1349-6336
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Design and Synthesis of a 4-Nitrobromobenzene Derivative Bearing an Ethylene Glycol Tetraacetic Acid Unit for a New Generation of Caged Calcium Compounds with Two-Photon Absorption Properties in the Near-IR Region and Their Application in Vivo2016

    • Author(s)
      Satish Jakkampudi, Manabu Abe, Naomitsu Komori Ryukichi Takagi, Ko Furukawa, Claudine Katan, Wakako Sawada, Noriko Takahashi, and Haruo Kasai
    • Journal Title

      ACS Omega

      Volume: 1 Pages: 193-201

    • DOI

      10.1021/acsomega.6b00119

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] State-dependent diffusion of actin-depolymerizing factor/cofilin underlies the enlargement and shrinkage of dendritic spines.2016

    • Author(s)
      Noguchi, J., Hayama, T., Watanabe, S., Ucar, H., Yagishita, S., Takahashi, N. & Kasai, H.
    • Journal Title

      Sci Rep.

      Volume: 6 Pages: 32897-32897

    • DOI

      10.1038/srep32897

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Opposing roles for SNAP23 in secretion in exocrine and endocrine pancreatic cells2016

    • Author(s)
      Masataka Kunii, et al,
    • Journal Title

      J Cell Biol.

      Volume: 215 Pages: 121-138

    • DOI

      10.1083/jcb.201604030

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Design and synthesis of a new chromophore, 2-(4-nitrophenyl)benzofuran, for two-photon uncaging using near-IR light2016

    • Author(s)
      Komori, N.; Jakkampudi, S.; Motoishi, R.; Abe, M.; Kamada, K.; Furukawa, K.; Katan, C.; Sawada, W.; Takahashi, N.; Kasai, H.; Xue, B.; Kobayashi, T.
    • Journal Title

      Chem Commun (Camb)

      Volume: 52 Pages: 331-334

    • DOI

      10.1039/c5cc07664a

    • Related Report
      2015 Annual Research Report 2014 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Labelling and optical erasure of synaptic memory traces in the motor cortex.2015

    • Author(s)
      Hayashi-Takagi A, Yagishita S, Nakamura M, Shirai F, Wu YI, Loshbaugh AL, Kuhlman B, Hahn KM, Kasai H
    • Journal Title

      Nature

      Volume: 525 Pages: 333-338

    • DOI

      10.1038/nature15257

    • Related Report
      2015 Annual Research Report 2014 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Two-photon fluorescence lifetime imaging of primed SNARE complexes in presynaptic terminals and β cells.2015

    • Author(s)
      Takahashi N#, Sawada W#, Noguchi J#, Watanabe S#, Ucar H, Hayashi-Takagi A, Yagishita S, Ohno M, Tokumaru H & Kasai H. (#Equally contributed).
    • Journal Title

      Nat Commun. 2015 Oct 6;6:8531. doi:

      Volume: 6 Pages: 1-15

    • DOI

      10.1038/ncomms9531

    • Related Report
      2015 Annual Research Report 2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] Dopamine receptors, synaptic plasticity and psychiatric disorders2019

    • Author(s)
      H. Kasai
    • Organizer
      Japan-UK Neuroscience Symposium 2019
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Mechanical forces of spine enlargement detected by presynaptic FRET/FLIM imaging2019

    • Author(s)
      H. Kasai
    • Organizer
      Federation of the Asian and Oceanian Physiolgocial Societies (FAOPS), Symposium
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Synaptic optogenetics for memory structures.2018

    • Author(s)
      H. Kasai
    • Organizer
      World Congress of Pharmacological Sciences 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Dopamine actions on the dendritic spines for reward and aversive learning in the nucleus accumbens2018

    • Author(s)
      H. Kasai
    • Organizer
      World Congress of Pharmacological Sciences
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Bidirectional tuning of behavioral conditioning and synaptic plasticity by dopamine in the nucleus accumbens, Japan-Canadian Joint Symposium2018

    • Author(s)
      H. Kasai, Y. Iino, R. Nakazato, K. Yamaguchi, T. Sawada, S. Yagishita
    • Organizer
      Japanese Society of Neuroscience 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Synaptic optogenetics for memory structures2018

    • Author(s)
      H. Kasai
    • Organizer
      Mini-Symposium, Japanese Society of Neuroscience 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Identification of the synapses involved in memory formation2017

    • Author(s)
      Haruo Kasai
    • Organizer
      The brain Conferences
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Dopamine actions on the dendritic spines of medium spiny neurons in the nucleus accumbens for classical conditioning2017

    • Author(s)
      Haruo Kasai, Yusuke Iino, Yoshitomo Maeda, Ryo Nakazato, Sho Yagishita
    • Organizer
      新学術国際シンポジウム
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Dopamine actions on the structural plasticity of dendritic spines2017

    • Author(s)
      Haruo Kasai
    • Organizer
      Gordon Research Conference on Synaptic Transmission
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Plasticity and fluctuations of dendritic spines; synaptic bases of memory and mental disorders2017

    • Author(s)
      Haruo Kasai
    • Organizer
      Neurosci 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Dopamine actions on the dendritic spines and conditioned behaviors2017

    • Author(s)
      Haruo Kasai
    • Organizer
      The 48th NIPS International Symposium on “Neural circuitry and plasticity underlying brain functions”
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 2光子励起蛍光寿命画像法で解析した開口放出部位におけるSNAP25の分子構造、第94回日本生理学会2017

    • Author(s)
      高橋、渡辺、澤田、河西
    • Organizer
      第94回日本生理学会
    • Place of Presentation
      アクトシティ浜松(静岡県浜松市)
    • Related Report
      2016 Annual Research Report
  • [Presentation] Plasticity and fluctuations of dendritic spines studied with synaptic optogenetics.2016

    • Author(s)
      Haruo Kasai
    • Organizer
      iCeMS, MRC and AMED workshop
    • Place of Presentation
      Cambridge, UK
    • Year and Date
      2016-03-22
    • Related Report
      2015 Annual Research Report 2014 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Structural Plasticity of Dendritic Spines in NAc for Reinforcement Learning2016

    • Author(s)
      Haruo Kasai
    • Organizer
      Gordon Conference
    • Place of Presentation
      Ventura, CA, USA
    • Year and Date
      2016-03-03
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Structural Plasticity of Dendritic Spines in NAc for Reinforcement Learning2016

    • Author(s)
      Haruo Kasai
    • Organizer
      Gordon Conference
    • Place of Presentation
      Ventural, CA, USA
    • Year and Date
      2016-03-03
    • Related Report
      2014 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Synaptic optogenetics2016

    • Author(s)
      Haruo Kasai
    • Organizer
      Neocortical Organization Ⅲ
    • Place of Presentation
      東京大学小柴ホール(東京都文京区)
    • Year and Date
      2016-02-12
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Synaptic optogenetics2016

    • Author(s)
      Haruo Kasai
    • Organizer
      Neocortical Organization Ⅲ
    • Place of Presentation
      東京大学小柴ホール(東京都,文京区)
    • Year and Date
      2016-02-12
    • Related Report
      2014 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Rapid regulations of spine plasticity by dopamine in the D1 and D2 projection neurons in the nucleus accumbens. Cold Spring Harbor Asia Conference2016

    • Author(s)
      Haruo Kasai, Sho Yagishita, Yusuke Iino, Yosuke Nakazato, Yoshitomo Maeda
    • Organizer
      Cold Spring Harbor Asia Conference
    • Place of Presentation
      Suzhou, China
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Plasticity and fluctuations of dendritic spines in mice models of autism and schizophrenia.2016

    • Author(s)
      Haruo Kasai
    • Organizer
      Symposium in JNS meeting 2016
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Dendritic spines shaping memory and behaviors2016

    • Author(s)
      Haruo Kasai
    • Organizer
      Special Lecture, Society for Neuroscience
    • Place of Presentation
      San Diego, CA, USA
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Spine synapses shaping memory and behavior, Lecture, Nanyang Technical University2016

    • Author(s)
      Haruo Kasai
    • Organizer
      Lecture, Nanyang Technical University
    • Place of Presentation
      Nanyang Drive, Singapore
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 大脳シナプスの生理と精神神経疾患2015

    • Author(s)
      河西春郎
    • Organizer
      青森ドーパミン研究会
    • Place of Presentation
      ホテルJALシティ青森(青森県青森市)
    • Year and Date
      2015-11-18
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] 大脳シナプスの生理と精神神経疾患2015

    • Author(s)
      河西春郎
    • Organizer
      青森ドーパミン研究会
    • Place of Presentation
      ホテルJALシティ青森(青森県,青森市)
    • Year and Date
      2015-11-18
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Remarks] 河西研究室

    • URL

      http://www.bm2.m.u-tokyo.ac.jp/index.html

    • Related Report
      2017 Annual Research Report
  • [Remarks] 河西研究室ホームページ

    • URL

      http://www.bm2.m.u-tokyo.ac.jp

    • Related Report
      2016 Annual Research Report
  • [Remarks] 河西研究室

    • URL

      http://www.bm2.m.u-tokyo.ac.jp

    • Related Report
      2015 Annual Research Report 2014 Annual Research Report

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Published: 2014-06-05   Modified: 2022-04-28  

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