記憶・情動における多領野間脳情報動態の光学的計測と制御

• Project Area: Brain information dynamics underlying multi-area interconnectivity and parallel processing
• Project/Area Number: 17H06312
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: The University of Tokyo
• Principal Investigator: 尾藤 晴彦 東京大学, 大学院医学系研究科(医学部), 教授 (00291964)
• Project Period (FY): 2017-06-30 – 2022-03-31
• Project Status: Granted (Fiscal Year 2021)
• Budget Amount: ¥219,440,000 (Direct Cost: ¥168,800,000、Indirect Cost: ¥50,640,000); Fiscal Year 2021: ¥40,560,000 (Direct Cost: ¥31,200,000、Indirect Cost: ¥9,360,000); Fiscal Year 2020: ¥43,680,000 (Direct Cost: ¥33,600,000、Indirect Cost: ¥10,080,000); Fiscal Year 2019: ¥43,680,000 (Direct Cost: ¥33,600,000、Indirect Cost: ¥10,080,000); Fiscal Year 2018: ¥46,800,000 (Direct Cost: ¥36,000,000、Indirect Cost: ¥10,800,000); Fiscal Year 2017: ¥44,720,000 (Direct Cost: ¥34,400,000、Indirect Cost: ¥10,320,000)
• Keywords: 神経科学 / 脳・神経 / カルシウム / 海馬

Outline of Annual Research Achievements

本計画では、以下の３点の研究項目に焦点を絞り、計画研究を実施してしている。項目１）活性化細胞集団と記憶痕跡を多領野で同時に標識する活性化回路標識操作法を実現し、Ca2+イメージングと組み合わせ、海馬から大脳皮質に至る記憶構造ループにおける脳情報動態を解明する。項目２）記憶痕跡の大脳皮質での創発・覚醒を制御する興奮性・抑制性細胞の活動バランスを、記憶課題遂行中の自由行動下マウス脳のライブCa2+イメージングにより明らかにする。項目３）記憶・情動における多領野間連関・並列処理を司る脳情報動態を光遺伝学的に再現し、情報表現にとって必要十分な成分を解明する。
令和２年度には、前年度までに得た成果に基づき、以下のような研究を実施した。項目１では、脳全体での記憶痕跡標識操作を実現する遺伝子改変マウスを用い、記憶痕跡の性質を持ちうる海馬歯状回細胞ならびに前頭皮質細胞のそれぞれが、近時記憶の想起、遠隔記憶の想起に必要十分かについて検討した。さらに記憶痕跡活性化の新たな指標としてCREBリン酸化のリアルタイムイメージングを試みた。項目２では、活動依存的人工プロモータの改変実験により、行動課題遂行中の抑制性神経細胞アンサンブル操作が実現可能かについて予備的検討を実施した。項目3では、近時記憶から遠隔記憶へ切り替わるタイミングにおいて、大脳皮質記憶痕跡の修飾が行われるのか、その際に、記銘期の海馬中心的記憶痕跡細胞と相互作用するか否かについて、実証実験を続けた。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

本研究では、項目１）について、活性化細胞集団と記憶痕跡を多領野で同時に標識する活性化回路標識操作法を実現し、現在Ca2+イメージングとの組み合わせを試みている。また、項目２）における興奮性・抑制性細胞の活動バランスを、頭蓋固定化でイメージングする手法を確立している。さらに、項目３）では、記憶・情動における多領野間連関・並列処理を司る脳情報動態を光遺伝学的に再現している。以上より、各研究項目について、順調に検討が進んでいると考えている。

Strategy for Future Research Activity

本研究の目標とする各項目について、最終年度においては、海馬から大脳皮質に至る記憶構造ループにおける脳情報動態を解明し、記憶課題遂行中の自由行動下マウス脳の興奮性・抑制性細胞のライブCa2+イメージングを実現していく。これにより、記憶・情動の長期記憶に関わる情報表現にとって必要十分な各種成分のさらなる理解を進め、最終年度研究成果の取りまとめに役立てる計画である。

Research Products

• [Int'l Joint Research] Stanford University(米国)
• [Int'l Joint Research] Cornell University/Stanford University(米国)
• [Int'l Joint Research] Stanford University(米国)
• [Int'l Joint Research] Cornell University/Stanford University(米国)
• [Int'l Joint Research] MIT(米国)
• [Int'l Joint Research] Stanford University(米国)
• [Journal Article] A Photodeactivatable Antagonist for Controlling CREB-Dependent Gene Expression (2020)
  • Author(s): Imoto Takuma、Minoshima Masafumi、Yokoyama Tatsushi、Emery Ben P.、Bull Steven D.、Bito Haruhiko、Kikuchi Kazuya
  • Journal Title: ACS Central Science Volume: 6 Issue: 10 Pages: 1813-1818
  • DOI: 10.1021/acscentsci.0c00736
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comparative Studies of the Fluorescence Properties of Microbial Rhodopsins: Spontaneous Emission Versus Photointermediate Fluorescence (2020)
  • Author(s): Kojima Keiichi、Kurihara Rika、Sakamoto Masayuki、Takanashi Tsukasa、Kuramochi Hikaru、Zhang Xiao Min、Bito Haruhiko、Tahara Tahei、Sudo Yuki
  • Journal Title: The Journal of Physical Chemistry B Volume: 124 Issue: 34 Pages: 7361-7367
  • DOI: 10.1021/acs.jpcb.0c06560
  • Peer Reviewed
• [Journal Article] Development of an L-type Ca 2+ channel-dependent Ca 2+ transient during the radial migration of cortical excitatory neurons (2020)
  • Author(s): Horigane S, Hamada S, Kamijo S, Yamada H, Yamasaki M, Watanabe M, Bito H, Ohtsuka T, Takemoto-Kimura S
  • Journal Title: Neurosci Res Volume: S0168-0102(20)30391-6 Pages: 30391-6
  • DOI: 10.1016/j.neures.2020.06.003
  • Peer Reviewed / Open Access
• [Journal Article] Photolytic Release of a Caged Inhibitor of an Endogenous Transcription Factor Enables Optochemical Control of CREB-Mediated Gene Expression (2019)
  • Author(s): Imoto Takuma、Kawase Akihiro、Minoshima Masafumi、Yokoyama Tatsushi、Bito Haruhiko、Kikuchi Kazuya
  • Journal Title: Organic Letters Volume: 22 Issue: 1 Pages: 22-25
  • DOI: 10.1021/acs.orglett.9b03568
  • Peer Reviewed
• [Journal Article] Kilohertz two-photon brain imaging in awake mice. (2019)
  • Author(s): Zhang T, Hernandez O, Chrapkiewicz R, Shai A, Wagner MJ, Zhang Y, Wu CH, Li JZ, Inoue M, Gong Y, Ahanonu B, Zeng H, Bito H, Schnitzer MJ.
  • Journal Title: Nature Methods Volume: 16 Issue: 11 Pages: 1119-1122
  • DOI: 10.1038/s41592-019-0597-2
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Rational engineering of XCaMPs, a multicolor GECI suite for in vivo imaging of complex brain circuit dynamics. (2019)
  • Author(s): Inoue M, Takeuchi A, Manita S, Horigane S-i, Sakamoto M, Kawakami R, Yamaguchi K, Otomo K, Yokoyama H, Kim R, Yokoyama T, Takemoto-Kimura S, Abe M, Okamura M, Kondo Y, Quirin S, Ramakrishnan C, Imamura T, Sakimura K, Nemoto T, Kano M, Fujii H, Deisseroth K, Kitamura K, Bito H.
  • Journal Title: Cell Volume: 177 Issue: 5 Pages: 1346-1360
  • DOI: 10.1016/j.cell.2019.04.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. (2019)
  • Author(s): Moda-Sava RN, Murdock MH, Parekh PK, Fetcho RN, Huang BS, Huynh TN, Witztum J, Shaver DC, Rosenthal DL, Alway EJ, Lopez K, Meng Y, Nellissen L, Grosenick L, Milner TA, Deisseroth K, Bito H, Kasai H, Liston C.
  • Journal Title: Science Volume: 364 Issue: 6436
  • DOI: 10.1126/science.aat8078
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Involvement of SRF coactivator MKL2 in BDNF-mediated activation of the synaptic activity-responsive element in the Arc gene. (2019)
  • Author(s): Kikuchi K, Ihara D, Fukuchi M, Tanabe H, Ishibashi Y, Tsujii J, Tsuda M, Kaneda M, Sakagami H, Okuno H, Bito H, Yamazaki Y, Ishikawa M, Tabuchi A.
  • Journal Title: Journal of Neurochemistry Volume: 148 Issue: 2 Pages: 204-218
  • DOI: 10.1111/jnc.14596
  • Peer Reviewed / Open Access
• [Journal Article] Long-term consolidation of ensemble neural plasticity patterns in hippocampal area CA1. (2018)
  • Author(s): Attardo A, Lu J, Kawashima T, Okuno H, Fitzgerald JE, Bito H, Schnitzer MJ.
  • Journal Title: Cell Reports Volume: 25 Issue: 3 Pages: 640-650
  • DOI: 10.1016/j.celrep.2018.09.064
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Astrocytes in the mouse visual cortex reliably respond to visual stimulation (2018)
  • Author(s): Sonoda Keita、Matsui Teppei、Bito Haruhiko、Ohki Kenichi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 505 Issue: 4 Pages: 1216-1222
  • DOI: 10.1016/j.bbrc.2018.10.027
  • Peer Reviewed
• [Journal Article] Locally coordinated synaptic plasticity of visual cortex neurons in vivo. (2018)
  • Author(s): El-Boustani S, Ip JPK, Breton-Provencher V, Knott GW, Okuno H, Bito H, Sur M.
  • Journal Title: Science Volume: 360 Issue: 6395 Pages: 1349-1354
  • DOI: 10.1126/science.aao0862
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A Critical Neurodevelopmental Role for L-Type Voltage-Gated Calcium Channels in Neurite Extension and Radial Migration (2018)
  • Author(s): Kamijo Satoshi、Ishii Yuichiro、Horigane Shin-ichiro、Suzuki Kanzo、Ohkura Masamichi、Nakai Junichi、Fujii Hajime、Takemoto-Kimura Sayaka、Bito Haruhiko
  • Journal Title: The Journal of Neuroscience Volume: 38 Issue: 24 Pages: 5551-5566
  • DOI: 10.1523/jneurosci.2357-17.2018
  • Peer Reviewed
• [Journal Article] CaMKIIβ is localized in dendritic spines as both drebrin-dependent and drebrin-independent pools. (2018)
  • Author(s): Yamazaki H, Sasagawa Y, Yamamoto H, Bito H, Shirao T.
  • Journal Title: Journal of Neurochemistry Volume: 146 Issue: 2 Pages: 145-159
  • DOI: 10.1111/jnc.14449
  • Peer Reviewed
• [Journal Article] Delayed Degradation and Impaired Dendritic Delivery of Intron-Lacking EGFP-Arc/Arg3.1 mRNA in EGFP-Arc Transgenic Mice. (2018)
  • Author(s): Steward O, Matsudaira Yee K, Farris S, Pirbhoy PS, Worley P, Okamura K, Okuno H, Bito H.
  • Journal Title: Front Mol Neurosci. Volume: 10 Pages: 435-435
  • DOI: 10.3389/fnmol.2017.00435
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inverse synaptic tagging: An inactive synapse-specific mechanism to capture activity-induced Arc/arg3.1 and to locally regulate spatial distribution of synaptic weights. (2018)
  • Author(s): Okuno H, Minatohara K, Bito H.
  • Journal Title: Semin Cell Dev Biol. Volume: 77 Pages: 43-50
  • DOI: 10.1016/j.semcdb.2017.09.025
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Higher Arc Nucleus-to-Cytoplasm Ratio during Sleep in the Superficial Layers of the Mouse Cortex. (2017)
  • Author(s): Honjoh S, de Vivo L, Okuno H, Bito H, Tononi G, Cirelli C.
  • Journal Title: Front Neural Circuits. Volume: 11 Pages: 60-60
  • DOI: 10.3389/fncir.2017.00060
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Plasticity and memory mechanisms in vivo (2020)
  • Author(s): Bito H
  • Organizer: Stockholm Trio & University of Tokyo Strategic Partnership Workshop
  • Int'l Joint Research / Invited
• [Presentation] Lessons learned from elucidating calcium-dependent neural circuit control mechanisms (2020)
  • Author(s): Bito H
  • Organizer: Japanese Pharmacology Society Annual Meeting
  • Invited
• [Presentation] Multiplex Imaging of Neural Activity and Signaling Dynamics. (2020)
  • Author(s): Bito H
  • Organizer: 8th International Neural Microcircuit Conference
  • Int'l Joint Research / Invited
• [Presentation] Arc-dependent regulation of long-term synaptic plasticity. (2019)
  • Author(s): Bito H, Ishii Y, Fujii H, Okuno H.
  • Organizer: 2019 Meeting of the Australasian Neuroscience Society
  • Int'l Joint Research / Invited
• [Presentation] Multiplex Imaging of Neural Activity and Signaling Dynamics. (2019)
  • Author(s): Bito H
  • Organizer: 13th Biennial Conference of the Chinese Neuroscience Society
  • Int'l Joint Research / Invited
• [Presentation] Arc-dependent regulation of long-term synaptic plasticity. (2019)
  • Author(s): Bito H, Ishii Y, Fujii H, Hayashi T, Okamura M, Kondo Y, Abe M, Sakimura K, Okuno H.
  • Organizer: 10th IBRO World Congress satellite meeting "Synaptic Function and Neural Circuitry".
  • Int'l Joint Research / Invited
• [Presentation] Towards multiplex imaging of neural activity and signaling dynamics (2019)
  • Author(s): Bito H
  • Organizer: The 42nd Annual Meeting of the Japan Neuroscience Society; The 62nd Annual Meeting of the Japanese Society for Neurochemistry
  • Invited
• [Presentation] Inverse synaptic tagging: an inactive synapse-targeted mechanism to capture activity-induced Arc (2019)
  • Author(s): Haruhiko Bito, Yuichiro Ishii, Hiroyuki Okuno
  • Organizer: 9th FAOPS Congress
  • Int'l Joint Research / Invited
• [Presentation] Arc-dependent long-term memory control (2018)
  • Author(s): Bito H
  • Organizer: 13th International Conference of Neurons and Brain Diseases
  • Int'l Joint Research / Invited
• [Presentation] Ca2+-dependent signaling in regulation of cognitive behavior (2018)
  • Author(s): Bito H
  • Organizer: 41st Annual Meeting of the Japan Neuroscience Society
  • Invited
• [Presentation] Probing Ca2+ and Ca2+-dependent gene expression in vivo to decipher information processing underlying cognitive behavior. (2018)
  • Author(s): Inoue M, Yokoyama T, Fujii H, Sakamoto M, Bito H.
  • Organizer: Janelia Conference Fluorescent Proteins and Biological Sensors VI
  • Int'l Joint Research / Invited
• [Presentation] Multiplex imaging of neuronal Ca2+-mediated signal transduction. (2018)
  • Author(s): Hajime Fujii, Masatoshi Inoue, Haruhiko Bito.
  • Organizer: Janelia Conference Fluorescent Proteins and Biological Sensors VI
  • Int'l Joint Research
• [Presentation] Specification of a remote memory cell ensemble during cortical tagging. (2018)
  • Author(s): Ryang Kim, Yayoi Kondo, Takashi Kawashima, Michiko Okamura, Masatoshi Inoue, Yuichiro Ishii, Kasumi Inokuchi, Kazuki Sakai, Mio Nonaka, Masayuki Sakamoto, Hiroyuki Okuno, Haruhiko Bito.
  • Organizer: Annual Meeting of the Society for Neuroscience 2018
  • Int'l Joint Research
• [Presentation] Specification of a remote memory cell ensemble during cortical tagging. (2018)
  • Author(s): Ryang Kim, Yayoi Kondo, Takashi Kawashima, Michiko Okamura, Masatoshi Inoue, Yuichiro Ishii, Kasumi Inokuchi, Kazuki Sakai, Mio Nonaka, Masayuki Sakamoto, Hiroyuki Okuno, Haruhiko Bito.
  • Organizer: The 17th Annual Molecular Cellular Cognition Society Symposium.
  • Int'l Joint Research / Invited
• [Presentation] Multiplex imaging of neural activity and signaling dynamics. (2018)
  • Author(s): Bito H
  • Organizer: Cold Spring Harbor Asia Meeting Announcement: Advances in Optical Imaging of Living Cells & Organisms: Focus on the Brain
  • Int'l Joint Research / Invited
• [Presentation] Ultrafast two-photon microscopy for high-speed brain imaging in awake mice. (2018)
  • Author(s): Radoslaw Chrapkiewicz, Tong Zhang, Oscar Hernandez, Adam S. Shai, Mark J. Wagner, Yanping Zhang, Cheng-Hsun Wu, Jin Zhong Li, Yiyang Gong, Masatoshi Inoue, Haruhiko Bito, Mark J. Schnitzer.
  • Organizer: SPIE Photonics Europe
  • Int'l Joint Research
• [Presentation] Arc-haeology of long-term memory. (2018)
  • Author(s): Bito H
  • Organizer: Brain Research Program International Symposium, Korean Brain Science Institute, Daegu, Korea.
  • Invited
• [Presentation] Multiplex imaging of neural activity and signaling dynamics. (2017)
  • Author(s): Bito H
  • Organizer: 16th Annual Meeting of the Molecular & Cellular Cognition Society-ASIA. Center for Life Sciences, National University of Singapore.
  • Int'l Joint Research / Invited
• [Presentation] Arc-haeology of long-term memory. (2017)
  • Author(s): Bito H
  • Organizer: Friedrich Miescher Institute for Biomedical Research.Basel, Switzerland
  • Invited
• [Presentation] Genetically encoded calcium indicators. (2017)
  • Author(s): Bito H
  • Organizer: EMBO Practical Course “Two-photon imaging of brain dynamics: Illuminating neuronal and glial function”University of Zurich, Switzerland.
  • Int'l Joint Research / Invited
• [Presentation] CREB-Arc signaling in long-term memory formation. (2017)
  • Author(s): Bito H
  • Organizer: Department of Neuroscience Seminar, Karolinska Institutet, Stockholm, Sweden.
  • Invited
• [Funded Workshop] Cold Spring Harbor Asia Meeting Announcement: Advances in Optical Imaging of Living Cells & Organisms: Focus on the Brain (2018)