Interrogation and manipulation of Ca2+/CaMK signaling mechanisms underlying cognitive behavior

• Project/Area Number: 15H02358
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: The University of Tokyo
• Principal Investigator: BITO HARUHIKO 東京大学, 大学院医学系研究科(医学部), 教授 (00291964)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥42,510,000 (Direct Cost: ¥32,700,000、Indirect Cost: ¥9,810,000); Fiscal Year 2017: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2016: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2015: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
• Keywords: 神経科学 / 脳・神経 / 遺伝子 / シグナル伝達

Outline of Final Research Achievements

In this project, we aimed to obtain mechanistic insights on the Ca2+/calmodulin-dependent information “writing” process that neurons utilize in the living brain. To address this, 1) we developed new improved Ca2+ signaling sensors, and 2) took advantage of these tools to dissect the spread and information processing encoded by Ca2+ signals and Ca2+ effector activation. Furthermore, we investigated the role of Ca2+/calmodulin-dependent signaling in long-term memory consolidation, and identified several new key molecular players involved in this process. These results shed new light on basic principles on how the brain works, and epitomizes the urgent need to developing foundational technologies to record and manipulate brain functions.

Research Products

• [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] 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
• [Journal Article] Arc restores juvenile plasticity in adult mouse visual cortex. (2017)
  • Author(s): Jenks KR, Kim T, Pastuzyn ED, Okuno H, Taibi AV, Bito H, Bear MF, Shepherd JD.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 114 Issue: 34 Pages: 9182-9187
  • DOI: 10.1073/pnas.1700866114
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Stimulus-evoked ERK-dependent phosphorylation of activity-regulated cytoskeleton-associated protein (Arc) regulates its neuronal subcellular localization. (2017)
  • Author(s): Nikolaienko O, Eriksen MS, Patil S, Bito H, Bramham CR.
  • Journal Title: Neuroscience. Volume: 360 Pages: 68-80
  • DOI: 10.1016/j.neuroscience.2017.07.026
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Nrp2 is sufficient to instruct circuit formation of mitral-cells to mediate odour-induced attractive social responses (2017)
  • Author(s): K. Inokuchi, F. Imamura, H. Takeuchi, R. Kim, H. Okuno, H. Nishizumi, H. Bito, T. Kikusui, H. Sakano
  • Journal Title: Nature Communications Volume: 8 Issue: 1 Pages: 15977-15977
  • DOI: 10.1038/ncomms15977
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Histamine modulation of the basal ganglia circuitry in the development of pathological grooming. (2017)
  • Author(s): Rapanelli M, Frick L, Bito H, Pittenger C
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 114 Issue: 25 Pages: 6599-6604
  • DOI: 10.1073/pnas.1704547114
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Calmodulin kinases: essential regulators in health and disease. (2017)
  • Author(s): Takemoto-Kimura S, Suzuki K, Horigane SI, Kamijo S, Inoue M, Sakamoto M, Fujii H, Bito H.
  • Journal Title: J Neurochem. Volume: - Issue: 6 Pages: 808-818
  • DOI: 10.1111/jnc.14020
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Simultaneous fast measurement of circuit dynamics at multiple sites across the mammalian brain. (2016)
  • Author(s): Kim CK, Yang SJ, Pichamoorthy N, Young NP, Kauvar I, Jennings JH, Lerner TN, Berndt A, Lee SY, Ramakrishnan C, Davidson TJ, Inoue M, Bito H, Deisseroth K.
  • Journal Title: Nature Methods Volume: 13 Issue: 4 Pages: 325-328
  • DOI: 10.1038/nmeth.3770
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Chronic imaging of Purkinje cell calcium activity in awake behaving mice. (2016)
  • Author(s): Gaffield MA, Amat SB, Bito H, Christie JM.
  • Journal Title: Journal of Neurophysiology Volume: 115 Issue: 1 Pages: 413-422
  • DOI: 10.1152/jn.00834.2015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Facilitation of axon outgrowth via a Wnt5a-CaMKK-CaMKIα pathway during neuronal polarization. (2016)
  • Author(s): Horigane S, Ageta-Ishihara N, Kamijo S, Fujii H, Okamura M, Kinoshita M, Takemoto-Kimura S, Bito H
  • Journal Title: Mol Brain. Volume: 9 Issue: 1 Pages: 8-8
  • DOI: 10.1186/s13041-016-0189-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chronic optogenetic activation augments Aβ pathology in a mouse model of Alzheimer disease (2015)
  • Author(s): Kaoru Yamamoto, Zen-ichi Tanei, Tadafumi Hashimoto, Tomoko Wakabayashi, Hiroyuki Okuno, Yasushi Naka, Ofer Yizhar, Lief E. Fenno, Masashi Fukayama, Haruhiko Bito, John R. Cirrito, David M. Holtzman, Karl Deisseroth, Takeshi Iwatsubo
  • Journal Title: Cell reports Volume: 11 Issue: 6 Pages: 859-865
  • DOI: 10.1016/j.celrep.2015.04.017
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] CREB-Arc signaling in long-term memory formation. (2017)
  • Author(s): Bito H.
  • Organizer: Department of Neuroscience Seminar, Karolinska Institutet, Stockholm, Sweden.
  • Invited
• [Presentation] New roles for amygdalar calcium signaling during fear memory formation and in social behavior. (2016)
  • Author(s): Bito H.
  • Organizer: Nature Conference on Neural Circuitry of Emotion.
  • Place of Presentation: Shenzhen, China
  • Year and Date: 2016-11-02
  • Invited
• [Presentation] Illuminating activity-dependent signaling and circuits. (2016)
  • Author(s): Bito H.
  • Organizer: Gordon Research Conference (Synaptic Transmission)
  • Place of Presentation: New Hampshire, USA
  • Year and Date: 2016-08-14
  • Invited
• [Presentation] Development and imaging of new color indicators for Ca2+ signaling in living neurons. (2016)
  • Author(s): Fujii H, Inoue M, Bito H
  • Organizer: 第39回日本神経科学大会シンポジウム
  • Place of Presentation: 横浜パシフィコ（横浜市、神奈川県）
  • Year and Date: 2016-07-20
• [Presentation] 扁桃体神経回路におけるカルシウム依存的リン酸化経路と情動行動. (2016)
  • Author(s): 竹本さやか、遠藤俊裕、金亮、鈴木敢三、藤井哉、尾藤晴彦.
  • Organizer: 第46回日本神経精神薬理学会
  • Place of Presentation: ソウル、大韓民国
  • Year and Date: 2016-07-02
• [Presentation] Multiplex imaging of neural activity and signaling dynamics. (2016)
  • Author(s): Bito H.
  • Organizer: Frontiers in Neurophotonics Summer School
  • Place of Presentation: Quebec, Canada
  • Year and Date: 2016-06-20
  • Invited
• [Presentation] Postsynaptic mechanisms underlying activity-dependent adaptation of glutamatergic synapses. (2016)
  • Author(s): Bito H, Kim R, Inoue M, Nonaka M, Ishii Y, Sakai K, Kawashima T, Yagishita-Kyo N, Matsushima A, Kamijo S, Okamura M, Goto M, Endo T, Horigane S, Okuno H, Takemoto-Kimura S, Fujii H.
  • Organizer: 第93回日本生理学会大会
  • Place of Presentation: 札幌コンベンションセンター（札幌市）
  • Year and Date: 2016-03-22
• [Presentation] Rational design of ultrafast, high-affinity red calcium indicator for monitoring neuronal activity. (2015)
  • Author(s): Inoue M, Takeuchi A, Horigane S, Fujii H, Kamijo S, Takemoto-Kimura S, Ohkura M, Gengyo-Ando K, Kano M, Nakai J, Kitamura K, Bito H.
  • Organizer: The 45th Annual Meeting of the Society for Neuroscience
  • Place of Presentation: Chicago, USA
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] Synapse-to-Nucleus Signaling and CREB Regulation in Fear Memory. (2015)
  • Author(s): Bito H
  • Organizer: Gordon Research Conference on Amygdala in Health & Disease.
  • Place of Presentation: Stonehill College, Easton, Massachusetts, USA
  • Year and Date: 2015-08-02
  • Int'l Joint Research / Invited
• [Presentation] Novel functions of Ca2+-dependent phosphorylation cascades in dendritogenesis and emotional behavior. (2015)
  • Author(s): Takemoto-Kimura S, Suzuki K, Kamijo S, Horigane S, Kim R, Bito H.
  • Organizer: Gordon Research Conference on Amygdala in Health & Disease.
  • Place of Presentation: Stonehill College, Easton, Massachusetts, USA
  • Year and Date: 2015-08-02
  • Int'l Joint Research
• [Presentation] 高感度、超高速赤色カルシウムインディケーターの合理的設計による開発. (2015)
  • Author(s): 井上昌俊, 竹内敦也, 堀金慎一郎, 大倉正道, 安藤恵子, 藤井哉, 上條諭志, 竹本-木村 さやか, 狩野方伸, 中井淳一, 喜多村和郎, 尾藤晴彦.
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸国際会議場・神戸国際展示場（神戸）
  • Year and Date: 2015-07-28
• [Presentation] 樹状突起形成および情動行動におけるカルシウム依存的リン酸化経路の新規機能解明. (2015)
  • Author(s): 竹本ー木村さやか, 鈴木敢三, 上條諭志, 金 亮, 堀金慎一郎, 尾藤晴彦.
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸国際会議場・神戸国際展示場（神戸）
  • Year and Date: 2015-07-28
• [Presentation] Imaging of active neuronal ensembles in vivo. (2015)
  • Author(s): Bito H
  • Organizer: 10th International Conference for Neurons and Brain Diseases.
  • Place of Presentation: Xian Jiatong University, Xian, China
  • Year and Date: 2015-06-22
  • Int'l Joint Research / Invited
• [Presentation] Understanding Arc to understand a memory engram (2015)
  • Author(s): Bito H
  • Organizer: The 28th Annual Meeting on the Neurobiology of Learning and Memory.
  • Place of Presentation: University of California at Irvine, Irvine, California, USA
  • Year and Date: 2015-04-23
  • Int'l Joint Research / Invited
• [Patent(Industrial Property Rights)] カルシウム指示遺伝子 (2015)
  • Inventor(s): 尾藤晴彦、井上昌俊、竹内敦也、中井淳一、大倉正道
  • Industrial Property Rights Holder: 尾藤晴彦、井上昌俊、竹内敦也、中井淳一、大倉正道
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-06-08
  • Overseas