Dynamics of neuronal activity-dependent gene expression

• Project/Area Number: 19H03325
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 46010:Neuroscience-general-related
• Research Institution: Osaka University
• Principal Investigator: Yamamoto Nobuhiko 大阪大学, 大学院生命機能研究科, 招へい教授 (00191429)
• Co-Investigator(Kenkyū-buntansha): 菅生 紀之 大阪大学, 大学院生命機能研究科, 特任准教授(常勤) (20372625)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2021: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2020: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2019: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
• Keywords: 大脳皮質 / 神経活動 / 遺伝子発現 / CREB / CBP / BDNF / １分子イメージング / プロモーター活性 / 神経活動依存性 / ヒトニューロン / ヒト / 転写調節 / 神経回路 / 光遺伝学 / 刺激生理学

Outline of Research at the Start

発達期脳の神経回路は環境刺激や自発発火によって可塑的に変化するが、生理学的な神経活動パターンが遺伝子発現を介して回路形成に作用するメカニズムについてはほとんど判っていない。本研究では、これまで明らかにしてきた大脳皮質での神経活動依存的な回路形成の制御機構に関する結果をもとに、神経活動パターンによる皮質ニューロンの遺伝子発現の制御機構を個々の細胞レベルで明らかにすることを目指す。そのために、転写調節因子やエピジェネティック制御因子のライブイメージング法を駆使し、光遺伝学的手法や自然刺激による刺激法を用いて大脳皮質ニューロンにおける転写調節機構を調べる。

Outline of Final Research Achievements

Neural circuits in the brain are plastically altered by electrical activity of neurons. In the present study, we investigated the neuronal activity-molecular signal transduction mechanisms which underlie the remodeling process by ustilizing live imaging of gene promoter activity and single-molecule imaging of transcriptional factors. As a result, we found that specific environmental stimuli increase gene expression efficiently and that second-by-second repetitive binding of transcription fators to DNA and co-factors plays an important role in expression of the down-stream activity-dependent genes.

Academic Significance and Societal Importance of the Research Achievements

本研究成果の特徴は転写調節因子、共因子、DNAの結合を時空間的に明らかにしたことである。分子生物学と神経生理学とを融合させた新たな研究戦略を提供するもので、分野横断的な研究も促進する。神経活動パターンが生み出す遺伝子発現調節、これこそが、後天的神経回路形成の本質であり、本研究の目指す点であり、これは次の一手にも繋がる結果である。さらに、子供の正常な脳発達や可塑性のメカニズムにも通ずるものとしても価値がある。

Research Products

• [Int'l Joint Research] VIB-KU Leuven(ベルギー)
• [Int'l Joint Research] VIB Center for Brain & Disease Research(ベルギー)
• [Journal Article] Molecular mechanisms of lesion-induced axonal sprouting in the corticofugal projection: the role of glial cells (2023)
  • Author(s): Chang L, Yamamoto N
  • Journal Title: Neural Regen Res Volume: 18 Issue: 6 Pages: 1259-1260
  • DOI: 10.4103/1673-5374.360168
  • Peer Reviewed / Open Access
• [Journal Article] Thalamocortical axons control the cytoarchitecture of neocortical layers by area-specific supply of VGF (2022)
  • Author(s): Sato Haruka、Hatakeyama Jun、Iwasato Takuji、Araki Kimi、Yamamoto Nobuhiko、Shimamura Kenji
  • Journal Title: eLife Volume: 11 Pages: 67549-67549
  • DOI: 10.7554/elife.67549
  • Peer Reviewed / Open Access
• [Journal Article] Neuronal Activity Patterns Regulate Brain-Derived Neurotrophic Factor Expression in Cortical Cells via Neuronal Circuits (2021)
  • Author(s): Miyasaka Yumi、Yamamoto Nobuhiko
  • Journal Title: Frontiers in Neuroscience Volume: 15 Pages: 699583-699583
  • DOI: 10.3389/fnins.2021.699583
  • Peer Reviewed / Open Access
• [Journal Article] Dynamic erectile responses of a novel penile organ model utilizing TPEM. (2021)
  • Author(s): Hashimoto D, Hirashima T, Yamamura H, Kataoka T, Fujimoto K, Hyuga T, Yoshiki A, Kimura K, Kuroki S, Tachibana M, Suzuki K, Yamamoto N, Morioka S, Sasaki T, Yamada G.
  • Journal Title: Biol Reprod. Volume: in press Issue: 4 Pages: 875-886
  • DOI: 10.1093/biolre/ioab011
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of Denervated Midbrain-Derived Factors in the Formation of Ectopic Cortico-Mesencephalic Projection after Hemispherectomy (2021)
  • Author(s): Chang Leechung、Masada Mayuko、Kojima Masami、Yamamoto Nobuhiko
  • Journal Title: The Journal of Neuroscience Volume: 42 Issue: 5 Pages: 749-761
  • DOI: 10.1523/jneurosci.1371-21.2021
  • Peer Reviewed / Open Access
• [Journal Article] Suppression of DNA Double-Strand Break Formation by DNA Polymerase β in Active DNA Demethylation Is Required for Development of Hippocampal Pyramidal Neurons (2020)
  • Author(s): Uyeda A, Onishi K, Hirayama T, Hattori S, Miyakawa T, Yagi T, Yamamoto N, Sugo N.
  • Journal Title: J Neurosci. Volume: 40 Issue: 47 Pages: 9012-9027
  • DOI: 10.1523/jneurosci.0319-20.2020
  • Peer Reviewed
• [Journal Article] Rho guanine nucleotide exchange factors regulate horizontal axon branching of cortical upper layer neurons. (2019)
  • Author(s): Sasaki K, Arimoto K, Kankawa K, Terada C, Yamamori T, Watakabe K, Yamamoto, N., epub bhz256.
  • Journal Title: Cereb Cortex Volume: 30 Issue: 4 Pages: 2506-2518
  • DOI: 10.1093/cercor/bhz256
  • Peer Reviewed / Open Access
• [Presentation] ヒト由来大脳皮質ニューロンにおいてCREBと共因子の時空間的な動態が神経活動依存的な遺伝子発現を制御する (2022)
  • Author(s): 渥美 友梨、菅生 紀之、岩田 亮平、Pierre Vanderhaeghen 、山本 亘彦
  • Organizer: NEURO2022
• [Presentation] Spatiotemporal dynamics of CREB with cofactors regulate activity-dependent gene expression in human cortical neurons (2022)
  • Author(s): Yuri Atsumi, Noriyuki Sugo, Hiroshi Kimura, Ryohei Iwata, Pierre Vanderhaeghen, Nobuhiko Yamamoto
  • Organizer: Cortical development and plasticity of the Brain
  • Int'l Joint Research
• [Presentation] ctivity-dependent dynamics of CREB via cofactor CBP in human cortical neurons (2021)
  • Author(s): Atsumi Y, Sugo N, Iwata R, Vanderhaeghen P, Yamamoto N
  • Organizer: The 44th Annual Meeting of the Japan Neuroscience Society
• [Presentation] Glial cell-derived axon-growth promoting factors are involved in remodeling of the cortico-mesencephalic projection after hemispherectomy (2021)
  • Author(s): Chang L, Masada M, Kojima M, Yamamoto N
  • Organizer: The 44th Annual Meeting of the Japan Neuroscience Society
• [Presentation] Spatiotemporal patterns of neuronal activity-dependent BDNF expression in upper layer cortical neurons (2020)
  • Author(s): Miyasaka Y, Yamamoto N
  • Organizer: FENS 2020 Virtual Forum
  • Int'l Joint Research
• [Presentation] Activity-dependent dynamics of the transcription factor CREB in human cortical-like neurons: A study using single-molecule imaging (2020)
  • Author(s): Atsumi Y, Sugo N, Iwata R, Vanderhaeghen P, Yamamoto N
  • Organizer: FENS 2020 Virtual Forum
  • Int'l Joint Research
• [Presentation] Denervated midbrain-derived factors induce the remodeling of the cortico-midbrain projection after unilateral cortical ablation (2020)
  • Author(s): Chang L, Yamamoto N
  • Organizer: The 43rd Annual Meeting of the Japan Neuroscience Society
• [Presentation] Spatiotemporal patterns of BDNF expression in the neocortex induced by physiological neuronal activity (2020)
  • Author(s): Yamamoto N, Miyasaka Y
  • Organizer: The 43rd Annual Meeting of the Japan Neuroscience Society
• [Presentation] Single-molecule imaging of the activity-dependent transcription factor CREB in human cortical-like neurons (2020)
  • Author(s): Atsumi Y, Sugo N, Iwata, R, Vanderhaeghen P, Yamamoto N
  • Organizer: The 43rd Annual Meeting of the Japan Neuroscience Society
• [Presentation] he involvement of glial cell-derived factors in remodeling of the cortico-mesencephalic projection after unilateral cortical ablation (2020)
  • Author(s): Chang L, Yamamoto N
  • Organizer: CSHL Molecular Mechanisms of Neuronal Connectivity
  • Int'l Joint Research
• [Presentation] Patterned stimulation regulates Bdnf promoter activity spatiotemporally in upper layer cortical neurons (2020)
  • Author(s): Miyasaka Y, Yamamoto N
  • Organizer: CSHL Molecular Mechanisms of Neuronal Connectivity
• [Presentation] Spatiotemporal patterns of BDNF expression in the cortex induced by physiological neuronal activity (2020)
  • Author(s): Miyasaka, Y., Yamamoto, N.
  • Organizer: New Frontier in Neuroscience 2020
  • Int'l Joint Research / Invited
• [Presentation] Regulation of axonal branching in cortical neurons by multiple RhoA-GEFs (2019)
  • Author(s): Sasaki, K., Arimoto, K., Kankawa, K., Terada, C., Yamamori, T., Watakabe, A., Yamamoto, N.
  • Organizer: The 40th Annual Meeting of the Japan Neuroscience Society
• [Presentation] Regulation of BDNF promoter activity by patterned neuronal firing in developing cortical neurons (2019)
  • Author(s): Miyasaka, Y., Yamamoto, N.
  • Organizer: The 40th Annual Meeting of the Japan Neuroscience Society
• [Presentation] Particular patterns of stimulation induce BDNF promoter activity preferentially in developing cortical neurons (2019)
  • Author(s): Miyasaka, Y., Yamamoto, N.
  • Organizer: The 10th IBRO World Congress of Neuroscience
  • Int'l Joint Research
• [Presentation] Analysis of the mechanisms underlying injury-induced corticofugal projections by CRISPR/ Cas9-mediated gene knock-out (2019)
  • Author(s): Chang, L., Yamamoto, N.
  • Organizer: The 10th IBRO World Congress of Neuroscience
  • Int'l Joint Research
• [Presentation] Single-molecule imaging of CREB transcription factor in human cortical-like neurons (2019)
  • Author(s): Atsumi, Y., Sugo, N., Iwata, R., Vanderhaeghen, P., Yamamoto, N.
  • Organizer: The 10th IBRO World Congress of Neuroscience
  • Int'l Joint Research
• [Presentation] Physiological stimuli-dependent BDNF promoter activity in cortical cells revealed by live imaging with luciferase assay (2019)
  • Author(s): Miyasaka, Y., Yamamoto, N.
  • Organizer: Society for Neuroscience
  • Int'l Joint Research
• [Presentation] The involvement of reactive glial cells in the formation of ectopic corticofugal projections after cortical ablation (2019)
  • Author(s): Chang, L., Sugo, N., Yamamoto, N.
  • Organizer: Society for Neuroscience
  • Int'l Joint Research
• [Presentation] Activity-dependent transcription regulation in developing neocortical neurons (2019)
  • Author(s): Yamamoto, N.
  • Organizer: TMIMS International Symposium on Principles of Neocortical Development and Evolution
  • Int'l Joint Research / Invited
• [Funded Workshop] Development and Plasticity of the Brain (2022)