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Mechanisms of microvascular flow regulation in neurovascular coupling and responsiveness to ischemia by using optogenetics

Research Project

Project/Area Number 20K06929
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 46030:Function of nervous system-related
Research InstitutionKeio University

Principal Investigator

Tomita Yutaka  慶應義塾大学, 医学部(信濃町), 講師(非常勤) (60276251)

Co-Investigator(Kenkyū-buntansha) 畝川 美悠紀  慶應義塾大学, 医学部(信濃町), 研究員 (10548481)
伊澤 良兼  慶應義塾大学, 医学部(信濃町), 講師 (90468471)
Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords光遺伝学 / 脳微小循環 / アストロサイト / ペリサイト / 脳微小塞栓 / オプトジェネティクス / Neurovascular unit / 脳虚血 / 神経科学
Outline of Research at the Start

オプトジェネティクスを利用してNVUを構成する特定の細胞種にChR2を発現させたマウスを用い、レーザースペックル血流計や二光子顕微鏡を用いて特定の細胞種ごとに刺激した際の血管挙動の解析、薬理学的手法を組み合わせることによって各細胞の役割や微小血流調節に関わるメカニズムをin vivo で検証する。さらに、中大脳動脈閉塞術を施行した脳梗塞モデル、総頸動脈にマイクロコイルを装着することによる慢性低灌流モデルなどを組み合わせ、独自の微小脳血流定量解析法(KEIO-IS1、KEIO-IS2)を用いて、病態下での特定の細胞間相互作用による脳血流調節機序を詳細に明らかにし、将来の脳疾患治療へと結びつける。

Outline of Final Research Achievements

Transgenic mice expressing the light-sensitive membrane protein channelrhodopsin 2 (ChR2) only in specific cell types were used to analyze the role of neurons, astrocytes, vascular smooth muscle and pericytes in the regulation of brain microcirculation. Photo-stimulation of astrocytes alone elicited an intensity-dependent increase in blood flow response as in the case of neurons, and pharmacological study revealed that astrocytes and neurons might modulate arterial diameter through different mechanisms. Furthermore, experiments using transgenic mice expressing ChR2 in vascular smooth muscle and pericytes showed that pericytes themselves have vasoconstrictive effects and that photo-stimulation-induced local vasoconstriction causes transient blood flow arrest in microvessels (microcirculation embolism) on the venous side.

Academic Significance and Societal Importance of the Research Achievements

脳内では神経・グリア細胞・血管は NVUを形成し、相互に連絡を取り合っている。オプトジェネティクスを用いて特定の細胞種だけに非侵襲的に刺激を加えてin vivoで多角的に解析することによって微小血流調節機序を詳細に検証することが可能になった。本研究では健康な動物を用いているが、脳虚血に伴う脳血管障害、認知症モデルを作製し、同様な検証を行うことによって病態下における細胞種に特化した詳細な機序、光刺激によって特定の細胞種活性化の関与の検証など、幅広い分野での応用が期待される。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (36 results)

All 2024 2023 2022 2021 2020

All Journal Article (13 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 13 results,  Open Access: 11 results) Presentation (23 results) (of which Int'l Joint Research: 5 results,  Invited: 2 results)

  • [Journal Article] Striatal blood flow changes by middle cerebral artery occlusion and its effect on neurological deficits in mice.2024

    • Author(s)
      Unekawa M., Tsukada N., Takizawa T., Tomita Y., Nakahara J., Izawa Y.
    • Journal Title

      Microcirculation

      Volume: - Issue: 6

    • DOI

      10.1111/micc.12861

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Acceleration of the Development of Microcirculation Embolism in the Brain due to Capillary Narrowing2023

    • Author(s)
      Murata Juri、Unekawa Miyuki、Kudo Yuya、Kotani Maho、Kanno Iwao、Izawa Yoshikane、Tomita Yutaka、Tanaka Kenji F.、Nakahara Jin、Masamoto Kazuto
    • Journal Title

      Stroke

      Volume: 54 Issue: 8 Pages: 2135-2144

    • DOI

      10.1161/strokeaha.122.042416

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Selective dysfunction of fast-spiking inhibitory interneurons and disruption of perineuronal nets in a tauopathy mouse model.2023

    • Author(s)
      Kudo T, Takuwa H, Takahashi M, Urushihata T, Shimojo M, Sampei K, Yamanaka M, Tomita Y, Sahara N, Suhara T, Higuchi M
    • Journal Title

      iScience

      Volume: 26 Issue: 4 Pages: 106342-106342

    • DOI

      10.1016/j.isci.2023.106342

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Close association between spreading depolarization and development of infarction under experimental ischemia in anesthetized male mice.2022

    • Author(s)
      Unekawa M, Tomita Y, Masamoto K, Kanno I, Nakahara J, Izawa Y
    • Journal Title

      Brain Res

      Volume: 1792 Pages: 148023-148023

    • DOI

      10.1016/j.brainres.2022.148023

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] MRS-measured glutamate versus GABA reflects excitatory versus inhibitory neural activities in awake mice2021

    • Author(s)
      Takado Yuhei、Takuwa Hiroyuki、Sampei Kazuaki、Urushihata Takuya、Takahashi Manami、Shimojo Masafumi、Uchida Shoko、Nitta Nobuhiro、Shibata Sayaka、Nagashima Keisuke、Ochi Yoshihiro、Ono Maiko、Maeda Jun、Tomita Yutaka、Sahara Naruhiko、Near Jamie、Aoki Ichio、Shibata Kazuhisa、Higuchi Makoto
    • Journal Title

      Journal of Cerebral Blood Flow & Metabolism

      Volume: 42 Issue: 1 Pages: 197-212

    • DOI

      10.1177/0271678x211045449

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Time Series Tracking of Cerebral Microvascular Adaptation to Hypoxia and Hyperoxia Imaged with Repeated In Vivo Two-Photon Microscopy.2021

    • Author(s)
      Sugashi T., Niizawa T., Suzuki H., Takuwa H., Unekawa M., Tomita Y., Kanno I., Masamoto K.
    • Journal Title

      Adv. Exp. Med. Biol.

      Volume: 1269 Pages: 323-327

    • DOI

      10.1007/978-3-030-48238-1_51

    • ISBN
      9783030482367, 9783030482381
    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] A genetically targeted reporter for PET imaging of deep neuronal circuits in mammalian brains2021

    • Author(s)
      Shimojo M、Ono M、Takuwa H、Mimura K、Nagai Y、Fujinaga M、Kikuchi T、Okada M、Seki C、Tokunaga M、Maeda J、Takado Y、Takahashi M、Minamihisamatsu T、Zhang M‐R、Tomita Y、Suzuki N、Maximov A、Suhara T、Minamimoto T、Sahara N、Higuchi M
    • Journal Title

      The EMBO Journal

      Volume: 40 Issue: 22

    • DOI

      10.15252/embj.2021107757

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A first-in-human study of 11C-MTP38, a novel PET ligand for phosphodiesterase 72021

    • Author(s)
      Kubota Manabu、Seki Chie、Kimura Yasuyuki、Takahata Keisuke、Shimada Hitoshi、Takado Yuhei、Matsuoka Kiwamu、Tagai Kenji、Sano Yasunori、Yamamoto Yasuharu、Okada Maki、Kikuchi Tatsuya、Ichise Masanori、Kawamura Kazunori、Zhang Ming-Rong、Higuchi Makoto
    • Journal Title

      European Journal of Nuclear Medicine and Molecular Imaging

      Volume: 41 Issue: 11 Pages: 2928-2943

    • DOI

      10.1177/0271678x211004150

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Optical manipulation of local cerebral blood flow in the deep brain of freely moving mice2021

    • Author(s)
      Abe Yoshifumi、Kwon Soojin、Oishi Mitsuhiro、Unekawa Miyuki、Takata Norio、Seki Fumiko、Koyama Ryuta、Abe Manabu、Sakimura Kenji、Masamoto Kazuto、Tomita Yutaka、Okano Hideyuki、Mushiake Hajime、Tanaka Kenji F.
    • Journal Title

      Cell Reports

      Volume: 36 Issue: 4 Pages: 109427-109427

    • DOI

      10.1016/j.celrep.2021.109427

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Differential pial and penetrating arterial responses examined by optogenetic activation of astrocytes and neurons2021

    • Author(s)
      Hatakeyama N., Unekawa M., Tomita Y. Suzuki N. Nakahara J. Takuwa H., Kanno I., Matsui K., Tanaka K.F., Masamoto K.
    • Journal Title

      J Cereb Blood Flo Metab

      Volume: - Issue: 10 Pages: 2676-2689

    • DOI

      10.1177/0271678x211010355

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] High-Contrast In Vivo Imaging of Tau Pathologies in Alzheimer’s and Non-Alzheimer’s Disease Tauopathies2021

    • Author(s)
      Tagai K, Ono M, Kubota M, Kitamura S, Takahata K, Seki C, Takado Y, Shinotoh H, Sano Y, Yamamoto Y, Matsuoka K, Takuwa H, Shimojo M, (24人省略), Shimada H.
    • Journal Title

      Neuron

      Volume: 109 Issue: 1 Pages: 42-58

    • DOI

      10.1016/j.neuron.2020.09.042

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Characteristics of cortical spreading depression and c-Fos expression in transgenic mice having a mutation associated with familial hemiplegic migraine 22020

    • Author(s)
      Tang Chunhua、Unekawa Miyuki、Shibata Mamoru、Tomita Yutaka、Izawa Yoshikane、Sugimoto Hiroki、Ikeda Keiko、Kawakami Kiyoshi、Suzuki Norihiro、Nakahara Jin
    • Journal Title

      Cephalalgia

      Volume: 40 Issue: 11 Pages: 1177-1190

    • DOI

      10.1177/0333102420929028

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys2020

    • Author(s)
      Nagai Yuji, Miyakawa Naohisa et al.
    • Journal Title

      Nature Neuroscience

      Volume: 23 Issue: 9 Pages: 1157-1167

    • DOI

      10.1038/s41593-020-0661-3

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Hemodynamics and infarct formation at the striatum and cerebral cortex in stroke model mice.2023

    • Author(s)
      Unekawa M., Tsukada N., Takizawa T., Tomita Y., Nakahara J., Izawa Y.
    • Organizer
      31st International Symposium on Cerebral Blood Flow and Metabolism
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Quantitative characterization of the microglial response to chronic hypoxia in the mouse cortex.2023

    • Author(s)
      Kudo Y., Sugashi T., Yuki H., Soga N., Unekawa M., Tomita Y., Izawa Y., Nakahara J., Kanno I., Masamoto K.
    • Organizer
      31st International Symposium on Cerebral Blood Flow and Metabolism
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ミクログリアの個性を示す画像化手法の提案:生体二光子顕微鏡による検討2023

    • Author(s)
      工藤雄也, 須貸琢磨, 結城浩弥, 曽我直人, 畝川美悠紀, 冨田裕, 伊澤良兼, 中原仁, 菅野巖, 正本和人.
    • Organizer
      第66回日本脳循環代謝学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Development of the pericytes-specific optogenic tool.2023

    • Author(s)
      Iba C, Abe Y, Unekawa M, Tomita Y, Tanaka KF
    • Organizer
      US-Japan Joint Workshop on the Neurovascular Unit 2023
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] Capillary constriction enhances microcirculation embolism in the mouse cortex.2023

    • Author(s)
      Kudo Y, Murata J, Unekawa M, Kanno I, Izawa Y, Tomita Y, Tanaka KF, Nakahara J, Masamoto K
    • Organizer
      US-Japan Joint Workshop on the Neurovascular Unit 2023
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] Hemodynamics and infarct formation at the striatum and cerebral cortex by transient occlusion of middle cerebral artery in mice.2023

    • Author(s)
      Unekawa M, Takizawa T, Tomita Y, Nakahara J, Izawa Y
    • Organizer
      第48回日本微小循環学会総会
    • Related Report
      2022 Research-status Report
  • [Presentation] 塞栓糸を用いた中大脳動脈一過性閉塞術による大脳皮質および線条体の血流変化と虚血・梗塞巣の形成2023

    • Author(s)
      畝川美悠紀, 塚田直己, 滝沢翼, 冨田裕, 中原仁, 伊澤良兼
    • Organizer
      第48回日本脳卒中会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] 塞栓糸を用いた中大脳動脈一過性閉塞術による大脳皮質および線条体の血流動態と梗塞形成2022

    • Author(s)
      畝川美悠紀, 塚田直己, 滝沢翼, 冨田裕, 中原仁, 伊澤良兼
    • Organizer
      第65回日本脳循環代謝学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] 脳微小血管の収縮による微小塞栓の形成2022

    • Author(s)
      工藤雄也, 村田樹里, 小谷真穂, 畝川美悠紀, 伊澤良兼, 菅野巖, 冨田裕, 田中謙二, 中原仁, 正本和人
    • Organizer
      第65回日本脳循環代謝学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] Increased miroembolism caused by capillary constriction in the brain.2022

    • Author(s)
      Kotani M, Murata J, Unekawa M, Kanno I, Tomita Y, Tanaka KF, Nakahara J, Masamoto K
    • Organizer
      9th World Congress of Biomechanics
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] Vasoconstriction and hypoperfusion induced by photoactivation of the ChR2-expressing vascular cells.2021

    • Author(s)
      冨田裕, 村田樹里, 畠山菜緒, 畝川美悠紀, 伊澤良兼, 菅野巌, 田中謙二, 正本和人, 中原仁
    • Organizer
      第62回日本神経学会学術大会
    • Related Report
      2021 Research-status Report
  • [Presentation] オプトジェネティクスを用いた脳微小血管の操作2021

    • Author(s)
      小谷真穂, 村田樹里, 大石光洋, 畠山菜緒, 畝川美悠紀, 伊澤良兼, 菅野巖, 冨田裕, 田中謙二, 中原仁, 正本和人
    • Organizer
      第25回酸素ダイナミクス研究会
    • Related Report
      2021 Research-status Report
  • [Presentation] マウス大脳皮質におけるミクログリアの長期観察と低酸素暴露への適応2021

    • Author(s)
      須貸拓馬, 結城浩弥, 畝川美悠紀, 冨田裕, 菅野巖, 中原仁, 正本和人
    • Organizer
      第25回酸素ダイナミクス研究会
    • Related Report
      2021 Research-status Report
  • [Presentation] 生体脳イメージングを用いたタウ凝集体を有する神経細胞の脳外排出メカニ ズムの実証2021

    • Author(s)
      高橋真奈美, 田桑弘之, 漆畑拓弥, 下條雅文, 折原あすみ, 小野麻衣子, 高堂祐平, 冨田裕, 佐原成彦, 須原哲也, 樋口真人
    • Organizer
      第64回日本脳循環代謝学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] Imaging of Cerebral Microcirculation and Expectations for Biomedical Engineering2021

    • Author(s)
      Tomita Y., Unekawa M., Izawa Y., Masamoto K., Kanno I., Nakahara J.
    • Organizer
      第46回日本微小循環学会総会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] Manipulation of cerebral microcirculation flow via photo-stimulation to vascular mural cells with optogenetics.2021

    • Author(s)
      Murata J., Oishi M., Unekawa M., Kanno I., Tomita Y., Tanaka K., Nakahara J., Masamoto K.
    • Organizer
      第46回日本微小循環学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 光を用いた脳微小循環動態のイメージングと操作2021

    • Author(s)
      正本和人, 村田樹里, 畝川美悠紀, 冨田裕, 菅野巖.
    • Organizer
      第37回スパズム・シンポジウム
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] Imaging of water kinetics during cytotoxic edema using indirect MRI with O17-labeled water.2021

    • Author(s)
      Ishikawa T., Hoshino Y., Kameda H., Komaki Y., Unekawa M., Tomita Y., Nakahara J., Kudo K., Yasui M.
    • Organizer
      第94回日本薬理学会年会
    • Related Report
      2020 Research-status Report
  • [Presentation] Analysis of red blood cell velocity in intraparenchymal capillaries and arterial diameter in mice.2020

    • Author(s)
      冨田裕, 畝川美悠紀, 伊澤良兼, 正本和人, 菅野巌, 中原仁.
    • Organizer
      第61回日本神経学会学術大会
    • Related Report
      2020 Research-status Report
  • [Presentation] アクアポリン4は水中毒によるparavascular spaceの閉塞と脳神経活動の低下を促進する2020

    • Author(s)
      石川智愛, 畝川美悠紀, 冨田裕, 中原仁, 安井正人.
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 生体脳イメージングによる病原性蛋白質の脳外排出メカニズムの解明2020

    • Author(s)
      高橋真奈美, 田桑弘之, 漆畑拓弥, 下條雅文, 冨田裕, 中原仁, 佐原成彦, 樋口真人.
    • Organizer
      第63回日本脳循環代謝学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] Dynamic response of arterial diameter and red blood cell velocity in capillaries associated with cortical spreading depolarization/depression2020

    • Author(s)
      Tang C., Unekawa M., Tomita Y., Masamoto K., Kanno I., Nakahara J.
    • Organizer
      第45回日本微小循環学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] Optogenetic manipulation of cerebral microcirculation by transcranial photostimulation to the channelrhodopsin-2 expressing mouse brains.2020

    • Author(s)
      Murata J., Unekawa M., Kanno I., Tomita Y., Tanaka K., Nakahara J., Masamoto K.
    • Organizer
      第45回日本微小循環学会総会
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2025-01-30  

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