Investigation of Neurovascular Coupling by using cerebral focal ischemia model

• Project/Area Number: 24500422
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Keio University
• Principal Investigator: TOMITA Yutaka 慶應義塾大学, 医学部, 講師(非常勤) (60276251)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: Neurovascular coupling / 脳虚血 / 共焦点顕微鏡 / 二光子顕微鏡 / Neurovacular coupling

Outline of Final Research Achievements

A focal cerebral ischemia murine model with a cranial window was prepared. After systemic administration of fluorescently labelled red blood cells, the dynamic changes of the brain cortex microcirculation and the capillaries were repeatedly video-monitored in vivo for up to one month by means of confocal microscopy and analyzed in real time, while local blood flow in the brain was measured. The velocity of the brain microcirculation was also analyzed. In addition, vital staining of microvessels and astrocytes was performed, and the morphological changes of microvessels, nerve cells, and astrocytes after cerebral ischemia were simultaneously and repeatedly observed in vivo with a two-photon microscope. The results obtained were compared with ex-vivo results. This work has uncovered details of neurovascular coupling during blood flow regulation in the brain under cerebral ischemia was observed, and established its importance.

Research Products

• [Journal Article] Hyperperfusion counteracted by transient rapid vasoconstriction followed by long-lasting oligemia induced by cortical spreading depression in anesthetized mice. (2015)
  • Author(s): Unekawa M, Tomita Y, Toriumi H, Osada T, Masamoto K, Kawaguchi H, Itoh Y, Kanno I, Suzuki N.
  • Journal Title: J Cereb Blood Flow Metab Volume: 35 Issue: 4 Pages: 689-698
  • DOI: 10.1038/jcbfm.2014.250
  • Peer Reviewed / Open Access
• [Journal Article] 34. Microvascular sprouting, extension, and creation of new capillary connection with adaptation of the neighboring astrocytes in adult mouse cortex under chronic hypoxia (2014)
  • Author(s): Masamoto K, Takuwa H, Seki C, Taniguchi J, Itoh Y, Tomita Y, Toriumi H, Unekawa M, Kawaguchi H, Ito H, Suzuki N, Kanno I
  • Journal Title: J Cereb Blood Flow Metab Volume: 34 Issue: 2 Pages: 325-31
  • DOI: 10.1038/jcbfm.2013.201
  • Peer Reviewed / Open Access
• [Journal Article] Vessel specific imaging of glucose transfer with fluorescent glucose analogue in anesthetized mouse cortex. (2014)
  • Author(s): Murata R, Takada Y, Takuwa H, Kawaguchi H, Ito H, Kanno I, Tottori N, Yamada Y, Tomita Y, Itoh Y, Suzuki N, Yamada K, Masamoto K.
  • Journal Title: Adv Exp Med Biol. Volume: 812 Pages: 241-246
  • DOI: 10.1007/978-1-4939-0620-8_32
  • ISBN: 9781493905836, 9781493906208
  • Peer Reviewed / Open Access
• [Journal Article] Changes in cortical microvasculature during misery perfusion measured by two-photon laser scanning microscopy. (2014)
  • Author(s): Tajima Y, Takuwa H, Kokuryo D, Kawaguchi H, Seki C, Masamoto K, Ikoma Y, Taniguchi J, Aoki I, Tomita Y, Suzuki N, Kanno I, Saeki N, Ito H.
  • Journal Title: J Cereb Blood Flow Metab. Volume: 34 Issue: 8 Pages: 1363-1372
  • DOI: 10.1038/jcbfm.2014.91
  • Peer Reviewed / Open Access
• [Journal Article] Pial arteries respond earlier than penetrating arterioles to neural activation in the somatosensory cortex in awake mice exposed to chronic hypoxia: an additional mechanism to proximal integration signaling? (2014)
  • Author(s): Sekiguchi Y, Takuwa H, Kawaguchi H, Kikuchi T, Okada E, Kanno I, Ito H, Tomita Y, Itoh Y, Suzuki N, Sudo R, Tanishita K, Masamoto K.
  • Journal Title: J Cereb Blood Flow Metab. Volume: 34 Issue: 11 Pages: 1761-1770
  • DOI: 10.1038/jcbfm.2014.140
  • Peer Reviewed / Open Access
• [Journal Article] In vivo imaging of the mouse neurovascular unit under chronic cerebral hypoperfusion. (2014)
  • Author(s): Yata K, Nishimura Y, Unekawa M, Tomita Y, Suzuki N, Tanaka T, Mizoguchi A, Tomimoto H.
  • Journal Title: Stroke. Volume: 45 Issue: 12 Pages: 3698-3703
  • DOI: 10.1161/strokeaha.114.005891
  • Peer Reviewed / Open Access
• [Journal Article] “Long-term adaptation of cerebral hemodynamic response to somatosensory stimulation during chronic hypoxia in awake mice.” (2013)
  • Author(s): Takuwa H, Masamoto K, Yamazaki K, Kawaguchi H, Ikoma Y, Tajima Y, Obata T, Tomita Y, Suzuki N, Kanno I, Ito H.
  • Journal Title: J Cereb Blood Flow Metab. Volume: 33(5) Issue: 5 Pages: 774-779
  • DOI: 10.1038/jcbfm.2013.16
  • Peer Reviewed
• [Journal Article] Measuring the vascular diameter of brain surface and parenchymal arteries in awake mouse (2013)
  • Author(s): Sekiguchi Y, Masamoto K, Takuwa H, Kawaguchi H, Kanno I, Ito H, Tomita Y, Itoh Y, Suzuki N, Sudo R, Tanishita K
  • Journal Title: Advances in experimental medicine and biology Volume: 789 Pages: 419-25
  • DOI: 10.1007/978-1-4614-7411-1_56
  • ISBN: 9781461472568, 9781461474111
  • Peer Reviewed
• [Journal Article] “Hypoxia-induced cerebral angiogenesis in mouse cortex with two-photon microscopy.” (2013)
  • Author(s): Masamoto K, Takuwa H, Tomita Y, Toriumi H, Unekawa M, Taniguchi J, Kawaguchi H, Itoh Y, Suzuki N, Ito H, Kanno I.
  • Journal Title: Adv Exp Med Biol. Volume: 789 Pages: 15-20
  • DOI: 10.1007/978-1-4614-7411-1_3
  • ISBN: 9781461472568, 9781461474111
  • Peer Reviewed
• [Journal Article] “Potassium-induced cortical spreading depression bilaterally suppresses the electroencephalogram but only ipsilaterally affects red blood cell velocity in intraparenchymal capillaries.” (2013)
  • Author(s): Unekawa M, Tomita Y, Toriumi H, Masamoto K, Kanno I, Suzuki N.
  • Journal Title: J Neurosci Res. Volume: 91 Issue: 4 Pages: 578-584
  • DOI: 10.1002/jnr.23184
  • Peer Reviewed
• [Journal Article] “Spatial and temporal MRI profile of ischemic tissue after the acute stages of a permanent mouse model of stroke.” (2013)
  • Author(s): Bogaert-Buchmann A, Poittevin M, Po C, Dupont D, Sebrie C, Tomita Y, Trandinh A, Seylaz J, Pinard E, Meric P, Kubis N, Gillet B.
  • Journal Title: Open Neuroimage J. Volume: 7 Pages: 4-14
  • DOI: 10.2174/1874440001307010004
  • Peer Reviewed
• [Journal Article] “Hemodynamic changes during neural deactivation in awake mice: A measurement by laser-Doppler flowmetry in crossed cerebellar diaschisis.” (2013)
  • Author(s): Takuwa H, Tajima Y, Kokuryo D, Matsuura T, Kawaguchi H, Masamoto K, Taniguchi J, Ikoma Y, Seki C, Aoki I, Tomita Y, Suzuki N, Kanno I, ItoH.
  • Journal Title: Brain Res. Volume: 1537 Pages: 350-355
  • DOI: 10.1016/j.brainres.2013.09.023
  • Peer Reviewed
• [Journal Article] Sustained decrease and remarkable increase in red blood cell velocity in intraparenchymal capillaries associated with potassium-induced cortical spreading depression (2012)
  • Author(s): Unekawa M, Tomita M, Tomita Y, Toriumi H, Suzuki N
  • Journal Title: Microcirculation Volume: 19 Issue: 2 Pages: 166-74
  • DOI: 10.1111/j.1549-8719.2011.00143.x
  • Peer Reviewed
• [Journal Article] Suppressive effect of chronic peroral topiramate on potassium-induced cortical spreading depression in rats (2012)
  • Author(s): Unekawa M, Tomita Y, Toriumi H, Suzuki N
  • Journal Title: Cephalalgia Volume: 32 Issue: 7 Pages: 518-527
  • DOI: 10.1177/0333102412444015
  • Peer Reviewed
• [Journal Article] Repeated longitudinal in vivo imaging of neuro-glio-vascular unit at the peripheral boundary of ischemia inmouse cerebral cortex (2012)
  • Author(s): Masamoto K, TomitaY, Toriumi H, Aoki I, Unekawa M, Takuwa H, Itoh Y, Suzuki N, Kanno I
  • Journal Title: Neuroscience Volume: (未)(Epub ahead of print) Pages: 190-200
  • DOI: 10.1016/j.neuroscience.2012.03.034
  • Peer Reviewed
• [Presentation] Astrocytic depolarization induced rapid and broad increase in CBF in in vivo mouse cortex. (2015)
  • Author(s): Masamoto K, Unekawa M, Watanabe T, Toriumi H, Takuwa H, Kawaguchi H, Kanno I, Matsui K, Tanaka K, Tomita Y, Suzuki N
  • Organizer: 27th International Symposium on Cerebral Blood Flow, Metabolism & Function
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2015-06-27 – 2015-06-30
• [Presentation] The behavior of red blood cell in intraparenchymal capillaries during cortical spreading depression observed with high-speed camera confocal fluorescence microscope in anesthetized mice. (2015)
  • Author(s): Tomita Y, Unekawa M, Toriumi H, Osada T, Masamoto K, Kawaguchi H, Itoh Y, Kanno I, Suzuki N
  • Organizer: 27th International Symposium on Cerebral Blood Flow, Metabolism & Function
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2015-06-27 – 2015-06-30
• [Presentation] Temporal diametric change of intracortical penetrating arteries in response to cortical spreading depression observed with two-photon microscopy in anesthetized mice. (2015)
  • Author(s): Unekawa M, Tomita Y, Toriumi H, Osada T, Masamoto K, Kanno I, Suzuki N
  • Organizer: 27th International Symposium on Cerebral Blood Flow, Metabolism & Function
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2015-06-27 – 2015-06-30
• [Presentation] Optogenetic activation of astrocyte-blood flow signaling in the anesthetized mouse cortex. (2015)
  • Author(s): Tomita Y, Masamoto K, Unekawa M, Watanabe T, Toriumi H, TakuwaH, Kawaguchi H, Kanno I, Matsui K, Tanaka K, Suzuki N
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 新潟
  • Year and Date: 2015-05-20 – 2015-05-23
• [Presentation] 麻酔下マウスにおける大脳皮質性拡延性抑制誘発時の実質内穿通動脈の口径変化 (2014)
  • Author(s): 畝川美悠紀, 冨田裕, 鳥海春樹, 長田高志, 正本和人, 菅野巖, 鈴木則宏
  • Organizer: 第26回日本脳循環代謝学会総会
  • Place of Presentation: 岡山
  • Year and Date: 2014-11-21 – 2014-11-22
• [Presentation] アストロサイト賦活による局所脳血流反応の空間伝播の解析 (2014)
  • Author(s): 渡部竜志, 正本和人, 畝川美悠紀, 結城浩弥, 新夕雅啓, 鳥海春樹, 田桑弘之, 川口拓之, 菅野巖, 松井広, 田中謙二, 冨田裕, 鈴木則宏
  • Organizer: 第26回日本脳循環代謝学会総会
  • Place of Presentation: 岡山
  • Year and Date: 2014-11-21 – 2014-11-22
• [Presentation] 大脳皮質性拡延性抑制誘発時の脳表軟膜動脈および実質内穿通動脈の口径変化 (2014)
  • Author(s): 畝川美悠紀, 冨田裕, 鳥海春樹, 長田高志, 正本和人, 菅野巖, 鈴木則宏
  • Organizer: 第42回日本頭痛学会総会
  • Place of Presentation: 下関
  • Year and Date: 2014-11-14 – 2014-11-15
• [Presentation] 光遺伝学による脳血流の操作 (2014)
  • Author(s): 正本和人, 畝川美悠紀, 渡部竜志, 結城浩弥, 田桑弘之, 川口拓之, 菅野 巖, 松井 広, 田中謙二, 冨田 裕, 鈴木則宏
  • Organizer: 第3回ニューロフォトニクス研究会
  • Place of Presentation: 北海道
  • Year and Date: 2014-11-07
• [Presentation] “Impairment of CO2 reactivity in RBC velocity and CBF after cortical spreading depression in anesthetized mice.” (2014)
  • Author(s): Unekawa M, Tomita Y, Toriumi H, Osada T, Masamoto K, Kawaguchi H, ItohY, Kanno I, Suzuki N.
  • Organizer: 第39回日本微小循環学会総会.
  • Place of Presentation: 北里大学薬学部 (東京).
• [Presentation] “Spatio-temporal dynamics of morphological changes in neuro-glia-vascular unit after cerebral ischemia measured with two-photon microscopy in mouse cortex.” (2013)
  • Author(s): Masamoto K, Abe T, Takuwa H, Toriumi H, Tomita Y, Unekawa M, Itoh Y, Kawaguchi H, Ito H, Suzuki N, Kanno I.
  • Organizer: 26th International Symposium on Cerebral Blood Flow, Metabolism & Function.
  • Place of Presentation: Shanghai, China (中国).
• [Presentation] “Reduced response in penetrating artery but sustained response in surface artery to whisker stimulation in chronic hypoxia mice.” (2013)
  • Author(s): Kanno I, Sekiguchi Y, Takuwa H, Masamoto K, Kawaguchi H, Taniguchi J, Tomita Y, Sudo R, Tanishita K, Suzuki N, Ito H.
  • Organizer: 26th International Symposium on Cerebral Blood Flow, Metabolism & Function.
  • Place of Presentation: Shanghai, China (中国).
• [Presentation] “Different response in diameter of pial vessels and in cerebral blood flow associated with cortical spreading depression in anesthetized mice.” (2013)
  • Author(s): Unekawa M, Tomita Y, Toriumi H, Osada T, Masamoto K, Kawaguchi H, Itoh Y, Kanno I, Suzuki N.
  • Organizer: 26th International Symposium on Cerebral Blood Flow, Metabolism & Function.
  • Place of Presentation: Shanghai, China (中国).
• [Presentation] “Cellular-scale imaging of glucose transfer in cerebral microvasculature with fluorescent glucose analogue in anesthetized mouse cortex.” (2013)
  • Author(s): Murata R, Takada Y, Takuwa H, Kawaguchi H, Ito H, Kanno I, Tottori N, Yamada Y, Tomita Y, Itoh Y, Suzuki N, Yamada K, Masamoto K.
  • Organizer: The 41st Annual ISOTT meeting.
  • Place of Presentation: The EPR center of the Geisel School of Medicine at Dartmouth College, Hanover. NH (米国).
• [Presentation] “Optogeneticsを用いたアストロサイト賦活による脳血流反応.” (2013)
  • Author(s): 渡部竜志, 正本和人, 畝川美悠紀, 鳥海春樹, 谷口順子, 田桑弘之, 川口拓之, 伊藤浩, 菅野巖, 松井広, 田中謙二, 冨田裕, 鈴木則宏.
  • Organizer: 第25回日本脳循環代謝学会総会.
  • Place of Presentation: 京王プラザホテル札幌 (札幌).
• [Presentation] “マウス大脳虚血辺縁部における脳微小血管とアストロサイトの時空間展開：永久閉塞と再潅流モデルでの比較.” (2013)
  • Author(s): 正本和人, 安部貴人, 田桑弘之, 鳥海春樹, 冨田裕, 畝川美悠紀, 伊藤義彰, 谷口順子, 田島洋佑, 川口拓之, 伊藤浩, 鈴木則宏, 菅野巖.
  • Organizer: 第25回日本脳循環代謝学会総会.
  • Place of Presentation: 京王プラザホテル札幌 (札幌).
• [Presentation] “麻酔下マウスにおける大脳皮質性拡延性抑制誘発時の実質毛細血管内赤血球速度と局所脳血流の経時的変化.” (2013)
  • Author(s): 畝川美悠紀, 冨田裕, 鳥海春樹, 長田高志, 正本和人, 川口拓之, 伊藤義彰, 菅野巖, 鈴木則宏.
  • Organizer: 第25回日本脳循環代謝学会総会.
  • Place of Presentation: 京王プラザホテル札幌 (札幌).
• [Presentation] “麻酔下マウスにおける大脳皮質性拡延性抑制誘発時の脳表軟膜動脈と脳血流の変化.” (2013)
  • Author(s): 畝川美悠紀, 冨田裕, 鳥海春樹, 長田高志, 正本和人, 伊藤義彰, 菅野巖, 鈴木則宏.
  • Organizer: 第41回日本頭痛学会総会.
  • Place of Presentation: いわて県民情報交流センター (盛岡).
• [Presentation] マウス体性感覚野における1本ひげ刺激に対する脳表動脈および穿通動脈応答の比較 (2013)
  • Author(s): 関口優太，正本和人，田桑弘之，川口拓之，菅野 巖，伊藤 浩，冨田 裕，鈴木則宏，須藤 亮，谷下一夫
  • Organizer: 日本機械学会第25回バイオエンジニアリング講演会
  • Place of Presentation: つくば(茨城)
• [Presentation] Propagation of changes in diameter of pial arteries and cerebral blood flow following cortical spreading depression in anesthetized mice (2013)
  • Author(s): Unekawa M, Tomita Y, Toriumi H, Osada T, Masamoto K, Itoh Y, Kanno I, Suzuki N
  • Organizer: 第38回日本微小循環学会総会
  • Place of Presentation: 東京
• [Presentation] Repeated 3D live imaging of microvascular-astroglia restructuring induced by hypoxia in mouse cerebral cortex (2013)
  • Author(s): Masamoto K, Takuwa H, Sugashi T, Yamada Y, Tomita Y, Unekawa M, Toriumi H, Itoh Y, Suzuki N, Ito H, Kanno I
  • Organizer: 第38回日本微小循環学会総会
  • Place of Presentation: 東京
• [Presentation] 異なる閉塞部位によるMCAO後の経時的in vivo微小血流動態変化の違いの検討 (2012)
  • Author(s): 冨田裕, 畝川美悠紀, 鳥海春樹, 正本和人, 青木伊知男, 菅野巖, 鈴木則宏
  • Organizer: 第53回日本神経学会学術大会
  • Place of Presentation: 東京
• [Presentation] Live Cell Imaging of Cerebral Angiogenesis in Mouse Cortex with Two-Photon Microscopy (2012)
  • Author(s): Masamoto K, Tomita Y, Toriumi H, Unekawa M, Takuwa H, Taniguchi J, Kawaguchi H, Itoh Y, Suzuki NI, H, Kanno I
  • Organizer: ISOTT's (International Society on Oxygen Transport to Tissue) 40th meeting
  • Place of Presentation: ブルージュ(ベルギー)
• [Presentation] Effects of chronic oral topiramate administration on potassium-induced cortidal spreading depression in rats (2012)
  • Author(s): Unekawa M, Tomita Y, Toriumi H, Suzuki N
  • Organizer: 4th Asian Regional Conference for Headache
  • Place of Presentation: 台北(台湾)
• [Presentation] 慢性低酸素飼育下マウスの大脳皮質体性感覚野における脳表動脈と穿通動脈のひげ刺激応答 (2012)
  • Author(s): 菅野巖, 関口優太, 田桑弘之, 正本和人, 川口拓之, 谷口順子, 冨田裕, 須藤亮, 鈴木則宏, 谷下一夫, 伊藤浩
  • Organizer: 第24回日本脳循環代謝学会総会
  • Place of Presentation: 広島
• [Presentation] 麻酔下マウスにおける大脳皮質性拡延性抑制誘発時の脳表動静脈および毛細血管の口径と脳血流の変化 (2012)
  • Author(s): 畝川美悠紀, 冨田裕, 鳥海春樹, 長田高志, 正本和人, 川口拓之, 伊藤義彰, 菅野巖, 鈴木則宏
  • Organizer: 第24回日本脳循環代謝学会総会
  • Place of Presentation: 広島
• [Presentation] マウス大脳皮質虚血辺縁部におけるNeuro-glio-vascular unitのin vivo形態解析 (2012)
  • Author(s): 正本和人, 冨田裕, 鳥海春樹, 青木伊知男, 畝川美悠紀, 田桑弘之, 伊藤浩, 伊藤義彰, 鈴木則宏, 菅野巖
  • Organizer: 第24回日本脳循環代謝学会総会
  • Place of Presentation: 広島