Microglial contribution on higher order of brain function and their pathology

• Project/Area Number: 18H02598
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 48020:Physiology-related
• Research Institution: Nagoya University (2020); Kobe University (2018-2019)
• Principal Investigator: WAKE Hiroaki 名古屋大学, 医学系研究科, 教授 (90455220)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2020: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2019: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2018: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: ミクログリア / 血液脳関門 / シナプス / 学習 / 免疫

Outline of Final Research Achievements

In this study, we focused on microglia and aimed to elucidate psychiatric pathology from their physiological functions on synapses and blood vessels. Using in vivo imaging, we found that microglia migrate into cerebral blood vessels during systemic inflammation and contribute to the permeability of the blood-brain barrier in a time-specific manner by altering the expression of tight junction-related factors and phagocytic factors. In addition, we found that microglia modulate their synaptic effects by regulating their projection dynamics during higher brain functions (motor learning). These synaptic modulation mechanisms are dependent on the sensory input in the sensory cortex, suggesting a role for microglia in heterogeneous sensory plasticity.

Academic Significance and Societal Importance of the Research Achievements

本研究成果によって、ミクログリアを標的とした中枢神経系疾患に対する新たな創薬の可能性を創出することができた。さらにミクログリアによるシナプス可塑性を制御することで、中枢神経系疾患の回復期に介入する可能性も考えられる。さらに異種感覚の可塑性のミクログリアによる制御の解明は学術的にも非常に意義深い。

Research Products

• [Int'l Joint Research] マウントサイナイ大学(米国)
• [Int'l Joint Research] UNSW(オーストラリア)
• [Int'l Joint Research] UNSW(オーストラリア)
• [Journal Article] Pain induces stable, active microcircuits in the somatosensory cortex that provide a new therapeutic target. (2021)
  • Author(s): Okada T, Kato D, Nomura Y, Obata N, Quan X, Morinaga A, Yano H, Guo Z, Aoyama Y, Tachibana Y, Moorhouse AJ, Matoba O, Takiguchi T, Mizobuchi S and Wake H
  • Journal Title: Sci Adv Volume: 7 Issue: 12 Pages: 8261-8261
  • DOI: 10.1126/sciadv.abd8261
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Myelin plasticity modulates neural circuitry required for learning and behavior. (2021)
  • Author(s): Kato D, Wake H
  • Journal Title: Neurosci Res. Volume: - Pages: 11-16
  • DOI: 10.1016/j.neures.2020.12.005
  • NAID: 120007185093
  • Peer Reviewed / Open Access
• [Journal Article] Maternal Immune activation induces sustained changes in fetal microglia motility (2020)
  • Author(s): Ozaki K, Kato D, Ikegami A, Hashimoto A, Sugio S, Guo Z, Shibushita M, Tatematsu T, Haruwaka K, Moorhouse AJ, Yamada H, Wake H
  • Journal Title: Sci Rep Volume: 10 Issue: 1 Pages: 21378-21378
  • DOI: 10.1038/s41598-020-78294-2
  • NAID: 120006954848
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Negative feedback control of neuronal activity by microglia. (2020)
  • Author(s): Badimon A, Strasburger HJ, Ayata P, Chen X, Nair A, Ikegami A, Hwang P, Chan AT, Graves SM, Uweru JO, Ledderose C, Kutlu MG, Wheeler MA, Kahan A, Ishikawa M, Wang YC, Loh YE, Jiang JX, Surmeier DJ, Robson SC, Junger WG, Sebra R, Calipari ES, Kenny PJ, Eyo UB, Colonna M, Quintana FJ, Wake H, Gradinaru V, Schaefer A.
  • Journal Title: Nature Volume: 586 Issue: 7829 Pages: 417-423
  • DOI: 10.1038/s41586-020-2777-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transient microglial absence assists postmigratory cortical neurons in proper differentiation (2020)
  • Author(s): Yuki Hattori, Yu Naito, Yoji Tsugawa, Shigenori Nonaka, Hiroaki Wake, Takashi Nagasawa, Takaki Miyata
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 1631-1631
  • DOI: 10.1038/s41467-020-15409-3
  • NAID: 120006841707
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] YAP1 mediates survival of ALK-rearranged lung cancer cells treated with alectinib via pro-apoptotic protein regulation (2020)
  • Author(s): Tsuji Takahiro、Ozasa Hiroaki、Aoki Wataru、Aburaya Shunsuke、Yamamoto Funazo Tomoko、Furugaki Koh、Yoshimura Yasushi、Yamazoe Masatoshi、Ajimizu Hitomi、Yasuda Yuto、Nomizo Takashi、Yoshida Hironori、Sakamori Yuichi、Wake Hiroaki、Ueda Mitsuyoshi、Kim Young Hak、Hirai Toyohiro
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 19-19
  • DOI: 10.1038/s41467-019-13771-5
  • NAID: 120006782216
  • Peer Reviewed / Open Access
• [Journal Article] Physiological Implications of Microglia-Synapse Interactions (2019)
  • Author(s): Wake Hiroaki、Horiuchi Hiroshi、Kato Daisuke、Moorhouse Andrew J.、Nabekura Junichi
  • Journal Title: Methods Mol Biol. Volume: 2034 Pages: 69-80
  • DOI: 10.1007/978-1-4939-9658-2_6
  • ISBN: 9781493996575, 9781493996582
  • Peer Reviewed
• [Journal Article] In Vivo Two-Photon Imaging of Microglial Synapse Contacts (2019)
  • Author(s): Kato Daisuke、Ikegami Ako、Horiuchi Hiroshi、Moorhouse Andrew J.、Nabekura Junichi、Wake Hiroaki
  • Journal Title: Methods Mol Biol. Volume: 2034 Pages: 281-286
  • DOI: 10.1007/978-1-4939-9658-2_20
  • ISBN: 9781493996575, 9781493996582
  • Peer Reviewed
• [Journal Article] Oral splint ameliorates tic symptoms in patients with tourette syndrome (2019)
  • Author(s): Murakami Jumpei、Tachibana Yoshihisa、Akiyama Shigehisa、Kato Takafumi、Taniguchi Aya、Nakajima Yoshiaki、Shimoda Mao、Wake Hiroaki、Kano Yukiko、Takada Masahiko、Nambu Atsushi、Yoshida Atsushi
  • Journal Title: Movement Disorders Volume: 34 Issue: 10 Pages: 1577-1578
  • DOI: 10.1002/mds.27819
  • NAID: 120006799316
  • Peer Reviewed / Open Access
• [Journal Article] Motor learning requires myelination to reduce asynchrony and spontaneity in neural activity (2019)
  • Author(s): Kato Daisuke、Wake Hiroaki、Lee Philip R.、Tachibana Yoshihisa、Ono Riho、Sugio Shouta、Tsuji Yukio、Tanaka Yasuyo H.、Tanaka Yasuhiro R.、Masamizu Yoshito、Hira Riichiro、Moorhouse Andrew J.、Tamamaki Nobuaki、Ikenaka Kazuhiro、Matsukawa Noriyuki、Fields R. Douglas、Nabekura Junichi、Matsuzaki Masanori
  • Journal Title: Glia Volume: 68 Issue: 1 Pages: 193-210
  • DOI: 10.1002/glia.23713
  • NAID: 120006775953
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Activity-Dependent Myelination (2019)
  • Author(s): Kato Daisuke、Wake Hiroaki
  • Journal Title: Adv Exp Med Biol Volume: 1190 Pages: 43-51
  • DOI: 10.1007/978-981-32-9636-7_4
  • ISBN: 9789813296350, 9789813296367
  • Peer Reviewed
• [Journal Article] Dual microglia effects on blood brain barrier permeability induced by systemic inflammation (2019)
  • Author(s): Haruwaka Koichiro、Ikegami Ako、Tachibana Yoshihisa、Ohno Nobuhiko、Konishi Hiroyuki、Hashimoto Akari、Matsumoto Mami、Kato Daisuke、Ono Riho、Kiyama Hiroshi、Moorhouse Andrew J.、Nabekura Junichi、Wake Hiroaki
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 5816-5816
  • DOI: 10.1038/s41467-019-13812-z
  • NAID: 120006786954
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Microglia Enhance Synapse Activity to Promote Local Network Synchronization (2018)
  • Author(s): Ryohei Akiyoshi, Hiroaki Wake, Daisuke Kato, Hiroshi Horiuchi, Riho Ono, Ako Ikegami, Koichiro Haruwaka, Toshiaki Omori, Yoshihisa Tachibana, Andrew Moorhouse, Junichi Nabekura
  • Journal Title: eNeuro Volume: 5 Issue: 5 Pages: 0088-18
  • DOI: 10.1523/eneuro.0088-18.2018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 3D stimulation and imaging-based functional optical microscopy (SIFOM) of biological cells (2018)
  • Author(s): Xiangyu Quan, Manoj Kumar, Osamu Matoba, Yasuhiro Awatsuji, Yoshio Hayasaki, Satoshi Hasegawa, and Hiroki Wake
  • Journal Title: Optics Letters Volume: 43 Issue: 21 Pages: 5447-5450
  • DOI: 10.1364/ol.43.005447
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulation of myelin structure and conduction velocity by perinodal astrocytes. (2018)
  • Author(s): 3.Dutta D, Woo DH, Lee PR, Pajevic S, Bukalo O, Huffman WC, Wake H, Basser PJ, Sheikhbahaei S, Lazarevic V, Smith JC & Fields RD.
  • Journal Title: Proc Natl Acad Sci USA Volume: Nov 13;115(46) Pages: 11832-11837
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Microglia mediate non-cell-autonomous cell death of retinal ganglion cells. (2018)
  • Author(s): Takeda A, Shinozaki Y, Kashiwagi K, Ohno N, Eto K, Wake H, Nabekura J, Koizumi S.
  • Journal Title: Glia Volume: 66 Issue: 11 Pages: 2366-2384
  • DOI: 10.1002/glia.23475
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cortical astrocytes prime the induction of spine plasticity and mirror image pain. (2018)
  • Author(s): Ishikawa T, Eto K, Kim SK, Wake H, Takeda I, Horiuchi H, Moorhouse AJ, Ishibashi H, Nabekura J.
  • Journal Title: Pain Volume: 印刷中 Issue: 8 Pages: 1592-1606
  • DOI: 10.1097/j.pain.0000000000001248
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Activity-dependent functions of non-electrical glial cells (2018)
  • Author(s): Kato Daisuke、Eto Kei、Nabekura Junichi、Wake Hiroaki
  • Journal Title: The Journal of Biochemistry Volume: 印刷中 Issue: 6 Pages: 457-464
  • DOI: 10.1093/jb/mvy023
  • Peer Reviewed / Open Access
• [Presentation] Illuminate the physiological and pathological function of microglia (2021)
  • Author(s): Hiroaki Wake
  • Organizer: JSPS-NIH forum
  • Int'l Joint Research / Invited
• [Presentation] 脳免疫細胞ミクログリアの生理機能と病態への寄与 (2020)
  • Author(s): 和氣弘明
  • Organizer: 第41回日本炎症・再生医学会
  • Invited
• [Presentation] ミクログリアによる微小脳環境の創造的破壊 (2020)
  • Author(s): 和氣弘明
  • Organizer: 第43回日本神経科学大会
  • Int'l Joint Research
• [Presentation] 神経細胞の計測・操作一体型顕微鏡の開発 (2020)
  • Author(s): 和氣弘明
  • Organizer: 第43回日本神経科学大会
  • Int'l Joint Research / Invited
• [Presentation] グリア細胞の生体内での挙動について (2020)
  • Author(s): 和氣弘明
  • Organizer: 日本臨床視覚生理学会
  • Invited
• [Presentation] 疼痛制御における大脳皮質第一次体性感覚野の神経細胞活動変化とN型カルシウムイオンチャネルの役割 (2020)
  • Author(s): 岡田卓也, 野村有紀, 小幡典彦, 橘吉寿, 和氣弘明, 溝渕知司
  • Organizer: 第67回日本麻酔科学会
• [Presentation] 解き明かされる環境依存的可変型ミクログリアの生理機能 (2020)
  • Author(s): 和氣弘明
  • Organizer: 第63回日本神経化学会大会
• [Presentation] Effects of N-type calcium ion channel function on the neuronal activities of the primary somatosensory cortex in inflammatory pain model (2020)
  • Author(s): Okada T, Nomura Y, Tachibana Y, Obata N, Wake H, Mizobuchi S
  • Organizer: European Society of Anesthesiologist Annual Meeting 2020
  • Int'l Joint Research
• [Presentation] Functional connectivity of neural circuitry necessary for pain behavior elucidated using a holographic system (2020)
  • Author(s): Daisuke Kato, Takuya Okada and Hiroaki Wake
  • Organizer: 第126回 日本解剖学会総会・全国学術集会／ 第98回 日本生理学会大会 合同大会
• [Presentation] Microglia ‘strip’ inhibitory synapse to promote cross-modal plasticity (2020)
  • Author(s): Akari Hashimoto, Nanami Kawamura, Etsuko Tarusawa, Daisuke Kato, Koichiro Haruwaka, Ako Ikegami, Andrew J Moorhouse, Takeshi Yagi, Hiroaki Wake
  • Organizer: 2020 Cold Spring Harbor meeting: Glia in Health & Disease
  • Int'l Joint Research