Therapeutic strategy for the abnormal neuronal circuit activity associated with systemic inflammation

• Project/Area Number: 17K19458
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Neuroscience and related fields
• Research Institution: Kobe University
• Principal Investigator: WAKE Hiroaki 神戸大学, 医学研究科, 教授 (90455220)
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: ミクログリア / 血液脳関門 / 体循環系炎症 / シナプス / 精神症状 / 全身炎症

Outline of Final Research Achievements

Microglia survey brain parenchyma and respond to any disruptions. Microglia also respond to systemic disease, but how this relates to blood brain barrier (BBB) integrity is largely unknown. Here we use simultaneous in vivo imaging to demonstrate that systemic inflammation induces migration of brain resident microglia to cerebral vessels. Vessel-associated microglia initially maintain BBB integrity, associated with expression of the tight junction protein Claudin-5. Further sustained inflammation results in microglia phagocytosing astrocytic end-feet and impairing BBB function. Our results show dual microglial role for BBB and have important implications for understanding how systemic immune-activation can impact on neural circuit functions.

Academic Significance and Societal Importance of the Research Achievements

この一連の研究により体循環炎症に伴う中枢神経系ミクログリアの変化およびそのBBBの透過性制御機構さらにはその分子機序を明らかにすることができた。今後これらの分子を標的にした創薬戦略をすすめていくことで、体循環系の炎症に伴う精神症状の発症機序の一端をしめすことができた。

Research Products

• [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] 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] Regulation of myelin structure and conduction velocity by perinodal astrocytes (2018)
  • Author(s): Dutta Dipankar J.、Woo Dong Ho、Lee Philip R.、Pajevic Sinisa、Bukalo Olena、Huffman William C.、Wake Hiroaki、Basser Peter J.、SheikhBahaei Shahriar、Lazarevic Vanja、Smith Jeffrey C.、Fields R. Douglas
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 115 Issue: 46 Pages: 11832-11837
  • DOI: 10.1073/pnas.1811013115
  • Peer Reviewed / 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
• [Journal Article] Reduced Mastication Impairs Memory Function (2017)
  • Author(s): Fukushima-Nakayama Y.、Ono Takehito、Hayashi M.、Inoue M.、Wake H.、Ono Takashi、Nakashima T.
  • Journal Title: Journal of Dental Research Volume: 96 Issue: 9 Pages: 1058-1066
  • DOI: 10.1177/0022034517708771
  • Peer Reviewed
• [Presentation] Systemic - CNS immune interaction to regulate neuronal activity (2017)
  • Author(s): Hiroaki WAKE
  • Organizer: 第４０回日本神経科学大会
• [Presentation] Myelination for information processing (2017)
  • Author(s): Hiroaki WAKE
  • Organizer: 第90回日本神経化学会大会（仙台）
• [Presentation] Physiology of microglia -New Insights- (2017)
  • Author(s): Hiroaki WAKE
  • Organizer: ＸＸⅢ World Congres of Neurology
  • Int'l Joint Research / Invited
• [Presentation] 髄鞘のスクラップアンドビルドによる脳情報処理の効率化 (2017)
  • Author(s): 和氣弘明
  • Organizer: 次世代脳冬のシンポジウム（東京）
• [Presentation] Spatial and temporal regulation of neuronal circuit activity by glial cells (2017)
  • Author(s): Hiroaki WAKE
  • Organizer: The UK-Japan Spring Neuroscience Symposium （ロンドン）
  • Invited
• [Presentation] Activity dependent myelin regulation in information processing (2017)
  • Author(s): Hiroaki WAKE
  • Organizer: 第123回日本解剖学会総会・全国学術集会（東京）
  • Invited