Identification of molecules which are released from nerons to induce neuroinflammation

• Project/Area Number: 17K08593
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Kobe University
• Principal Investigator: Kitaoka Shiho 神戸大学, 医学研究科, 講師 (00545246)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 反復ストレス / 脳内炎症 / ミクログリア / TLR / PGE2 / DREADD / 神経細胞 / DAMPs / 薬理学

Outline of Final Research Achievements

Social stress activates microglia through Toll-like receptor in the medial prefrontal cortex. The inflammatory cytokines such as IL-1αand TNFα released from prefrontal microglia are required to induce social avoidance. In the subcortical region, stress produces prostaglandin E2 in a Toll-like receptor dependent manner. In addition, monoacylglycerol lipase, is crucial for stress-induced PGE2 production and social avoidance. These results show that social stress releases different inflammation-related molecules from microglia in the respective brain regions.

Academic Significance and Societal Importance of the Research Achievements

脳内には神経細胞のほか、ミクログリアなどのグリア細胞が存在し、脳機能の維持に関与している。近年、生理条件下で、ミクログリアの遺伝子発現が脳領域間で異なることが報告されているものの、機能的意義については不明な点が多い。本研究成果は、炎症に関わるToll様受容体とプロスタグランジンE2を手掛かりとして、反復ストレスが異なる脳領域のミクログリアで誘導する変化を明らかにし、さらに脳機能変化との関連性を示した点において学術的意義があると考えられる。

Research Products

• [Journal Article] Iso-α-acids, the bitter components of beer, improve hippocampus-dependent memory through vagus nerve activation (2019)
  • Author(s): Ano Yasuhisa、Hoshi Ayaka、Ayabe Tatsuhiro、Ohya Rena、Uchida Shinichi、Yamada Koji、Kondo Keiji、Kitaoka Shiho、Furuyashiki Tomoyuki
  • Journal Title: The FASEB Journal Volume: ー Issue: 4 Pages: 4987-4995
  • DOI: 10.1096/fj.201801868rr
  • NAID: 120006619816
  • Peer Reviewed
• [Journal Article] Roles of multiple lipid mediators in stress and depression (2019)
  • Author(s): Furuyashiki Tomoyuki、Akiyama Satoshi、Kitaoka Shiho
  • Journal Title: International Immunology Volume: 未定 Issue: 9 Pages: 579-587
  • DOI: 10.1093/intimm/dxz023
  • Peer Reviewed / Open Access
• [Journal Article] Neural mechanisms underlying adaptive and maladaptive consequences of stress: Roles of dopaminergic and inflammatory responses (2019)
  • Author(s): Furuyashiki Tomoyuki、Kitaoka Shiho
  • Journal Title: Psychiatry and Clinical Neurosciences Volume: 73 Issue: 11 Pages: 669-675
  • DOI: 10.1111/pcn.12901
  • Peer Reviewed / Open Access
• [Journal Article] Leucine-Histidine dipeptide attenuates microglial activation and emotional disturbances induced by brain inflammation and repeated social defeat stress (2019)
  • Author(s): Ano Yasuhisa、Kita Masahiro、Kitaoka Shiho、Furuyashiki Tomoyuki
  • Journal Title: Nutrients Volume: 11 Issue: 9 Pages: 2161-2161
  • DOI: 10.3390/nu11092161
  • NAID: 120006733168
  • Peer Reviewed / Open Access
• [Journal Article] Improvement of PTSD-like behavior by the forgetting effect of hippocampal neurogenesis enhancer memantine in a social defeat stress paradigm (2019)
  • Author(s): Ishikawa Rie、Uchida Chiaki、Kitaoka Shiho、Furuyashiki Tomoyuki、Kida Satoshi
  • Journal Title: Molecular Brain Volume: 12 Issue: 1 Pages: 68-68
  • DOI: 10.1186/s13041-019-0488-6
  • NAID: 120006713566
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Roles of Toll-like receptor 2/4, monoacylglycerol lipase, and cyclooxygenase in social defeat stress-induced prostaglandin E2 synthesis in the brain and their behavioral relevance (2019)
  • Author(s): Nie Xiang、Kitaoka Shiho、Shinohara Masakazu、Kakizuka Akira、Narumiya Shuh、Furuyashiki Tomoyuki
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 17548-17548
  • DOI: 10.1038/s41598-019-54082-5
  • NAID: 120006996939
  • Peer Reviewed / Open Access
• [Journal Article] The Lacto-tetrapeptide Gly-Thr-Trp-Tyr, β-lactolin, improves spatial memory functions via dopamine release and D1 receptor activation in the hippocampus (2019)
  • Author(s): Ayabe Tatsuhiro、Ano Yasuhisa、Ohya Rena、Kitaoka Shiho、Furuyashiki Tomoyuki
  • Journal Title: Nutrients Volume: 11 Issue: 10 Pages: 2469-2469
  • DOI: 10.3390/nu11102469
  • NAID: 120006779839
  • Peer Reviewed / Open Access
• [Journal Article] The Innate Immune Receptors TLR2/4 Mediate Repeated Social Defeat Stress-Induced Social Avoidance through Prefrontal Microglial Activation (2018)
  • Author(s): Nie Xiang、Kitaoka Shiho、Tanaka Kohei、Segi-Nishida Eri、Imoto Yuki、Ogawa Atsubumi、Nakano Fumitake、Tomohiro Ayaka、Nakayama Kazuki、Taniguchi Masayuki、Mimori-Kiyosue Yuko、Kakizuka Akira、Narumiya Shuh、Furuyashiki Tomoyuki
  • Journal Title: Neuron Volume: 99 Issue: 3 Pages: 464-479
  • DOI: 10.1016/j.neuron.2018.06.035
  • Peer Reviewed / Open Access
• [Journal Article] Repeated social defeat stress impairs attentional set shifting irrespective of social avoidance and increases female preference associated with heightened anxiety (2018)
  • Author(s): Higashida Shu、Nagai Hirotaka、Nakayama Kazuki、Shinohara Ryota、Taniguchi Masayuki、Nagai Midori、Hikida Takatoshi、Yawata Satoshi、Ago Yukio、Kitaoka Shiho、Narumiya Shuh、Furuyashiki Tomoyuki
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 10454-10454
  • DOI: 10.1038/s41598-018-28803-1
  • NAID: 120006501224
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ulk2 controls cortical excitatory?inhibitory balance via autophagic regulation of p62 and GABAA receptor trafficking in pyramidal neurons (2018)
  • Author(s): Sumitomo Akiko、Yukitake Hiroshi、Hirai Kazuko、Horike Kouta、Ueta Keisho、Chung Youjin、Warabi Eiji、Yanagawa Toru、Kitaoka Shiho、Furuyashiki Tomoyuki、Narumiya Shuh、Hirano Tomoo、Niwa Minae、Sibille Etienne、Hikida Takatoshi、Sakurai Takeshi、Ishizuka Koko、Sawa Akira、Tomoda Toshifumi
  • Journal Title: Human Molecular Genetics Volume: 27 Issue: 18 Pages: 3165-3176
  • DOI: 10.1093/hmg/ddy219
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dopamine D1 receptor subtype mediates acute stress-induced dendritic growth in excitatory neurons of the medial prefrontal cortex and contributes to suppression of stress susceptibility in mice (2017)
  • Author(s): Shinohara R, Taniguchi M, Ehrlich AT, Yokogawa K, Deguchi Y, Cherasse Y, Lazarus M, Urade Y, Ogawa A, Kitaoka S, Sawa A, Narumiya S, *Furuyashiki T.
  • Journal Title: Mol Psychiatry Volume: - Issue: 8 Pages: 1717-1730
  • DOI: 10.1038/mp.2017.177
  • NAID: 120006599256
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Depressive-like behaviors are regulated by NOX1/NADPH oxidase by redox modification of NMDA receptor 1. (2017)
  • Author(s): Ibi M, Liu J, Arakawa N, Kitaoka S, Kawaji A, Matsuda KI, Iwata K, Matsumoto M, Katsuyama M, Zhu K, Teramukai S, Furuyashiki T, Yabe-Nishimura C.
  • Journal Title: J Neurosci Volume: 37 Issue: 15 Pages: 4200-4212
  • DOI: 10.1523/jneurosci.2988-16.2017
  • Peer Reviewed / Open Access
• [Journal Article] iPSC-based drug repositioning identifies Src/c-Abl as a therapeutic target for ALS motor neurons (2017)
  • Author(s): Imamura K, Izumi Y, 他24名, Hosokawa M, Akiyama H, Ayaki T, Ito H, Takahashi R, Yamanaka S, Inoue H
  • Journal Title: Science Translational Medicine Volume: 9 Issue: 391 Pages: 391-391
  • DOI: 10.1126/scitranslmed.aaf3962
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ストレス・うつにおける炎症反応の役割 (2017)
  • Author(s): 北岡志保、古屋敷智之
  • Journal Title: Farumashia Volume: 53 Issue: 7 Pages: 681-685
  • DOI: 10.14894/faruawpsj.53.7_681
  • NAID: 130006833073
  • ISSN: 0014-8601, 2189-7026
  • Peer Reviewed / Open Access
• [Journal Article] Roles of Inflammation in Stress-induced Emotional Changes (2017)
  • Author(s): 北岡志保、古屋敷智之
  • Journal Title: Japanese Journal of Psychosomatic Medicine Volume: 57 Issue: 9 Pages: 922-928
  • DOI: 10.15064/jjpm.57.9_922
  • NAID: 130006039495
  • ISSN: 0385-0307, 2189-5996
  • Open Access
• [Presentation] Iron metabolism disturbance induced by repeated social defeat stress (2020)
  • Author(s): 北岡 志保
  • Organizer: 第93回日本薬理学会年会
  • Invited
• [Presentation] ミクログリアを中心とした脳内炎症様反応による抑うつ行動の誘導 (2019)
  • Author(s): 北岡 志保
  • Organizer: 第115回日本精神神経学会学術総会
  • Invited
• [Presentation] マウス反復社会挫折ストレスによる社会忌避行動の誘導におけるHMGB1の役割 (2019)
  • Author(s): 北岡志保、友廣彩夏、請島慎也、劉克約、和氣秀徳、勅使川原匡、西堀正洋、古屋敷智之
  • Organizer: 第１３５回日本薬理学会近畿部会
• [Presentation] The innate immune receptors in prefrontal microglia are crucial for repeated stress-induced behavioral changes (2019)
  • Author(s): 北岡 志保、聶 翔、田中 昂平、小川 惇史、井本 有基、瀬木（西田）恵里、成宮 周、古屋敷 智之
  • Organizer: NEURO 2019
• [Presentation] Roles of innate immune molecules in repeated stress-induced neuronal and behavioral changes (2019)
  • Author(s): Shiho Kitaoka, Shinya Ukeshima, Ayaka Tomohiro, Yumika Motooka, Yugo Fukazawa , Keyue Liu, Hidenori Wake, Kiyoshi Teshigawara, Masahiro Nishibori, Tomoyuki Furuyashiki
  • Organizer: 9th iDEAs
  • Int'l Joint Research
• [Presentation] Repeated stress induces behavioral changes through inflammation-like response. (2019)
  • Author(s): Shiho Kitaoka, Xiang Nie, Kohei Tanaka, Atsubumi Ogawa, Fumitake Nakano, Ayaka Tomohiro, Kazuki Nakayama, Yuki Imoto, Eri Segi-Nishida, Shuh Narumiya, Tomoyuki Furuyashiki
  • Organizer: Japan-UK Neuroscience Symposium
  • Invited
• [Presentation] Repeated stress-induced behavioral changes and inflammation-like responses (2019)
  • Author(s): Shiho Kitaoka, Xiang Nie, Kohei Tanaka, Atsubumi Ogawa, Fumitake Nakano, Ayaka Tomohiro, Kazuki Nakayama, Yuki Imoto, Eri Segi-Nishida, Shuh Narumiya, Tomoyuki Furuyashiki
  • Organizer: 第92回日本薬理学会年会
  • Invited
• [Presentation] マウス反復社会挫折ストレスによる情動変容における自然免疫分子の役割 (2018)
  • Author(s): 北岡志保、聶翔、田中昂平、小川惇史、中野史健、井本有基、瀬木（西田）恵里、成宮周、古屋敷智之
  • Organizer: 第133回日本薬理学会近畿部会
• [Presentation] Repeated Stress-induced Inflammation-like response in the Brain and Future Prospects (2018)
  • Author(s): 北岡 志保
  • Organizer: 第29回 京都大学オープンイノベーション勉強会
  • Invited
• [Presentation] The role of innate immune pathway in repeated social defeat stress-induced behavioral changes in mice (2018)
  • Author(s): Shiho Kitaoka, Xiang Nie, Kohei Tanaka, Atsubumi Ogawa, Fumitake Nakano, Yuki Imoto, Eri Segi-Nishida, Shuh Narumiya, Tomoyuki Furuyashiki
  • Organizer: 第18回国際基礎臨床薬理学会
  • Int'l Joint Research
• [Presentation] マウス反復社会挫折ストレスによる脳内炎症様反応を介した情動変容の誘導 (2018)
  • Author(s): 北岡 志保
  • Organizer: 『情動の神経回路機構とその破綻』
  • Invited
• [Presentation] Innate immune molecules mediated microglial activation in the medial prefrontal cortex are critical for repeated stress-induced behavioral changes in mice (2018)
  • Author(s): Shiho Kitaoka, Xiang Nie, Kohei Tanaka, Atsubumi Ogawa, Fumitake Nakano, Ayaka Tomohiro, Kazuki Nakayama, Yuki Imoto, Eri Segi-Nishida, Shuh Narumiya, Tomoyuki Furuyashiki
  • Organizer: Young Glia
  • Int'l Joint Research
• [Presentation] 反復社会挫折ストレスモデルにおける自然免疫分子を介した炎症様反応の役割 (2018)
  • Author(s): 北岡 志保、聶 翔、田中 昂平、小川 惇史、井本 有基、瀬木（西田） 恵里、成宮 周、古屋敷 智之
  • Organizer: 第34回日本ストレス学会学術総会
  • Invited
• [Presentation] 反復ストレスは脳内炎症様反応を介して情動変容を誘導する (2018)
  • Author(s): 北岡 志保
  • Organizer: 次世代脳プロジェクト 冬のシンポジウム
  • Invited
• [Presentation] 反復ストレスによる情動変容と脳内炎症様反応 (2017)
  • Author(s): 北岡志保
  • Organizer: 第39回 日本生物学的精神医学会・第47回 日本神経精神薬理学会 合同年会
  • Invited
• [Presentation] 反復ストレスによるミクログリアの活性化と情動変容 (2017)
  • Author(s): 北岡志保
  • Organizer: 平成29年度日本アルコール・薬物依存関連学会合同学術総会
  • Invited
• [Presentation] Innate immune receptors in microglia in the medial prefrontal cortex are critical for social avoidance induced by repeated social defeat stress in mice. (2017)
  • Author(s): Shiho Kitaoka, Xiang Nie, Kohei Tanaka, Atsubumi Ogawa, Fumitake Nakano, Ayaka Tomohiro, Kazuki Nakayama, Yabin Lu, Yuki Imoto, Eri Segi-Nishida, Shuh Narumiya, Tomoyuki Furuyashiki
  • Organizer: 第40回日本神経科学大会
• [Book] 分子精神医学 (2019)
  • Author(s): 北岡志保、古屋敷智之
  • Total Pages: 3
  • Publisher: 先端医学社
• [Book] ストレスによる脳内炎症：現在の理解と今後の展望 (2018)
  • Author(s): 北岡志保、古屋敷智之
  • Total Pages: 5
  • Publisher: 先端医学社
  • ISBN: 9784865503340
• [Remarks] Research at Kobe
  • URL: http://www.kobe-u.ac.jp/research_at_kobe/NEWS/news/2018_07_20_01.html