非定型炎症を伴う精神疾患モデル動物を活用したマイクロ精神病態の同定と分子機序解明

• Project Area: Unraveling micro-endophenotypes of psychiatric disorders at the molecular, cellular and circuit levels.
• Project/Area Number: 15H01297
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Fujita Health University
• Principal Investigator: 宮川 剛 藤田保健衛生大学, 総合医科学研究所, 教授 (10301780)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Discontinued (Fiscal Year 2016)
• Budget Amount: ¥13,520,000 (Direct Cost: ¥10,400,000、Indirect Cost: ¥3,120,000); Fiscal Year 2016: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000); Fiscal Year 2015: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: 炎症 / プロテオーム / 脳神経疾患 / 中間表現型 / トランスレーショナルリサーチ / 遺伝学 / 脳・神経

Outline of Annual Research Achievements

（1）遺伝的・環境的要因が脳の軽度慢性炎症を引き起こすメカニズムの解明：昨年度に引き続き、統合失調症様の行動異常と非成熟歯状回を示すNeurogranin（Nrgn）KOマウスの歯状回において、RNAseqを行い網羅的に遺伝子を解析した。
（2）軽度慢性炎症の抑制によるマイクロエンドフェノタイプのレスキュー：昨年度に引き続き、in silicoで異なるプラットフォーム間で遺伝子発現パターンを比較するバイオインフォマティクス手法（NextBio、イルミナ社）を用いて、軽度慢性炎症を伴うマウスに共通して生じている分子の探索を行った。統合失調症モデルSchnurri-2（Shn2）KOマウス及び統合失調症患者の脳で共通して発現変化した遺伝子群について、逆相関する変化をもたらす薬物を複数同定した。3D電子顕微鏡解析においては、Shn2 KOマウスのミトコンドリアの形態異常に関するプレリミナリーな知見を得た。微細構造の変化は新規のマイクロエンドフェノタイプとなる可能性があるため、今後詳細に検討を行う。加えて今年度は、in vivoカルシウムイメージング解析装置を導入し、系の立ち上げを行った。今後継続してin vivoカルシウムイメージングを行っていくことにより、軽度慢性炎症による神経活動のマイクロエンドフェノタイプを明らかにできるものと考える。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Cohort removal induces changes in body temperature, pain sensitivity, and anxiety-like behavior. (2016)
  • Author(s): Takao K, Shoji H, Hattori S, Miyakawa T.
  • Journal Title: Frontiers in Behavioral Neuroscience Volume: 10 Pages: 99-99
  • DOI: 10.3389/fnbeh.2016.00099
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comprehensive behavioral phenotyping of a new semaphorin 3 F mutant mouse. (2016)
  • Author(s): Matsuda I, Shoji H, Yamasaki N, Miyakawa T, Aiba A.
  • Journal Title: Mol Brain. Volume: 9(1) Issue: 1 Pages: 15-15
  • DOI: 10.1186/s13041-016-0196-4
  • NAID: 120005758427
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive behavioral analysis of RNG105 (Caprin1) heterozygous mice: Reduced social interaction and attenuated response to novelty. (2016)
  • Author(s): Ohashi R, Takao K, Miyakawa T, Shiina N
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 20775-20775
  • DOI: 10.1038/srep20775
  • Peer Reviewed / Open Access
• [Journal Article] Circadian gene circuitry predicts hyperactive behavior in a mood disorder mouse model. (2016)
  • Author(s): Hagihara H, Horikawa T, Nakamura HK, Umemori J, Shoji H, Kamitani Y, Miyakawa T.
  • Journal Title: Cell Reports, Volume: 14(12) Issue: 12 Pages: 2784-96
  • DOI: 10.1016/j.celrep.2016.02.067
  • NAID: 120005829372
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] IRBIT is novel determinant of catecholamine homeostasis through the TH phosphorylation by CaMKIIα (2015)
  • Author(s): Katsuhiro Kawaai, Akihiro Mizutani, Hirotaka Shoji, Naoko Ogawa, Etsuko Ebisui, Yukiko Kuroda, Shigeharu Wakana, Tsuyoshi Miyakawa, Chihiro Hisatsune, Katsuhiko Mikoshiba
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 未定 Issue: 17 Pages: 5515-5520
  • DOI: 10.1073/pnas.1503310112
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive behavioral analysis of voltage-gated calcium channel beta-anchoring and -regulatory protein knockout mice (2015)
  • Author(s): Akito Nakao, Takafumi Miki, Hirotaka Shoji, Miyuki Nishi, Hiroshi Takeshima, Tsuyoshi Miyakawa, Yasuo Mori
  • Journal Title: Frontiers in Behavioral Neuroscience Volume: 9 Pages: 141-141
  • DOI: 10.3389/fnbeh.2015.00141
  • NAID: 120005848244
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] TRPV4 activation at the physiological temperature is a critical determinant of neuronal excitability and behavior. (2015)
  • Author(s): Shibasaki K, Sugio S, Takao K, Yamanaka A, Miyakawa T, Tominaga M, Ishizaki Y
  • Journal Title: Pflugers Arch Volume: 467 (12) Issue: 12 Pages: 2495-2507
  • DOI: 10.1007/s00424-015-1726-0
  • Peer Reviewed / Open Access
• [Journal Article] Combined behavioral studies and in vivo imaging of inflammatory response and expression of mGlu5 receptors in schnurri-2 knockout mice. (2015)
  • Author(s): Choi JK, Zhu A, Jenkins BG, Hattori S, Kil KE, Takagi T, Ishii S, Miyakawa T, Brownell AL.
  • Journal Title: Neurosci Lett. Volume: 609 Pages: 159-64
  • DOI: 10.1016/j.neulet.2015.10.037
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A CDC42EP4/septin-based perisynaptic glial scaffold facilitates glutamate clearance. (2015)
  • Author(s): Ageta-Ishihara N, Yamazaki M, Konno K, Nakayama H, Abe M, Hashimoto K, Nishioka T, Kaibuchi K, Hattori S, Miyakawa T, Tanaka K, Huda F, Hirai H, Hashimoto K, Watanabe M, Sakimura K, Kinoshita M.
  • Journal Title: Nat Commun. Volume: 6 Issue: 1 Pages: 10090-10090
  • DOI: 10.1038/ncomms10090
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comprehensive Behavioral Analysis of Male Ox1r (-/-) Mice Showed Implication of OrexinReceptor-1 in Mood, Anxiety, and Social Behavior. (2015)
  • Author(s): Abbas MG, Shoji H, Soya S, Hondo M, Miyakawa T, Sakurai T.
  • Journal Title: Front Behav Neurosci. Volume: ９ Pages: 324-324
  • DOI: 10.3389/fnbeh.2015.00324
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Age-related changes in behavior in C57BL/6J mice from young adulthood to middle age. (2015)
  • Author(s): Shoji H, Takao K, Hattori S, Miyakawa T
  • Journal Title: Mol Brain. Volume: 9(1) Issue: 1 Pages: 11-11
  • DOI: 10.1186/s13041-016-0191-9
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Deficiency of neurogranin, a susceptible gene for schizophrenia, causes behavioral phenotypes related to schizophrenia and immaturity of the dentate gyrus in mice. (2016)
  • Author(s): Satoko Hattori, Hideo Hagihara, Yoshihiro Takamiya, Toshiki Kameyama, Yuya Ouchi, Hidehito Inagaki, Hiroki Kurahashi, Freesia L Huang, KuoPing Huang, Tsuyoshi Miyakawa.
  • Organizer: 25th Aannual IBNS Meeting-International Behavioral Neuroscience Society (IBNS)
  • Place of Presentation: Budapest, Hungary
  • Year and Date: 2016-06-07
  • Int'l Joint Research
• [Presentation] Genomic responses in mouse models greatly mimic human inflammatory / psychiatric diseases. (2016)
  • Author(s): Tsuyoshi Miyakawa, Keizo Takao, Hideo Hagihara.
  • Organizer: 18th Annual Genes, Brain and Behavior Meeting-International Behavioral and Neural Genetics Society (IBANGS)
  • Place of Presentation: Bar Harbor, United States
  • Year and Date: 2016-05-13
  • Int'l Joint Research
• [Presentation] Deficiency of neurogranin, a Susceptible Gene for schizophrenia, Confers Multiple Molecular and Behavioral Phenotypes Related to Schizophrenia (2015)
  • Author(s): Tsuyoshi Miyakawa
  • Organizer: 54th Annual Meeting of the American College of Neuropsychopharmacology
  • Place of Presentation: Hollywood, Florida, USA
  • Year and Date: 2015-12-06
  • Int'l Joint Research
• [Presentation] Effect of time-of-day on mouse behavior measured in a comprehensive behavioral test battery (2015)
  • Author(s): Keizo Takao, Hirotaka Shoji, Satoko Hattori, Tsuyoshi Miyakawa
  • Organizer: Society for Neuroscience 2015 Annual Meeting
  • Place of Presentation: Chicago, USA
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] Neurogranin deficiency causes neuronal immaturity in the dentate gyrus and frontal cortex of adult mice (2015)
  • Author(s): Hideo Hagihara, Satoko Hattori, Yoshihiro Takamiya, Freesia L Huang, Kuo-Ping Huang, Tsuyoshi Miyakawa
  • Organizer: Society for Neuroscience 2015 Annual Meeting
  • Place of Presentation: Chicago, USA
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] Neurogranin-deficient mice reveal schizophrenia-related behaviors and immaturity of the dentate gyrus (2015)
  • Author(s): Satoko Hattori, Hideo Hagihara, Hirotaka Shoji, Yoshihiro Takamiya, Freesia L Huang , Kuo-Ping Huang, Tsuyoshi Miyakawa
  • Organizer: Society for Neuroscience 2015 Annual Meeting
  • Place of Presentation: Chicago, USA
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] Comprehensive behavioral analysis of voltage-gated calcium channel beta-anchoring and -regulatory protein (BARP) knockout mice (2015)
  • Author(s): Akito Nakao, Takafumi Miki, Hirotaka Shoji, Yasuo Mori, Tsuyoshi Miyakawa
  • Organizer: Society for Neuroscience 2015 Annual Meeting
  • Place of Presentation: Chicago, USA
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] 脳内中間表現型 (2015)
  • Author(s): 宮川剛
  • Organizer: 第45回日本神経精神薬理学会・第37回日本生物学的精神医学会合同年会
  • Place of Presentation: 東京
  • Year and Date: 2015-09-24
• [Presentation] Immaturity of the brain cells and mild chronic inflammation: Candidate endophenotype of neuropsychiatric disorders (2015)
  • Author(s): Tsuyoshi Miyakawa
  • Organizer: 第58回日本神経化学会大会
  • Place of Presentation: 大宮
  • Year and Date: 2015-09-11
• [Presentation] Endophenotype in the brain: A key concept to understand the relationships between genes and behavior (2015)
  • Author(s): Tsuyoshi Miyakawa
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-07-28
  • Invited
• [Presentation] BARP is involved in behavioral abnormalities rekated to psychiatric disoeders (2015)
  • Author(s): Akito Nakao, Hirotaka Shoji, Yasuo Mori, Tsuyoshi Miyakawa
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-07-28
• [Presentation] Neurogranin deficiency causes schizophrenia-related behaviors and immaturityof the dentate gyrus in mice (2015)
  • Author(s): Satoko Hattori, Hideo Hagihara, Hirotaka Shoji, Yoshihiro Takamiya, Freesia L. Huang, Kuo-Ping Huang, Tsuyoshi Miyakawa
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-07-28
• [Presentation] Transcriptomic “hyper-maturity” of the hippocampal dentate gyrus in mice (2015)
  • Author(s): Hisatsugu Koshimizu, Hideo Hagihara, Koji Ohira, Keizo Takao, Tsuyoshi Miyakawa
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-07-28
• [Presentation] Alterations in diurnal expression patterns of circadian genes in the dentate gyrus of mice showing exaggerated infradian rhythm (2015)
  • Author(s): Hideo Hagihara, Tsuyoshi Miyakawa
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-07-28
• [Presentation] Antidepressant-induced immaturity of hippocampus and cortical adult neurogenesis in the common marmoset (2015)
  • Author(s): Koji Ohira, Rika Takeuchi, Miki Miwa, Katsuki Nakamura, Tsuyoshi Miyakawa
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-07-28
• [Presentation] Retrospective predictiction of behavioral state by hippocampal transcriptome analysis (2015)
  • Author(s): Tsuyoshi Miyakawa
  • Organizer: 10th International Conference for Neurons and Brain Disease
  • Place of Presentation: Xian, China
  • Year and Date: 2015-06-22
  • Int'l Joint Research
• [Presentation] マウスはヒト疾患のモデルになるー精神疾患と炎症性疾患の研究からー (2015)
  • Author(s): 宮川剛
  • Organizer: 第62回日本実験動物学会総会
  • Place of Presentation: 京都
  • Year and Date: 2015-05-28
  • Invited