双方向性神経成熟度変化のメカニズム解明とその制御

2016 Fiscal Year Annual Research Report

• Project/Area Number: 25242078
• 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): 2013-10-21 – 2018-03-31
• Keywords: 脳・神経 / トランスレーショナルリサーチ

Outline of Annual Research Achievements

(1) [神経の双方向性の成熟度変化の分子機序の解明]・iDGを引き起こす必須のコモンパスウェイの検討 ：バイオインフォマティクスツール・BaseSpace (イルミナ)を用いたバイオインフォマティクス的解析により、非成熟歯状回で変動している遺伝子群の絞り込みを進めた。
(2) [神経成熟度を薬物や各種刺激により自在に制御する方法の探索と確立]・部位特異的遺伝子改変による神経成熟度の制御：部位特異的遺伝子改変による神経成熟度の制御：Shn2遺伝子について各種脳領域・細胞種特異的Creマウスの掛け合わせたマウスについて繁殖を進め、部位特異性を検証した。線条体特異的KOマウスについては部位特異性が得られなかった。前頭葉および歯状回特異的KOマウスについて歯状回の成熟度を検討したが、顕著なiDG化は認められなかった。
(3) [神経細胞の双方向性成熟度変化の機能的意義の解明]・成熟度の変化が神経細胞の形態に及ぼす効果の解析：非成熟歯状回では、遺伝子発現や神経細胞の電気生理学的興奮性が大きく変化していることから、シナプス、スパイン、樹状突起などの形態的変化も生じていることが予測される。Shn2欠損マウスの歯状回ニューロンについて、3D電顕コネクトーム解析により神経細胞の形態的変化を詳細に調べた。スパインやミトコンドリアに形態異常が生じている可能性が示された。・神経成熟度の変化が各種行動に及ぼす効果の解析：部位・細胞種ごとの神経成熟度が行動レベルでどのような効果を持つか、上述の部位特異的遺伝子改変マウスにおいて行動解析を実施した。歯状回特異的Shn2欠損マウスについて網羅的行動テストバッテリーにより行動表現型を調べた。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

(1) [神経の双方向性の成熟度変化の分子機序の解明]バイオインフォマティクス的解析により、非成熟歯状回が生じる過程で変動している遺伝子群について新規の知見を得た。
(2) [神経成熟度を薬物や各種刺激により自在に制御する方法の探索と確立] 作製した歯状回特異的な遺伝子改変マウスにより、iDGマウスの示す様々な表現型の発現において歯状回が果たす役割についてより詳細に評価できるようになった。
(3) [神経細胞の双方向性成熟度変化の機能的意義の解明] 3D電顕コネクトーム解析により、細胞レベルでの表現型について新たに知見を得た。

Strategy for Future Research Activity

前年度に引き続き、1) 神経の双方向性の成熟度変化の分子機序の解明、2) 神経成熟度を薬物や各種刺激により自在に制御する方法の探索と確立、3) 神経細胞の双方向性成熟度変化の機能的意義の解明、を目的とした研究を継続し進め（平成２９年度交付申請書および交付請求書参照）、さらに成果の取りまとめを実施する。
なお、最終年度は項目・3D電顕コネクトーム解析については、新学術「スクラップ＆ビルドによる脳機能の動的制御」の下で行う。

Research Products

• [Journal Article] Ts1Cje Down syndrome model mice exhibit environmental stimuli-triggered locomotor hyperactivity and sociability concurrent with increased flux through central dopamine and serotonin metabolism. (2017)
  • Author(s): Shimohata A, Ishihara K, Hattori S, Miyamoto H, Morishita H, Ornthanalai G, Raveau M, Ebrahim AS, Amano K, Yamada K, Sago H, Akiba S, Mataga N, Murphy NP, Miyakawa T, *Yamakawa K.
  • Journal Title: Exp Neurol. Volume: S0014-4886(17) Pages: 30069-9
  • DOI: doi: 10.1016/j.expneurol.2017.03.009
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Transcriptomic immaturity of the hippocampus and prefrontal cortex in patients with alcoholism. (2017)
  • Author(s): Murano T, Koshimizu H, Hagihara H, *Miyakawa T.
  • Journal Title: Sci Rep. Volume: 7 Pages: 44531
  • DOI: doi: 10.1038/srep44531
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Prothymosin alpha-deficiency enhances anxiety-like behaviors and impairs learning/memory-functions and neurogenesis. (2017)
  • Author(s): *Ueda H, Sasaki K, Halder SK, Dequchi Y, Takao K, Miyakawa T, Tajima A.
  • Journal Title: J Neurochem Volume: 141(1) Pages: 124-136
  • DOI: doi: 10.1111/jnc.13963.
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] QRFP-Deficient Mice Are Hypophagic, Lean, Hypoactive and Exhibit Increased Anxiety-Like Behavior. (2016)
  • Author(s): Okamoto K, Yamasaki M, Takao K, Soya S, Iwasaki M, Sasaki K, Magoori K, Sakakibara I, Miyakawa T, Mieda M, Watanabe M, Sakai J, Yanagisawa M, *Sakurai T.
  • Journal Title: PLoS One. Volume: 11;11(11) Pages: e0164716
  • DOI: doi: 10.1371/journal.pone.0164716
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Immaturity of brain as an endophenotype of neuropsychiatric disorders. (2016)
  • Author(s): Hagihara H, Shoji H, *Miyakawa T.
  • Journal Title: Nihon Yakurigaku Zasshi Volume: 148(4) Pages: 168-175
  • DOI: doi: 10.1254/fpj.148.168
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Distribution of Silver Nanoparticles to Breast Milk and Their Biological Effects on Breast-Fed Offspring Mice. (2016)
  • Author(s): Morishita Y, Yoshioka Y, Takimura Y, Shimizu Y, Namba Y, Nojiri N, Ishizaka T, Takao K, Yamashita F, Takuma K, Ago Y, Nagano K, Mukai Y, Kamada H, Tsunoda S, Saito S, Matsuda T, Hashida M, Miyakawa T, Higashisaka K, Tsutsumi Y.
  • Journal Title: ACS Nano Volume: 10(9) Pages: 8180-91
  • DOI: doi: 10.1021/acsnano.6b01782
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] CHD8 haploinsufficiency results in autistic-like phenotypes in mice. (2016)
  • Author(s): Katayama Y, *Nishiyama M, Shoji H, Ohkawa Y, Kawamura A, Sato T, Suyama M, Takumi T, *Miyakawa T, Nakayama K.I.
  • Journal Title: Nature Volume: 537 Pages: 675–679
  • DOI: doi:10.1038/nature19357
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Mice that lack the C-terminal region of Reelin exhibit behavioral abnormalities related to neuropsychiatric disorders. (2016)
  • Author(s): Sakai K, Shoji H, Kohno T, Miyakawa T, *Hattori M.
  • Journal Title: Scientific Reports Volume: 6 Pages: 28636
  • DOI: doi:10.1038/srep28636
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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
  • DOI: doi: 10.3389/fnbeh.2016.00099
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Endophenotype in the brain: A key concept for understanding the relationships between genes and behavior. (2017)
  • Author(s): Miyakawa T.
  • Organizer: The 2017 Japan-NIH Joint Symposium on Advances in Biomedical Research and Disease
  • Place of Presentation: Sendai, Japan
  • Year and Date: 2017-02-15 – 2017-02-17
  • Int'l Joint Research / Invited
• [Presentation] Lower Brain pH as a Shared Endophenotype of Psychiatric Disorders (2016)
  • Author(s): Hagihara H., Catts V., Katayama Y., Takagi T., Huang F.L., Huang LP., Ishii S., Graef I.A., Crabtree G.R., Nakayama K.I., Weickert C.S., Miyakawa T.*
  • Organizer: 55th Annual Meeting of American College of Neuropsychoparmacology (ACNP)
  • Place of Presentation: Hollywood, Florida, USA
  • Year and Date: 2016-12-04 – 2016-12-08
  • Int'l Joint Research
• [Presentation] iPS細胞を用いた認知症モデルの可能性：iPS細胞モデルとマウスモデルについて (2016)
  • Author(s): 宮川 剛
  • Organizer: 第35回日本認知症学会学術集会
  • Place of Presentation: 東京国際フォーラム
  • Year and Date: 2016-12-03 – 2016-12-03
  • Invited
• [Presentation] [1P-0527(1AS13-7)] 発生期におけるクロマチンリモデリング異常は自閉症の原因となる (2016)
  • Author(s): 片山 雄太、西山 正章、昌子 浩孝、大川 恭行、川村 敦生、佐藤 哲也、須山 幹太、内匠 透、宮川 剛、中山 敬一
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30 – 2016-12-02
• [Presentation] Tutorial contents on neuroinfomrmatics platforms. (2016)
  • Author(s): Yamaguchi Y., Hattori S., Takao K., Okumura Y., Suenaga S., Ishii I., Honda A., Ogawa M., Usui S., Miyakawa T.
  • Organizer: 46th Annual meeting of Society for Neuroscience
  • Place of Presentation: San Diego, California, USA
  • Year and Date: 2016-11-12 – 2016-11-16
  • Int'l Joint Research
• [Presentation] Transcriptomic immaturity of the hippocampus and prefrontal cortex in patients with alcoholism. (2016)
  • Author(s): Murano T., Miyakawa T.
  • Organizer: 46th Annual meeting of Society for Neuroscience
  • Place of Presentation: San Diego, California, USA
  • Year and Date: 2016-11-12 – 2016-11-16
  • Int'l Joint Research
• [Presentation] Role of R-type calcium channel (Cav2.3) in medial habenula to interpeduncular nucleus pathway. (2016)
  • Author(s): Bhandari P., Parajuli LK., Takao K., Miyakawa T., Kobayashi Y., Tanaka KF., Shigemoto R.
  • Organizer: 46th Annual meeting of Society for Neuroscience
  • Place of Presentation: San Diego, California, USA
  • Year and Date: 2016-11-12 – 2016-11-16
  • Int'l Joint Research
• [Presentation] Three-dimensional analysis of dendritic spines and mitochondria in dentate gyrus granule cells in Schnurri-2 knockout mice, an animal model for schizophrenia. (2016)
  • Author(s): Nakao A., Takao K., Ohira K., Miyazaki N., Murata K., Miyakawa T.
  • Organizer: 46th Annual meeting of Society for Neuroscience
  • Place of Presentation: San Diego, California, USA
  • Year and Date: 2016-11-12 – 2016-11-16
  • Int'l Joint Research
• [Presentation] Repeated restraint stress causes alteration in neuronal maturation makers in the dentate gyrus in BALB/c mice. (2016)
  • Author(s): Shoji H, Hagihara H, Miyakawa T.
  • Organizer: 46th Annual meeting of Society for Neuroscience
  • Place of Presentation: San Diego, California, USA
  • Year and Date: 2016-11-12 – 2016-11-16
  • Int'l Joint Research
• [Presentation] Mice that lack the C-terminal region of Reelin exhibit behavioral abnormalities related to neuropsychiatric disorders. (2016)
  • Author(s): Sakai K, Shoji H, Kahn T, Miyakawa T, Hattori M.
  • Organizer: 46th Annual meeting of Society for Neuroscience
  • Place of Presentation: San Diego, California, USA
  • Year and Date: 2016-11-12 – 2016-11-16
  • Int'l Joint Research
• [Presentation] Contrasting expression patterns of inflammation-related genes in mouse models of depression and psychosis. (2016)
  • Author(s): Koshimizu H., Hagihara H., Miyakawa T.
  • Organizer: 46th Annual meeting of Society for Neuroscience
  • Place of Presentation: San Diego, California, USA
  • Year and Date: 2016-11-12 – 2016-11-16
  • Int'l Joint Research
• [Presentation] Contrasting expression patterns of inflammation-related genes in mouse models of depression and psychosis (2016)
  • Author(s): Koshimizu H., Hagihara H., Miyakawa T.
  • Organizer: 15th Annual Molecular and Cellular Cognition Society Meeting
  • Place of Presentation: San Diego, California, USA
  • Year and Date: 2016-11-10 – 2016-11-11
  • Int'l Joint Research
• [Presentation] Three-dimensional analysis of dendritic spines and mitochondria in dentate gyrus granule cells in Schnurri-2 knockout mice, an animal model for schizophrenia. (2016)
  • Author(s): Nakao A., Takao K., Ohira K., Miyazaki N., Murata K., Miyakawa T.
  • Organizer: 15th Annual Molecular and Cellular Cognition Society Meeting
  • Place of Presentation: San Diego, California, USA
  • Year and Date: 2016-11-10 – 2016-11-11
  • Int'l Joint Research
• [Presentation] Molecular evidences in psychiatric disorders. (2016)
  • Author(s): Miyakawa T.
  • Organizer: The 19th Korean Society for Brain and Neural Science Annual Meeting
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-09-27 – 2016-09-29
  • Int'l Joint Research / Invited
• [Presentation] CDKL5 controls postsynaptic NMDA receptor localization and regulates memory, emotion and seizure susceptibility. (2016)
  • Author(s): 村上拓冬, 奥田耕助, 小林静香, 深谷昌弘, 高雄啓三, 渡邉紀, 萩原舞, 阪上洋行, 水口雅, 宮川剛, 真鍋俊也, 田中輝幸
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-07-20 – 2016-07-22
• [Presentation] omprehensive behavioral analysis of RNG105 heterozygous mice: reduced social interaction and attenuated response to novelty. (2016)
  • Author(s): 大橋りえ, 高雄啓三, 宮川剛, 椎名伸之
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-07-20 – 2016-07-22
• [Presentation] Contrasting expression patterns of inflammation-related genes in mouse models of depression and psychosis. (2016)
  • Author(s): 小清水久嗣, 萩原英雄, 宮川剛
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-07-20 – 2016-07-22
• [Presentation] Transcriptomic evidence for dematuration of the mouse frontal cortex and hippocampus by chronic antidepressant treatment. (2016)
  • Author(s): 萩原英雄, 大平耕司, 宮川剛
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-07-20 – 2016-07-22
• [Presentation] Increased acidity of the brain as a shared endophenotype of mice model of psychotic disorders. (2016)
  • Author(s): Miyakawa T.
  • Organizer: The 11th International Conference for Neurons and Brain Disease
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2016-07-14 – 2016-07-16
  • Int'l Joint Research
• [Presentation] Contrasting expression patterns of inflammation-related genes in mouse models of depression and psychosis. (2016)
  • Author(s): Koshimizu H., Hagihara H., Miyakawa T.
  • Organizer: 30th CINP（The International College of Neuropsychopharmacology） World Congress of Neuropsychopharmacology
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-07-03 – 2016-07-05
  • Int'l Joint Research
• [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): Hattori S., Hagihara H., Takamiya Y., Kameyama T., Ouchi Y., Inagaki H., Kurahashi H., Huang F.L., Huang K.P., Miyakawa T.
  • Organizer: 30th CINP（The International College of Neuropsychopharmacology） World Congress of Neuropsychopharmacology
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-07-03 – 2016-07-05
  • Int'l Joint Research
• [Presentation] Three-dimensional analysis of morphological changes in dendritic spines and mitochondria in dentate gyrus granule cells in Schnurri-2 knockout mice, an animal model for schizophrenia (2016)
  • Author(s): Nakao A., Takao K., Ohira K., Miyazaki N., Murata K., Miyakawa T.
  • Organizer: 30th CINP（The International College of Neuropsychopharmacology） World Congress of Neuropsychopharmacology
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-07-03 – 2016-07-05
  • Int'l Joint Research
• [Presentation] Repeated restraint stress induces alteration in maturation makers of dentate gyrus neurons in BALB/c mice. (2016)
  • Author(s): Shoji H, Hagihara H, Miyakawa T.
  • Organizer: 30th CINP（The International College of Neuropsychopharmacology） World Congress of Neuropsychopharmacology
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-07-03 – 2016-07-05
  • Int'l Joint Research
• [Presentation] Transcriptomic immaturity of hippocampus and prefrontal cortex in patients with alcoholism. (2016)
  • Author(s): Murano T., Hagihara H., Miyakawa T.
  • Organizer: 30th CINP（The International College of Neuropsychopharmacology） World Congress of Neuropsychopharmacology
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-07-03 – 2016-07-05
  • Int'l Joint Research
• [Presentation] Contrasting expression patterns of inflammation-related genes in mouse models of depression and psychosis. (2016)
  • Author(s): Koshimizu H., Hagihara H., Miyakawa T.
  • Organizer: (JSNP) 第46回日本神経精神薬理学会年会
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-07-02 – 2016-07-03
  • Int'l Joint Research
• [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): Hattori S., Hagihara H., Takamiya Y., Kameyama T., Ouchi Y., Inagaki H., Kurahashi H., Huang F.L., Huang K.P., Miyakawa T.
  • Organizer: (JSNP) 第46回日本神経精神薬理学会年会
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-07-02 – 2016-07-03
  • Int'l Joint Research
• [Presentation] Three-dimensional analysis of morphological changes in dendritic spines and mitochondria in dentate gyrus granule cells in Schnurri-2 knockout mice, an animal model for schizophrenia. (2016)
  • Author(s): Nakao A., Takao K., Ohira K., Miyazaki N., Murata K., Miyakawa T.
  • Organizer: (JSNP) 第46回日本神経精神薬理学会年会
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-07-02 – 2016-07-03
  • Int'l Joint Research
• [Presentation] Repeated restraint stress-induced alterations in maturation makers of dentate gyrus neurons in BALB/c mice. (2016)
  • Author(s): Shoji H, Hagihara H, Miyakawa T.
  • Organizer: (JSNP) 第46回日本神経精神薬理学会年会
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-07-02 – 2016-07-03
  • Int'l Joint Research
• [Presentation] Transcriptomic immaturity of hippocampus and prefrontal cortex in patients with alcoholism. (2016)
  • Author(s): Murano T., Hagihara H., Miyakawa T.
  • Organizer: (JSNP) 第46回日本神経精神薬理学会年会
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-07-02 – 2016-07-03
  • Int'l Joint Research
• [Presentation] Hyper-locomotor activity in the mice lacking in an enzyme synthesizing chondroitin sulfate. (2016)
  • Author(s): Igarashi M., Takeuchi K., Yoshioka N., Takao K., Miyakawa T.
  • Organizer: IBNS (International Behavioral Neuroscience Society) 25th Annual Meeting
  • Place of Presentation: Budapest, Hungary
  • Year and Date: 2016-06-06 – 2016-06-14
  • Int'l Joint Research
• [Presentation] Genomic responses in mouse models greatly mimic human inflammatory / psychiatric diseases. (2016)
  • Author(s): Miyakawa T., Takao K., Hagihara H.
  • Organizer: 2016 IBANCS (International Behavioral and Neural Genetics Society) Meeting
  • Place of Presentation: Bar Harbor Maine, USA
  • Year and Date: 2016-05-12 – 2016-05-18
  • Int'l Joint Research