Dynamic regulation of brain function by Scrap & Build system

2016 Fiscal Year Annual Research Report

• Project Area: Dynamic regulation of brain function by Scrap & Build system
• Project/Area Number: 16H06462
• 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): 2016-06-30 – 2021-03-31
• Keywords: 脳神経疾患 / 遺伝学 / トランスレーショナルリサーチ

Outline of Annual Research Achievements

A. 脱成熟現象の際に生じるスクラップ&ビルド機構の分子機序・機能解明に用いるマウスの準備と最適パラメーター探索：申請者らは、顕著な行動異常を示す複数の遺伝子変異マウスや精神疾患患者の脳の研究から、成熟した神経細胞が、神経活動や炎症等の刺激で擬似的な未成熟状態に舞い戻ってしまう現象(脱成熟)を見出している。今年度は光遺伝学的技術を用いて、歯状回特異的に刺激の強度・頻度を体系的に操作し、脱成熟が一過性に終わる段階から長期的に持続する段階へ移行する際のパラメーターを探索した。以前我々は、MHCエンハンサー結合タンパクSchnurri-2（Shn2）を欠損したマウスが、脳内に軽度な慢性炎症を起こし、統合失調症に関連した種々の表現型を示すことを報告している。このマウスは発達期のシナプス除去に関わるC1q ファミリー遺伝子の発現が上昇しており、スクラップ＆ビルド現象による新旧のシナプス入出力のバランスが変化していると考えられる。Shn2欠損マウスの歯状回の形態変化を明らかにするため、SBF-SEMを用いた電子顕微鏡解析を行っている。また、その分子基盤及び行動レベルでの機能を明らかにするために、Shn2とC1qのダブルノックアウトマウスを繁殖中である。
B. 各種スクラップ&ビルド機構の神経回路・行動レベルでの機能評価と遺伝子発現パターン比較のためのマウスの準備：野生型マウスの歯状回において、in vivo 神経活動モニタリングシステムを用いて数十個の神経細胞の活動を取得し、オープンフィールドテスト時の基礎データの取得を行った。

Current Status of Research Progress

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

Reason

A. 脱成熟現象の際に生じるスクラップ&ビルド機構の分子機序・機能解明に用いるマウスの準備と最適パラメーター探索：今年度は、光遺伝学的技術を用いて、歯状回特異的に刺激の強度・頻度を体系的に操作し、脱成熟が一過性に終わる段階から長期的に持続する段階へ移行する際の刺激条件を見出した。脱成熟に伴う形態変化を明らかにするための電子顕微鏡解析も進行中である。また、脱成熟やそれに関わる分子の遺伝子改変マウスを準備中である。
B. 各種スクラップ&ビルド機構の神経回路・行動レベルでの機能評価と遺伝子発現パターン比較のためのマウスの準備：今年度はin vivo 神経活動モニタリングシステムの測定系の立ち上げ、オープンフィールドテスト時に数十個の神経活動のデータが取得可能となった。

Strategy for Future Research Activity

引き続き、A. 脱成熟現象の際に生じるスクラップ&ビルド機構の分子機序・機能解明に用いるマウスの準備と最適パラメーター探索及びB. 各種スクラップ&ビルド機構の神経回路・行動レベルでの機能評価と遺伝子発現パターン比較のためのマウスの準備を進める。

Research Products

• [Journal Article] Transcriptomic immaturity of the hippocampus and prefrontal cortex in patients with alcoholism (2017)
  • Author(s): Murano Tomoyuki、Koshimizu Hisatsugu、Hagihara Hideo、Miyakawa Tsuyoshi
  • Journal Title: Scientific Reports Volume: 7 Pages: 44531～44531
  • DOI: doi: 10.1038/srep44531
  • Peer Reviewed / Open Access
• [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] 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
• [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: 6 Pages: 28636
  • 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
  • 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] Comprehensive 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] 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] 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