全脳イメージング法による精神疾患の病態と治療機序の新たな薬理学的研究法の確立

2017 Fiscal Year Annual Research Report

• Project/Area Number: 17H03989
• Research Institution: Osaka University
• Principal Investigator: 橋本 均 大阪大学, 薬学研究科, 教授 (30240849)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 全脳イメージング / 精神疾患

Outline of Annual Research Achievements

本研究では、最新の全脳イメージング法FASTを用いて、精神疾患モデル動物脳の神経活動を全脳細胞レベルで解析し、疾患病態と治療薬機序を解明する新たな薬理学的研究法の確立することを目的としている。本年度は、疾患病態の新たな解析手法を確立するため、様々な精神疾患モデルマウスを作成し、全脳から脳領域毎の構造および神経活動を標識・評価し、以下の結果を得た。
１）自家蛍光などの脳構造の情報だけでは判別できない脳領域を特定するため、脳領域マーカーとなる分子の抗体を用いて、全脳イメージング後の脳切片を免疫染色し、その結果を元の全脳画像の区分けに用いることにより、関心領域(ROI)を3次元空間で設定する方法を確立した。
２）細胞種特異的および活動依存的なプロモーターとタモキシフェン依存的なCreリコンビナーゼを用いたアデノ随伴ウイルスベクターを作成し、細胞種特異的に活性化神経を蛍光標識した。本手法を用いて、マウス脳内のストレス応答性神経細胞を特異的に蛍光標識し、全脳イメージングを実施したところ、ストレス応答に関わる神経回路構造が明らかになった。
３）神経活動レポーターマウスであるArc-dVenusマウスを用いて、社会性行動障害を示すモデルマウスを作成し、dVenus陽性細胞の全脳マッピングを実施した。得られたdVenus陽性細胞の空間座標データを解析したところ、体性感覚皮質などの複数の脳領域においてdVenus陽性細胞の数が特に多いことが明らかになった。

Current Status of Research Progress

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

Reason

全脳イメージング法を用いて、複数の精神疾患モデル動物脳の神経活動や形態変化を解析した結果、これまで知られていなかった脳領域の同定などに成功しており、疾患病態解析に有用であることを示した。

Strategy for Future Research Activity

特異的な活動操作法などを用いて、特定の細胞集団の機能を明らかにするとともに、神経結合解析や遺伝子発現解析なども合わせて、細胞特性の同定、病態・薬物応答性機序の推定に加え、新たな創薬標的因子の探索を目指す。

Research Products

• [Int'l Joint Research] University of California, Los Angeles/Northwestern University/New York Medical College(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: University of California, Los Angeles/Northwestern University/New York Medical College
• [Int'l Joint Research] University of Pecs/University of Szeged/University of Debrecen(ハンガリー)
  • Country Name: HUNGARY
  • Counterpart Institution: University of Pecs/University of Szeged/University of Debrecen
  • # of Other Institutions: 1
• [Int'l Joint Research] University of Bristol(英国)
  • Country Name: UNITED KINGDOM
  • Counterpart Institution: University of Bristol
• [Int'l Joint Research] University of Heidelberg(ドイツ)
  • Country Name: GERMANY
  • Counterpart Institution: University of Heidelberg
• [Int'l Joint Research] University of Liege(ベルギー)
  • Country Name: BELGIUM
  • Counterpart Institution: University of Liege
• [Int'l Joint Research]
  • # of Other Countries: 1
• [Journal Article] mS-11, a mimetic of the mSin3-binding helix in NRSF, ameliorates social interaction deficits in a prenatal valproic acid-induced autism mouse model (2019)
  • Author(s): Kawase Haruki、Ago Yukio、Naito Megumi、Higuchi Momoko、Hara Yuta、Hasebe Shigeru、Tsukada Shinji、Kasai Atsushi、Nakazawa Takanobu、Mishina Tadashi、Kouji Hiroyuki、Takuma Kazuhiro、Hashimoto Hitoshi
  • Journal Title: Pharmacology Biochemistry and Behavior Volume: 176 Pages: 1～5
  • DOI: 10.1016/j.pbb.2018.11.003
• [Journal Article] VPAC1 receptors play a dominant role in PACAP-induced vasorelaxation in female mice (2019)
  • Author(s): Ivic I, Balasko M, Fulop BD, Hashimoto H, Toth G, Tamas A, Juhasz T, Koller A, Reglodi D, Solymár M.
  • Journal Title: PLOS ONE Volume: 14 Pages: e0211433
  • DOI: 10.1371/journal.pone.0211433
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association of Serotonin2c Receptor Polymorphisms With Antipsychotic Drug Response in Schizophrenia (2019)
  • Author(s): Li J, Hashimoto H, Meltzer HY.
  • Journal Title: Frontiers in Psychiatry Volume: 10 Pages: 58
  • DOI: 10.3389/fpsyt.2019.00058
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pituitary adenylate cyclase-activating polypeptide modulates dendritic spine maturation and morphogenesis via microRNA-132 upregulation (2019)
  • Author(s): Hayata-Takano A, Kamo T, Kijima H, Seiriki K, Ogata K, Ago Y, Nakazawa T, Shintani Y, Higashino K, Nagayasu K, Shintani N, Kasai A, Waschek JA, Hashimoto H.
  • Journal Title: J Neurosci Volume: in press Pages: -
  • DOI: 10.1523/JNEUROSCI.2468-18.2019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] β-Arrestin1 and 2 differentially regulate PACAP-induced PAC1 receptor signaling and trafficking (2018)
  • Author(s): Shintani Yusuke、Hayata-Takano Atsuko、Moriguchi Keita、Nakazawa Takanobu、Ago Yukio、Kasai Atsushi、Seiriki Kaoru、Shintani Norihito、Hashimoto Hitoshi
  • Journal Title: PLOS ONE Volume: 13 Pages: e0196946
  • DOI: 10.1371/journal.pone.0196946
• [Journal Article] Unbiased compound screening with a reporter gene assay highlights the role of p13 in the cardiac cellular stress response (2018)
  • Author(s): Inoue N, Hirouchi T, Kasai A, Higashi S, Hiraki N, Tanaka S, Nakazawa T, Nunomura K, Lin B, Omori A, Hayata-Takano A, Kim YJ, Doi T, Baba A, Hashimoto H, Shintani N.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 495 Pages: 1992～1997
  • DOI: 10.1016/j.bbrc.2017.11.116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Knockdown of the mitochondria‐localized protein p13 protects against experimental parkinsonism (2018)
  • Author(s): Inoue N, Ogura S, Kasai A, Nakazawa T, Ikeda K, Higashi S, Isotani A, Baba K, Mochizuki H, Fujimura H, Ago Y, Hayata-Takano A, Seiriki K, Shintani Y, Shintani N, Hashimoto H.
  • Journal Title: EMBO reports Volume: 19 Pages: e44860～e44860
  • DOI: 10.15252/embr.201744860
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Accelerated pre-senile systemic amyloidosis in PACAP knockout mice?-?a protective role of PACAP in age-related degenerative processes (2018)
  • Author(s): Reglodi D, Jungling A, Longuespée R, Kriegsmann J, Casadonte R, Kriegsmann M, Juhasz T, Bardosi S, Tamas A, Fulop BD, Kovacs K, Nagy Z, Sparks J, Miseta A, Mazzucchelli G, Hashimoto H, Bardosi A.
  • Journal Title: The Journal of Pathology Volume: 245 Pages: 478～490
  • DOI: 10.1002/path.5100
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Manipulation of dorsal raphe serotonergic neurons modulates active coping to inescapable stress and anxiety-related behaviors in mice and rats (2018)
  • Author(s): Nishitani N, Nagayasu K, Asaoka N, Yamashiro M, Andoh C, Nagai Y, Kinoshita H, Kawai H, Shibui N, Liu B, Hewinson J, Shirakawa H, Nakagawa T, Hashimoto H, Kasparov S, Kaneko S.
  • Journal Title: Neuropsychopharmacology Volume: 44 Pages: 721～732
  • DOI: 10.1038/s41386-018-0254-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High-Speed and Scalable Whole-Brain Imaging in Rodents and Primates (2017)
  • Author(s): Seiriki K, Kasai A, Hashimoto T, Schulze W, Niu M, Yamaguchi S, Nakazawa T, Inoue KI, Uezono S, Takada M, Naka Y, Igarashi H, Tanuma M, Waschek JA, Ago Y, Tanaka KF, Hayata-Takano A, Nagayasu K, Shintani N, Hashimoto R, Kunii Y, Hino M, Matsumoto J, Yabe H, Nagai T, Fujita K, Matsuda T, Takuma K, Baba A, Hashimoto H.
  • Journal Title: Neuron Volume: 94 Pages: 1085～1100
  • DOI: 10.1016/j.neuron.2017.05.017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impaired extinction of cued fear memory and abnormal dendritic morphology in the prelimbic and infralimbic cortices in VPAC2 receptor (VIPR2)-deficient mice (2017)
  • Author(s): Ago Y, Hayata-Takano A, Kawanai T, Yamauchi R, Takeuchi S, Cushman JD, Rajbhandari AK, Fanselow MS, Hashimoto H, Waschek JA.
  • Journal Title: Neurobiology of Learning and Memory Volume: 145 Pages: 222～231
  • DOI: 10.1016/j.nlm.2017.10.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 脳疾患の病態解析と創薬へ向けたアンバイアス全脳イメージング (2019)
  • Author(s): 橋本均
  • Organizer: 第92回日本薬理学会年会
  • Invited
• [Presentation] Involvement of miR-132 in PACAP-dependent morphological changes of dendritic spines (2018)
  • Author(s): Hayata-Takano A., Kijima H., Kamo T., Shintani Y., Ago Y., Seiriki K., Nakazawa T., Shintani N., Hashimoto H.
  • Organizer: CINP2018
  • Int'l Joint Research
• [Presentation] Whole-brain mapping of neuronal activity in mice after social defeat stress (2018)
  • Author(s): H. Igarashi, A. Kasai, M. Niu, K. Seiriki, T. Kuwaki, M. Tanuma, S. Yamaguchi, T. Nakazawa, H.Hashimoto
  • Organizer: The 18th World Congress of Basic and Clinical Pharmacology (WCP2018)
  • Int'l Joint Research
• [Presentation] Protein kinase D2 ( PRKD2 ) regulates embryonic neural development (2018)
  • Author(s): M.Baba, K. Matsumura, T. Nakazawa, K. Nagayasu, A. Kasai, K. Takuma, H. Hashimoto
  • Organizer: The 18th World Congress of Basic and Clinical Pharmacology (WCP2018)
  • Int'l Joint Research
• [Presentation] The de novo Q1042R POGZ mutation in sporadic ASD disrupts the neuronal differentiation (2018)
  • Author(s): Matsumura K., Nakazawa T., Okada S., Nagayasu K., Miura H., Kasai A., Takuma K., Yamamori H., Yasuda Y., Hashimoto R., Hashimoto H.
  • Organizer: The 18th World Congress of Basic and Clinical Pharmacology (WCP2018)
  • Int'l Joint Research
• [Presentation] An interaction between PAC1 receptor and serotonin 2A receptor involved in receptor trafficking and signal transduction (2018)
  • Author(s): Shintani Y., Hayata-Takano A., Moriguchi K., Encho N., Hashimoto H
  • Organizer: The 18th World Congress of Basic and Clinical Pharmacology (WCP2018)
  • Int'l Joint Research
• [Presentation] Reduction of the mitochondria-localized protein p13 protects against experi- (2018)
  • Author(s): Shintani N, Inoue N, Ogura S, Morota Y, Hashimoto H
  • Organizer: The 18th World Congress of Basic and Clinical Pharmacology (WCP2018)
  • Int'l Joint Research
• [Presentation] PACAP-provoked PAC1 receptor signaling and internalization through two isoform of β-arrestins dependent mechanisms (2018)
  • Author(s): Shintani Y., Hayata-Takano A., Moriguchi K., Hashimoto H
  • Organizer: International GPCR Symposium
  • Int'l Joint Research
• [Presentation] Whole-brain analysis of the NMDA receptor antagonist-induced neuronal activation in mice using high-speed and high-resolution imaging system FAST (block-face serial microscopy tomography) (2018)
  • Author(s): eiriki K, Kasai A, Nakazawa T, Hashimoto H
  • Organizer: Cold Spring Harbor Asia meeting, Advances in Optical Imaging of Living Cells & Organisms: Focus on the Brain 2018
  • Int'l Joint Research
• [Presentation] High-speed and high-resolution whole-brain imaging system FAST (block-face-rerial-microscopy tomography) (2018)
  • Author(s): Hashimoto H, Seiriki K, Kasai A, Nakazawa T
  • Organizer: Cold Spring Harbor Asia meeting, Advances in Optical Imaging of Living Cells & Organisms: Focus on the Brain 2018
  • Int'l Joint Research / Invited
• [Presentation] 高速・高拡張性全脳イメージングシステムFAST:アンバイアスで仮説フリーに脳内のシンギュラリティを検出する手法へ (2018)
  • Author(s): 橋本均、笠井淳司、勢力薫、中澤敬信
  • Organizer: 第56回日本生物物理学会年会
  • Invited
• [Presentation] Claustrum is involbed in stress-induced anxiety-like behaviors (2018)
  • Author(s): Kasai A, Niu M, Seiriki K, Igarashi H, Tanuma M, Kuwaki T, Nagayasu K, Yamaguchi S, Nakazawa T, Yamanaka A, Hashimoto H
  • Organizer: Cold Spring Harbor Laboratory Meeting (Molecular mechanisms of neuronal connectivity)
  • Int'l Joint Research
• [Presentation] (R)-ketamine, (S)-ketamine and their metabolites affect fidderentially in vivo monoamine release in the prefrontal cortex of mice: Different involvement of AMPA receptors (2018)
  • Author(s): Ago Y, Tanabe W, Higuchi M, Tsukada S, Hashimoto K, Hashimoto H
  • Organizer: the 57th annual meeting of ACNP
  • Int'l Joint Research
• [Presentation] MODELING VIPR2 LINKAGES TO SCHIZOPHRENIA IN MICE (2017)
  • Author(s): Ago Y, Hayata-Takano A, Rajbhandari A, Fanselow M, Hashimoto H, Waschek JA
  • Organizer: 13th International Symposium on VIP, PACAP and Related Peptides
  • Int'l Joint Research
• [Presentation] FAST, High-speed serial-sectioning imaging for whole brain analysis with high scalability (2017)
  • Author(s): Kasai A, Seiriki K, Hashimoto T, Niu M, Yamaguchi S, Naka Y, Igarashi H, Tanuma M, Nakazawa T, Inoue KI, Takada M, Fujita K, Hashimoto H
  • Organizer: 47th annual meeting of Society for Neuroscience 2017
  • Int'l Joint Research
• [Presentation] Comparative effects of ketamine isomers, R-ketamine and S-ketamine, in mouse models of depression (2017)
  • Author(s): Ago Y, Higuchi M, Tanabe W, Seiriki K, Igarashi H, Kasai A, Hashimoto K, Hashimoto H
  • Organizer: 47th annual meeting of Society for Neuroscience 2017
  • Int'l Joint Research
• [Presentation] Whole-brain mapping analysis of the NMDAR antagonist-induced neuronal activity. (2017)
  • Author(s): Seiriki K, Kasai A, Kuwaki T, Niu M, Naka Y, Igarashi H, Nakazawa T, Yamaguchi S, Ago Y, Hashimoto H
  • Organizer: 47th annual meeting of Society for Neuroscience 2017
  • Int'l Joint Research
• [Presentation] 自閉スペクトラム症に高頻度に認めるPOGZ遺伝子座の患者特異的de novo変異の表現型解析 (2017)
  • Author(s): 中澤敬信、田熊一敞、橋本亮太、橋本均
  • 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
• [Remarks] 大阪大学大学院薬学研究科神経薬理学分野ホームページ
  • URL: http://molpharm.umin.jp/