A novel whole-brain imaging analysis for the pathogenesis and therapeutic mechanisms of psychiatric disorders

• Project/Area Number: 17H03989
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pharmacology in pharmacy
• Research Institution: Osaka University
• Principal Investigator: Hashimoto Hitoshi 大阪大学, 薬学研究科, 教授 (30240849)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2017: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: 精神疾患 / 全脳イメージング / 全脳活動地図 / 仮説フリー / 全脳イメージ / 全脳 / FAST / 神経薬理学 / 画像 / 共焦点顕微鏡 / 神経科学 / 脳神経疾患 / 薬理学

Outline of Final Research Achievements

The pathogenesis and therapeutic mechanisms of psychiatric disorders remain unclear. To solve these problems, it is needed to develop a new pharmacological research strategy, which is a data-driven whole-brain analysis for psychiatric disorders. Here, we unbiasedly analyzed whole-brain activation maps in various mouse models of psychiatric disorders and in drug-treated mice, and revealed new insights into pathological mechanisms in psychiatric disorders and action mechanisms of therapeutic drugs. These results show that our strategy used in this study is a useful pipeline for research on psychiatric disorders.

Academic Significance and Societal Importance of the Research Achievements

本研究課題の成果は、病態に伴う全脳活動の捕捉に加え、既存薬がそれをどのように変化させて治療効果を発揮するのか、さらには新規候補薬による変化パターンを解析し、それらの結果を行動薬理学にも結び付けることによって、有効性や治療効果の機序を解明するものである。高用量による有害作用の機序についても同様に解析できる。動物モデル等を用いた精神疾患の前臨床研究が、新規候補薬のヒト疾患での有効性と有害作用を必ずしも十分に予測できない、”lost-in-translation”の克服に本研究成果が貢献し、社会的急務の中枢創薬が加速することが期待される。

Research Products

• [Int'l Joint Research] University of California, Los Angeles/Northwestern University/New York Medical College(米国)
• [Int'l Joint Research] University of Pecs/University of Szeged/University of Debrecen(ハンガリー)
• [Int'l Joint Research] University of Bristol(英国)
• [Int'l Joint Research] University of Heidelberg(ドイツ)
• [Int'l Joint Research] University of Liege(ベルギー)
• [Int'l Joint Research]
• [Journal Article] Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes. (2020)
  • Author(s): Matsumura K, (33名中略）, Hashimoto R, (37名中35番目）,Hashimoto H, Nakazawa T.
  • Journal Title: Nat. Commun Volume: 11(1) Issue: 1 Pages: 859-859
  • DOI: 10.1038/s41467-020-14697-z
  • Peer Reviewed / Open Access
• [Journal Article] Direct visualization of an antidepressant analog using surface-enhanced Raman scattering in the brain (2020)
  • Author(s): Masato Tanuma, Atsushi Kasai, Kazuki Bando, Naoyuki Kotoku, Kazuo Harada, Masafumi Minoshima, Kosuke Higashino, Atsushi Kimishima, Masayoshi Arai, Yukio Ago, Kaoru Seiriki, Kazuya Kikuchi, Satoshi Kawata, Katsumasa Fujita, Hitoshi Hashimoto
  • Journal Title: JCI Insight Volume: 5 Issue: 6
  • DOI: 10.1172/jci.insight.133348
  • Peer Reviewed / Open Access
• [Journal Article] Whole-brain block-face serial microscopy tomography at subcellular resolution using FAST. (2019)
  • Author(s): Seiriki K, Kasai A, Nakazawa T, Niu M, Naka Y, Tanuma M, Igarashi H, Yamaura K, Hayata-Takano A, Ago Y, Hashimoto H.
  • Journal Title: Nat Protoc. Volume: 印刷中 Issue: 5 Pages: 1509-1529
  • DOI: 10.1038/s41596-019-0148-4
  • Peer Reviewed / Open Access
• [Journal Article] Psychiatric-disorder-related behavioral phenotypes and cortical hyperactivity in a mouse model of 3q29 deletion syndrome. (2019)
  • Author(s): Baba M, Yokoyama K, Seiriki K, Naka Y, Matsumura K, Kondo M, Yamamoto K, Hayashida M, Kasai A, Ago Y, Nagayasu K, Hayata-Takano A, Takahashi A, Yamaguchi S, Mori D, Ozaki N, Yamamoto T, Takuma K, Hashimoto R, Hashimoto H, Nakazawa T.
  • Journal Title: Neuropsychopharmacology Volume: 44(12) Issue: 12 Pages: 2125-2135
  • DOI: 10.1038/s41386-019-0441-5
  • NAID: 130007811380
  • Peer Reviewed / Open Access
• [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 H, Ago Y, Naito M, Higuchi M, Hara Y, Hasebe S, Tsukada S, Kasai A, Nakazawa T, Mishina T, Kouji H, Takuma K, Hashimoto H.
  • Journal Title: Pharmacol Biochem Behav. Volume: 176 Pages: 1-5
  • DOI: 10.1016/j.pbb.2018.11.003
  • Peer Reviewed / Open Access
• [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: 印刷中 Issue: 22 Pages: 4208-4220
  • DOI: 10.1523/jneurosci.2468-18.2019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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, Solymar M.
  • Journal Title: PLoS One Volume: 14 Issue: 1 Pages: e0211433-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: Front Psychiatry. Volume: 10 Pages: 58-58
  • DOI: 10.3389/fpsyt.2019.00058
  • 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 Y, Hayata-Takano A, Moriguchi K, Nakazawa T, Ago Y, Kasai A, Seiriki K, Shintani N, Hashimoto H.
  • Journal Title: PLoS One Volume: 13 Issue: 5 Pages: e0196946-e0196946
  • DOI: 10.1371/journal.pone.0196946
  • Peer Reviewed / Open Access
• [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: Biochem Biophys Res Commun. Volume: 495(2) Issue: 2 Pages: 1992-1997
  • DOI: 10.1016/j.bbrc.2017.11.116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Targeted 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 N, Hashimoto H
  • Journal Title: EMBO Reports Volume: 19(3) Issue: 3
  • DOI: 10.15252/embr.201744860
  • Peer Reviewed / Open Access / 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, Longueesp 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: J. Pathol. Volume: 245 Issue: 4 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 Issue: 4 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 K, 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 Issue: 6 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 of 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] 高精細全脳イメージングによる精神・神経疾患の分子病態研究 (2019)
  • Author(s): 橋本均
  • Organizer: 新潟脳神経研究会特別例会
  • Invited
• [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] 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): Kaoru Seiriki, Atsushi Kasai, Takanobu Nakazawa, Hitoshi Hashimoto
  • Organizer: Cold Spring Harbor Asia, Advances in Optical Imaging of Living Cells & Organisms: Focus on the Brain
  • Int'l Joint Research / Invited
• [Presentation] iPS細胞関連技術とヒト型疾患モデルマウスを用いた精神疾患の分子病態解析 (2018)
  • Author(s): 中澤敬信、橋本亮太、田熊一敞、橋本均
  • Organizer: 第48回日本神経精神薬理学会年会
  • 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
• [Book] 精神疾患におけるVPAC2受容体の病態生理学的役割 (2018)
  • Author(s): 吾郷由希夫, 早田敦子, 橋本均
  • Total Pages: 5
  • Publisher: 日本薬理学雑誌 151(6): 249-253, 2018
• [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/
• [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/