Identification and characterization of brain disorder-related singularity cells by whole-brain imaging

• Project Area: Singularity biology
• Project/Area Number: 18H05416
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: Osaka University
• Principal Investigator: Hashimoto Hitoshi 大阪大学, 大学院薬学研究科, 教授 (30240849)
• Co-Investigator(Kenkyū-buntansha): 中澤 敬信 東京農業大学, 生命科学部, 教授 (00447335)
• Project Period (FY): 2018-06-29 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥128,960,000 (Direct Cost: ¥99,200,000、Indirect Cost: ¥29,760,000); Fiscal Year 2022: ¥25,870,000 (Direct Cost: ¥19,900,000、Indirect Cost: ¥5,970,000); Fiscal Year 2021: ¥26,910,000 (Direct Cost: ¥20,700,000、Indirect Cost: ¥6,210,000); Fiscal Year 2020: ¥25,480,000 (Direct Cost: ¥19,600,000、Indirect Cost: ¥5,880,000); Fiscal Year 2019: ¥24,050,000 (Direct Cost: ¥18,500,000、Indirect Cost: ¥5,550,000); Fiscal Year 2018: ¥26,650,000 (Direct Cost: ¥20,500,000、Indirect Cost: ¥6,150,000)
• Keywords: シンギュラリティ細胞 / 自閉スペクトラム症 / ストレス / シンギュラリティ / 脳疾患 / iPS / シンギュラリティ現象 / 高精細組織全細胞イメージング / ビッグデータ解析 / 精神疾患 / 全脳 / イメージング

Outline of Final Research Achievements

The aim of this study was to elucidate the singularity phenomenon in brain disorders, such as mental illnesses, which occur when the activity of a specific subset of brain cells explosively spreads to a wide brain region, leading to widespread changes in neuronal activity. We developed methodologies to comprehensively observe and analyze a vast number of brain cells, as well as neuronal activation reporter systems and foundational technologies related to induced pluripotent stem cells. Furthermore, we revealed the significance of abnormal activity in an exceedingly small number of neurons within the brains in stress-exposed mice and a mouse model of autism spectrum disorder, as it relates to the expression of behavioral abnormalities.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は、創薬の標的としての脳疾患におけるシンギュラリティ現象の同定が可能になったことである。精神疾患分野では、新規分子病態を標的とする創薬が難航しており、既存薬の治療効果も限定的である。本研究の実施により創薬につながる新しい分子病態情報を得ることができ、急務である中枢神経系創薬の推進に貢献することが期待される点で、本研究は社会的要求が著しく高いといえる。

Research Products

• [Int'l Joint Research] UCLA(米国)
• [Journal Article] Molecular basis of astrocyte diversity and morphology across the CNS in health and disease (2022)
  • Author(s): Endo F, Kasai A, Soto JS, Yu X, Qu Z, Hashimoto H, Gradinaru V, Kawaguchi R, Khakh BS.
  • Journal Title: Science Volume: 378 Issue: 6619
  • DOI: 10.1126/science.adc9020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Claustrum mediates bidirectional and reversible control of stress-induced anxiety responses (2022)
  • Author(s): Niu M et al.
  • Journal Title: Science Advances Volume: 8
  • Peer Reviewed / Open Access
• [Journal Article] Autism-associated ANK2 regulates embryonic neurodevelopment (2022)
  • Author(s): Kawano Shotaro、Baba Masayuki、Fukushima Hotaka、Miura Daiki、Hashimoto Hitoshi、Nakazawa Takanobu
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 605 Pages: 45-50
  • DOI: 10.1016/j.bbrc.2022.03.058
  • Peer Reviewed / Open Access
• [Journal Article] Oxytocin ameliorates impaired social behavior in a mouse model of 3q29 deletion syndrome (2022)
  • Author(s): Takemoto Tomoya、Baba Masayuki、Yokoyama Kazumasa、Kitagawa Kohei、Nagayasu Kazuki、Ago Yukio、Seiriki Kaoru、Hayata-Takano Atsuko、Kasai Atsushi、Mori Daisuke、Ozaki Norio、Takuma Kazuhiro、Hashimoto Ryota、Hashimoto Hitoshi、Nakazawa Takanobu
  • Journal Title: Molecular Brain Volume: 15 Issue: 1 Pages: 26-26
  • DOI: 10.1186/s13041-022-00915-w
  • Peer Reviewed / Open Access
• [Journal Article] Altered Functional Connectivity of the Orbital Cortex and Striatum Associated with Catalepsy Induced by Dopamine D1 and D2 Antagonists (2021)
  • Author(s): Misaki Niu, Atsushi Kasai, Kaoru Seiriki, Misuzu Hayashida, Masato Tanuma, Rei Yokoyama, Yumi Hirato, Hitoshi Hashimoto
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 44 Issue: 3 Pages: 442-447
  • DOI: 10.1248/bpb.b20-01006
  • NAID: 130007993460
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2021-03-01
  • Peer Reviewed / Open Access
• [Journal Article] Multiple alterations in glutamatergic transmission and dopamine D2 receptor splicing in induced pluripotent stem cell-derived neurons from patients with familial schizophrenia (2021)
  • Author(s): Yamamoto Kana、Kuriu Toshihiko、Takuma Kazuhiro、Ono Fumihito、Matsumoto Naomichi、Hashimoto Ryota、Hashimoto Hitoshi、Nakazawa Takanobu
  • Journal Title: Translational Psychiatry Volume: 11 Issue: 1 Pages: 548-548
  • DOI: 10.1038/s41398-021-01676-1
  • Peer Reviewed / Open Access
• [Journal Article] PACAP-PAC1 Signaling Regulates Serotonin 2A Receptor Internalization (2021)
  • Author(s): Hayata-Takano A et al.
  • Journal Title: Frontiers in Endocrinology Volume: 12 Pages: 732456-732456
  • DOI: 10.3389/fendo.2021.732456
  • Peer Reviewed / Open Access
• [Journal Article] Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder (2021)
  • Author(s): Kitagawa Kohei、Matsumura Kensuke、Baba Masayuki、Kondo Momoka、Takemoto Tomoya、Nagayasu Kazuki、Ago Yukio、Seiriki Kaoru、Hayata-Takano Atsuko、Kasai Atsushi、Takuma Kazuhiro、Hashimoto Ryota、Hashimoto Hitoshi、Nakazawa Takanobu
  • Journal Title: Molecular Brain Volume: 14 Issue: 1 Pages: 56-56
  • DOI: 10.1186/s13041-021-00769-8
  • Peer Reviewed / Open Access
• [Journal Article] Lipocalin-type prostaglandin D synthase regulates light-induced phase advance of the central circadian rhythm in mice (2020)
  • Author(s): Kawaguchi, C., Shintani, N., Hayata-Takano, A., Hatanaka, M., Kuromi, A., Nakamura, R., Yamano, Y., Shintani, Y., Nagai, K., Tsuchiya, S., Sugimoto, Y., Ichikawa, A., Okuno, Y., Urade, Y., Hirai, H., Nagata, K., Nakamura, M., Narumiya, S., Nakazawa, T., Kasai, A., Ago, Y., Takuma, K., Baba, A., and Hashimoto, H.
  • Journal Title: Communications Biology Volume: 3 Issue: 1 Pages: 557-557
  • DOI: 10.1038/s42003-020-01281-w
  • Peer Reviewed / Open Access
• [Journal Article] Activation of the VPAC2 Receptor Impairs Axon Outgrowth and Decreases Dendritic Arborization in Mouse Cortical Neurons by a PKA-Dependent Mechanism (2020)
  • Author(s): Takeuchi Shuto、Kawanai Takuya、Yamauchi Ryosuke、Chen Lu、Miyaoka Tatsunori、Yamada Mei、Asano Satoshi、Hayata-Takano Atsuko、Nakazawa Takanobu、Yano Koji、Horiguchi Naotaka、Nakagawa Shinsaku、Takuma Kazuhiro、Waschek James A.、Hashimoto Hitoshi、Ago Yukio
  • Journal Title: Frontiers in Neuroscience Volume: 14 Pages: 521-532
  • DOI: 10.3389/fnins.2020.00521
  • Peer Reviewed / Open Access / 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] Autism-associated protein kinase D2 regulates embryonic cortical neuron development. (2019)
  • Author(s): Matsumura K, Baba M, Nagayasu K, Yamamoto K, Kondo M, Kitagawa K, Takemoto T, Seiriki K, Kasai A, Ago Y, Hayata-Takano A, Shintani N, Kuriu T, Iguchi T, Sato M, Takuma K, Hashimoto R, Hashimoto H.
  • Journal Title: Biochem Biophys Res Commun Volume: 519(3) Issue: 3 Pages: 626-632
  • DOI: 10.1016/j.bbrc.2019.09.048
  • 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
• [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] Ｈigh-speed and scalable whole-brain imaging system FAST (2018)
  • Author(s): 橋本均
  • Organizer: 第56回日本生物物理学会
• [Presentation] High-speed and high-resolution whole-brain imaging system FAST (block-face serial microscopy tomography) (2018)
  • Author(s): Hitoshi Hashimoto, Kaoru Seiriki, Atsushi Kasai, Takanobu Nakazawa
  • Organizer: Cold Spring Harbor Asia, Advances in Optical Imaging of Living Cells & Organisms: Focus on the Brain
  • 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): 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
• [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/