Neural mechanisms underlying attention deficits in schizophrenia

• Project/Area Number: 18KK0442
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research (A))
• Allocation Type: Multi-year Fund
• Research Field: Basic / Social brain science
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: Miwa Hideki 国立研究開発法人国立精神・神経医療研究センター, 精神保健研究所 精神薬理研究部, 室長 (80468488)
• Project Period (FY): 2019 – 2023
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥15,600,000 (Direct Cost: ¥12,000,000、Indirect Cost: ¥3,600,000)
• Keywords: 注意選択機構 / 統合失調症 / in vivo電気生理学 / 多点電極 / 幻覚 / モデルマウス / 神経基盤 / 視床 / 妄想 / 陽性症状 / 認知機能障害 / 幻覚・妄想 / 視床網様核

Outline of Research at the Start

統合失調症は陽性症状、陰性症状、認知機能障害などの症状を示すが、特に認知機能障害に関して、適切な治療薬が開発されておらず、早急の問題である。近年、統合失調症患者においてスピンドル波発生異常が報告され、その機能部位として視床網様核の機能異常が疑われる。本研究では、視床網様核と認知機能障害との関連性について、視床網様核におけるマルチユニット記録やin vivoイメージング法など世界最先端の研究手法を用いて明らかにする。

Outline of Final Research Achievements

In this study, we advanced our collaborative research with Dr. Michael Halassa, a globally famous expert in in vivo electrophysiological analysis of the thalamic reticular nucleus and the thalamus, which have been reported to be associated with schizophrenia. Through this international collaboration, I was able to learn in vivo electrophysiological techniques using tetrodes and the methods for analyzing the resulting data. During my stay, I had the opportunity to introduce my own research, engaged in discussions and exchanges of ideas, and received advice on research topics beyond this study. We successfully established a good international collaborative research relationship and plan to stay in touch and continue our collaborative research in the future.

Academic Significance and Societal Importance of the Research Achievements

本研究で着目している視床網様核はノンレム睡眠スピンドル波発生のリズムジェネレーターだと考えられている。採択者はこれまで複数ラインのSZモデルマウスを用いてノンレム睡眠スピンドル波の解析を行い、臨床研究結果と同様に動物モデルでもノンレム睡眠スピンドル波の異常を検出している。本国際共同研究によりこれらのマウスラインの視床網様核のスパイク活動を直接測定することが可能になったため、現在、習得した測定方法・データ解析方法を用いて、細胞レベルのより詳細な機構を明らかにし、注意選択異常の神経基盤を明らかにしている。これらの成果をもとに治療薬の分子標的を今後探索する予定である。

Research Products

• [Int'l Joint Research] マサチューセッツ工科大(米国) (2019)
• [Journal Article] Normal cortical laminar formation in RP58+/? mice (2023)
  • Author(s): Hirai Sayaka、Miwa Hideki、Shimbo Hiroko、Nakajima Keisuke、Kondo Masahiro、Tanaka Tomoko、Ohtaka-Maruyama Chiaki、Hirai Shinobu、Okado Haruo
  • Journal Title: Molecular Psychiatry Volume: 28 Issue: 6 Pages: 2173-2173
  • DOI: 10.1038/s41380-023-02299-2
  • Peer Reviewed / Open Access
• [Journal Article] 統合失調症とスピンドル活動 (2023)
  • Author(s): 三輪秀樹
  • Journal Title: 睡眠医療 Volume: 17 Pages: 371-377
• [Journal Article] The mouse model of intellectual disability by ZBTB18/RP58 haploinsufficiency shows cognitive dysfunction with synaptic impairment (2023)
  • Author(s): Hirai Sayaka、Miwa Hideki、Shimbo Hiroko、Nakajima Keisuke、Kondo Masahiro、Tanaka Tomoko、Ohtaka-Maruyama Chiaki、Hirai Shinobu、Okado Haruo
  • Journal Title: Molecular Psychiatry Volume: Online ahead of print. Issue: 6 Pages: 2370-2381
  • DOI: 10.1038/s41380-023-01941-3
  • Peer Reviewed / Open Access
• [Journal Article] Contribution of astrocytic histamine N-methyltransferase to histamine clearance and brain function in mice (2022)
  • Author(s): Otsuka Rina、Naganuma Fumito、Nakamura Tadaho、Miwa Hideki、Nakayama-Naono Rumi、Matsuzawa Takuro、Komatsu Yurika、Sato Yuki、Takahashi Yuna、Tatsuoka-Kitano Haruna、Yanai Kazuhiko、Yoshikawa Takeo
  • Journal Title: Neuropharmacology Volume: 212 Pages: 109065-109065
  • DOI: 10.1016/j.neuropharm.2022.109065
  • Peer Reviewed / Open Access
• [Journal Article] Mice Lacking Cerebellar Cortex and Related Structures Show a Decrease in Slow-Wave Activity With Normal Non-REM Sleep Amount and Sleep Homeostasis (2022)
  • Author(s): Fujiyama Tomoyuki、Takenaka Henri、Asano Fuyuki、Miyanishi Kazuya、Hotta-Hirashima Noriko、Ishikawa Yukiko、Kanno Satomi、Seoane-Collazo Patricia、Miwa Hideki、Hoshino Mikio、Yanagisawa Masashi、Funato Hiromasa
  • Journal Title: Frontiers in Behavioral Neuroscience Volume: 16 Pages: 910461-910461
  • DOI: 10.3389/fnbeh.2022.910461
  • Peer Reviewed / Open Access
• [Journal Article] Targeting Neurons with Functional Oxytocin Receptors: A Novel Set of Simple Knock-In Mouse Lines for Oxytocin Receptor Visualization and Manipulation (2022)
  • Author(s): Inoue Yukiko U.、Miwa Hideki、Hori Kei、Kaneko Ryosuke、Morimoto Yuki、Koike Eriko、Asami Junko、Kamijo Satoshi、Yamada Mitsuhiko、Hoshino Mikio、Inoue Takayoshi
  • Journal Title: eneuro Volume: 9 Issue: 1 Pages: 0423-21
  • DOI: 10.1523/eneuro.0423-21.2022
  • Peer Reviewed / Open Access
• [Journal Article] GAD67-mediated GABA Synthesis and Signaling Impinges on Directing Basket Cell Axonal Projections Toward Purkinje Cells in the Cerebellum (2021)
  • Author(s): Miwa Hideki、Kobayashi Ken、Hirai Shinobu、Yamada Mitsuhiko、Watanabe Masahiko、Okado Haruo、Yanagawa Yuchio
  • Journal Title: The Cerebellum Volume: Published: 21 October 2021 Issue: 6 Pages: 1-15
  • DOI: 10.1007/s12311-021-01334-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High-sucrose diets contribute to brain angiopathy with impaired glucose uptake and psychosis-related higher brain dysfunctions in mice (2021)
  • Author(s): Hirai Shinobu, Toriumi Kazuya (4番目/24人中), et al.
  • Journal Title: Science Advances Volume: 7 Issue: 46 Pages: 1-5
  • DOI: 10.1126/sciadv.abl6077
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Brain Angiopathy and Impaired Glucose Metabolism in Model Mice with Psychiatric-Related Phenotypes. (2020)
  • Author(s): Shinobu Hirai, Hideki Miwa, Tomoko Tanaka, Kazuya Toriumi, Yasuto Kunii, Takuya Sakamoto, Mizuki Hino, Ryuta Izumi, Atsuko Nagaoka, Hirooki Yabe, Tomoya Nakamachi, Seiji Shioda, Takashi Dan, Toshio Miyata, Yasumasa Nishito, Hiroko Shimbo, Kazuhiro Suzuki, Mitsuhiro Miyashita, Masanari Itokawa, Makoto Arai, Haruo Okado
  • Journal Title: bioRxiv. Volume: Posted October 06 Pages: 1-64
  • DOI: 10.1101/2020.02.14.939546
  • Open Access
• [Journal Article] Roles of GABA Signaling in Directing Basket Cell Axonal Projections Toward Purkinje Cells in the Cerebellum. (2020)
  • Author(s): Miwa H, Kobayashi K, Hirai S, Yamada M, Watanabe M, Okado H, Yanagawa Y.
  • Journal Title: Research Square Volume: Posted October 27 Pages: 1-34
  • DOI: 10.21203/rs.3.rs-95440/v1
  • Open Access
• [Journal Article] Translatable neurophysiological indices for schizophrenia：gamma band oscillation and NREM sleep spindle (2020)
  • Author(s): 三輪秀樹, 平野羊嗣
  • Journal Title: Japanese Journal of Biological Psychiatry Volume: 31 Issue: 4 Pages: 190
  • DOI: 10.11249/jsbpjjpp.31.4_190
  • NAID: 130007961382
  • ISSN: 2186-6465, 2186-6619
  • Open Access
• [Journal Article] Temperature elevation in epileptogenic foci exacerbates epileptic discharge through TRPV4 activation (2019)
  • Author(s): Shibasaki Koji、Yamada Katsuya、Miwa Hideki、Yanagawa Yuchio、Suzuki Michiyasu、Tominaga Makoto、Ishizaki Yasuki
  • Journal Title: Laboratory Investigation Volume: 100 Issue: 2 Pages: 274-284
  • DOI: 10.1038/s41374-019-0335-5
  • Peer Reviewed
• [Presentation] ransient inactivation of developing Purkinje neurons causes male-specific social deficits (2023)
  • Author(s): Satoshi Kamijo, Mitsuhiko Yamada, Hideki Miwa
  • Organizer: Society for Neuroscience
  • Int'l Joint Research
• [Presentation] 発達期小脳プルキンエ細胞活動の抑制による性特異的な社会性の障害 (2023)
  • Author(s): 上條諭志, 三輪秀樹, 山田光彦
  • Organizer: 日本神経精神薬理学会
• [Presentation] 統合失調症GABA仮説に基づく動物モデルと妥当性評価指標-ガンマオシレーションとスピンドル波 (2022)
  • Author(s): 三輪秀樹
  • Organizer: 日本薬理学会 第73回日本薬理学会次世代の会
  • Invited
• [Presentation] 視床網様核におけるGAD67遺伝子欠損のノンレム睡眠スピンドル波発生及び睡眠依存 性記憶固定への影響 (2019)
  • Author(s): 三輪秀樹
  • Organizer: 日本睡眠学会第44回定期学術集会
  • Invited
• [Presentation] オプトジェネティクスによる精神疾患病態解明」 (2019)
  • Author(s): 三輪秀樹
  • Organizer: 東京工業大学 生命理工オープンイノベーション 第6回 LiHubフォーラム 光先進医療
  • Invited
• [Presentation] 統合失調症モデルマウスにおけるノンレム睡眠スピンドル波異常 (2019)
  • Author(s): 三輪秀樹
  • Organizer: 第21回応用薬理シンポジウム
  • Invited
• [Presentation] An animal model based on GABA hypothesis of schizophrenia and its phenotypes (2019)
  • Author(s): Hideki Miwa
  • Organizer: Tthe 6th Congress of Asian College of Neuropsychopharmacology (AsCNP2019)
  • Int'l Joint Research / Invited
• [Book] Optogenetics, Light-Sensing Proteins and Their Applications in Neuroscience and Beyond (2021)
  • Author(s): Makoto Osanai, Hideki Miwa, Atsushi Tamura, Satomi Kikuta, Yoshio Iguchi, Yuchio Yanagawa et al.
  • Total Pages: 639
  • Publisher: Springer
  • ISBN: 9789811587627
• [Remarks] RP58/ZBTB18ハプロ不全の原因として興奮性シナプス障害を発見
  • URL: https://www.ncnp.go.jp/topics/2023/20230201p.html
• [Remarks] 三輪秀樹(Researchmap)
  • URL: https://researchmap.jp/HMIWA/?lang=japanese