認知学習と精神疾患病態の臨界期におけるドーパミン神経伝達機構の解析

• Project Area: Inducing lifelong plasticity (iPlasticity) by brain rejuvenation: elucidation and manipulation of critical period mechanisms
• Project/Area Number: 21H05694
• Research Category: Grant-in-Aid for Transformative Research Areas (A)
• Allocation Type: Single-year Grants
• Review Section: Transformative Research Areas, Section (III)
• Research Institution: Osaka University
• Principal Investigator: 疋田 貴俊 大阪大学, 蛋白質研究所, 教授 (70421378)
• Project Period (FY): 2021-09-10 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000); Fiscal Year 2022: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2021: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 神経回路 / 大脳基底核 / ドーパミン / 精神疾患 / 臨界期 / 社会的孤立 / 遺伝-環境相互作用

Outline of Research at the Start

臨界期での社会的孤立ストレスにより発症する精神疾患遺伝モデルマウスを用いて、神経回路病態を明らかにする。特に、ドーパミン動態と大脳基底核神経回路に着目し、モデルマウスの認知行動中のドーパミンイメージングおよび回路特異的なカルシウムイメージングを行う。また、同定した神経回路病態を是正する回路操作を行い、モデルマウスの認知行動の正常化を試みる。これらから、認知行動の回路機構の理論化を行い、臨界期の操作・再開における標的を推定する。

Outline of Annual Research Achievements

本研究は、ドーパミン動態と大脳基底核神経回路に着目し、精神疾患の発症における臨界期機構の解明を目的とした。本年度は、大脳基底核神経回路において、ドーパミン入力を受けるD1経路とD2経路の認知行動における役割を、可逆的神経伝達阻止法、DREADD法、光遺伝学手法による神経回路操作および回路特異的なカルシウムイメージングにより明らかにすることを目的とした。
研究代表者が開発した大脳基底核神経回路に特異的な可逆的神経伝達阻止法を用いて、　ドーパミンD1受容体を発現する側坐核中型有棘神経細胞(D1ニューロン)とドーパミンD2受容体を発現する側坐核中型有棘神経細胞（D2ニューロン）のそれぞれ特異的に破傷風菌毒素を発現させることで神経伝達遮断を行い、Attentional set-shifting課題への影響を調べた。その結果、Attentional set-shifting課題における逆転課題において、側坐核のD2ニューロンが重要な役割を担っていることを示した。
さらに、視覚性図形弁別学習課題において、無報酬と図形(CS-)を関連付けさせ、CS-への反応を抑制する必要のある認知行動課題を開発し、行動中のD1ニューロンとD2ニューロンの神経活動を回路特異的なカルシウムイメージングを行い、小型顕微鏡により一細胞レベルで観察した。すると、D2ニューロンが無報酬の結果（誤答）の直後のタイミングで特異的に活性化していることがわかった。そこで、光遺伝学手法により、活性化しているタイミングでD2ニューロンの光による抑制を行うと、次の試行での課題正答率が低下することが示された。このことは、誤答直後のD2ニューロンの活性化が同じ失敗を繰り返さないために必要であることを示す。

Research Progress Status

令和4年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和4年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] ブリュッセル自由大学(ベルギー)
• [Int'l Joint Research] トロント大学/ブリティッシュ・コロンビア大学(カナダ)
• [Int'l Joint Research] ジョンズ・ホプキンス大学/ソーク研究所/マサチューセッツ工科大学(米国)
• [Journal Article] Error-related signaling in nucleus accumbens D2 receptor-expressing neurons guides inhibition-based choice behavior in mice (2023)
  • Author(s): Nishioka Tadaaki、Attachaipanich Suthinee、Hamaguchi Kosuke、Lazarus Michael、de Kerchove d’Exaerde Alban、Macpherson Tom、Hikida Takatoshi
  • Journal Title: Nature Communications Volume: 14 Issue: 1 Pages: 2284-2284
  • DOI: 10.1038/s41467-023-38025-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Editorial: Circuit, molecular, and developmental mechanisms in decision-making behavior (2023)
  • Author(s): Macpherson Tom、Niwa Minae、Morishita Hirofumi、Hikida Takatoshi
  • Journal Title: Frontiers in Neuroscience Volume: 17 Pages: 1192237-1192237
  • DOI: 10.3389/fnins.2023.1192237
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Importin α3 (KPNA3) Deficiency Augments Effortful Reward-Seeking Behavior in Mice (2022)
  • Author(s): Aomine Yoshiatsu、Sakurai Koki、Macpherson Tom、Ozawa Takaaki、Miyamoto Yoichi、Yoneda Yoshihiro、Oka Masahiro、Hikida Takatoshi
  • Journal Title: Frontiers in Neuroscience Volume: 16 Pages: 1-13
  • DOI: 10.3389/fnins.2022.905991
  • Peer Reviewed / Open Access
• [Journal Article] Nucleus Accumbens Core Dopamine D2 Receptor-Expressing Neurons Control Reversal Learning but Not Set-Shifting in Behavioral Flexibility in Male Mice (2022)
  • Author(s): Macpherson Tom、Kim Ji Yoon、Hikida Takatoshi
  • Journal Title: Frontiers in Neuroscience Volume: 16 Pages: 885380-885380
  • DOI: 10.3389/fnins.2022.885380
  • Peer Reviewed / Open Access
• [Journal Article] Computational Mechanisms of Osmoregulation: A Reinforcement Learning Model for Sodium Appetite (2022)
  • Author(s): Uchida Yuuki、Hikida Takatoshi、Yamashita Yuichi
  • Journal Title: Frontiers in Neuroscience Volume: 16 Pages: 857009-857009
  • DOI: 10.3389/fnins.2022.857009
  • Peer Reviewed / Open Access
• [Journal Article] Trends in Big Data Analyses by Multicenter Collaborative Translational Research in Psychiatry (2022)
  • Author(s): Toshiaki Onitsuka, Yoji Hirano, Kiyotaka Nemoto, Naoki Hashimoto, Itaru Kushima, Daisuke Koshiyama, Michihiko Koeda, Tsutomu Takahashi, Yoshihiro Noda, Junya Matsumoto, Kenichiro Miura, Takanobu Nakazawa, Takatoshi Hikida, Kiyoto Kasai, Norio Ozaki, Ryota Hashimoto
  • Journal Title: Psychiatry and Clinical Neurosciences Volume: 76 Issue: 1 Pages: 1-14
  • DOI: 10.1111/pcn.13311
  • Peer Reviewed / Open Access
• [Journal Article] Vrk2 deficiency elicits aggressive behavior in female zebrafish (2022)
  • Author(s): Umeda Ryohei、Teranishi Hitoshi、Hada Kazumasa、Shimizu Nobuyuki、Shiraishi Hiroshi、Urushibata Hirotaro、Lai Shaohong、Shide Masahito、Carrasco Apolinario Magdeline E.、Higa Ryoko、Shikano Kenshiro、Shin Toshitaka、Mimata Hiromitsu、Hikida Takatoshi、Hanada Toshikatsu、Hanada Reiko
  • Journal Title: Genes to Cells Volume: 27(4) Issue: 4 Pages: 254-265
  • DOI: 10.1111/gtc.12924
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulation of sensorimotor gating via Disc1/Huntingtin-mediated Bdnf transport in the cortico-striatal circuit (2022)
  • Author(s): Jaaro-Peled H、Kumar S、Hughes D、Sumitomo A、Kim S-H、Zoubovsky S、Hirota-Tsuyada Y、Zala D、Bruyere J、Katz BM.、Huang B、Flores R、Narayan S、Hou Z、Economides AN、Hikida T、Wetsel WC、Deisseroth K、Mori S、Brandon NJ、Tanaka M、Ishizuka K、Houslay MD、Saudou F、Dzirasa K、Sawa A、Tomoda T
  • Journal Title: Molecular Psychiatry Volume: - Issue: 3 Pages: 1805-1815
  • DOI: 10.1038/s41380-021-01389-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of Importin α1/KPNA1 deletion and adolescent social isolation stress on psychiatric disorder-associated behaviors in mice (2021)
  • Author(s): Sakurai Koki, Itou Taichi, Morita Makiko, Kasahara Emiko, Moriyama Tetsuji, Macpherson Tom, Ozawa Takaaki, Miyamoto Yoichi, Yoneda Yoshihiro, Sekiyama Atsuo, Oka Masahiro, Hikida Takatoshi
  • Journal Title: PLOS ONE Volume: 16 Issue: 11 Pages: e0258364-e0258364
  • DOI: 10.1371/journal.pone.0258364
  • Peer Reviewed / Open Access
• [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] Parallel and hierarchical neural mechanisms for adaptive and predictive behavioral control (2021)
  • Author(s): Tom Macpherson, Masayuki Matsumoto, Hiroaki Gomi, Jun Morimoto, Eiji Uchibe, Takatoshi Hikida
  • Journal Title: Neural Networks Volume: 144 Pages: 507-521
  • DOI: 10.1016/j.neunet.2021.09.009
  • Peer Reviewed / Open Access
• [Journal Article] Natural and Artificial Intelligence: A brief introduction to the interplay between AI and neuroscience research (2021)
  • Author(s): Macpherson Tom、Churchland Anne、Sejnowski Terry、DiCarlo James、Kamitani Yukiyasu、Takahashi Hidehiko、Hikida Takatoshi
  • Journal Title: Neural Networks Volume: 144 Pages: 603-613
  • DOI: 10.1016/j.neunet.2021.09.018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Analysis of dopamine dynamics in cortex, striatum, and amygdala during differential auditory fear conditioning in mice. (2023)
  • Author(s): Takaaki Ozawa, Kazuhiro Umemoto, Moe Nakamura, Ryotaro Iwamoto, Yuma Matsumoto, Tomohiro Shibata, Yoshinobu Oyama, Tom Macpherson, Takatoshi Hikida.
  • Organizer: IRCN-iPlasticity International Symposium
  • Int'l Joint Research
• [Presentation] Dopamine neurotransmission mechanisms in the nucleus accumbens for flexible cognitive behavior. (2023)
  • Author(s): Hikida T, Nishioka T, Macpherson T, Hamaguchi K
  • Organizer: 日本生理学会第100回記念大会
  • Invited
• [Presentation] Extracellular sugar modification regulates neuronal signaling in the nucleus accumbens. (2023)
  • Author(s): Masu M, Miya K, Masu K, Okada T, Ohta K, Macpherson T, Hikida T, Suzuki E, Momiyama T.
  • Organizer: 日本生理学会第100回記念大会
  • Invited
• [Presentation] Cell-type-specific control of reward and aversive signaling in the nucleus accumbens. (2023)
  • Author(s): Macpherson T, Attachaipanich S, Nishioka T, Ozawa T, Hikida T
  • Organizer: 日本生理学会第100回記念大会
  • Invited
• [Presentation] Neural mechanism of salt and umami seeking behavior (2023)
  • Author(s): Ozawa T, Shibata T, Oyama Y, Abe M, Goto K, Yonemaru H, Matsumoto Y, Iwamoto R, Sakurai K, Macpherson T, Hikida T
  • Organizer: 日本生理学会第100回記念大会
  • Invited
• [Presentation] Neural mechanisms for the strategy to avoid a choice that leads to negative outcome in visual discrimination learning. (2022)
  • Author(s): Takatoshi Hikida, Tadaaki Nishioka, Tom Macpherson, Kosuke Hamaguchi
  • Organizer: 4th International Touchscreen Symposium
  • Int'l Joint Research / Invited
• [Presentation] Cell type-specific control of reward learning in the brain. (2022)
  • Author(s): Tom Macpherson, Takatoshi Hikida
  • Organizer: The 17th International Symposium of the Institute Network for Biomedical Sciences.
  • Int'l Joint Research / Invited
• [Presentation] Effects of Importin α1(KPNA1) depletion and adolescent social stress on psychiatric disorder-associated behaviors in mice. (2022)
  • Author(s): Sakurai K, Kasahara E, Ozawa T, Macpherson T, Miyamoto Y, Yoneda Y, Sekiyama A, Oka M, Hikida T.
  • Organizer: Neuroscience 2022
  • Int'l Joint Research
• [Presentation] Motivational increase and brain network variation based on functional connectivity in Importin α3 (KPNA3) deficient mice. (2022)
  • Author(s): Aomine Y, Sakurai K, Macpherson T, Ozawa T, Miyamoto Y, Yoneda Y, Oka M, Hikida T
  • Organizer: Neuroscience 2022
  • Int'l Joint Research
• [Presentation] Motivational increase and brain network variation based on functional connectivity in Importin α3 (KPNA3) deficient mice. (2022)
  • Author(s): Hikida T, Aomine Y, Sakurai K, Macpherson T, Ozawa T, Miyamoto Y, Yoneda Y, Oka M.
  • Organizer: 61st Annual Meeting of Neuropsychopharmacology
  • Int'l Joint Research
• [Presentation] 行動柔軟性における側坐核の並列神経回路機構 (2022)
  • Author(s): 疋田 貴俊、マクファーソン トム.
  • Organizer: Neuro2022
  • Invited
• [Presentation] 柔軟な認知行動のための神経回路機構 (2022)
  • Author(s): 疋田 貴俊
  • Organizer: BPCNPNPPP4学会合同年会
  • Invited
• [Presentation] 側坐核のドーパミン動態の解析 (2022)
  • Author(s): 疋田 貴俊
  • Organizer: 第19回COCORO会議、第19回脳表現型の分子メカニズム研究会
  • Invited
• [Presentation] 認知学習と精神疾患病態の大脳基底核神経回路機構 (2022)
  • Author(s): 疋田 貴俊
  • Organizer: 臨界期生物学】第11回「オンライン研究交流会」
  • Invited
• [Presentation] Diverse activity patterns of medium spiny neurons in the nucleus accumbens in reward and aversion. (2022)
  • Author(s): 疋田貴俊、マクファーソン トム
  • Organizer: 第95回日本薬理学会年会
  • Invited
• [Presentation] Homeostatic regulation of neural circuit mechanisms in flexible cognitive behavior and psychiatric disorders. (2022)
  • Author(s): 疋田貴俊
  • Organizer: 第95回日本薬理学会年会
  • Invited
• [Presentation] 腹側淡蒼球のドーパミンの役割 (2021)
  • Author(s): 疋田貴俊
  • Organizer: 第17回COCORO会議、第17回脳表現型の分子メカニズム研究会
  • Invited
• [Presentation] Distinct Roles of Dopamine D1 and D2 Receptor-expressing Neurons in the Nucleus Accumbens for a Strategy Dependent Decision Making. (2021)
  • Author(s): Tadaaki Nishioka, Tom Macpherson, Kosuke Hamaguchi, Takatoshi Hikida.
  • Organizer: Neuroscience 2021, 50th Annual meeting of Society for Neuroscience
  • Int'l Joint Research
• [Presentation] Distinct Roles of Dopamine D1 and D2 Receptor-expressing Neurons in the Nucleus Accumbens for a Strategy Dependent Decision Making. (2021)
  • Author(s): Tadaaki Nishioka, Tom Macpherson, Kosuke Hamaguchi, Takatoshi Hikida.
  • Organizer: 60th Annual Meeting of the American College of Neuropsychopharmacology
  • Int'l Joint Research
• [Remarks] 同じ失敗を繰り返さないために必要な脳内メカニズムを解明
  • URL: http://www.protein.osaka-u.ac.jp/achievements/20230428/