霊長類における経路選択的回路操作の技術開発と疾病モデルへの応用

• Project/Area Number: 21H02798
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 51010:Basic brain sciences-related
• Research Institution: Kyoto University
• Principal Investigator: 山口 玲欧奈 京都大学, 高等研究院, 特定助教 (50812640)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥15,730,000 (Direct Cost: ¥12,100,000、Indirect Cost: ¥3,630,000); Fiscal Year 2023: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2022: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2021: ¥12,090,000 (Direct Cost: ¥9,300,000、Indirect Cost: ¥2,790,000)
• Keywords: 脊髄損傷 / サル / 機能回復 / ウイルスベクター / DREADD

Outline of Research at the Start

本研究では、ヒトに近い脳構造を持つマカクザルを対象とし、広範囲の脳領域に対して経路選択的かつ可逆的に操作ができる技術開発に取り組む。これを実現するために、広範囲にウイルスベクターを注入できるCED、特定の経路を選択できるウイルスベクター2重感染法、可逆的に経路を操作できるDREADDsという手法を組み合わせる。また、注入部位に脳波皮質電極を留置し、回路操作による脳活動の変化を明らかにする。さらに、当該回路操作技術をサル脊髄損傷モデルに適用し、脊髄損傷モデルからの機能回復に関わる脳機能を明らかにする。

Outline of Annual Research Achievements

本研究では、脊髄損傷からの回復過程において、損傷反対側の運動前野から損傷同側の運動前野への経路が機能回復に及ぼす影響を調べる。今年度はこれまで得られた2頭のサルの行動データおよび回路操作中の脳データの詳細な解析を行った。脊髄損傷後、精密把持課題ができ始める回復早期にDCZを投与し半球間経路を抑制すると、精密把持の成功率が著しく低下した。一方、回復後期になるとDCZを投与しても成功率や精密把持運動に影響は見られなかった。手指の運動をDeepLabCutを用いて解析したところ、回復早期の回路操作によって、特に親指の動きが緩慢になり課題の成功率が低下することが明らかになった。回路操作中の脳活動において、損傷前は半球間経路遮断すると損傷同側の運動前野のα帯域の活動が大きくなった。一方、回復早期に半球間経路を遮断すると損傷同側の運動前野のα帯域の活動は小さくなることが示された。これらの結果から半球間経路は損傷前は抑制性に働くが、回復早期には興奮性に働くことが示唆された。

Research Progress Status

令和5年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和5年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] How to study subjective experience in an animal model of blindsight? (2024)
  • Author(s): Yu Xiyao、Yamaguchi Reona、Isa Tadashi
  • Journal Title: Neuroscience Research Volume: 201 Pages: 39-45
  • DOI: 10.1016/j.neures.2023.09.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Balancing risk-return decisions by manipulating the mesofrontal circuits in primates (2024)
  • Author(s): Sasaki R., Ohta Y., Onoe H., Yamaguchi R., Miyamoto T., Tokuda T., Tamaki Y., Isa K., Takahashi J., Kobayashi K., Ohta J., Isa T.
  • Journal Title: Science Volume: 383 Issue: 6678 Pages: 55-61
  • DOI: 10.1126/science.adj6645
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Protocol for making an animal model of "blindsight" in macaque monkeys. (2022)
  • Author(s): Takakuwa N, Isa K, Yamaguchi R, Onoe H, Takahashi J, Yoshida M, Isa T
  • Journal Title: STAR Protoc Volume: 4(1) Issue: 1 Pages: 101960-101960
  • DOI: 10.1016/j.xpro.2022.101960
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Micro-LED Array-Based Photo-Stimulation Devices for Optogenetics in Rat and Macaque Monkey Brains (2021)
  • Author(s): Ohta Yasumi、Guinto Mark Christian、Tokuda Takashi、Kawahara Mamiko、Haruta Makito、Takehara Hironari、Tashiro Hiroyuki、Sasagawa Kiyotaka、Onoe Hirotaka、Yamaguchi Reona、Koshimizu Yoshinori、Isa Kaoru、Isa Tadashi、Kobayashi Kenta、Akay Yasemin M.、Akay Metin、Ohta Jun
  • Journal Title: IEEE Access Volume: 9 Pages: 127937-127949
  • DOI: 10.1109/access.2021.3111666
  • Peer Reviewed / Open Access
• [Journal Article] IL-23 production in human macrophages is regulated negatively by tumor necrosis factor α-induced protein 3 and positively by specificity protein 1 after stimulation of the toll-like receptor 7/8 signaling pathway (2021)
  • Author(s): Rui Yamaguchi, Arisa Sakamoto, Reona Yamaguchi, Misa Haraguchi, Shinji Narahara, Hiroyuki Sugiuchi, Yasuo Yamaguch
  • Journal Title: Heliyon Volume: 7 Issue: 2 Pages: e08887-e08887
  • DOI: 10.1016/j.heliyon.2022.e08887
  • Peer Reviewed / Open Access
• [Presentation] Supraspinal plasticity of the corticospinal projections after motor recovery from spinal cord injury in macaque monkeys (2024)
  • Author(s): Satoko Ueno, Reona Yamaguchi, Kaoru Isa, Toshinari Kawasaki, Masahiro Mitsuhashi, Tadashi Isa
  • Organizer: 第101回日本生理学会大会
• [Presentation] Dexterous Finger Function Recovers Earlier In Spinal Cord Injury Monkeys Injected With The Synthetic Synaptic Organizing Protein CPTX (2024)
  • Author(s): Stefan Peyda, Reona Yamaguchi, Satoko Ueno, Kaoru Isa, Erika Omae, Kunimichi Suzuki, Veronica Chang, Hiroyuki Sasakura, Keiko Matsuda, Kenta Kobayashi, Kousei Takeuchi, Radu Aricescu, Hirotaka Onoe, Michisuke Yuzaki, Tadashi Isa
  • Organizer: 第101回日本生理学会大会
• [Presentation] GLOBAL DISINHIBITION ASSOCIATED WITH RECOVERY OF HAND MOVEMENTS AFTER SPINAL CORD INJURY IN MONKEYS (2023)
  • Author(s): Reona Yamaguchi, Satoko Ueno, Toshinari Kawasaki, Zenas C. Chao, Masahiro Mitsuhashi, Kaoru Isa, Tomohiko Takei, K enta Kobayashi, Jun Takahashi, Hirotaka Onoe, Tadashi Isa
  • Organizer: Benzon symposium no. 67
  • Int'l Joint Research
• [Presentation] STATE-DEPENDENT ROLE OF INTERHEMISPHERIC PATHWAY FOR MOTOR RECOVERY IN PRIMATES (2023)
  • Author(s): Masahiro Mitsuhashi, Reona Yamaguchi, Toshinari Kawasaki, SatokoUeno, Kaoru Isa, Hirotaka Onoe, Tadashi Isa
  • Organizer: Benzon symposium no. 67
  • Int'l Joint Research
• [Presentation] Multi-hierarchical plasticity of the collaterals from corticospinal tract axons after spinal cord injury in the macaque monkeys (2023)
  • Author(s): Satoko Ueno, Reona Yamaguchi, Kaoru Isa, Toshinari Kawasaki, Masahiro Mitsuhashi, Tadashi Isa
  • Organizer: NEURO2023: The 46th Annual Meeting of the Japan Neuroscience Society
• [Presentation] Deep learning-based quantitative analysis for macaque hand dexterity (2023)
  • Author(s): Yiping Sun, Reona Yamaguchi, Tadashi Isa
  • Organizer: 第17回MotorControl研究会
• [Presentation] Changes in cortical response to non-paretic hand stimulation in monkeys after spinal cord injury: a longitudinal fMRI study (2022)
  • Author(s): Takamichi Tohyama, Reona Yamaguchi, Naokazu Goda, Tetsuya Yamamoto, Kaoru Isa, Norihiro Sadoto, Tadashi Isa, Masaki Fukunaga
  • Organizer: The 45th Annual Meeting of the Japan Neuroscience Society
• [Presentation] A Skull-Fit 8-channel phased-array Coil (SFiC) for high-resolution macaque MRI (2022)
  • Author(s): Shin-ichi Urayama, Tomohisa Okada, Reona Yamaguchi, Keigo Hikishima, Kei Kubota, Jun Takahashi, Yoshihiko Kawabata, Wim Vanduffel, Tadashi Isa, Hirotaka Onoe
  • Organizer: The 45th Annual Meeting of the Japan Neuroscience Society
• [Presentation] Global disinhibition associated with recovery of hand movements after spinal cord injury (2022)
  • Author(s): Reona Yamaguchi, Toshinari Kawasaki, Zenas C Chao, Masahiro Mitsuhashi, Satoko Ueno, Tadashi Isa
  • Organizer: The 45th Annual Meeting of the Japan Neuroscience Society
• [Presentation] Optogenetical adjustment of the balance between risky and safer decision (2022)
  • Author(s): Ryo Sasaki, Yasumi Ohta, Hirotaka Onoe, Reona Yamaguchi, Takashi Tokuda, Kaoru Isa, Jun Takahashi, Kenta Kobayashi, Jun Ohta, Tadashi Isa
  • Organizer: The 45th Annual Meeting of the Japan Neuroscience Society
• [Presentation] マカクザル皮質脊髄路損傷後の運動機能回復における大脳半球間連絡の役割 (2022)
  • Author(s): 三橋賢大, 山口玲欧奈, 川崎敏生, 上野里子, 高橋淳, 尾上浩隆,伊佐正
  • Organizer: 第 114 回近畿生理学談話
• [Presentation] リスク/リターンのバランスに基づく意思決定に関与する前頭皮質神経振動の解読 (2022)
  • Author(s): 宮本健史, 山口玲欧奈, 尾上浩隆, 伊佐正, 佐々木亮
  • Organizer: 第 114 回近畿生理学談話
• [Presentation] Brain activity in V1-lesioned Monkey (2022)
  • Author(s): Xiyao Yu, Reona Yamaguchi, Hakwan Lau, Tadashi Isa
  • Organizer: The 100th Anniversary Annual Meeting of The Physiological Society of Japan
• [Presentation] Contribution of the interhemispheric pathways to the recovery of dexterous hand movements after the corticospinal tract lesion in macaque monkeys (2022)
  • Author(s): Masahiro Mitsuhashi, Reona Yamaguchi, Toshinari Kawasaki, Satoko Ueno, Tadashi Isa
  • Organizer: The 100th Anniversary Annual Meeting of The Physiological Society of Japan
• [Presentation] The corticospinal projections after the motor recovery from spinal cord injury in macaque monkeys (2022)
  • Author(s): Satoko Ueno, Reona Yamaguchi, Kaoru Isa, Kawasaki Toshinari, Masahiro Mitsuhashi, Tadashi Isa
  • Organizer: The 100th Anniversary Annual Meeting of The Physiological Society of Japan
• [Presentation] Deep learning-based quantitative analysis for macaque hand dexterity (2022)
  • Author(s): Yiping Sun, Reona Yamaguchi, Tadashi Isa
  • Organizer: The 100th Anniversary Annual Meeting of The Physiological Society of Japan
• [Presentation] Excitatory and inhibitory connectivities associated with global disinhibition promoting functional recovery from spinal cord injury (2022)
  • Author(s): Reona Yamaguchi, Yusuke Imoto, Tadashi Isa
  • Organizer: The 100th Anniversary Annual Meeting of The Physiological Society of Japan
• [Presentation] Decoding oscillatory power signals during risk-return decision-making in the prefrontal and premotor cortices. (2022)
  • Author(s): Takeshi Miyamoto, Reona Yamaguchi, Hirotaka Onoe, Tadashi Isa, Ryo Sasaki
  • Organizer: The 100th Anniversary Annual Meeting of The Physiological Society of Japan
• [Presentation] Global disinhibition associated with recovery of hand movements after spinal cord injury (2021)
  • Author(s): Reona Yamaguchi, Toshinari Kawasaki, Zenas C Chao, Masahiro Mitsuhashi, Satoko Ueno, Tadashi Isa
  • Organizer: The 44th Annual Meeting of the Japan Neuroscience Society
• [Presentation] Massive re-routing of the corticospinal tract after spinal cord injury in the macaque monkeys (2021)
  • Author(s): Satoko Ueno, Reona Yamaguchi, Kaoru Isa, Toshinari Kawasaki, Masahiro Mitsuhashi, Tadashi Isa
  • Organizer: The 44th Annual Meeting of the Japan Neuroscience Society
• [Presentation] Role of the interhemispheric pathways for the recovery of dexterous hand movements after the corticospinal tract lesion in macaque monkeys (2021)
  • Author(s): Masahiro Mitsuhashi, Reona Yamaguchi, Toshinari Kawasaki, Satoko Ueno, Tadashi Isa
  • Organizer: The 44th Annual Meeting of the Japan Neuroscience Society
• [Presentation] Activity of frontal network for performance of arm movement in a blindsight monkey (2021)
  • Author(s): Saya Kitazume, Yusuke Yamamoto, Reona Yamaguchi, Tadashi Isa
  • Organizer: The 44th Annual Meeting of the Japan Neuroscience Society
• [Presentation] 脊髄損傷後における皮質脊髄路の大規模再構成 (2021)
  • Author(s): 上野里子、山口玲欧奈、伊佐かおる、川崎敏生、三橋賢大、伊佐正
  • Organizer: 第 113 回近畿生理学談話
• [Presentation] Global disinhibition associated with recovery of hand movements after spinal cord injury (2021)
  • Author(s): Reona Yamaguchi
  • Organizer: The 99th Anniversary Annual Meeting of The Physiological Society of Japan
• [Presentation] Global disinhibition associated with recovery of hand movements after spinal cord injury (2021)
  • Author(s): Reona Yamaguchi
  • Organizer: CIN-NIPS-Asia Pacific Systems Neuroscience Symposium 2022
• [Book] 霊長類学の百科事典 = The encyclopedia of primatology (2023)
  • Author(s): (分担執筆) 伊佐 正, 上野 里子, 山口 玲欧奈
  • Total Pages: 2
  • Publisher: 丸善出版
  • ISBN: 9784621308042
• [Book] 計測と制御 (2022)
  • Author(s): 山口 玲欧奈, 伊佐 正
  • Total Pages: 6
  • Publisher: 計測と制御
• [Book] 特集 運動制御の神経生理・機能解剖update-大脳,小脳,脊髄の連関 損傷脊髄の機能回復における運動野からの間接経路の関与 (2022)
  • Author(s): 伊佐 正, 三橋 賢大, 山口 玲欧奈
  • Total Pages: 7
  • Publisher: 脊椎脊髄ジャーナル