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Elucidation of the neural and molecular basis of functional recovery in the ventral striatum after spinal cord injury in non-human primates

Research Project

Project/Area Number 20H00573
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Review Section Medium-sized Section 59:Sports sciences, physical education, health sciences, and related fields
Research InstitutionKobe Gakuin University (2024)
Kyoto University (2020-2023)

Principal Investigator

尾上 浩隆  神戸学院大学, 薬学部, 教授 (80214196)

Co-Investigator(Kenkyū-buntansha) 田原 強  国立研究開発法人理化学研究所, 生命機能科学研究センター, 客員研究員 (20419708)
山口 玲欧奈  京都大学, 高等研究院, 特定助教 (50812640)
笠井 昌俊  京都大学, 医学研究科, 助教 (70625269)
Veale Richard  京都大学, 医学研究科, 助教 (80828880)
Project Period (FY) 2020-04-01 – 2025-03-31
Project Status Granted (Fiscal Year 2024)
Budget Amount *help
¥45,370,000 (Direct Cost: ¥34,900,000、Indirect Cost: ¥10,470,000)
Fiscal Year 2024: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Fiscal Year 2023: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Fiscal Year 2022: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Fiscal Year 2021: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
Fiscal Year 2020: ¥15,080,000 (Direct Cost: ¥11,600,000、Indirect Cost: ¥3,480,000)
Keywords脊髄損傷 / 前脳基底部 / motivation / rsfMRI / アセチルコリン / マカクザル / fMRI / siRNA / AAVベクター / ECoG / COMS / モチベーション / ドパミン / CMOS / マカクサル / AAV / Tet制御 / Ca2+イメージング / 腹側線条体
Outline of Research at the Start

脳梗塞や脊髄損傷患者の多くは運動機能の麻痺と併発して鬱症状を示し、意欲の減退が運動機能回復の妨げとなる。腹側線条体は意欲や動機付けに関係する重要な部位であるが、脊髄損傷後の運動回復過程にどのように関与するのかは不明である。本研究では、ウイルスベクターによる光遺伝学的、化学遺伝学的手法による経路選択的機能操作に加え、新たにp11やドーパミン受容体等の分子特異的siRNAを組み込んだAAVベクターのTet制御による神経機能修飾法を開発し、ECoG、fMRI、Ca2+イメージングによる解析により、脊髄損傷後の機能回復過程における意欲や動機付けによる神経回路再編についての神経・分子機構を明らかにする。

Outline of Annual Research Achievements

非ヒト霊長類動物であるマカクザルの脊髄損傷モデルを用い、運動機能回復過程における腹側線条体の本質的な役割、神経・分子機構を解明するために、以下の3つの項目について検討を行った。
1)分子特異的siRNAを組み込んだAAVベクターのTet発現誘導システムの開発: 前年度に引き続きp11のマカクサルに特異的なsiRNAを作製し、Tetで発現が制御可能なAAVベクターの開発を行った。今年度、新たにセロタイプの違うAAVベクター、1と2のミックス型とDJ/8型、9型を作製した。ラットを用いて、in vivoにおけるアセチルコリン神経に対する発現効率について検討した結果、1と2のミックス型が最も効率良く感染し、ChAT陽性細胞の約50%の細胞がリポータータンパクであるEGFPと共染色されることが明らかになった。
2)ECoG、fMRIよるによるマクロ解析: これまでに、サルの感覚―運動野にECoGを埋め込み、脊髄損傷後の回復過程における皮質領域間の機能的結合の動的変遷における接続性について検討し、抑制性結合の強度が、損傷後の回復早期と後期で有意に減少することが明らかした。これらの結合性の変化に対する腹側線条体の影響について検討するために、MRIコンパチブルなカーボン電極からなるECoGを作製し、ECoG電極の電気信号の特性、MRIの磁場均一性への影響等を検討した。
3)一次運動野や補足運動野におけるCa2+イメージング:光遺伝学的方法により一次運動野、運動前野など運動機能回復過程におけるCa2+、神経伝達物質の動態を解析するために、CMOSとLEDを組み合わせた刺入型のイメージセンサーを開発した。また、ニホンザルの脳に埋め込むための特製のチャンバーを設計し、3Dプリンターで試作を行った。

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

新たにセロタイプの違うAAVベクター、1と2のミック型、DJ/8型、9型を作製し、1と2のミックス型がアセチルコリン神経細胞への感染効率がもっとも高いことを明らかにした。今後、p11のsiRNAを組み込んだ1と2のミックス型のAAVベクターを作製し、ニホンザルの腹側線状体へ投与し、タンパク質の発現を待って、安静時fMRIを撮像して、p11-siRNAシステムの脳機能結合性への効果を解析するとともに、運動機能回復過程に対する影響を検討する。

Strategy for Future Research Activity

それぞれの研究項目において、ニホンザルへのウィルスベクターの投与、ECoGやデバイスの埋め込み等の準備が整った。今後は、それぞれについて、埋め込み等の手術を行い、適宜、実験を行う。研究代表者は今年4月より、京都大学を離れ神戸学院大学に異動となった。ニホンザルを用いた動物実験は、神戸学院大学ではできないことから、人手や時間的な制約はあるが、京都大学の研究分担者とこれまで以上に、綿密に連絡を取り合い、効率的に実験を進めることで、引き続き研究計画の変更せずに研究を遂行する。

Report

(5 results)
  • 2023 Annual Research Report
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • 2020 Comments on the Screening Results   Annual Research Report
  • Research Products

    (36 results)

All 2024 2023 2022 2021 2020 Other

All Int'l Joint Research (4 results) Journal Article (5 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (24 results) (of which Int'l Joint Research: 2 results) Book (1 results) Remarks (2 results)

  • [Int'l Joint Research] KU Leuven(ベルギー)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] CERMEP Imaging Platform(フランス)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] KU Leuven(ベルギー)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] CERMEP Imaging Platform(フランス)

    • Related Report
      2021 Annual Research Report
  • [Journal Article] Editorial: Manganese-Enhanced MRI: A New Avenue of Functional and Structural Imaging in Neuroscience2022

    • Author(s)
      Osanai M, Hikishima K and Onoe H
    • Journal Title

      Frontiers in Neural Circuits

      Volume: 16 Pages: 918500-918500

    • DOI

      10.3389/fncir.2022.918500

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [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

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 脊髄損傷からの回復過程における 「超適応」2022

    • Author(s)
      山口玲欧奈, 伊佐正
    • Journal Title

      計測と制御

      Volume: 61(4) Pages: 270-275

    • Related Report
      2022 Annual Research Report
  • [Journal Article] "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
    • Journal Title

      脊椎脊髄ジャーナル

      Volume: 35(6) Pages: 425-431

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Insertable inductively coupled volumetric coils for MR microscopy in a human 7T MR system2021

    • Author(s)
      Okada Tomohisa、Handa Shinya、Ding Bill、Urayama Shin‐ichi、Fujimoto Koji、Shima Atsushi、Yoshii Daisuke、Ayaki Takashi、Sawamoto Nobukatsu、Takahashi Ryosuke、Onoe Hirotaka、Isa Tadashi、Petropoulos Labros
    • Journal Title

      Magnetic Resonance in Medicine

      Volume: 87 Issue: 3 Pages: 1613-1620

    • DOI

      10.1002/mrm.29062

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Supraspinal plasticity of the corticospinal projections after motor recovery from spinal cord injury in macaque monkeys2024

    • 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
    • Related Report
      2023 Annual Research Report
  • [Presentation] GLOBAL DISINHIBITION ASSOCIATED WITH RECOVERY OF HAND MOVEMENTS AFTER SPINAL CORD INJURY IN MONKEYS2023

    • 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, Copenhagen
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] STATE-DEPENDENT ROLE OF INTERHEMISPHERIC PATHWAY FOR MOTOR RECOVERY IN PRIMATES2023

    • Author(s)
      Masahiro Mitsuhashi, Reona Yamaguchi, Toshinari Kawasaki, SatokoUeno, Kaoru Isa, Hirotaka Onoe, Tadashi Isa
    • Organizer
      Benzon symposium no. 67, Copenhagen.
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Multi-hierarchical plasticity of the collaterals from corticospinal tract axons after spinal cord injury in the macaque monkeys2023

    • 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
    • Related Report
      2023 Annual Research Report
  • [Presentation] Deep learning-based quantitative analysis for macaque hand dexterity2023

    • Author(s)
      Yiping Sun, Reona Yamaguchi, Tadashi Isa
    • Organizer
      第17回MotorControl研究会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Changes in cortical response to non-paretic hand stimulation in monkeys after spinal cord injury: a longitudinal fMRI study2022

    • 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
    • Related Report
      2022 Annual Research Report
  • [Presentation] A Skull-Fit 8-channel phased-array Coil (SFiC) for high-resolution macaque MRI2022

    • 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
    • Related Report
      2022 Annual Research Report
  • [Presentation] Global disinhibition associated with recovery of hand movements after spinal cord injury2022

    • 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
    • Related Report
      2022 Annual Research Report
  • [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
    • Related Report
      2022 Annual Research Report
  • [Presentation] Contribution of the interhemispheric pathways to the recovery of dexterous hand movements after the corticospinal tract lesion in macaque monkeys2022

    • Author(s)
      Masahiro Mitsuhashi, Reona Yamaguchi, Toshinari Kawasaki, Satoko Ueno, Tadashi Isa
    • Organizer
      The 100th Anniversary Annual Meeting of The Physiological Society of Japan
    • Related Report
      2022 Annual Research Report
  • [Presentation] The corticospinal projections after the motor recovery from spinal cord injury in macaque monkeys2022

    • 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
    • Related Report
      2022 Annual Research Report
  • [Presentation] Deep learning-based quantitative analysis for macaque hand dexterity2022

    • Author(s)
      Yiping Sun, Reona Yamaguchi, Tadashi Isa
    • Organizer
      The 100th Anniversary Annual Meeting of The Physiological Society of Japan
    • Related Report
      2022 Annual Research Report
  • [Presentation] Excitatory and inhibitory connectivities associated with global disinhibition promoting functional recovery from spinal cord injury2022

    • Author(s)
      Reona Yamaguchi, Yusuke Imoto, Tadashi Isa
    • Organizer
      The 100th Anniversary Annual Meeting of The Physiological Society of Japan
    • Related Report
      2022 Annual Research Report
  • [Presentation] Global disinhibition associated with recovery of hand movements after spinal cord injury2021

    • 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
    • Related Report
      2021 Annual Research Report
  • [Presentation] Massive re-routing of the corticospinal tract after spinal cord injury in the macaque monkeys2021

    • Author(s)
      Satoko Ueno, Reona Yamaguchi, Kaoru Isa, Toshinari Kawasaki, Masahiro Mitsuhashi, Tadashi Isa
    • Organizer
      The 44th Annual Meeting of the Japan Neuroscience Society
    • Related Report
      2021 Annual Research Report
  • [Presentation] Role of the interhemispheric pathways for the recovery of dexterous hand movements after the corticospinal tract lesion in macaque monkeys2021

    • Author(s)
      Masahiro Mitsuhashi, Reona Yamaguchi, Toshinari Kawasaki, Satoko Ueno, Tadashi Isa
    • Organizer
      The 44th Annual Meeting of the Japan Neuroscience Society
    • Related Report
      2021 Annual Research Report
  • [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
    • Related Report
      2021 Annual Research Report
  • [Presentation] Global disinhibition associated with recovery of hand movements after spinal cord injury2021

    • Author(s)
      Reona Yamaguchi
    • Organizer
      The 99th Anniversary Annual Meeting of The Physiological Society of Japan
    • Related Report
      2021 Annual Research Report
  • [Presentation] Global disinhibition associated with recovery of hand movements after spinal cord injury2021

    • Author(s)
      Reona Yamaguchi
    • Organizer
      CIN-NIPS-Asia Pacific Systems Neuroscience Symposium 2022
    • Related Report
      2021 Annual Research Report
  • [Presentation] Massive re-routing of corticospinal projection after functional recovery from spinal cord injury in the macaque monkey2021

    • Author(s)
      Satoko Ueno, Reona Yamaguchi, Kaoru Isa, Toshinari Kawasaki, Masahiro Mitsuhashi, Tadashi Isa
    • Organizer
      The 98th Annual Meeting of The Physiological Society of Japan Joint Meeting
    • Related Report
      2020 Annual Research Report
  • [Presentation] Massive re-routing of the corticospinal tract fibers accompanying recovery from spinal cord injury in macaque monkey2020

    • Author(s)
      Satoko Ueno, Reona Yamaguchi, Kaoru Isa, Toshinari Kawasaki, Masahiro Mitsuhashi, Tadashi Isa
    • Organizer
      The 43rd Annual Meeting of the Japan Neuroscience Society
    • Related Report
      2020 Annual Research Report
  • [Presentation] Contribution of interhemispheric pathways between the motor-related cortical areas during recovery after the corticospinal tract lesion in macaque monkeys2020

    • Author(s)
      Masahiro Mitsuhashi, Reona Yamaguchi, Toshinari Kawasaki, Satoko Ueno, Tadashi Isa
    • Organizer
      The 43rd Annual Meeting of the Japan Neuroscience Society
    • Related Report
      2020 Annual Research Report
  • [Presentation] Global disinhibition across cortical networks for recovery of hand movements after spinal cord injury2020

    • Author(s)
      Reona Yamaguchi, Toshinari Kawasaki, Zenas C Chao, Masahiro Mitsuhashi, Satoko Ueno, Tadashi Isa
    • Organizer
      The 43rd Annual Meeting of the Japan Neuroscience Society
    • Related Report
      2020 Annual Research Report
  • [Presentation] Resting-state functional connectivity with electrocorticography as a biomarker of motor recovery after spinal cord injury in macaque monkeys2020

    • Author(s)
      Toshinari Kawasaki, Reona Yamaguchi, Zenas C Chao, Masahiro Mitsuhashi, Satoko Ueno, Yukihiro Yamao, Takayuki Kikuchi, Kazumichi Yoshida, Susumu Miyamoto, Tadashi Isa
    • Organizer
      The 43rd Annual Meeting of the Japan Neuroscience Society
    • Related Report
      2020 Annual Research Report
  • [Book] 霊長類学の百科事典 第5章16 皮質脊髄路 272-2732023

    • Author(s)
      伊佐 正, 上野 里子, 山口 玲欧奈
    • Total Pages
      752
    • Publisher
      丸善出版
    • ISBN
      9784621308042
    • Related Report
      2023 Annual Research Report
  • [Remarks] 脳・脊髄損傷からの機能回復機構

    • URL

      https://nscinbiol.med.kyoto-u.ac.jp/projects/

    • Related Report
      2020 Annual Research Report
  • [Remarks] 選択的神経回路操作技術の開発

    • URL

      https://nscinbiol.med.kyoto-u.ac.jp/projects/#p6

    • Related Report
      2020 Annual Research Report

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Published: 2020-04-28   Modified: 2024-12-25  

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