脊髄損傷後機能代償回路の特定と新規回復促進戦略の開発

• Project Area: Generation of synapse-neurocircuit pathology
• Project/Area Number: 25110735
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: National Institute for Physiological Sciences
• Principal Investigator: 伊佐 正 生理学研究所, 発達生理学研究系, 教授 (20212805)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Discontinued (Fiscal Year 2014)
• Budget Amount: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000); Fiscal Year 2014: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2013: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
• Keywords: 脊髄損傷 / 機能代償 / ウィルスベクター / 脊髄固有ニューロン / 可塑性 / 精密把持 / 成長因子 / 機能回復 / 霊長類

Outline of Annual Research Achievements

本研究課題では、脊髄部分損傷後の機能回復過程において、脊髄固有ニューロン(PN)系が機能回復に重要な役割を果たしていることを実証し、さらにウィルスベクターによってPN系に選択的に成長因子などを発現させることで可塑性を誘導し、「経路標的治療戦略」を開発することを目的として研究を進めてきた。まずマカクザルにおいて、皮質脊髄路を頸髄C5レベルで切断した後、訓練によって、１―３カ月以内に手指の巧緻運動が回復するというモデルにおいて、回復過程に重要な役割を果たす可能性が考えられてきたPN系を我々が開発したウィルスベクター２重感染法を用いて選択的に遮断する。そして回復過程への影響を解析することで、PNが回復過程に果たす役割を検証した。そのために、２頭のサルで、高頻度逆行性レンチウィルスベクターにTREと破傷風毒素とGFPを搭載したHiRet-TRE-eGFP.eTeNTを頸髄C6-Th1髄節の前角に注入し、さらにAAV2-CMV-rtTAV16を頸髄C2-C5髄節に注入した。これによって、C2-C5に細胞体があって、C6-Th1の上肢や手の筋の運動ニューロンに結合するPNにドキシサイクリン投与時に破傷風毒素が発現し、シナプス伝達が阻害されるようにした。このようにしてPNの伝達が阻害された状況で、C5で皮質脊髄路を遮断した。１頭のサルは４か月経過しても精密把持運動は回復しなかった。現在、２頭目の回復過程を調べているが、これまでの結果はPNが機能回復に重要な役割を果たしていることが推定された。一方、脊髄損傷からの機能回復が起きた後にPN系の伝達を阻害した２頭のサルでは、予想に反して、回復した精密把持運動に対する障害効果は軽微であった。以上の結果は、PNは、皮質脊髄路の障害後の機能回復が起きるためには必須であるが、一旦機能回復が完成した段階での寄与は部分的であるという事が示唆された。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Decoding grasp force profile from electrocorticography signals in non-human primate sensorimotor cortex. (2014)
  • Author(s): Chen, C., Shin, D., Watanabe, H., Nakanishi, Y., Kambara, H., Yoshimura, N., Nambu, A. and Isa, T., Nishimura, Y. & Koike, Y.
  • Journal Title: Neurosci Res Volume: S0168-0102(14). Pages: 00047-9
  • DOI: 10.1016/j.neures.2014.03.010
  • Peer Reviewed / Open Access
• [Journal Article] Cervical Dystonia: a disorder of the midbrain network for covert attentional orienting. (2014)
  • Author(s): Hutchinson M, Isa T, Molloy A, Williams L, Kimmich O, Molloy F, Moore H, Healy DG, Lynch T, Walsh C, Butler J, Reilly R, Walsh R, O’Riordan S
  • Journal Title: Frontiers in Neurology Volume: なし
  • DOI: 10.3389/fneur.2014.00054
  • Peer Reviewed
• [Journal Article] Distinct local circuit properties of the superficial and intermediate layers of the rodent superior colliculus. (2014)
  • Author(s): Phongphanphanee, P., Marino, R., Kaneda, K., Yanagawa, Y., Munoz, D.P. and Isa, T.
  • Journal Title: Eur J Neurosci. Volume: 40（2） Issue: 2 Pages: 2329-43
  • DOI: 10.1111/ejn.12579
  • Peer Reviewed / Open Access
• [Journal Article] Reconstruction of intracortical whisker-evoked local field potential fromelectrocorticogram using a model trained for spontaneous activity in the rat barrel cortex. (2014)
  • Author(s): Watanabe H, Sakatani T, Suzuki T, Sato MA, Nishimura Y, Nambu A, Kawato M, Isa T
  • Journal Title: Neurosci Res. Volume: Ｓ0168-0102（14） Pages: 00121-7
  • Peer Reviewed
• [Journal Article] Decoding of the spike timing of primary afferents during voluntary arm movements in monkeys. (2014)
  • Author(s): Umeda T, Watanabe H, Sato MA, Kawato M, Isa T, Nishimura Y
  • Journal Title: Frontiers in Neuroscience Volume: なし Pages: 97-97
  • DOI: 10.3389/fnins.2014.00097
  • Peer Reviewed / Open Access
• [Journal Article] Reorganization of sensory pathways after neonatal hemidecortication in rats. (2014)
  • Author(s): Wanakhachornkrai, O., Umeda, T., Isa, K., Tantisira, M., Tantisira, B. and Isa, T.
  • Journal Title: Neuroscience Research Volume: 79 Pages: 94-98
  • DOI: 10.1016/j.neures.2013.11.003
  • Peer Reviewed
• [Journal Article] Plasticity for recovery after partial spinal cord injury-Hierarchical organization- (2014)
  • Author(s): Isa, T. and Nishimura, Y.
  • Journal Title: Neuroscience Research Volume: 78 Pages: 3-8
  • DOI: 10.1016/j.neures.2013.10.008
  • Peer Reviewed
• [Journal Article] Viral vector-mediated selective and reversible blockade of the pathway for visual orienting in mice. (2013)
  • Author(s): Sooksawate T, Isa K, Matsui R, Kato S, Kinoshita M, Kobayashi K, Watanabe D, Kobayashi K, Isa T.
  • Journal Title: Frontiers in Neural Circuits Volume: 7 Pages: 162-162
  • DOI: 10.3389/fncir.2013.00162
  • Peer Reviewed
• [Journal Article] Effects of early versus late rehabilitative training on manual dexterity after corticospinal tract lesion in macaque monkeys. (2013)
  • Author(s): Sugiyama Y, Higo N, Yoshino-Saito K, Murata Y, Nishimura Y, Oishi T, Isa T
  • Journal Title: Jornal of Neurophysiology Volume: 109 Issue: 12 Pages: 2853-2865
  • DOI: 10.1152/jn.00814.2012
  • Peer Reviewed
• [Journal Article] Differential Expression of Secreted Phosphoprotein l in the Motor Cortex among Primate Species and during Postnatal Development and Functional Recovery (2013)
  • Author(s): T. Yamamoto, T. Oishi, N. Higo, S. Murayama, A. Sato, I. Takashima, Y. Sugiyama, Y. Nishimura, Y. Murata, K. Yoshino-Saito, T. Isa, T. Kojima
  • Journal Title: PLOS ONE Volume: 8(5) Issue: 5 Pages: 1-13
  • DOI: 10.1371/journal.pone.0065701
  • Peer Reviewed
• [Journal Article] GABAergic mechanisms for shaping transient visual responses in the mouse superior colliculus. (2013)
  • Author(s): Kaneda K, Isa T
  • Journal Title: Neuroscience Volume: 235 Pages: 129-140
  • DOI: 10.1016/j.neuroscience.2012.12.061
  • Peer Reviewed
• [Journal Article] DNA Methylation and Methyl-Binding Proteins Control Differential Gene Expression in Distinct Cortical Areas of Macaque Monkey. (2013)
  • Author(s): Katsusuke Hata, Hiroaki Mizukami, Osamu Sadakane, Akiya Watakabe, Masanari Ohtsuka, Masafumi Takaji, Masaharu Kinoshita, Tadashi Isa, Keiya Ozawa, and Tetsuo Yamamori
  • Journal Title: The Journal of Neuroscience Volume: 33 Issue: 50 Pages: 19704-19714
  • DOI: 10.1523/jneurosci.2355-13.2013
  • Peer Reviewed
• [Journal Article] Prediction of hand trajectory from electrocorticography signals in primary motor cortex. (2013)
  • Author(s): Chen, D., Shin, D., Watanabe, H., Nakanishi, Y., Kambara, H., Yoshimura, N., Nambu, A., Isa, T., Nishimura, Y. and Koike, Y.
  • Journal Title: PLos One Volume: 8
  • Peer Reviewed
• [Journal Article] Roles of direct vs indirect pathways from the motor cortex to spinal motoneurons in the control of hand dexterity. (2013)
  • Author(s): Isa, T., Kinoshita, M. and Nishimura, Y.
  • Journal Title: Frontiers in Neurology Volume: 4 Pages: 191-191
  • Peer Reviewed
• [Presentation] マウス上丘浅層におけるニューロン集団活動の空間的解析 (2014)
  • Author(s): 笠井昌俊，伊佐正
  • Organizer: バイオイメージ・インフォマティクスワークショップ２０１４
  • Place of Presentation: 岡崎コンファレンスセンター(愛知県、岡崎市）
  • Year and Date: 2014-06-09
• [Presentation] 障害脳が示す新たな機能 (2014)
  • Author(s): 伊佐正
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡国際会議場(福岡県、福岡市）
  • Year and Date: 2014-05-22
  • Invited
• [Presentation] Pathway-selective blocking technique with double viral vectors for dissecting large-scaled neural network (2014)
  • Author(s): Tadahi Isa
  • Organizer: Emerging technologies for exploring the normal and epileptic brain A Segerfalk-Pufendorf Symposium
  • Place of Presentation: Lund University(Sweden)
  • Year and Date: 2014-05-06
  • Invited
• [Presentation] Estimation of Firing of Primary Afferents from Joint Kinematics During Voluntary Arm Movements of Monkeys.
  • Author(s): Umeda T, Sato M, Kawato M, Isa T, Nishimura Y.
  • Organizer: 第35回国際IEEE大会
  • Place of Presentation: 大阪国際会議場(大阪）
  • Invited
• [Presentation] Selective blocakde of crossed tecto-reticular pathway by double infection of viral vectors impaired orienting responses in mice; methodological considarations.
  • Author(s): Kaoru Isa, Thongchai Sooksawate, Ryosuke Matsui, Masaharu Kinoshita, Shigeki Kato, Kenta Kobayashi, Dai Watanabe, Kazuto Kobayashi, Tadashi Isa
  • Organizer: Gordon Research Conference
  • Place of Presentation: Stonhill College(MA, USA)
• [Presentation] Acquisition of novel behaviour by visual reinforcement without awareness: instrumental learning in blindsight monkeys.
  • Author(s): Rikako Kato, Norihiro Takakuwa, Abdelhafid Zeghbib, Peter Redgrave, Tadashi Isa
  • Organizer: Gordon Research Conference
  • Place of Presentation: Stonhill College(MA, USA)
• [Presentation] Verified contribution of propriospinal neurons to recovery of hand dexterity after a corticospinal tract lesion in the monkey.
  • Author(s): Tohyama T, Kinoshita M, Matsui R, Kato S, Isa K, Watanabe D, Kobayashi K, Liu M, Isa T
  • Organizer: Neuroscience2013
  • Place of Presentation: サンディエゴ国際会議場(USA)
• [Presentation] Process of forming novel behavior by visual reinforcement without awareness: Instrumental conditioning in blindsight monkeys.
  • Author(s): Kato R, Takakuwa N, Zeghbib A, Redgrave P, Isa T
  • Organizer: Neuroscience2013
  • Place of Presentation: サンディエゴ国際会議場(USA)
• [Presentation] Classical conditioning reinforced by visual stimuli in blindsight monkeys.
  • Author(s): Takakuwa N, Kato R, Redgrave P, Isa T
  • Organizer: Neuroscience2013
  • Place of Presentation: サンディエゴ国際会議場(USA)
• [Presentation] Key elements for functional recovery from the partial spinal cord injury; spinal cord, cortex and beyond
  • Author(s): Tadashi Isa
  • Organizer: Weekly Colloquium, The Winifred Masterson Burke Medical Research Institute (NY, USA)
  • Place of Presentation: The Winifred Masterson Burke Medical Research Institute (NY, USA)
  • Invited
• [Presentation] Key elements for functional recovery from the partial spinal cord injury; spinal cord, cortex and beyond
  • Author(s): Tadashi Isa
  • Organizer: 15th Spinal Research Network Meeting
  • Place of Presentation: London, UK
  • Invited
• [Presentation] Dissectiong the circuit for functional recovery after neuronal damage
  • Author(s): Tadashi Isa
  • Organizer: Plenary Lecture, the 10th Biennial Conference of the Chinese Neuroscience Society
  • Place of Presentation: Beijin International Convention & Exhibition Centre(China)
  • Invited
• [Presentation] Large-scaled network reorganization during recovery from partial spinal cord injury
  • Author(s): Tadahi Isa
  • Organizer: Distinguished Lecture Program
  • Place of Presentation: Katholic University Leuven (Belgium)
  • Invited