成体神経新生を利用した障害脳神経回路の機能的再建

• Project Area: Mechanisms underlying the functional shift of brain neural circuitry for behavioral adaptation
• Project/Area Number: 15H01446
• 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: Nara Medical University
• Principal Investigator: 坪井 昭夫 奈良県立医科大学, 医学部, 教授 (20163868)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000); Fiscal Year 2016: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2015: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 神経科学 / 脳・神経 / 脳神経疾患 / 再生医学 / 成体神経新生 / 脳梗塞モデルマウス / 神経回路形成 / 嗅覚系

Outline of Annual Research Achievements

申請者は、嗅球の新生介在ニューロンで起こる“健常時の適応回路シフト”の意義を解析し、神経活動依存的な新生ニューロンの発達が、匂いの情報処理に必須な役割を果たすことを明らかにした（J. Neurosci 36, 8210, 2016）。また、脳梗塞に伴う“病態時の適応回路シフト”に関与する遺伝子として、転写因子Npas4を同定した（申請者ら，投稿準備中）。

１）健常時の適応回路シフト（嗅球介在ニューロンの神経活動依存的な発達の意義）：申請者は、嗅球介在ニューロンにおいて、神経活動依存的に樹状突起の発達を促進する１回膜貫通型糖蛋白質5T4に着目し、その遺伝子欠損マウスの嗅覚行動を解析した。その結果5T4欠損マウスは、匂いの検出感度が低下し、他の匂いの存在下で目的の匂いを識別する能力にも異常が生じることが明らかになった。これらの成果は、米国科学誌 The Journal of Neuroscience（2016年8月3日号）に掲載され、その表紙を飾り、9月15日付の朝日新聞（全国版 科学欄）など複数のマスメディアで取り上げられた。

２）病態時の適応回路シフト（脳梗塞モデルマウスを用いた解析）：申請者は、障害脳神経回路の機能的再建を果たすために、“病態時の適応回路シフト”の基盤となる遺伝子について、RNA-Seq解析を用いて網羅的に探索した。その結果、脳梗塞マウスにおいて、梗塞直後にその発現が変動する27個の候補遺伝子が得られた。興味深いことに、転写因子Npas4がその解析リストの最上位にあったので更に解析を進めたところ、Npas4欠損マウスは中大脳動脈閉塞手術により、梗塞巣のサイズが顕著に増大し、予後の運動機能も増悪化することを見出した。以上の結果から、脳梗塞に伴う“病態時の適応回路シフト”において、Npas4は重要な役割を果たすことが示唆されたので、今後もさらなる解析を進める。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] The University of Manchester(United Kingdom)
• [Int'l Joint Research] University of Manchester(United Kingdom)
• [Int'l Joint Research] Kantonsspital Aarau(Switzerland)
• [Journal Article] Olfactory Habituation-dishabituation Test (Mouse) (2017)
  • Author(s): Takahashi H and Tsuboi A
  • Journal Title: Bio-Protocol Volume: 7 Issue: 5
  • DOI: 10.21769/bioprotoc.2154
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Olfactory Avoidance Test (Mouse) (2017)
  • Author(s): Takahashi H and Tsuboi A
  • Journal Title: Bio-Protocol Volume: 7 Issue: 5 Pages: 8210-8227
  • DOI: 10.21769/bioprotoc.2153
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Transcription factor Npas4 regulates the development of dendritic spines in newborn olfactory bulb interneurons depending on sensory experience (2016)
  • Author(s): 吉原誠一，坪井昭夫
  • Journal Title: 生化学 Volume: 88 Issue: 2 Pages: 220-224
  • DOI: 10.14952/SEIKAGAKU.2016.880220
  • NAID: 40020843392
  • ISSN: 0037-1017
  • Year and Date: 2016-04-25
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A subtype of olfactory bulb interneurons is required for odor detection and discrimination behaviors (2016)
  • Author(s): Takahashi H, Ogawa Y, Yoshihara S, Asahina R, Kinoshita M, Kitano T, Kitsuki M, Tatsumi K, Okuda M, Tatsumi K, Wanaka A, Hirai H, Stern PL and Tsuboi A
  • Journal Title: The Journal of Neuroscience Volume: 36 Issue: 31 Pages: 8210-8227
  • DOI: 10.1523/jneurosci.2783-15.2016
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Distorted coarse axon targeting and reduced dendrite connectivity underlie dysosmia after olfactory axon (2016)
  • Author(s): Murai A, Iwata R, Fujimoto S, Aihara S, Tsuboi A, Muroyama Y, Saito T, Nishizaki K and Imai T
  • Journal Title: eNeuro Volume: 3 Issue: 5 Pages: 1-13
  • DOI: 10.1523/eneuro.0242-16.2016
  • Peer Reviewed / Open Access
• [Journal Article] 嗅球介在ニューロンのサブタイプが匂いの検出と識別という嗅覚行動に必須な役割を果たす (2016)
  • Author(s): 高橋弘雄、坪井昭夫
  • Journal Title: AROMA RESEARCH Volume: 17 Pages: 336-337
  • Peer Reviewed
• [Journal Article] Evaluation of a filament perforation model for mouse subarachnoid hemorrhage using 7.0 Tesla MRI (2016)
  • Author(s): Muroi C, Kashiwagi Y, Rokugawa T, Tonomura M, Obata A, Nevzati E, Tsuboi A, Okuchi K, Mishima K, Abe K, Fujioka M
  • Journal Title: J Clin Neurosci. Volume: 28 Pages: 141-147
  • DOI: 10.1016/j.jocn.2015.10.045
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Molecular mechanisms regulating the dendritic development of newborn olfactory bulb interneurons in a sensory experience-dependent manner. (2016)
  • Author(s): Yoshihara S, Takahashi H and Tsuboi A.
  • Journal Title: Frontiers in Neuroscience Volume: 9 Pages: 514-514
  • DOI: 10.3389/fnins.2015.00514
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Supersensitive odor discrimination is controlled in part by initial transient interactions between the most sensitive dorsal olfactory receptors and G-proteins (2016)
  • Author(s): Sato T, Kobayakawa R, Kobayakawa K, Emura M, Itohara S, Kawasaki T, Tsuboi A, Matsumura H
  • Journal Title: Receptors & Clinical Investigation Volume: 3
  • DOI: 10.14800/rci.1117
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Supersensitive detection and discrimination of enantiomers by dorsal olfactory receptors: evidence for hierarchical odour coding (2015)
  • Author(s): Sato T, Kobayakawa R, Kobayakawa K, Emura M, Itohara S, Kizumi M, Hamana H, Tsuboi A, Hirono J
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 14073-14073
  • DOI: 10.1038/srep14073
  • Peer Reviewed / Open Access
• [Journal Article] 嗅覚系におけるCO2センシングの分子機構 (2015)
  • Author(s): 高橋弘雄，坪井昭夫
  • Journal Title: におい・かおり環境学会誌 Volume: 46 Pages: 209-217
  • NAID: 130007602381
  • Peer Reviewed
• [Presentation] Neural activity-dependent transcription factor Npas4 plays a crucial role in neuroprotection and survival after ischemic stroke (2017)
  • Author(s): Tsuboi A, Asahina R, Yoshihara S and Takahashi H
  • Organizer: Cortical Development Conference 2017
  • Place of Presentation: Chania, Crete, Greece
  • Year and Date: 2017-05-17
  • Int'l Joint Research
• [Presentation] Neural activity-induced transcription factor Npas4 is required for neuroprotection and survival after stroke (2017)
  • Author(s): Takahashi H, Asahina R, Kitano T, Yoshihara S and Tsuboi A
  • Organizer: Keystone Symposia: Neurogenesis during Development and in the Adult Brain
  • Place of Presentation: Olympic Valley, CA, USA
  • Year and Date: 2017-01-08
  • Int'l Joint Research
• [Presentation] Neural activity-induced transcription factor Npas4 is required for neuroprotection and survival after stroke (2016)
  • Author(s): Takahashi H, Asahina R, Kitano T, Yoshihara S and Tsuboi A
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
• [Presentation] A specific subtype of newborn olfactory bulb interneurons is required for behaviors on odor detection and discrimination (2016)
  • Author(s): Takahashi H, Yoshihara S, Ogawa Y, Asahina R, Kitano T and Tsuboi A
  • Organizer: 第39回日本神経科学会大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-07-20
• [Presentation] A specific subtype of olfactory bulb interneurons is necessary for odor detection and odor-background segregation (2016)
  • Author(s): Takahashi H, Yoshihara S, Ogawa Y, Asahina R, Kitano T and Tsuboi A
  • Organizer: The 17th International Symposium on Olfaction and Taste (ISOT XVII)
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-06-05
  • Int'l Joint Research
• [Presentation] A specific subtype of olfactory bulb interneurons is necessary for odor detection and odor-background segregation (2016)
  • Author(s): Takahashi H, Yoshihara S, Ogawa Y, Asahina R, Kitano T, Tsuboi A
  • Organizer: The 17th International Symposium on Olfaction and Taste (ISOT 2016)
  • Place of Presentation: Yokohama (Japan)
  • Year and Date: 2016-06-05
  • Int'l Joint Research / Invited
• [Presentation] A specific subtype of newborn interneurons in the olfactory bulb is required for behaviors on odor detection and discrimination (2016)
  • Author(s): Takahashi H, Yoshihara S, Ogawa Y, Asahina R, Kinoshita M, Tsuboi A
  • Organizer: Conference on Neurogenesis 2016: Implications for Lifelong Development and Disease
  • Place of Presentation: Cancun (Mexico)
  • Year and Date: 2016-03-02
  • Int'l Joint Research
• [Presentation] A specific subtype of adult-born interneurons in the olfactory bulb is required for behaviors on odor detection and discrimination (2015)
  • Author(s): Tsuboi A, Yoshihara S, Ogawa Y, Asahina R, Kinoshita M, Takahashi H
  • Organizer: Current Trends in Biomedicine 2015: Development and Adult Neurogenesis in the Central Nervous System
  • Place of Presentation: Baeza (Spain)
  • Year and Date: 2015-10-05
  • Int'l Joint Research / Invited
• [Presentation] A specific subtype of newborn interneurons in the olfactory bulb play a crucial role in odor detection and discrimination (2015)
  • Author(s): Tsuboi A, Takahashi H, Yoshihara S, Ogawa Y, Stern PL
  • Organizer: The 2015 Bridging Biomedical Worlds Symposium: From Neural Circuitry to Neurotechnology
  • Place of Presentation: Tokyo (Japan)
  • Year and Date: 2015-05-11
  • Int'l Joint Research
• [Book] Electroporation Methods in Neuroscience (Neuromethods) (2015)
  • Author(s): Takahashi H, Yoshihara S, Asahina R, Tamada Y, Tsuboi A
  • Total Pages: 11
  • Publisher: Springer
• [Book] Handbook of Olfaction and Gustation, Third Edition (2015)
  • Author(s): Tsuboi A, Sakano H
  • Total Pages: 10
  • Publisher: Wiley-Blackwell
• [Remarks] 脳神経システム医科学HP
  • URL: http://www.naramed-u.ac.jp/~amrc-lab1/
• [Remarks] 奈良県立医科大学 > 先端医学研究機構 > 脳神経システム医科学
  • URL: http://www.naramed-u.ac.jp/university/subject_and_department_j/advanced_medical_research_center/noushinkei.html
• [Remarks] お知らせ 「においを感じる度合いを調節する神経メカニズムを世界で初めて解明！」
  • URL: http://www.naramed-u.ac.jp/university/kanrenshisetsu/sangakukan/oshirase.html
• [Remarks] ＨＯＭＥ（脳神経システム医科学）
  • URL: http://www.naramed-u.ac.jp/~amrc-lab1/