Innate fear odor orchestrate survival fate in mice

• Project/Area Number: 18K19350
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 44:Biology at cellular to organismal levels, and related fields
• Research Institution: Kansai Medical University
• Principal Investigator: KOBAYAKAWA Ko 関西医科大学, 医学部, 准教授 (60466802)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 抗炎症 / 免疫強化 / 低酸素抵抗性 / 危機応答 / 先天的恐怖 / チアゾリン類恐怖臭 / 生命保護 / 情動 / 嗅覚 / 低体温 / 低代謝 / 脳梗塞 / 心筋梗塞

Outline of Final Research Achievements

Therapeutic hypothermia protects the brain after cardiopulmonary arrest. Innate fear has evolved to orchestrate protective effects in life-threatening situations. Thus, strong fear perception may induce a specialized life-protective metabolism based on hypothermia/hypometabolism; however, such phenomena and their inducers are yet to be elucidated. Here, we report that thiazoline-related fear odors (tFOs), which are TRPA1 agonists and induce robust innate fear in mice, induced hibernation-like systemic hypothermia/hypometabolism, accelerated glucose uptake in the brain, and suppressed aerobic metabolism via phosphorylation of pyruvate dehydrogenase, thereby enabling long-term survival in a lethal hypoxic environment.

Academic Significance and Societal Importance of the Research Achievements

免疫機能全般が抑制される冬眠状態とは対照的に、tFO刺激は、抗低酸素能力に加え、自然免疫の強化と抗炎症作用の同時誘導を基盤とする危機応答免疫状態を誘導した。これら危機応答の統合により、皮膚および脳の虚血・再灌流障害モデルにおいて強力な治療効果が発揮された。さらに、全脳マッピングと薬理遺伝学により、tFOの感覚刺激情報は脳幹Sp5/NSTから中脳PBN経路へ接続する経路により生命保護作用を誘導することが明らかになった。TFOによって誘発された強い危機知覚は、低体温、低代謝、危機免疫を特徴とする危機対応モードに代謝を移行させ、潜在的な生命保護効果を最大化させる。本発見は革新的医療に応用できる。

Research Products

• [Int'l Joint Research] NIBS(中国)
• [Journal Article] Thiazoline-related TRPA1 agonist odorants orchestrate survival fate in mice. (2020)
  • Author(s): Matsuo T, Isosaka T, Tang L, Soga T, Kobayakawa R, Kobayakawa K.
  • Journal Title: bioRxiv Volume: -
  • DOI: 10.1101/2020.05.17.100933
  • Open Access
• [Journal Article] Spontaneous activity generated within the olfactory bulb establishes the discrete wiring of mitral cell dendrites (2019)
  • Author(s): Satoshi Fujimoto, Marcus N. Leiwe, Richi Sakaguchi, Yuko Muroyama, Reiko Kobayakawa, Ko Kobayakawa, Tetsuichiro Saito, Takeshi Imai
  • Journal Title: bioRxiv Volume: －
  • DOI: 10.1101/625616
  • Open Access / Int'l Joint Research
• [Journal Article] Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors (2018)
  • Author(s): Wang, Y., Cao, L., Lee, C-Y., Matsuo, M., Wu, K., Asher, G., Saitoh, T., Klewe-Nebenius, D., Wang, L., Soya, S., Hasegawa, E., Cherasse, Y., Miyoshi,C., Irukayama, Y., Wang, Z., Sakurai, K., Funato, H., Sakurai, T., Yanagisawa, M., Nagase, H., Kobayakawa, R., Kobayakawa, K., Beutler, B., Liu, Q
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 2041-2041
  • DOI: 10.1038/s41467-018-04324-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] nnate fear odors elicit a physiological crisis mode that promotes survival in life-threatening situations (2020)
  • Author(s): Ko Kobayakawa
  • Organizer: 第10回武田科学振興財団 薬科学シンポジウム
  • Int'l Joint Research / Invited
• [Presentation] Sensory TRPA1 activation by thiazoline-related odorants orchestrate life-protective effects (2019)
  • Author(s): Ko Kobayakawa
  • Organizer: 生理学研究所2019年度国際研究集会「Pain and Survival Strategy」
  • Int'l Joint Research / Invited
• [Presentation] 先天的恐怖誘導性危機応答モードによる生命保護 (2018)
  • Author(s): 小早川 高
  • Organizer: 生理研研究会『感覚免疫学研究会』
  • Invited
• [Presentation] 先天的と後天的な行動制御メカニズムとその生理学的意義 (2018)
  • Author(s): 小早川 高
  • Organizer: 第１１回北陸合同バイオシンポジウム
  • Invited
• [Presentation] Innate fear odors orchestrate life-or-death effects in mice. (2018)
  • Author(s): 小早川 高
  • Organizer: 遺伝研研究会「Circuit construction in the mammalian brain (哺乳類脳の機能的神経回路の構築メカニズム)」
  • Invited