Elucidation of life-protective effects induced by innate fear odor

• Project/Area Number: 18H02546
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 46030:Function of nervous system-related
• Research Institution: Kansai Medical University
• Principal Investigator: KOBAYAKAWA Reiko 関西医科大学, 医学部, 教授 (40372411)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 先天的恐怖 / 生命保護作用 / チアゾリン類恐怖臭 / 低体温 / 低代謝 / 低酸素抵抗性 / Trpa1 / 情動 / 嗅覚

Outline of Final Research Achievements

Innate fear intimately connects to the life preservation in crises, although this relationships is not fully understood. Here, we elucidated that presentation of a supernormal innate fear inducer 2-methyl-2-thiazoline (2MT), but not learned fear stimuli, induced robust systemic hypothermia/hypometabolism and suppressed aerobic metabolism via phosphorylation of pyruvate dehydrogenase, thereby enabling long-term survival in a lethal hypoxic environment. These responses exerted potent therapeutic effects in cutaneous and cerebral ischemia/reperfusion injury models. In contrast to hibernation, 2MT stimulation accelerated glucose uptake in the brain and suppressed oxygen saturation in the blood. Whole-brain mapping and chemogenetic activation revealed that the sensory representation of 2MT orchestrates physiological responses via brain stem Sp5/NST to midbrain PBN pathway. 2MT, as a supernormal stimulus of innate fear, induced exaggerated, latent life-protective effects in mice.

Academic Significance and Societal Importance of the Research Achievements

本研究により、先天的恐怖を誘発する超正常刺激である2MTは、マウスにおいて非常に強力な潜在的な生命保護効果を誘発し、複数の疾患モデルにおいて治療効果を持つことが明らかになった。このシステムがヒトにも保存されていれば、匂いによって潜在的な生命保護作用を引き起こす「感覚創薬」という全く新しい創薬が可能になると考えられる。

Research Products

• [Int'l Joint Research] NIBS(中国)
• [Journal Article] Artificial hibernation/life-protective state induced by thiazoline-related innate fear odors (2021)
  • Author(s): Matsuo Tomohiko、Isosaka Tomoko、Tang Lijun、Soga Tomoyoshi、Kobayakawa Reiko、Kobayakawa Ko
  • Journal Title: Communications Biology Volume: 4 Issue: 1 Pages: 101-101
  • DOI: 10.1038/s42003-020-01629-2
  • Peer Reviewed / Open Access
• [Journal Article] Thiazoline-related innate fear stimuli orchestrate hypothermia and anti-hypoxia via sensory TRPA1 activation (2021)
  • Author(s): Matsuo Tomohiko、Isosaka Tomoko、Hayashi Yuichiro、Tang Lijun、Doi Akihiro、Yasuda Aiko、Hayashi Mikio、Lee Chia-Ying、Cao Liqin、Kutsuna Natsumaro、Matsunaga Sachihiro、Matsuda Takeshi、Yao Ikuko、Setou Mitsuyoshi、Kanagawa Dai、Higasa Koichiro、Ikawa Masahito、Liu Qinghua、Kobayakawa Reiko、Kobayakawa Ko
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 2074-2074
  • DOI: 10.1038/s41467-021-22205-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Large-scale calcium imaging with a head-mount axial scanning 3D fluorescence microscope (2021)
  • Author(s): Hayashi Yuichiro、Kobayakawa Ko、Kobayakawa Reiko
  • Journal Title: bioRxiv Volume: -
  • DOI: 10.1101/2021.01.20.427512
  • 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] 人工冬眠・生命保護作用を誘導する匂い分子の発見とその作動機序 (2020)
  • Author(s): 小早川令子
  • Organizer: 第4回 感覚研究フロンティアシンポジウム
  • Invited
• [Presentation] Cerebral and systemic integration mechanisms to elicit the crisis-response state. (2019)
  • Author(s): Reiko Kobayakawa
  • Organizer: 第４2回日本神経科学大会
  • Int'l Joint Research / Invited
• [Presentation] 先天的と後天的な恐怖の統合メカニズムとその生物学的意義 (2019)
  • Author(s): 小早川 令子
  • Organizer: 第９２回日本生化学会大会
  • Invited
• [Presentation] Sensory representations and integrational processing for innate versus learned olfacoty behaviors and beyond. (2018)
  • Author(s): Reiko Kobayakawa
  • Organizer: 第４１回日本神経科学大会
  • Int'l Joint Research