新規恐怖反応異常マウスで切り拓く恐怖感情と意志力のダイナミクス

• Project Area: Creation and Promotion of the Will-Dynamics
• Project/Area Number: 17H06048
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: University of Tsukuba
• Principal Investigator: Liu Qinghua 筑波大学, 国際統合睡眠医科学研究機構, 教授 (90723792)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000); Fiscal Year 2018: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2017: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
• Keywords: 意志力 / 恐怖感情 / 恐怖

Outline of Annual Research Achievements

High willpower is essential to overcome difficulties and show higher performance in daily life activities. Fear is a basic emotion that impacts willpower by causing the “fight or flight” response or paralysis. However, the molecular and neural mechanisms underlying the cross-relationship between fear and willpower remain elusive. We developed a forward genetic screen, using a novel predator odor-evoked innate fear assay, to identify ethylnitrosourea (ENU)-mutagenized mice with abnormal fear behaviors. This screen identified a recessive mutant that exhibited “fearless” phenotype and a dominant mutant pedigree that exhibited stereotypic phenotype in the presence of predator odor.
We identified that the causative mutation responsible for “fearless” phenotype is a null mutation in Trpa1. We carried out a set of behavior tests, brain c-fos mapping, tissue-specific lesion, and AAV-Trpa1 virus injection to rescue fear behavior in Trpa1－/－ mice, and made novel findings that Trpa1 functions as a chemosensor for predator odor, and the trigeminal system besides olfactory plays important roles in predator odor-evoked innate fear behaviors. Our results are published in Nature Communications 9, 2041 (2018). For the dominant mutant pedigree, we performed a battery of behavior tests. The mutants exhibited “schizophrenia-like” phenotypes in these tests (herein named Psycho pedigree). Moreover, Psychom/+ mutants showed social withdrawal and anhedonia. Trpa1－/－ “fearless” mice and Psychom/+ mutants can be useful for studying antagonistic relationship between fear and will-power.

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [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
• [Journal Article] Quantitative phosphoproteomic analysis of the molecular substrates of sleep need (2018)
  • Author(s): Z. Wang, J. Ma, C. Miyoshi, Y. Li, M Sato, Y. Ogawa, T. Lou, C. Ma, X. Gao, C. Lee, T. Fujiyama, X. Yang, S. Zhou, N. Hotta-Hirashima, D. Klewe-Nebenus, A. Ikkyu, M. Kakizaki, S. Kanno, L. Cao, S. Takahashi, J. Peng, Y. Yu, H. Funato, M. Yanagisawa, Q. Liu
  • Journal Title: Nature Volume: 558 Issue: 7710 Pages: 435-439
  • DOI: 10.1038/s41586-018-0218-8
  • Peer Reviewed / 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., et al.
  • Journal Title: Nature Communications (accepted) Volume: -
  • Peer Reviewed
• [Presentation] Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors (2019)
  • Author(s): Yibing Wang, Liqin Cao, Chia-Ying Lee et al.
  • Organizer: Keystone Symposia, Mammalian Sensory System (C4)
  • Int'l Joint Research
• [Presentation] Psycho, a potential mouse model of schizophrenia (2018)
  • Author(s): Liqin Cao, Daniela Klewe-Nebenius, Greg Asher, Makito Sato, Chika Miyoshi, Hiromasa Funato, Masashi Yanagisawa, Qinghua Liu
  • Organizer: The 7th Annual IIIS International Symposium
  • Int'l Joint Research
• [Presentation] Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors (2018)
  • Author(s): Yibing Wang, Liqin Cao, Chia-Ying Lee et al.
  • Organizer: The 7th Annual IIIS International Symposium
  • Int'l Joint Research