Elucidate the molecular mechanisms of innate fear and its relation to mental disorders

• Project/Area Number: 17K08133
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Integrative animal science
• Research Institution: University of Tsukuba
• Principal Investigator: Cao Liqin 筑波大学, 国際統合睡眠医科学研究機構, 助教 (60399475)
• Co-Investigator(Kenkyū-buntansha): クレウエ・ネベニウス ダニエラ 筑波大学, 国際統合睡眠医科学研究機構, 研究員 (60737667)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 先天的恐怖 / 恐怖感情 / 精神疾患

Outline of Final Research Achievements

Irrational fears are linked to a variety of mental illnesses. However, the molecular mechanisms of fear remain largely unknown. To this end, we conducted a novel predator odor-based “innate fear” forward genetic screen of ethylnitrosourea (ENU)-mutagenized mice, and identified a recessive mutation in Trpa1 gene that led to diminished innate fear responses and a dominant mutation that led to an abnormal fear response, jumping phenotype (hence named Popcorn mutant), upon predator odor exposure. By using a host of biochemical, cellular, neuroscience and behavior assays, we demonstrated that Trpa1 functions as a novel chemosensor for predator odors and Trpa1-expressing trigeminal ganglion (TG) neurons contribute critically to predator odor-evoked innate fear/defense behaviors. We found that Popcorn mutation causes schizophrenia-like behaviors in mice.

Academic Significance and Societal Importance of the Research Achievements

We established the first forward genetics screen to uncover the molecular mechanism of fear, a basic emotion that is inextricably linked with mental health. The results have the potential to contribute greatly to developing medicines and therapeutic interventions for fear-related mental disorders.

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] Characterization of sleep architecture in CDKL5 knockout mice (2019)
  • Author(s): Liqin Cao, Jing Ma, Tingting Lou, Zhiqiang Wang, Qinghua Liu
  • Organizer: The 8th Annual IIIS Symposium
  • Int'l Joint Research
• [Presentation] Sleep architecture in CDKL5 KO mouse (2019)
  • Author(s): Liqin Cao
  • Organizer: 2019 CDKL5 Forum
  • Int'l Joint Research / Invited
• [Presentation] Sleep disruptions in CDKL5 knockout mice (2019)
  • Author(s): Liqin Cao
  • Organizer: CDKL5 ASIA Workshop 2019
  • Int'l Joint Research / Invited
• [Presentation] Identifying schizophrenia genes through a forward genetic screen in mice (2019)
  • Author(s): Liqin Cao, Daniela Klewe-Nebenius, Greg Asher, Takeshi Sakurai, Chika Miyoshi, Hiromasa Funato, Masashi Yanagisawa, Qinghua Liu
  • Organizer: Neuro2019
  • Int'l Joint Research
• [Presentation] Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors (2019)
  • 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
  • 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): 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
  • Organizer: The 7th Annual IIIS International Symposium
  • Int'l Joint Research