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

• 研究領域: 「意志動力学（ウィルダイナミクス）の創成と推進」に関する総合的研究
• 研究課題/領域番号: 17H06048
• 研究種目: 新学術領域研究(研究領域提案型)
• 配分区分: 補助金
• 審査区分: 複合領域
• 研究機関: 筑波大学
• 研究代表者: Liu Qinghua 筑波大学, 国際統合睡眠医科学研究機構, 教授 (90723792)
• 研究期間 (年度): 2017-04-01 – 2019-03-31
• 研究課題ステータス: 完了 (2018年度)
• 配分額: 9,100千円 (直接経費: 7,000千円、間接経費: 2,100千円); 2018年度: 4,550千円 (直接経費: 3,500千円、間接経費: 1,050千円); 2017年度: 4,550千円 (直接経費: 3,500千円、間接経費: 1,050千円)
• キーワード: 意志力 / 恐怖感情 / 恐怖

研究実績の概要

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.

現在までの達成度 (段落)

平成30年度が最終年度であるため、記入しない。

今後の研究の推進方策

平成30年度が最終年度であるため、記入しない。

研究成果

• [雑誌論文] Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors (2018)
  • 著者名/発表者名: 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
  • 雑誌名: Nature Communications 巻: 9 号: 1 ページ: 2041-2041
  • DOI: 10.1038/s41467-018-04324-3
  • 査読あり / オープンアクセス / 国際共著
• [雑誌論文] Quantitative phosphoproteomic analysis of the molecular substrates of sleep need (2018)
  • 著者名/発表者名: 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
  • 雑誌名: Nature 巻: 558 号: 7710 ページ: 435-439
  • DOI: 10.1038/s41586-018-0218-8
  • 査読あり / オープンアクセス / 国際共著
• [雑誌論文] Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors (2018)
  • 著者名/発表者名: Wang, Y., Cao, L., Lee, C-Y., et al.
  • 雑誌名: Nature Communications (accepted) 巻: -
  • 査読あり
• [学会発表] Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors (2019)
  • 著者名/発表者名: Yibing Wang, Liqin Cao, Chia-Ying Lee et al.
  • 学会等名: Keystone Symposia, Mammalian Sensory System (C4)
  • 国際学会
• [学会発表] Psycho, a potential mouse model of schizophrenia (2018)
  • 著者名/発表者名: Liqin Cao, Daniela Klewe-Nebenius, Greg Asher, Makito Sato, Chika Miyoshi, Hiromasa Funato, Masashi Yanagisawa, Qinghua Liu
  • 学会等名: The 7th Annual IIIS International Symposium
  • 国際学会
• [学会発表] Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors (2018)
  • 著者名/発表者名: Yibing Wang, Liqin Cao, Chia-Ying Lee et al.
  • 学会等名: The 7th Annual IIIS International Symposium
  • 国際学会