Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors

• Published in: Nature communications 2018-05, Vol.9 (1), p.2041-15, Article 2041
• Main Authors: Wang, Yibing, Cao, Liqin, Lee, Chia-Ying, Matsuo, Tomohiko, Wu, Kejia, Asher, Greg, Tang, Lijun, Saitoh, Tsuyoshi, Russell, Jamie, Klewe-Nebenius, Daniela, Wang, Li, Soya, Shingo, Hasegawa, Emi, Chérasse, Yoan, Zhou, Jiamin, Li, Yuwenbin, Wang, Tao, Zhan, Xiaowei, Miyoshi, Chika, Irukayama, Yoko, Cao, Jie, Meeks, Julian P., Gautron, Laurent, Wang, Zhiqiang, Sakurai, Katsuyasu, Funato, Hiromasa, Sakurai, Takeshi, Yanagisawa, Masashi, Nagase, Hiroshi, Kobayakawa, Reiko, Kobayakawa, Ko, Beutler, Bruce, Liu, Qinghua
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/106; 13/109; 13/44; 14; 14/1; 14/63; 38; 38/70; 42; 45; 45/23; 631/378/2583; 631/378/340; 96; Animals; Behavior, Animal - physiology; Brain; Chemical sensors; Chemoreceptors; Ethyl nitrosourea; Fear; Fear - physiology; Female; Footwear; Freezing; Genetic code; Genetics; Genotyping Techniques; Humanities and Social Sciences; Instinct; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular chains; Molecular modelling; multidisciplinary; Mutagenesis; Neurons - physiology; Nociception - physiology; Odorant receptors; Odorants; Odors; Pain perception; Pungent principles; Receptors; Science; Science (multidisciplinary); Skin; Smell; Smell - physiology; Thiazoles - chemistry; Thiazoline; Tonic immobility; Trigeminal ganglion; Trigeminal Ganglion - cytology; Trigeminal Ganglion - physiology; TRPA1 Cation Channel - physiology; Winter
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04324-3

Innate behaviors are genetically encoded, but their underlying molecular mechanisms remain largely unknown. Predator odor 2,4,5-trimethyl-3-thiazoline (TMT) and its potent analog 2-methyl-2-thiazoline (2MT) are believed to activate specific odorant receptors to elicit innate fear/defensive behaviors in naive mice. Here, we conduct a large-scale recessive genetics screen of ethylnitrosourea (ENU)-mutagenized mice. We find that loss of Trpa1, a pungency/irritancy receptor, diminishes TMT/2MT and snake skin-evoked innate fear/defensive responses. Accordingly, Trpa1 −/− mice fail to effectively activate known fear/stress brain centers upon 2MT exposure, despite their apparent ability to smell and learn to fear 2MT. Moreover, Trpa1 acts as a chemosensor for 2MT/TMT and Trpa1-expressing trigeminal ganglion neurons contribute critically to 2MT-evoked freezing. Our results indicate that Trpa1-mediated nociception plays a crucial role in predator odor-evoked innate fear/defensive behaviors. The work establishes the first forward genetics screen to uncover the molecular mechanism of innate fear, a basic emotion and evolutionarily conserved survival mechanism. TMT is a chemical that evokes innate defensive behaviors yet the molecular mechanisms are not well understood. Here the authors perform a large-scale forward genetics screen in mice and identify Trpa1, a pungency/irritancy receptor, as a chemosensor for predator odor-evoked innate fear and defensive behaviors.