TY - JOUR
T1 - Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors
AU - Wang, Yibing
AU - Cao, Liqin
AU - Lee, Chia Ying
AU - Matsuo, Tomohiko
AU - Wu, Kejia
AU - Asher, Greg
AU - Tang, Lijun
AU - Saitoh, Tsuyoshi
AU - Russell, Jamie L
AU - Klewe-Nebenius, Daniela
AU - Wang, Li
AU - Soya, Shingo
AU - Hasegawa, Emi
AU - Chérasse, Yoan
AU - Zhou, Jiamin
AU - Li, Yuwenbin
AU - Wang, Tao
AU - Zhan, Xiaowei
AU - Miyoshi, Chika
AU - Irukayama, Yoko
AU - Cao, Jie
AU - Meeks, Julian
AU - Gautron, Laurent
AU - Wang, Zhiqiang
AU - Sakurai, Katsuyasu
AU - Funato, Hiromasa
AU - Sakurai, Takeshi
AU - Yanagisawa, Masashi
AU - Nagase, Hiroshi
AU - Kobayakawa, Reiko
AU - Kobayakawa, Ko
AU - Beutler, Bruce A
AU - Liu, Qinghua
N1 - Funding Information:
We thank Drs. Y. Mori, R. Sakaguchi, M. Ding, T. Han, and J. Chen for sharing plasmids, Dr. Bart Carter for providing snake skin molts, and Drs. J. Cohen, H. Hu, and Y. Liu for comments on our manuscript. We acknowledge R. Potts, Y. Ogawa, W. Wang, T. Liang, H. Kim, and S. Kim for technical assistance. Q.L. is a W.A. “Tex” Moncrief Jr. Scholar in Biomedical Research. This work was supported by the National Institute of Health (GM111367 to Q.L.; R37GM067759 to B.B.), the Welch Foundation (I-1608 to Q.L.) and UT Southwestern Medical Center (High Impact/High Risk grant to Q.L.) as well as the Japan Society for the Promotion of Science (15K14874 and “Willdynamics” 17H06048 to Q.L.; 26220207 to M.Y., H.M.; 16H02591 to K.K.; 17K08133 to L.C.), the Japan Science and Technology Agency-step grant (AS271516U to K.K., R.K.), and the World Premier International Research Center Initiative (WPI) from MEXT, Japan.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-04324-3
DO - 10.1038/s41467-018-04324-3
M3 - Article
C2 - 29795268
AN - SCOPUS:85047428032
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2041
ER -