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

Nat Commun. 2018 May 23;9(1):2041. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / physiology*
  • Fear / physiology*
  • Female
  • Genotyping Techniques
  • Instinct*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutagenesis
  • Neurons / physiology
  • Nociception / physiology
  • Odorants
  • Smell / physiology*
  • TRPA1 Cation Channel / physiology*
  • Thiazoles / chemistry
  • Trigeminal Ganglion / cytology
  • Trigeminal Ganglion / physiology


  • TRPA1 Cation Channel
  • Thiazoles
  • Trpa1 protein, mouse
  • 2-methylthiazoline