Abstract
DEET (N,N-diethyl-meta-toluamide) is a synthetic chemical, identified by the United States Department of Agriculture in 1946 in a screen for repellents to protect soldiers from mosquito-borne diseases1,2. Since its discovery, DEET has become the world’s most widely used arthropod repellent3, and is effective against many invertebrates, including biting flies4, honeybees5, ticks6, and land leeches4,7. In insects, DEET acts on the olfactory system5,8-14 and requires the olfactory receptor co-receptor orco9,11-13, but its specific mechanism of action remains controversial. Here we show that the nematode Caenorhabditis elegans is sensitive to DEET, and use this genetically-tractable animal to test repellent hypotheses from insects to understand how this synthetic compound is able to affect the behaviour of invertebrates separated by millions of years of evolution. We found that DEET is not a volatile repellent, but interfered selectively with chemotaxis to a variety of attractant and repellent molecules, and induced pausing to disrupt chemotaxis to some odours but not others. In a forward genetic screen for DEET-resistant animals, we identified a single G-protein-coupled receptor, str-217, which is expressed in a single pair of DEET-responsive chemosensory neurons, ADL. Both engineered str-217 mutants and a wild isolate of C. elegans carrying a deletion in str-217 are DEET-resistant. DEET interferes with behaviour in an odour-selective manner by inducing an increase in average pause length during chemotaxis and exploration, and this increase in pausing requires both str-217 and ADL neurons. Finally, we found that ADL neurons are activated by DEET and that optogenetic activation of ADL increased average pause length. This is consistent with the “confusant” hypothesis, in which DEET is not a simple repellent but modulates multiple olfactory pathways to scramble the behavioural response to otherwise attractive stimuli12,13. Our results suggest a consistent motif for the effectiveness of DEET across widely divergent taxa: an effect on multiple chemosensory neurons to disrupt the pairing between odorant stimulus and behavioural response.