High-affinity olfactory receptor for the death-associated odor cadaverine

Abstract

Carrion smell is strongly repugnant to humans and triggers distinct innate behaviors in many other species. This smell is mainly carried by two small aliphatic diamines, putrescine and cadaverine, which are generated by bacterial decarboxylation of the basic amino acids ornithine and lysine. Depending on the species, these diamines may also serve as feeding attractants, oviposition attractants, or social cues. Behavioral responses to diamines have not been investigated in zebrafish, a powerful model system for studying vertebrate olfaction. Furthermore, olfactory receptors that detect cadaverine and putrescine have not been identified in any species so far. Here, we show robust olfactory-mediated avoidance behavior of zebrafish to cadaverine and related diamines, and concomitant activation of sparse olfactory sensory neurons by these diamines. The large majority of neurons activated by low concentrations of cadaverine expresses a particular olfactory receptor, trace amineassociated receptor 13c (TAAR13c). Structure-activity analysis indicates TAAR13c to be a general diamine sensor, with pronounced selectivity for odd chains of medium length. This receptor can also be activated by decaying fish extracts, a physiologically relevant source of diamines. The identification of a sensitive zebrafish olfactory receptor for these diamines provides a molecular basis for studying neural circuits connecting sensation, perception, and innate behavior.Danio rerio | aversion | heterologous expression | polyamines C adaverine, putrescine, and other biogenic diamines are strongly repulsive odors to humans, for whom these odors presumably signal bacterial contamination. It may be expected that animal species feeding on carcasses attribute a more positive valence to diamines, and indeed both putrescine and cadaverine have been reported to be feeding attractants for rats (1) as well as goldfish (2). Similarly, insects depositing their eggs in carcasses or other proteineacous materials are attracted by these diamines (3). Beyond signaling danger or food, putrescine and cadaverine also serve as social cues in several vertebrate species, both for marking of territories-for example, in feline species (4)-and for burial of conspecifics (5).Very little is known about the molecular and cellular basis of cadaverine-driven behaviors. Cadaverine and putrescine evoke electrophysiological responses in the olfactory epithelium of two fish species (2, 6) and cadaverine-responsive olfactory sensory neurons and glomeruli have been identified in the mouse (7,8). However, chemosensory receptors that detect cadaverine or related diamines are unknown in any species, and could provide valuable tools to study how the olfactory system mediates innate aversion or attraction.Here, we show that cadaverine is a major product of zebrafish tissue decay, activates a zebrafish olfactory receptor (trace amineassociated receptor 13c, TAAR13c) with high affinity, and elicits a strong, low-threshold, and olfactory-mediated avoidance response in zebrafish. In vivo me...

Combinatorial effects of odorants on mouse behavior

“…Moreover, TMA-induced attraction required TAAR5 and PEA-induced aversion required TAAR4 (22,23). Together with the finding that individual fish and human TAARs recognize volatile amines aversive to those species (17,(24)(25)(26), these findings have suggested that the evolutionary conservation of the TAAR family may be linked to an ability to induce innate behaviors to volatile amines.…”

“…At least some TAARs specifically recognize volatile amines, and two are required for behavioral attraction or avoidance to animal-derived amines (10,(21)(22)(23). In addition, one zebrafish TAAR ligand is aversive to fish (24), and one human TAAR detects an odorant aversive to humans as well as rotten fish (17,25,26). These observations have raised the possibility that the TAAR family may have an evolutionarily conserved ability to induce innate responses, particularly aversion.…”

Olfactory receptor genes expressed in distinct lineages are sequestered in different nuclear compartments

“…Ligands found thus far for TAARs are volatile amines, including several in mouse or predator urine (5,14,15). Ligands for a few mouse, fish, and human TAARs elicit aversive or attractive behaviors in their respective species, hinting at a conserved ability of TAARs to stimulate innate responses of potentially adaptive significance (5,6,14,16,17).…”

Calcium neuroimaging in behaving zebrafish larvae using a turn-key light field camera

“…We stimulated the larvae with the odorant cadaverine (Cad, 10-μM solution), a diamine generated by decarboxylation of the amino acid lysine during decomposition of flesh, which is known to evoke olfactory-related neural activity and avoidance responses in zebrafish larvae. 19,20 Figure 2 shows three image planes through the volumetrically reconstructed light field dataset [ Fig. 2(a)], as well as a top-down maximum intensity projection [ Fig.…”

“…2(b')]. Clusters of activity could be found in the olfactory bulb (OB) and habenula (Hb), the latter considered to be involved in relaying odorevoked behavioral responses, 19,20 as well as in some neurons of the optic tectum (OT) [Figs. 2(b)-2(c)].…”