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Combinatorial Effects of Odorants on Mouse Behavior PNAS PLUS Combinatorial effects of odorants on mouse behavior PNAS PLUS Luis R. Saraivaa,1, Kunio Kondoha, Xiaolan Yea, Kyoung-hye Yoona,2, Marcus Hernandeza,3, and Linda B. Bucka,4 aHoward Hughes Medical Institute, Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 Contributed by Linda B. Buck, April 14, 2016 (sent for review February 28, 2016; reviewed by Trese Leinders-Zufall and Lisa Stowers) The mechanisms by which odors induce instinctive behaviors are or combination of receptors has a high probability of eliciting a largely unknown. Odor detection in the mouse nose is mediated by specific response. Their similarity among individuals also suggests >1, 000 different odorant receptors (ORs) and trace amine-associated that these responses may be immune to other olfactory inputs. For receptors (TAARs). Odor perceptions are encoded combinatorially by example, whereas changes in the combination of activated ORs can ORs and can be altered by slight changes in the combination of acti- change a perceived odor, predator odor activation of a particular vated receptors. However, the stereotyped nature of instinctive odor receptor may induce instinctive aversive behavior regardless of what responses suggests the involvement of specific receptors and geneti- other receptors are simultaneously activated by other odorants in cally programmed neural circuits relatively immune to extraneous odor the environment. One receptor in the vomeronasal organ has been stimuli and receptor inputs. Here, we report that, contrary to expecta- linked to mating behavior (33). However, the only nasal receptors tion, innate odor-induced behaviors can be context-dependent. First, demonstrated to play a role in innate odor responses thus far are the different ligands for a given TAAR can vary in behavioral effect. Sec- two mouse TAARs mentioned above (22, 23), suggesting that fur- ond, when combined, some attractive and aversive odorants neutralize ther study of the TAAR family could provide added insight into the one another’s behavioral effects. Both a TAAR ligand and a common mechanisms underlying innate odor responses. odorant block aversion to a predator odor, indicating that this ability is Here, we initially set out to investigate whether other mouse notuniquetoTAARsandcanextendtoanaversiveresponseofpo- TAARs might also induce attraction or aversion. We conducted a tential importance to survival. In vitro testing of single receptors with high-throughput screen to identify additional mouse TAAR ligands binary odorant mixtures indicates that behavioral blocking can occur and then tested individual ligands for the ability to cause attractive without receptor antagonism in the nose. Moreover, genetic ablation or aversive behavior in mice. Many, but not all, TAAR ligands of a single receptor prevents its cognate ligand from blocking predator elicited attraction or aversion. However, different ligands for the odor aversion, indicating that the blocking requires sensory input same TAAR often had different effects. Even for a TAAR known NEUROSCIENCE from the receptor. Together, these findings indicate that innate to be involved in innate attraction, one ligand could be attractive odor-induced behaviors can depend on context, that signals from and another one neutral, despite similar affinity interactions with a single receptor can block innate odor aversion, and that instinctive the receptor. One potential explanation was that innate behavioral behavioral responses to odors can be modulated by interactions in responses to odors can be context-dependent and influenced by the the brain among signals derived from different receptors. combination of receptors activated by an odorant. Consistent with this model, some attractive and aversive odorants blocked each olfaction | behavior | TAAR | odorants Significance he mammalian olfactory system detects a multitude of volatile chemicals perceived as odors as well as social cues that elicit T Odor detection in the mouse nose is mediated by ∼1,000 different instinctive behaviors (1–3). The olfactory epithelium of the mouse odorant receptors (ORs) and 14 trace amine-associated receptors contains ∼1,000 different ORs and 14 trace amine-associated re- (TAARs). Different OR combinations generate different odor per- ceptors (TAARs), each expressed by a different subset of olfactory ceptions. However, a few TAARs are associated with innate odor sensory neurons (4–13). An accessory olfactory structure, the vom- attraction or aversion, suggesting they signal through hard-wired eronasal organ, also detects social cues but using different receptors neural circuits resistant to combinatorial receptor inputs. Contrary (1–3). ORs are used in a combinatorial fashion to detect structurally to this prediction, we find that different ligands for a given TAAR diverse odorants, allowing the discrimination of myriad odorants as can be attractive or aversive, or instead neutral. In addition, some having different scents (7, 14). attractive and aversive odorants block one another’s behavioral Like ORs, TAARs are evolutionarily conserved in vertebrates effects. Odor blocking can occur without receptor antagonism in (15–17), suggesting that TAARs may have a distinct function. the nose and can require sensory input from one receptor. Thus, Moreover, sensory neurons expressing TAARs appear to comprise – innate odor-induced behaviors can be context-dependent and a separate lineage (18 20), and genes encoding ORs and TAARs modulated by interactions in the brain among signals derived have different nuclear locations (20), which may contribute to from different receptors. TAARs’ segregated expression in different neurons. At least some TAARs specifically recognize volatile amines, and two are required Author contributions: L.R.S. and L.B.B. designed research; L.R.S., K.K., K.-h.Y., and M.H. for behavioral attraction or avoidance to animal-derived amines (10, performed research; L.R.S., K.K., and X.Y. analyzed data; and L.R.S., K.K., and L.B.B. wrote 21–23). In addition, one zebrafish TAAR ligand is aversive to fish the paper. (24), and one human TAAR detects an odorant aversive to humans Reviewers: T.L.-Z., University of Saarland School of Medicine; and L.S., Scripps as well as rotten fish (17, 25, 26). These observations have raised the Research Institute. possibility that the TAAR family may have an evolutionarily con- The authors declare no conflict of interest. served ability to induce innate responses, particularly aversion. Al- Freely available online through the PNAS open access option. 1 ternatively, or in addition, TAAR conservation could derive from Present address: Experimental Genetics Division, Sidra Medical and Research Center, Out- Patient Clinic, Qatar Foundation, Doha, Qatar. an ability for high-sensitivity detection of amines (23). 2Present address: Division of Biological Science and Technology, Yonsei University, Wonju, In mice, attractive and aversive responses can be either learned by 26493, South Korea. association with other attractive or aversive stimuli or innate. Innate 3Present address: Clinical Clerkship Program, American University of Antigua, New York, odor responses, such as aversive responses to predator odors (3, 21, NY 10004. – 23, 27 32), are similar among individuals. The stereotyped nature of 4To whom correspondence should be addressed. Email: [email protected]. these responses suggests the existence of genetically determined This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. neural circuits in which olfactory sensory input from a given receptor 1073/pnas.1605973113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1605973113 PNAS Early Edition | 1of7 Downloaded by guest on September 24, 2021 other’s behavioral effects. In vitro studies of ligand–receptor in- odorants activated one to six TAARs, and, consistent with previous teractions and behavioral studies of receptor knockout (KO) mice findings (10, 34), some TAARs responded to more than one odorant. indicated that the observed blocking effects can occur without re- ceptor antagonism in the nose and can require sensory input from Numerous TAAR Ligands, as Well as Other Odorants, Induce Innate Attraction or Aversion. We next examined individual TAAR ligands a single receptor. for the ability to stimulate attractive or aversive behavior in naïve Results male mice. We used the olfactory preference test, which measures whether animals spend significantly more time investigating filter Identification of Additional TAAR Ligands. We first sought to identify paper containing an odorant versus water (attraction) or signifi- additional mouse TAAR ligands beyond the small number already cantly less time (aversion) (30). Strikingly, over half of TAAR li- known (10, 34). To this end, we conducted a high-throughput gands tested (10 of 19) induced a behavioral response, including chemical screen for TAAR activators using TAARs expressed in- three previously reported to do so (Fig. 1B and Fig. S2)(21–23). dividually in HEK293 tissue culture cells (Fig. 1A and Fig. S1). We Seven ligands stimulated attraction, and three caused aversion. identified 16 additional TAAR agonists, all volatile amines. Single Aversion to the latter three ligands was also seen using an innate A C M1P EC50 +MEN *** OTHER DMB (μM) BZL *** DMO >500 CAM *** ODORANTS DMC 101-500 IPT *** ANI 51-100 ROX *** 2MB 11-50 HXT ** NMP ≤10 HXA *** AEP IBT *** HEP HXO ** +FCH ** OCT HPO PEA ** -FCH ** Odorant AST TMT ** IAA +LIM ** TMA 2PT * DME BFA
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