Mammals, including humans, can detect tens of thousands of different odors. Odor perception is important not just to recall a memorable meal but also for survival, for instance, mammalian pups rely on olfaction to obtain their milk. The proteins that mediate olfactory perception are called odorant receptors (ORs); with mice possessing more than 1,000 of these receptors whereas humans have roughly 400. The discovery of ORs led to the award of the 2004 Nobel Prize in Physiology or Medicine to Fred Hutch investigator Dr. Linda Buck together with Dr. Richard Axel of Columbia University. The plot thickened in 2006 when Dr. Buck’s Laboratory (Basic Sciences Division) discovered a second class of 14 chemosensory receptors called trace amine-associated receptors (TAARs), with both ORs and TAARs being expressed in olfactory sensory neurons in the nose. Previous studies showed that a class of chemicals known as amines function as TAAR ligands, with two such amines being aversive odorants to either fish or humans. However, the full complement of TAAR ligands remains to be unraveled and it is unknown whether activation of other mouse TAARs leads to innate aversion or attraction. A new study by the Buck Lab led by former postdoctoral fellow Dr. Luís Saraiva (now at Sidra Medical and Research Center, Qatar) not only carried out a high-throughput screen to identify additional TAAR ligands but also tested TAAR ligands as well as other odorants for their ability to induce either attractive or aversive innate behavior. This study was published in Proceedings of the National Academy of Sciences.
To identify additional TAAR ligands, the authors tested a library of chemicals for activation of each one of the 14 individual mouse TAARs expressed in tissue culture cells (HEK293). This screen uncovered 16 additional TAAR ligands. Next, the scientists used the olfactory preference test, which measures the time animals spend investigating filter paper containing either an odorant or water, to examine the ability of individual TAAR ligands to elicit attractive or aversive behavior. 10 out of the 19 ligands, as well as 28 out of 54 odorants belonging to diverse odorant classes, stimulated either attraction or aversion. Intriguingly, the behavior elicited by ligands for the same individual TAAR varied, as different ligands could be attractive, aversive or neutral for two TAARs. One well-described ligand-TAAR interaction is innate attraction caused by activation of TAAR5 by its cognate ligand trimethylamine (TMA). To test whether context-dependent function of ligands is due to the specific constellation of ORs and TAAR that may be activated by a given ligand, the authors tested binary combinations of attractive and aversive odorants. Strikingly, TMA blocked aversion both to the fear-inducing predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) and the TAAR ligand 2-phenylethylamine (PEA). However, because PEA blocks attraction to TMA without affecting TMA-mediated activation of TAAR5, the authors concluded that the behavioral blocking effects happen in the brain, rather than in the nose. Finally, by examining mice that lacked the Taar5 gene, the investigators found that Taar5 is required for TMA to block aversion to TMT. In summary, a high-throughput screen identified several novel TAAR ligands as well as known odorants that evoke either attraction or aversion in an olfactory preference test. Moreover, the observed behavioral effects are likely to be innate, as the animals were not previously exposed to either TAAR ligands or odorants. "In this study, we were surprised to find that that different ligands for the same chemosensory receptor in the nose can elicit different behaviors. We also found that some attractive and aversive odorants block one another’s behavioral effects, which may occur without receptor antagonism in the nose and can require sensory input from one receptor. Thus, innate odor-induced behaviors can be context-dependent and modulated by interactions in the brain among signals derived from different receptors. We are now interested in identifying specific regions of the brain regulating odor blocking, said Dr. Saraiva"
Saraiva LR,Kondoh K,Ye X,Yoon KH,Hernandez M,Buck LB. 2016. Combinatorial effects of odorants on mouse behavior. PNAS, 113(23): E3300-6.
Funding for this work was provided by the National Institutes of Health and the Howard Hughes Medical Institute.