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Social Signals: The Secret Language of Mice

2005; Elsevier BV; Volume: 15; Issue: 7 Linguagem: Inglês

10.1016/j.cub.2005.03.027

1879-0445

Leslie B. Vosshall,

Human-Animal Interaction Studies

Animals are known to produce substances that modulate social and sexual behavior of conspecifics, but the mechanistic details underlying these phenomena have been elusive. A recent paper identifies a male-specific compound in mouse urine that activates olfactory bulb neurons and mediates behavioral attraction. Animals are known to produce substances that modulate social and sexual behavior of conspecifics, but the mechanistic details underlying these phenomena have been elusive. A recent paper identifies a male-specific compound in mouse urine that activates olfactory bulb neurons and mediates behavioral attraction. While we humans go to great effort and expense to mask our animal scent with perfume, deodorant and hygienic sprays, other animals use such odors to communicate precise information about themselves to other members of their species. For instance, domesticated dogs intently sample scent marks left by other dogs, allowing them to determine the age, gender, sexual receptivity, and exact identity of the animal that left the mark behind [1Bekoff M. Observations of scent-marking and discriminating self from others by a domestic dog (Canis familiaris): tales of displaced yellow snow.Behav. Processes. 2001; 55: 75-79Crossref PubMed Scopus (58) Google Scholar, 2Mekosh-Rosenbaum V. Carr W.J. Goodwin J.L. Thomas P.L. D'Ver A. Wysocki C.J. Age-dependent responses to chemosensory cues mediating kin recognition in dogs (Canis familiaris).Physiol. Behav. 1994; 55: 495-499Crossref PubMed Scopus (7) Google Scholar]. Social communication in rodents is equally robust (reviewed in [3Dulac C. Torello A.T. Molecular detection of pheromone signals in mammals: from genes to behaviour.Nat. Rev. Neurosci. 2003; 4: 551-562Crossref PubMed Scopus (480) Google Scholar, 4Novotny M.V. Pheromones, binding proteins and receptor responses in rodents.Biochem. Soc. Trans. 2003; 31: 117-122Crossref PubMed Google Scholar, 5Restrepo D. Arellano J. Oliva A.M. Schaefer M.L. Lin W. Emerging views on the distinct but related roles of the main and accessory olfactory systems in responsiveness to chemosensory signals in mice.Horm. Behav. 2004; 46: 247-256Crossref PubMed Scopus (147) Google Scholar]). Male hamsters efficiently choose new female sexual partners over old ones, a phenomenon known as the Coolidge Effect [6Johnston R.E. Rasmussen K. Individual recognition of female hamsters by males: role of chemical cues and of the olfactory and vomeronasal systems.Physiol. Behav. 1984; 33: 95-104Crossref PubMed Scopus (81) Google Scholar]. The onset of estrus and successful fetal implantation in female mice are both modulated by male odors [7Gangrade B.K. Dominic C.J. Studies of the male-originating pheromones involved in the Whitten effect and Bruce effect in mice.Biol. Reprod. 1984; 31: 89-96Crossref PubMed Scopus (34) Google Scholar]. Mice have the ability to discriminate conspecifics that differ in MHC odortype [8Yamaguchi M. Yamazaki K. Beauchamp G.K. Bard J. Thomas L. Boyse E.A. Distinctive urinary odors governed by the major histocompatibility locus of the mouse.Proc. Natl. Acad. Sci. USA. 1981; 78: 5817-5820Crossref PubMed Scopus (190) Google Scholar] and can determine whether others of their species are infected by viruses or parasites, presumably a skill of use in selecting a healthy mate [9Beauchamp G.K. Yamazaki K. Individual differences and the chemical senses.Chem. Senses. 2005; 30: i6-i9Crossref PubMed Scopus (19) Google Scholar, 10Kavaliers M. Choleris E. Agmo A. Pfaff D.W. Olfactory-mediated parasite recognition and avoidance: linking genes to behavior.Horm. Behav. 2004; 46: 272-283Crossref PubMed Scopus (83) Google Scholar]. Such social odors are typically produced in urine or secreted from scent glands distributed over the body. Both volatile and non-volatile cues are known to be produced [11Leinders-Zufall T. Brennan P. Widmayer P.S.P.C. Maul-Pavicic A. Jager M. Li X.H. Breer H. Zufall F. Boehm T. MHC class I peptides as chemosensory signals in the vomeronasal organ.Science. 2004; 306: 1033-1037Crossref PubMed Scopus (452) Google Scholar, 12Rasmussen L.E. Lee T.D. Roelofs W.L. Zhang A. Daves Jr., G.D. Insect pheromone in elephants.Nature. 1996; 379: 684Crossref PubMed Scopus (128) Google Scholar, 13Schaal B. Coureaud G. Langlois D. Ginies C. Semon E. Perrier G. Chemical and behavioural characterization of the rabbit mammary pheromone.Nature. 2003; 424: 68-72Crossref PubMed Scopus (270) Google Scholar, 14Novotny M.V. Jemiolo B. Wiesler D. Ma W. Harvey S. Xu F. Xie T.M. Carmack M. A unique urinary constituent, 6-hydroxy-6-methyl-3-heptanone, is a pheromone that accelerates puberty in female mice.Chem. Biol. 1999; 6: 377-383Abstract Full Text PDF PubMed Scopus (114) Google Scholar]. The accessory olfactory system, comprising the vomeronasal organ and the accessory olfactory bulb, responds largely to non-volatile cues, while the main olfactory system receives volatile signals. Although mammalian pheromones are classically thought to activate the accessory olfactory system, several newly described pheromones are volatile and may act through the main olfactory system (for example [13Schaal B. Coureaud G. Langlois D. Ginies C. Semon E. Perrier G. Chemical and behavioural characterization of the rabbit mammary pheromone.Nature. 2003; 424: 68-72Crossref PubMed Scopus (270) Google Scholar]). Chemical signals have a number of advantages in social communication over signals that act on other sensory modalities: they are energetically cheap to produce, often being metabolic by-products; they are volatile and can therefore be broadcast within a large territory; and they can continue to emit signal after the animal has moved to a new location [15Wyatt T.D. Pheromones and Animal Behaviour: Communication by Smell and Taste. Oxford University Press, Oxford2003Crossref Google Scholar]. What are the specific, behaviorally active chemical signals present in urine? What sensory neurons respond to these cues? Can a single such compound be behaviorally active? A recent paper by Lin et al. [16Lin D.Y. Zhang S.Z. Block E. Katz L.C. Encoding social signals in the mouse main olfactory bulb.Nature. 2005; (2005 Feb 20[Epub ahead of print] PMID: 15724148)Google Scholar] succeeds spectacularly in answering all three questions. The authors applied chemistry, electrophysiology and behavior to this problem, and identified biologically active volatiles in male urine that activate both male and female main olfactory bulb mitral cells. They have elucidated the chemical identity of a single such male-specific urine component that both activates olfactory bulb mitral cells and elicits behaviors in female mice. The new study [16Lin D.Y. Zhang S.Z. Block E. Katz L.C. Encoding social signals in the mouse main olfactory bulb.Nature. 2005; (2005 Feb 20[Epub ahead of print] PMID: 15724148)Google Scholar] builds on earlier work from Diego Restrepo's group that described regions in the olfactory bulb activated upon exposure to whole mouse urine [17Schaefer M.L. Young D.A. Restrepo D. Olfactory fingerprints for major histocompatibility complex-determined body odors.J. Neurosci. 2001; 21: 2481-2487PubMed Google Scholar, 18Schaefer M.L. Yamazaki K. Osada K. Restrepo D. Beauchamp G.K. Olfactory fingerprints for major histocompatibility complex-determined body odors II: relationship among odor maps, genetics, odor composition, and behavior.J. Neurosci. 2002; 22: 9513-9521PubMed Google Scholar]. Larry Katz's group [16Lin D.Y. Zhang S.Z. Block E. Katz L.C. Encoding social signals in the mouse main olfactory bulb.Nature. 2005; (2005 Feb 20[Epub ahead of print] PMID: 15724148)Google Scholar] borrowed a technique from insect chemical ecology that has been classically used to identify insect pheromones (for example [19Nojima S. Schal C. Webster F.X. Santangelo R.G. Roelofs W.L. Identification of the sex pheromone of the German cockroach, Blattella germanica.Science. 2005; 307: 1104-1106Crossref PubMed Scopus (110) Google Scholar]) and used it to identify specific compounds in male urine that activate main olfactory bulb mitral cells. Solid phase microextraction (SPME; Figure 1A ) coupled to gas chromatography and single-unit electrophysiology (GC-E) combines chromatographic separation of complex volatiles using gas chromatography with direct recording of biological activity in neurons (Figure 1B). Using this approach, Lin et al. [16Lin D.Y. Zhang S.Z. Block E. Katz L.C. Encoding social signals in the mouse main olfactory bulb.Nature. 2005; (2005 Feb 20[Epub ahead of print] PMID: 15724148)Google Scholar] recorded from thousands of olfactory bulb mitral cells while fractions of male and female mouse urine volatiles wafted over the olfactory epithelium. By synchronizing the output of the gas chromatography with the electrophysiological traces, they linked specific mitral cell responses to identified peaks in the chromatogram (Figure 1B). Remarkably specific responses were obtained: male and female neurons selectively activated by male-specific urine components; strain-selective neurons; and very rarely, male neurons that preferred female urine. Identifying one of these active components among hundreds of male-specific volatiles required a major feat of chemical detective work. Lin et al. [16Lin D.Y. Zhang S.Z. Block E. Katz L.C. Encoding social signals in the mouse main olfactory bulb.Nature. 2005; (2005 Feb 20[Epub ahead of print] PMID: 15724148)Google Scholar] focused their attention on a biologically active peak in male urine, which was absent in urine from castrated males. Mitral cells in a restricted region of the main olfactory bulb fired robustly at precisely 508seconds into the gas chromatography run, a few seconds after a large peak corresponding to a known mouse pheromone, 6-hydroxy-6-methyl-3-heptanone (HMH) [14Novotny M.V. Jemiolo B. Wiesler D. Ma W. Harvey S. Xu F. Xie T.M. Carmack M. A unique urinary constituent, 6-hydroxy-6-methyl-3-heptanone, is a pheromone that accelerates puberty in female mice.Chem. Biol. 1999; 6: 377-383Abstract Full Text PDF PubMed Scopus (114) Google Scholar]. Further inspection, however, showed a small peak that matched the onset of neuronal activity more precisely. Separating the imposter HMH peak from the true stimulus required several additional rounds of analytical chemistry that definitively ruled HMH out as the biologically active signal and identified a sulfurous compound as the true signal. Mass spectroscopy narrowed down the possible list of suspects further and one of these, (methylthio)methanothiol (MTMT), was shown to be an exact match for the compound in urine. It elutes identically on gas chromatography, has the same biological activity in mouse olfactory bulb, and is perceived to have the same garlic odor by humans. Two aspects of MTMT-tuned mitral cell responses are of particular interest. First, these neurons are incredibly sensitive to this compound, responding at a threshold of 10 parts per billion. Secondly, the neurons do not respond to any other of the hundred or so volatiles present in urine or other sulfurous compounds that are structurally similar to MTMT. In this regard, they resemble the classical 'specialist' neurons of the insect that respond only to a single pheromonal component. Such specific responses are particularly surprising given many previous reports that mitral cells are broadly tuned. Finally, Lin et al. [16Lin D.Y. Zhang S.Z. Block E. Katz L.C. Encoding social signals in the mouse main olfactory bulb.Nature. 2005; (2005 Feb 20[Epub ahead of print] PMID: 15724148)Google Scholar] showed that MTMT elicits specific attraction in female mice. They confirmed the well-known result that females are more interested in urine produced by intact males than castrated ones (Figure 1C, left). Adding synthetic MTMT to castrated male urine increased the attractiveness of the urine to female mice (Figure 1C, center and right). These results show that even a single component of male urine can be behaviorally active in female mice. This study succeeds in analyzing a social signal from the specific chemical to its effect on identified olfactory bulb neurons all the way to the production of a behavior. A number of interesting questions remain for future studies. While female mice clearly prefer MTMT dissolved in urine over water, mitral cells do not discriminate between these stimuli. This suggests that integration of multiple urine-derived signals must be occurring higher up in the olfactory circuit. Lin et al. [16Lin D.Y. Zhang S.Z. Block E. Katz L.C. Encoding social signals in the mouse main olfactory bulb.Nature. 2005; (2005 Feb 20[Epub ahead of print] PMID: 15724148)Google Scholar] identified 112 peaks in intact male urine, but only 57 in castrated male urine. It will be of interest to determine how many of the 55 additional peaks in intact males provoke specific responses in the female mouse. Finally, in this year of the olfaction Nobel Prize [20Buck L. Axel R. A novel multigene family may encode odorant receptors: a molecular basis for odor recognition.Cell. 1991; 65: 175-187Abstract Full Text PDF PubMed Scopus (3675) Google Scholar], it seems irresistible to ask which odorant receptor genes and which specific olfactory bulb glomeruli process urine odors. Are these odorant receptors a specific sub-class dedicated to perceiving social odors? What has happened to these odorant receptors in the course of vertebrate evolution and do we have traces of such putative social signal receptors in our own genomes? Perhaps through the cloud of perfume and deodorant, our own unique scents are still sending a message that others can receive.