Olfactory Receptor and Neural Pathway Responsible for Highly Selective Sensing of Musk Odors

Musk odorants are used widely in cosmetic industries because of their fascinating animalic scent. However, how this aroma is perceived in the mammalian olfactory system remains a great mystery. Here, we show that muscone, one musk odor secreted by various animals from stink glands, activates a few glomeruli clustered in a neuroanatomically unique anteromedial olfactory bulb. The muscone-responsive glomeruli are highly specific to macrocyclic ketones; interestingly, other synthetic musk odorants with nitro or polycyclic moieties or ester bonds activate distinct but nearby glomeruli. Anterodorsal bulbar lesions cause muscone anosmia, suggesting that this region is involved in muscone perception. Finally, we identified the mouse olfactory receptor, MOR215-1, that was a specific muscone receptor expressed by neurons innervating the muscone-responsive anteromedial glomeruli and also the human muscone receptor, OR5AN1. The current study documents the olfactory neural pathway in mice that senses and transmits musk signals from receptor to brain.

[1]  Shin Nagayama,et al.  Molecular‐feature domains with posterodorsal–anteroventral polarity in the symmetrical sensory maps of the mouse olfactory bulb: mapping of odourant‐induced Zif268 expression , 2002, The European journal of neuroscience.

[2]  Hitoshi Sakano,et al.  Agonist-Independent GPCR Activity Regulates Anterior-Posterior Targeting of Olfactory Sensory Neurons , 2013, Cell.

[3]  Winfried Wiegraebe,et al.  Distributed representation of chemical features and tunotopic organization of glomeruli in the mouse olfactory bulb , 2012, Proceedings of the National Academy of Sciences.

[4]  Michael Leon,et al.  Spatial representations of odorants in olfactory bulbs of rats and mice: Similarities and differences in chemotopic organization , 2009, The Journal of comparative neurology.

[5]  M. Leon,et al.  Modular representations of odorants in the glomerular layer of the rat olfactory bulb and the effects of stimulus concentration , 2000, The Journal of comparative neurology.

[6]  K. Touhara,et al.  An unsaturated aliphatic alcohol as a natural ligand for a mouse odorant receptor. , 2013, Nature chemical biology.

[7]  Adam Dewan,et al.  An olfactory subsystem that mediates high-sensitivity detection of volatile amines. , 2012, Cell reports.

[8]  Ian R. Wickersham,et al.  Cortical representations of olfactory input by trans-synaptic tracing , 2011, Nature.

[9]  Dheeraj S. Roy,et al.  Neurons expressing trace amine-associated receptors project to discrete glomeruli and constitute an olfactory subsystem , 2012, Proceedings of the National Academy of Sciences.

[10]  J. Ward,et al.  The animal musks and a comment of their biogenesis , 1981, Experientia.

[11]  Markus Meister,et al.  Precision and diversity in an odor map on the olfactory bulb , 2009, Nature Neuroscience.

[12]  L. Ruzicka,et al.  Zur Kenntnis des Kohlenstoffringes II. Synthese der carbocyclischen Ketone vom Zehner- bis zum Achtzehnerring , 1926 .

[13]  Tom Misteli,et al.  In vivo imaging. , 2003, Methods.

[14]  H. Walbaum.  Das natürliche Moschusaroma , 1906 .

[15]  Harumi Saito,et al.  RTP Family Members Induce Functional Expression of Mammalian Odorant Receptors , 2004, Cell.

[16]  Shuichi Hirono,et al.  Topographic representation of odorant molecular features in the rat olfactory bulb. , 2004, Journal of neurophysiology.

[17]  J. Mainland,et al.  Odor Coding by a Mammalian Receptor Repertoire , 2009, Science Signaling.

[18]  Z. Peterlin,et al.  The importance of odorant conformation to the binding and activation of a representative olfactory receptor. , 2008, Chemistry & biology.

[19]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates, The coronal plates and diagrams Compact, 3rd Edition , 2008 .

[20]  P. Kraft,et al.  Enantioselectivity of the musk odor sensation. , 2001, Chirality.

[21]  S. Itohara,et al.  Innate versus learned odour processing in the mouse olfactory bulb , 2007, Nature.

[22]  M. T. Shipley,et al.  the connections of the mouse olfactory bulb: A study using orthograde and retrograde transport of wheat germ agglutinin conjugated to horseradish peroxidase , 1984, Brain Research Bulletin.

[23]  S. R. Datta,et al.  Distinct representations of olfactory information in different cortical centres , 2011, Nature.

[24]  Matt Wachowiak,et al.  In Vivo Imaging of Neuronal Activity by Targeted Expression of a Genetically Encoded Probe in the Mouse , 2004, Neuron.

[25]  L. Buck,et al.  Combinatorial Receptor Codes for Odors , 1999, Cell.

[26]  J. Price.  An autoradiographic study of complementary laminar patterns of termination of afferent fibers to the olfactory cortex , 1973, The Journal of comparative neurology.

[27]  L. Buck,et al.  A genetic approach to trace neural circuits. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Linda B. Buck,et al.  A Large-Scale Analysis of Odor Coding in the Olfactory Epithelium , 2011, The Journal of Neuroscience.

[29]  Wheeler Jw.  Insect and mammalian pheromones. , 1976 .

[30]  N. Onoda.  Odor-induced fos-like immunoreactivity in the rat olfactory bulb , 1992, Neuroscience Letters.

[31]  L. Cohen,et al.  Representation of Odorants by Receptor Neuron Input to the Mouse Olfactory Bulb , 2001, Neuron.

[32]  Thomas A. Cleland,et al.  The anatomical logic of smell , 2005, Trends in Neurosciences.

[33]  W. Agosta.  Chemical Communication: The Language of Pheromones , 1992 .

[34]  Kei M. Igarashi,et al.  Maps of odorant molecular features in the Mammalian olfactory bulb. , 2006, Physiological reviews.

[35]  Lewis B. Haberly,et al.  The axonal projection patterns of the mitral and tufted cells of the olfactory bulb in the rat , 1977, Brain Research.

[36]  K. Mori,et al.  Two mirror‐image sensory maps with domain organization in the mouse main olfactory bulb , 2000, Neuroreport.

[37]  L. Vosshall,et al.  Sensing odorants and pheromones with chemosensory receptors. , 2009, Annual review of physiology.

[38]  Y. Yoshihara,et al.  Odorant Receptor Map in the Mouse Olfactory Bulb: In Vivo Sensitivity and Specificity of Receptor-Defined Glomeruli , 2006, Neuron.

[39]  Naoshige Uchida,et al.  Odor Representations in Olfactory Cortex: Distributed Rate Coding and Decorrelated Population Activity , 2012, Neuron.

[40]  H. Matsuda,et al.  New Macrocyclic Musk Compounds , 2004, Chemistry & biodiversity.

[41]  Naoshige Uchida,et al.  Odor maps in the mammalian olfactory bulb: domain organization and odorant structural features , 2000, Nature Neuroscience.

[42]  Hajime Fukui,et al.  The effects of odor on cortisol and testosterone in healthy adults. , 2007, Neuro endocrinology letters.

[43]  L. Vosshall,et al.  Genetic variation in a human odorant receptor alters odour perception , 2007, Nature.

[44]  Hitoshi Sakano,et al.  Spatial arrangement of glomerular molecular-feature clusters in the odorant-receptor class domains of the mouse olfactory bulb. , 2010, Journal of neurophysiology.

[45]  Hanyi Zhuang,et al.  Evaluating cell-surface expression and measuring activation of mammalian odorant receptors in heterologous cells , 2008, Nature Protocols.

[46]  Makiko Suwa,et al.  Structural Basis for a Broad But Selective Ligand Spectrum of a Mouse Olfactory Receptor: Mapping the Odorant-Binding Site , 2005, The Journal of Neuroscience.

[47]  T. Cutforth,et al.  Sensory maps in the olfactory cortex defined by long-range viral tracing of single neurons , 2011, Nature.

[48]  H. Hayashi,et al.  OCAM: A New Member of the Neural Cell Adhesion Molecule Family Related to Zone-to-Zone Projection of Olfactory and Vomeronasal Axons , 1997, The Journal of Neuroscience.

[49]  Kei M. Igarashi,et al.  Spatial representation of hydrocarbon odorants in the ventrolateral zones of the rat olfactory bulb. , 2005, Journal of neurophysiology.

[50]  Y Ikawa,et al.  A novel ES cell line, TT2, with high germline-differentiating potency. , 1993, Analytical biochemistry.

[51]  Hiroshi Kataoka,et al.  Molecular Bases of Odor Discrimination: Reconstitution of Olfactory Receptors that Recognize Overlapping Sets of Odorants , 2001, The Journal of Neuroscience.

[52]  Peter Mombaerts,et al.  Mapping of Class I and Class II Odorant Receptors to Glomerular Domains by Two Distinct Types of Olfactory Sensory Neurons in the Mouse , 2009, Neuron.

[53]  H. Okano,et al.  A Genetic Approach to Visualization of Multisynaptic Neural Pathways Using Plant Lectin Transgene , 1999, Neuron.

[54]  D. Restrepo,et al.  Variability of position of the P2 glomerulus within a map of the mouse olfactory bulb , 2001, The Journal of comparative neurology.

[55]  Hitoshi Sakano,et al.  How is the olfactory map formed and interpreted in the mammalian brain? , 2011, Annual review of neuroscience.

[56]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[57]  L. Heimer,et al.  Synaptic distribution of centripetal and centrifugal nerve fibres in the olfactory system of the rat. An experimental anatomical study. , 1968, Journal of anatomy.

[58]  H. Sakano,et al.  Functional identification and reconstitution of an odorant receptor in single olfactory neurons. , 1999, Proceedings of the National Academy of Sciences of the United States of America.