Olfaction (the sense of smell)• Mammals can detect upwards of 1000-10000 different odors– Wide spectrum of chemical structures– Discrimination of structurally similarcompounds• How??General Concepts• Basic anatomy of the peripheral olfactory system• Principles of signal transduction• “Coding” of information at three levels:– Receptors - #’s and combinatorials– Neuronal specificity - 1 receptor type/sensory neuron– Spatial maps - how the brain keeps track of whichsensory neurons (and therefore which receptors) havebeen activatedNobelprize.orgFirestein, Nature 413: 211 (2001)Olfactory ciliumOlfactory epitheliumOlfactory bulbOlfactory neurons can respond to multiple (and different) odorsCineole Isoamyl AcetateAcetophenoneFirestein et al., J Physiol. 1993neuron 1neuron 2neuron 3Olfactory Signal Transduction• Conversion of a chemical signal (odor binding) to anelectrical signal (change in neuron’s Vm)• What is the nature of the odorant receptor?– Ligand (odor) - gated ion channel?– G protein-coupled receptor (GPCR)?• Delay in olfactory neuron’s response to odor (~500 ms)and odor-dependent generation of cAMP by olfactorycilia in vitro (dependent on GTP) => GPCRs• Diversity of odorants detected suggests a large numberof receptors• 1991: identification of large family of GPCRsexpressed in olfactory sensory neurons by Buck andAxel (2004 Nobel Prize in Physiology or Medicine)Firestein, Nature 413: 211 (2001)Olfactory Signal Transduction:How the chemical signal is converted toan electrical signal…Odorant Receptors• Belong to the superfamily of GPCRs• >1000 in rodents, ~350 in humans (other distantlyrelated families of GPCRs expressed in thevomeronasal system)• Large number of receptors suggests a model forthe detection and discrimination of an even largernumber of perceived odors– Each receptor binds to more than one odorant– Each odorant binds to a subset of receptors– The identity of the chemical being detected isdetermined by the combination of receptors that areactivatedMombaerts, Nature Reviews Neuroscience 5: 263 (2004)Neuronal Specificity• If a given odor activates a subset of odorantreceptors, how does the brain know whichreceptors are being activated (out of a possible~1000)?• Simplest model: each olfactory neuron expressesjust one type of odorant receptor• Problem of identifying which receptor(s) isactivated is reduced to identifying which neuron(s)is activatedSpatial Maps• Problem: how does the nervous system know whicholfactory neurons are being activated?• Cells expressing the same receptor type (and thereforeresponsive to the same odorants) converge to commonglomeruli in the olfactory bulb• Pattern of this convergence is invariant from animal toanimal• This forms the basis of a spatial map of olfactory sensoryinformation - the pattern of glomerular activation is a“read-out” for the chemical identity of the odorant beingdetected• (Big) future question: how is this “olfactory map”interpreted to form an olfactory percept?A Spatial Map Encodes Sensory Informationin the Olfactory SystemFirestein, Nature 413: 211 (2001)Additional assigned reading:• Firestein, S. (2001). How the olfactorysystem makes sense of scents. Nature 413,211-218.insight review articlesNATURE|VOL 413|13 SEPTEMBER 2001|www.nature.com 211The sensitivity and range of olfactory systems isremarkable, enabling organisms to detect anddiscriminate between thousands of lowmolecular mass, mostly organic compounds,which we commonly call odours. Representedin the olfactory repertoire are aliphatic and aromaticmolecules with varied carbon backbones and diversefunctional groups, including aldehydes, esters, ketones,alcohols, alkenes, carboxylic acids, amines, imines, thiols,halides, nitriles, sulphides and ethers. This remarkablechemical-detecting system, developed over eons ofevolutionary time, has received considerable attention inthe past decade, revealing sensing and signallingmechanisms common to other areas of the brain, butdeveloped here to unusual sophistication.How does the olfactory system manage this sophisticateddiscriminatory task? Beginning with the identification of alarge family of G-protein-coupled receptors (GPCRs) in thenose, the foundations of a comprehensive understandinghave emerged in surprisingly short order. The advent ofadvanced molecular and physiological techniques, as well asthe publication of eukaryotic genomes from Caenorhabditiselegans to Homo sapiens, has provided the critical tools forunveiling some of the secrets. We now possess a detaileddescription of the transduction mechanism responsible forgenerating the stimulus-induced signal in primary sensoryneurons, and also an explicit picture of the neural wiring, atleast in the early parts of the system. From this body of worka view of molecular coding in the olfactory system has arisenthat is surely incomplete, but nonetheless compelling in itssimplicity and power.Among higher eukaryotes, from flies through to mammals, there is a striking evolutionary convergencetowards a conserved organization of signalling pathways inolfactory systems1. Two olfactory systems have developed inmost animals. The common or main olfactory system is thesensor of the environment, the primary sense used by animals to find food, detect predators and prey, and markterritory. It is noteworthy for its breadth and discriminatorypower. Like the immune complex, it is an open system builton the condition that it is not possible to predict, a priori,what molecules it (that is, you) might run into. Therefore, itis necessary to maintain an indeterminate but nonethelessprecise sensory array. A second, or accessory, olfactory system has developed for the specific task of finding a recep-tive mate — a task of sufficient complexity that evolutionhas recognized the need for an independent and dedicatedsystem. Known as the vomeronasal system, it specializes inrecognizing species-specific olfactory signals produced byone sex and perceived by the other, and which contain infor-mation not only about location but also reproductive stateand availability. In addition to its role in sexual behaviours,it is important in influencing other social behaviours such asterritoriality, aggression and suckling. This review willdescribe the recent advances that have emerged from molec-ular, physiological, imaging and genetic studies, and willhighlight many of the remaining questions, especially asconcerns the