odour perception a review of an intricate signalling pathway

Review

Received: 23 January 2015, Revised: 13 October 2015, Accepted: 15 October 2015 Published online in Wiley Online Library

(wileyonlinelibrary.com) DOI 10.1002/ffj.3295

Odour perception: A review of an intricatesignalling pathwayAnne Tromelina,b,c*

Abstract: The perception of odours is the result of the complex processing of a signal, which initiates at peripheral receptors andends in the brain. Along this pathway, olfactory signal processing proceeds through several steps; each step possesses its owncomplexity, and all steps are also intricately connected. This review aims to describe themain intricate steps of olfactory process-ing in mammals, some of which remain unclear, and the close associations and overlapping nature of these steps. The causes ofboth the complexity and the variability of olfactory signals are examined: the nature of olfactory receptors, involving the diver-sity of the genome; the spatial organization of the olfactory epithelium (OE) and the olfactory bulb (OB); connections in the OBand from the OB to the brain; integration and processing in the brain, which leads to the final perception of odours; and odourrecognition and odour identification, which is associated with the difficulty to verbalize a reliable description of the perception inhumans. Finally, the last part of this review encompasses recent progressmade to decipher and understand olfactory coding andfocuses on computational approaches. Copyright © 2015 John Wiley & Sons, Ltd.

Keywords: odourant molecules; odours; odour perception; olfaction; olfactory system; review

* Correspondence to: Anne Tromelin, INRA, UMR1324 Centre des Sciences duGoût et de l’Alimentation, F-21000 Dijon, France. E-mail: [email protected]

a CNRS, UMR6265 Centre des Sciences du Goût et de l’Alimentation, F-21000Dijon, France

b INRA, UMR1324 Centre des Sciences du Goût et de l’Alimentation, F-21000Dijon, France

c Université de Bourgogne, UMR Centre des Sciences du Goût et del’Alimentation, F-21000 Dijon, France

IntroductionOlfaction is most likely the oldest sensory perception common toliving creatures,[1–4] and it is extremely important forcommunication.[5,6] Olfactory perception is one of the most com-plex and least understood senses,[7] constituting a fascinating re-search field. Several authors have highlighted the peculiarcomplexity and sophistication of olfactory signalling, involving sev-eral levels from odourant receptors in the nose to brainprocessing.[8–10] All the steps of the currently accepted olfactoryperception model have been investigated: the mechanisms in-volved at olfactory epithelium level[11]; the binding to the olfactoryreceptors, a peculiar group of GPCRs;[12–15] the common propertiesand the specificities of olfactory system and olfactory genome ofvertebrates,[16] and the consequence of human olfactory genomevariability on olfactory perception;[7] the organization at olfactorybulb level[10]; the treatment and the integration of olfactory signalin the brain,[15,17,18] and the role that can play concentration on per-ceived intensity;[19] the causes of odour quality;[20] the moodchanges induced by odours.[21] In addition, the olfactory systempossesses a high capacity of regeneration,[22–26] making it able toresist to diverse aggressions,[27–30] and confers a plasticity that en-ables it to adapt to some changes in olfactory environment andto maintain or restore its remarkable efficiency.[31–35]

To better understand olfactory perception, it is important to con-sider the possible number of odours that the mammalian nose isable to identify and discriminate. S. Arctander collected and identi-fied odours of molecules since 1935 and published the book ‘Per-fume and Flavor Chemicals (Aroma Chemicals)’ in 1969.[36] TheMonographs part of this book brings together the description of3102 odorant molecules. Among the more recent databases de-scribing odours, the Flavor-Base[37] is one one of the largest collec-tions of flavour molecules (4226 compounds) providing odoursdescriptions. Nevertheless, these databases report odorant descrip-tions of identified and known odourant molecules; thesemoleculescould represent only a small part of all the hypothetically existing

Flavour Fragr. J. 2015 Copyright © 2015 John

odourants having discriminable odours. For example, the numberof all synthetically feasible molecule of molecular weight less than500 Da (‘small molecule universe’ (SMU)) is estimated to reach10[60] and any volatile molecule of this set is likely to be anodourant.[38,39] It was first estimated that humans can discriminateapproximately 10,000 to 100,000 odourants.[40] Mombaerts refutedthe misconception that humans can smell only 10,000 odours andsuggested that the human nose can detect hundreds of thousands,even millions, of distinct odours.[41] Mori estimated this number tobe greater than 400,000,[42,43] whereas Cleland and Linster calcu-lated that approximately 21000 (1.07 10301) odours could bediscerned by mice based on the number of mouse olfactory recep-tors (ORs) and the number of states for each receptor (1,000 and 2,respectively).[44] More recently, approximately 1012 odours wereproposed to be detectable by humans on the basis of psychophys-ical testing results.[45] Nevertheless, this gigantic number is contro-versial and has been recently questioned.[46,47] In any case, itappears that mammals, and even humans, are able to discriminatea huge number of odour stimuli.At the initial stage of olfaction in the nose, the number of in-

volved receptors implies a combinatorial coding of odours,,[48]

whereas the final stage in the brain implicates the involvementof areas in the brain,[49,50] which play a central role inmemory,[51,52]

attention,[53,54] language[55] and consciousness.[56] Between both

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stages, numerous intricate events occur at each step of the olfac-tory process.

Inmammals, the olfactory process begins in the nasal cavity[57] atthe surface of the olfactory epithelium (OE) when a molecule bindsto an OR[58–63] (Figure 1). Mammalian ORs belong to theRhodopsin/family A of the G protein-coupled receptor (GPCR)superfamily,[61,64–67] which constitutes the largest receptorsubfamily.[68,69] ORs are expressed on olfactory cilia immersed intothe mucus that covers the surface of the nasal epithelium.[13,40,70,71]

These cilia leave from the dendrites of olfactory receptor neurons(ORNs)[72,73]; it is currently accepted as a rule formammals that eachneuron expresses only one receptor type (or a few types atmost).[71,74–79] A series of works carried out over the last decadeaims to identify the mechanims of OR gene choice underlying the‘one neuron one receptor’ rule.[80–82] The current results suggestthat the regulation of OR expression involves both enhancer ele-ments and an OR-elicited feedback pathway.[83]

The binding of a molecule to an OR induces a transduction cas-cade that produces changes in the neuron membrane potential.These changes generate an electrical signal that progresses alongthe cell’s axon to the glomeruli, at outside of olfactory bulb(OB)[84] (Figure 2). Each olfactory neuron projects a single axon ontothe same glomerulus,[58,85] and ORNs expressing the same OR con-verge onto the same glomeruli (typically one to a few glomeruli) inthe main olfactory bulb (MOB).[86] Olfactory glomeruli are sphericalneuropils that convergent axons from sensory neurons.[10,87] Com-plex interactions occur among synapses within the glomerularcircuit, and the resulting olfactory information is transmitted tothe brain[88–92] via axons of neuronal cells of OB.[93–96] In animals,the olfactory signal is interpreted by the brain to induce responsesfor vital behaviours, such as communicating,[5,6,97] reproducing,[98]

caring for young,[99] feeding and avoiding predators.[100] Inaddition, humans can verbally describe odour perception.[101,102]

Each of the steps listed above encompasses its own intricacies.The present work aims to portray the olfactory system in a mannerthat is clear to non-specialists in biology, neuroscience and cogni-tive science. It aspires to provide a general overview of the olfac-tory system and to describe the main intricate steps of olfactoryprocessing in mammals, some of which remain unclear, and theclose associations and overlapping nature of these steps.

Figure 1. Olfactory neurons in the human nasal cavity. Head anatomywith olfactory nerve, Patrick J. Lynch, medical illustrator, Permission Crea-tive Commons Attribution 2.5 License 2006 (http://patricklynch.net)

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Moreover, this work presents current efforts and research perspec-tives in understanding the olfactory process.

Causes of olfactory signal variability andcomplexity: the critical steps

Olfactory receptors

Genetics: inter-species diversity vs. constancy

One of the reasons for olfaction complexity is the remarkablestructural diversity of ORs, including both the large number ofORs for each species and variability across species as well as insidethe human genome. Since the initial discovery of ORs,[64] severalstudies have investigated these receptors. OR genes of numerousvertebrate species have been isolated and sequenced,[16,103] andthe mammalian genome has been especially studied.[77,104–107]

The human OR genome contains approximately 800 sequences,the mouse genome contains approximately 1400 sequences,[103,108]

whereas African elephants has the largest OR genome (4200).[108]

Thus, the OR genome constitutes one of the largest genefamilies.[3,109–111] However, depending on the species, a large num-ber of these genes are pseudogenes (i.e., genes that do not expressproteins).[3,41,108,112,113] Between 20–25% of the mouse OR genomeis composed of pseudogenes, whereas approximately 50% of ORgenes are pseudogenes in humans.[103,106–108,110,113–115] This resultreveals a peculiar loss in primate and more specifically human ORgenes.[58,116–120] Currently, the number of functional ORs is about390,[108,110] 399, 1063, 1259 and 1948 for humans, chimpanzees,mice, rats and African elephant, respectively.[108,114]

Specific aptitudes to perceive odours have been reported inmammals.[119] In the human genome, some variability across pop-ulations has been reported,[104,121–124] which induces variation inolfactory perception and in the hedonic appreciation of odourquality.[41,124–126] However, this effect appears limited,[124,127] andsome commonalities emerge across species.[1,2,4,12,128–131]

Mammalian olfactory receptors are G protein-coupled receptors(GPCR)

The fact that mammalian ORs belong to the family A of GPCRsimplies that ORs potentially possess the sophisticated propertiesof these versatile receptors.[132–136] GPCRs are characterized bya seven-helix hydrophobic transmembrane domain[67,136–138]

coupled with a heterotrimeric G protein (composed of α-, β- andγ-subunits). The binding of a ligand to the transmembrane domaininduces a transduction signal beginning by the GDP–GTP exchangeon the Gα-subunit, and following by the stimulation of effectorsmolecules, that depend of the nature of Gα-protein subunit, as illus-trated in (Figure 3).[67,139]

GPCRs are multifaceted proteins.[134,137] Their ligands act eitheras agonists, antagonists, or inverse agonists,[67] and they can alsobind to orthosteric or allosteric sites.[137,140–145] The conformationalflexibility and the consequences of ligand binding have also beendetermined,[137,146–149] andmultiple activation and signalling stateshave been reported and have been linked to desensitization andconformational changes.[150,151] Moreover, the seven-helix receptormolecules can couple to various G protein subtypes,[152] which playa key role in transforming the sophisticated modalities of the signaltransduction induced by ligand binding into an intracellularresponse.[13,61,66,132,153,154]

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http://patricklynch.net

Figure 2. Schematic representation of the olfactory neuron pathway from the olfactory epithelium to the olfactory bulb. Source: https://www.flickr.com/photos/94415613@N08/8657640053/in/photostream/

Figure 3. Signal transduction in GPCRs. The seven-helix transmembrane domains are numbered using consecutive Roman numerals (I to VII); the G proteinsubunits are identified as α-, β- and γ-subunits. Diverse signalling pathways are regulated according to the nature of Gα-subunit, as illustrated for the maineffectors (AC, PLC, Rho GEFs)

Olfactory system and odour perception

ORs also possess some of the same properties as GPCRs. As exam-ples, agonist-antagonist and inverse agonist effects as well as com-petitive interactions have been reported for ORs.[155–160] At leasttwo binding modes are involved in hOR1G1 activation,[159,161,162]

and the nature of the G protein appears to be crucial to determiningthe agonist or antagonist activity of the ligand aswell as the olfactorysignal transduction cascades.[94,163–168] Schematically, two signaltransductions are implicated, namely, the so-called cAMP transduc-tion pathway and the IP3 transduction pathway (which involve cyclicadenosine monophosphate (cAMP) and inositol 1,4,5-trisphosphate


(IP3), respectively). cAMPplays an essential role in the olfactory signaltransduction of most odourants. Not all odourants induce cAMPresponses; however, increased IP3[84,169–180] and other signallingpathways specific to neurons could also be involved.[181,182]

Role of other receptors and signalling pathways

Olfactory signals may also be associated with other signallingpathways. Beta-adrenergic receptors,[11,183–185] muscarinicreceptors,[11,186] nicotinic acetylcholine receptors,[187] ion channels

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of ORNs,[188,189] adrenaline,[190] some neuropeptides,[191] andperipheral events[192] modulate the olfactory signal and ORexpression on cell membranes.

Olfactory coding

In humans, the detection and discrimination of numerous odoursthrough less than 400 ORs implies a combinatorial coding ofodours, wherein one molecule can bind to several ORs and oneOR recognizes several odourants. Such olfactory coding was firstsuggested in the early 1970s,[193] subsequently established at theORN level,[194,195] and ultimately detailed and formalized at theOR level by B. Malnic et al.[48] (Figure 4). Therefore, odour identitiesare ensured by the recognition of odourants by different combina-tions of ORs.[58,63,196–198] However, more narrowly tuned ORNs arenoted in the OE compared with broadly tuned ORNs.[199]

Organisation in the olfactory epithelium

For ethical reasons, studies of OE ofmammals were and are carriedout on laboratory animals, mostly on rodents, and not on humans.The spatial organization of the OE was first observed in the middleof the last century, but histological studies were initially challeng-ing given the finesse and proximity of ORNs.[200] After discoveringthe gene family encoding ORs, some progress has beenmade.[42,70,201,202] It appears that the OE can be divided into fourzones, which roughly correspond to four zones in theOB.[203] ORNsexpressing a specific OR gene are typically localized to one of thefour zones within the OE, but they are dispersed across the respec-tive zone of the OE.[71,204,205] Moreover, despite the fact that ORNsexpressing the same OR are dispersed over a large area, theiraxons project to specific regions of the OB.[206,207]

Figure 4. Combinatorial olfactory coding. Molecular shapes are schematisedto the left in black. For eachmolecule, activatedORs are indicated in dark grey.Adapted from Malnic et al.[48] Source: Olfactory receptors ORs (principle ofsmell decoding); Author: Joanna Kośmider, 3 June 2011


In addition to the ORs, a second family of receptors is expressedat the OE. These receptors were called ‘trace amine-associated re-ceptors’ (TAARs) because they are involved in traces of aminesdetection.[208] TAARs belong to GPCR family, but they are distinctto ORs.[209,210] The role of TAARS in olfaction was discussed,[211]

but they are now recognized as an olfactory subsystem.[83,212]

OE zonal organization has been proposed to play a role in olfac-tory coding;[70,77,84,93] however, the lack of point-to-point connec-tions between the OE and OB suggests that the spatialorganization in the OE and in the OB constitute two distinct levelsof information processing of the olfactory system.[10,58,84,205,213]

Furthermore, the organization of ORs in the OE would explainthe differences observed between ortho- and retronasal odourperception.[214–217]

Olfactory bulb

The OB is the first site of synaptic processing in the vertebrateolfactory pathway,[218] and it was first studied at the end of the19th century.[219] A precise description was provided by Cajal,[220]

which was further elucidated by several works by Pinchinget al.[221,222] As for OE and also for ethical reasons, results reportexperiments mostly carried out on rodents.

Spatial organization of glomeruli

Does a glomeruli map exist in the OB?

The convergence of neuronal axons expressing the same OR ontodefined glomeruli in the OB has been observed in mammals,suggesting the existence of a stereotyped bilaterally symmetricmap of glomerular organization.[42,84,86,206,223–230] This glomerularorganization appears to be a general strategy for vertebrates;nevertheless, the location of activity domains is specific to eachspecies.[231–233]

Several studies have proposed a relationship between structuralfeatures, odours, odourant molecule concentrations and theglomerular-layer activity organization.[226,228,234–237] Thus, the spa-tial organization of the glomeruli forms an olfactory map thatcould possess fundamental functional meaning, likely related tovarious structural features of odourants and/or perceivedquality.[238–246]

Molecules that belong to the same chemical family but vary incarbon chain length activate glomeruli that are located near eachother; nevertheless, glomeruli activity patterns partly or do notoverlap.[227,247] Similar observations were made for enantiomers,but the overlap appears to differ according the species.[248,249]

However, such a map emerges at coarse scale observations forsome molecules as observed for molecules sharing certainfunctional groups and/or carbon chain length.[226,235,237,243,250]

Nevertheless, it is not the case for all molecules.[10,251] The scaleof observation is critically important, and no correspondenceemerges between the proximity of glomeruli and their odoursensitivities with fine-scale observations. Conversely, a sparseresponse of glomeruli and mitral cells is observed at moderateconcentrations of odourants (approximately 0.1 to 1% of the satu-rated vapour at room temperature; the number of recruited recep-tors depends on the odourant molecule concentration).[252–256]

These works indicate that the glomeruli and associated circuitsare organized ‘non-topographically’. In addition, the data suggestthat glomeruli containing similar information regarding odourstimuli are not necessarily neighbouring but rather connected by



the circuits in the glomerular layer and in the deep OB bymitral/tufted cells (M/T cells).[256,257] Thus, it may appear that thespatial organization of glomeruli does not adhere to the rule ofthe anatomical principle that ‘spatial organization, with neuronsbeing ordered according to their similarity in receptive fieldproperties’.[258] Nevertheless, despite the absence of chemotopicorganization, glomeruli can exhibit a tunotopic organization, i.e.,a hierarchical arrangement into clusters related to their odour-tuning similarities, thereby respecting the organization principlethat exists in other sensory systems.[259]

The apparent map observed at a coarse scale could resultfrom a developmental pattern and was not necessarily formedto play a role in olfactory coding.[260] Moreover, glomerularorganization is exclusively observed in laboratory animals andcould depend on environmental conditions.[260] Observationsperformed on human OBs revealed an abnormally increasednumber of glomeruli, suggesting that the convergence of axonsinto the OB is not the same for humans[261] and for some othermammals as marmoset[262] and whale.[263] These two recentresults are particularly striking. Indeed, the marmosets possessabout 400 intact OR genes, but the revealed total number ofglomeruli is about 3 000 to 3 600, so a ratio about 7.5 to 9.The case of whale is even more pronounced because the totalnumber of glomeruli reaches 4 000, while whales carry only 80intact OR genes, being a ratio of 50. This raises questions aboutthe number of glomeruli observed for laboratory mice, whichcould be hypothetically not the same for wild mice. In thisway, laboratory mice would be a unique and peculiarphenomenom.[260] Whatever be the case, the meaning of suchglomerular organization remains unexplained.

Axon guidance from ORNs to glomeruli

The rules governing axon guidance from ORNs to glomeruli arecurrently better known; nevertheless, they are still not completelyunderstood.[96,260,264,265] Axons generate a structure without targetguidance, and the role of receptors expressed in the OE appears tobe crucial in the formation of glomeruli.[213,224,264,266–272] More-over, such axon guidance was also observed for the β2-adrenergicreceptor in receptor substitution experiments.[185,273,274] The roleof cAMP signalling and the nature of the G protein are also essen-tial for suitable axonal convergence.[275–277] The study of the se-quential projection of ORN axons and the identification of OR-glomerulus pairs were made possible using a genetic approach,which permits the visualization of the axonal projections fromORNs to the OB and is a very promising method. However, thismethod is currently limited to some mouse ORs.[96,203,224,267,277]

Connections in the olfactory bulb

The connections between glomeruli as well as across the OB playkey roles in olfactory signal processing.[278] The electrical activityand the potential wave accompanying olfactory stimuli have re-ceived serious attention for many years.[279–281] However, despiteall of these efforts, the functional processes of the olfactorynetwork are still not fully understood.[260,282] Indeed, the OB isnot ‘just’ a structure where ORNs converge to glomeruli at thesurface of the OB before M/T cells convey the olfactory signal fromthe glomeruli to the brain.[278] It became apparent that connec-tions in theOB and from the OB to the brain are interlaced in a veryintricate manner,[283] and the axonal targets of M/T cells are


difficult to elucidate.[284] Each glomerulus is innervated by the pri-mary dendrites ofM/T cells, which submit the olfactory signal to beprocessed within the OB and modulate the olfactorysignal.[44,87,93,218,252,253,285–291]

The traditional view of the organization of the OB divides the OBin several layers, with each layer containing one type ofneuron.[292] A useful description of the organization of the OBcircuit was recently published that description differs from the tra-ditional view, showing that conventionally categorized neuronsare in fact composed by heterogeneous populations, and thatOB neurons belong to very diverse neuronal types.[282,293] How-ever, more recent studies revealed the imperfect meaning of sucha classification given neuronal diversity, which was seldom consid-ered until recently. According to the conventional classification,there are five types of cells, starting from the glomerular layer tothe deep OB: periglomerular (PG) cells, tufted cells (T) cells,external tufted cells (ET) cells, mitral cells (M) cells, and granulecells (GC). Nevertheless, several works suggest that encoding ofolfactory stimuli requires a higher neuronal complexity.[294,295]

The connections between glomeruli as well as the connectionsto the glomerular layer and to the deep OB have beeninvestigated.[95,278,296–300] PG cells most likely play a crucial role[297]

in modulating the input via an on/off mechanism.[301] Lateral in-hibitory interactions between M/T cells and GCs also exist,[287,302]

and a key role of the GCs has been discovered.[257,303] Moreover,additional cells and connections are likely also involved.[304] There-fore, the exact function of the connections and their organizationin the OB is not yet clearly understood.Broadly speaking, interactions in the OB can be described as a

sophisticated balance between inhibitory and excitatory interac-tions that are ensured by dendritic connections.[180,230,302,305–310]

These interactions participate in an ensemble of normalization,decorrelation, oscillation and synchronization of olfactorysignalling[281,311–316] and have been studied as a computationalsystem.[44,317–322] This signal processing appears to be extraordinarilycomplex, involving several independent signals[323] and resulting intemporary, dynamic modulations of olfactory signalling.[317,324–331]

Moreover, the activity of neurons in the OB depends onbreathing,[332,333] awake vs anesthetized states,[334–336] habitua-tion, experience and context.[337–342] The impact of the environ-ment and odour exposure concerns not only the activity ofneurons but also the structure of the OB (i.e,, the density of cellsand their connections) due to the great plasticity of thissystem.[343–347] Another source of the modulation of signalling isderived from cortical feedback projections to the OB, whichcontribute to plasticity in the OB.[328,333,348–356]

From olfactory bulb to brain areas

Encoded information by the OB is transmitted to brain areas as re-cently summarized (Figure 5).[278] M/T cells mainly project theiraxons to the piriform cortex[357]; however, several other corticalareas are also targeted, including the anterior olfactory nucleus,olfactory tubercle, lateral entorhinal cortex, and the corticalamygdala.[10,92,278,292,358–361] Moreover, M/T cells project to differ-ent cortical areas.[10,260,291,362–364] Axons of T cells project to areasclose to one another (e.g., anterior olfactory nucleus and olfactorytubercle). Conversely, axons of M cells project to scattered areas(e.g., anterior olfactory nucleus, piriform cortex, cortical region ofolfactory tubercle, tenia tecta, cortical amygdala, and lateral ento-rhinal cortex).[278] As a consequence, M cells and T cells possess dif-ferent roles in the olfactory process that contribute to odourant


Figure 5. Schematic representation of projection of mitral and tufted cells in brain areas of rodent as proposed by T Imai.[278,363,364] This schematic drawingrepresents the ventrolateral view of the brain. Tufted cells project their axons to the other side of the OB (intrabulbar projection) and to the anterior olfactorynucleus, which link to the contralateral OB, and also to the posteroventral part of anterior olfactory nucleus, ventrorostral part of anterior piriform cortex, andcap region of olfactory tubercle (these areas are adjacent to each other). Mitral cells project in a dispersed way in piriform cortex, lateral entorhinal cortex,cortical amygdala, anterior olfactory nucleus, tenia tecta, and cortical region of olfactory tubercle. Reprinted from Seminars in Cell & Developmental BiologyVol. 35, Imai, T, ‘Construction of functional neuronal circuitry in the olfactory bulb, 180-188’[278] (open access article under the CC BY-NC-SA license)

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discrimination.[365,366] Moreover, all of these connections aredynamic and exhibit great plasticity.[359,367] Temporal aspects oftransmission by M/T cells are also involved in odour identificationand discrimination.[291,364,368]

For most sensory perceptions, neurons are clustered accordingthe stimuli. Conversely, no clear olfactory map or at least no under-standable correspondence exists for the spatial organization ofneurons activated by a given odourant. The spatial distribution ofneurons activated by a given odourant does not exhibit a reliablepattern between the glomeruli and the cortex.[369–372] Piriformcortex neurons appear to respond cooperatively to glomerularcombinations[290]; on the other hand, only a few M/T cells are ableto activate a pyramidal cell in the cortex.[373] The possibility of theexistence of a simple map in the cortex appears to have beeneliminated; olfactory signal processing may be only understoodvia improved knowledge regarding cortical microcircuits.[374–379]

Another key peculiarity of the olfactory system is that olfactoryinformation projects directly to the cortex; other sensory systemsfirst project to the thalamus before information is relayed to thecortex.[88,90,91,380–385] However, a thalamic pathway is also involvedin the olfactory system; its role remains poorly understood, but ithas been proposed to concern memory and attention of olfactoryperception.[382,386–390]

Integration and processing in the central nervous system

Because the cortex receives olfactory signals via direct projectionswithout significant thalamic relay, olfactory perception is closelyassociated to brain areas related with cognitive functions.[359,391]

such as memory,[392] emotion[393,394] and language.[395,396] Unlikeas physiological studies of OE and OB, the studies knowledge inthis area concern largely humans.

The association between odour and memory was initially inves-tigated in the early 20th century[397] and was often exploredthereafter.[51,398] Odours are excellent reminders of past emotionsand experiences, as illustrated by the Proustian effect (i.e,, Proust’smadeleine).[399] Nonetheless, these interrelations between odoursand memory evoke conscious and unconscious components,which can disturb odour perception.[385]

Semantic aspects and episodic memory participate to the abilityto identify odours.[52,400–406] It should be noted that odour recogni-tion is often distinguished from odour identification; the first in-volves episodic memory,[52,406,407] whereas the latter implicates


semantic memory.[401,408] Odour identification is a very complexprocess. Indeed, humans refer to objects of the environment toprovide an odour description, but the odours of these objectsresult from a mixture of numerous odourant molecules.[409]

Perceived odours are encoded by the brain as ‘odour objects’ or‘odour images’,[384,395,409–414] and it appears difficult to find thewords to describe such odour objects, at least in Westernlanguages.[415,416]

Numerous results reported in the literature demonstrate thathumans have a poor ability to identify odours by objectnames.[51,392,417–420] Despite the fact that human language areasare located in the cortex, the descriptions of odours reveal anambiguous link between an odour perception and verbaldescription.[421,422] This is at least partially due to informationprocessing in the cortex as well as to the relationship betweenareas related to both naming and semantic association[423–426];nevertheless, semantic aspects most likely play a key role in odouridentification.[405,420] Interestingly, although it is difficult to verballydescribe an odour, words play a role in associative memory, insofaras the association between words, semantic knowledge, andodours improves the odour identification.[129,427–432] The difficultyfor humans to attach an appropriate word to an odourant appearsto be associated with personal memories,[401] and this emotionalfactor most likely plays a key role in this difficulty.[385,433] Indeed, ex-perience, familiarity and habituation play major roles in olfactoryperception and discrimination.[392,434] The context can improve,modulate or even disturb learning and/or recognition.[435–438] Forexample, when two odourants with distinct odours (A and B,respectively) are first presented simultaneously, the resultingencoding encompasses the two odour qualities. If each odourantis then smelled individually, its perception will be associated withthe other odourant with which it was originally simultaneouslyencoded. As a result, the odour of odourant A will be perceivedwith reminiscence of the odour of odourant B and vice versa. Inother words, for each odour, such encoding partially confers theperceptual quality from the other odour.[385,439] On the other hand,the link between an odour and a personal and emotionalmemory[52,440,441] possibly leads to a subjective description; as aresult, different words are used by different people to describethe same odour.[442] Moreover, even for the same person, thecapacity to name an odour is not constant over time, and the wordused to describe an odour can vary,[443] leading to lack of stability inthe verbal description of odours.



Interference with other modalities, such as pleasantness/unpleasantness, hedonic character, or associative context (whichincludes semantic context), adds to the difficulty in accuratelyidentifying and describing odours.[54,55,421,422,444–451] It alsoappears that mood, feelings, gender and cultural aspects maycontribute to odour identification and odourant qualityperception.[392,452–455] In some cases, such perception distur-bances may even cause perceptual illusions.[456–459] Moreover,on the basis of experiments carried out in rodents, the role ofolfactory perception appears to play a crucial role in mooddisorders,[460,461] and the bulbectomized rat is a well-knownmodel of depression.[462–464]

Other cause of variability of olfactory signalling

Additional factors may be involved in olfactory perceptionvariations. Aging modifies olfactory perception.[465–468] Severalpsychiatric or neurological disorders, such as Alzheimer’sdisease, schizophrenia and migraines, also induce olfactorydysfunctions.[465,469–472] In a less serious manner, metabolic statusand diet also modifies various aspects of olfactory perception. Forexample, obese rats are more interested in food odour than leanrats[473] and a similar observation was reported for humans.[474]

Moreover, experiments on humans showed that nonsatiated stateincrease the olfactory sensitivity, compared to satiated state.[474]

In mice, it was observed that hyperlipidemic diet decreasedolfactory discrimination.[475] Conversely, odourant moleculesthemselves may impact several psychological and/or biologicalparameters[21] as well as food intake,[476] suggesting that olfactorysystem plays a role in central nervous system function[477] and thatsome odourants could modify autonomic nerve activity.[478]

How olfactory coding will be deciphered?‘Point n’est besoin d’espérer pour entreprendre, ni de réussirpour persévérer’ (‘One need not hope in order to under-take, nor succeed in order to persevere’)

William I, PrinceofOrange– ‘William theSilent’ (1533–1584)

Faced with such complexity and a high level of sophistication,understanding olfactory coding can appear as a mirage and anunrealistic dream.[479] Nonetheless, numerous endeavours haveimproved the knowledge of several aspects of olfactory processingby addressing the successive steps in olfactory signalling.

Olfactory receptors strategy

The first step concerns the repertoire of ORs and consists ofdeorphanizing ORs. Indeed, similar to other GPCRs,[480] most ofthe ORs are orphan receptors, and several strategies have beendeveloped to identify their ligands. Several methods have beendeveloped,[481–489] and these state of the art approaches are regu-larly reviewed.[168,490,491] Heterologous expression of ORs has facedsome difficulties,[492–495] and the number of deorphaned ORsremains low (approximately 10% of human ORs).[168] Nevertheless,several works have led to the identification of ligands and signallingpathways for mammalian ORs.[115,491,496,497] Moreover, very recentworks carried out on rodents open a very promising way toimprove the deorphanization of ORs.[498,499] Research has alsoimproved knowledge regarding ligand binding site(s).[500] Indeed,in addition to in vitro approaches, computational approaches con-stitute a promising study path.[501] Three-dimensional models of


ORs can be built by molecular modelling, and OR folding can beperformed by homology with the structure of rhodopsin and thebeta-adrenergic receptor.[502] Docking and mutagenesis experi-ments can further allow for refinement of OR structure andlocalization of binding site(s) as well as virtual screening ofodourants[161,162,503–509]; however, the identification of the reper-toire of ORs using such approaches remains time consuming.Chemoinformatics and chemogenomics approaches constitute aninteresting alternative for receptor deorphanization, as they havebeen successfully used for several GPCRs.[510] These techniqueshave been used to link odourant molecules to their ORstargets.[508,511,512]

Olfactory bulb strategy

At the OB and brain level, progress in brain imaging techniquesallows for improvements in the knowledge about neuronalconnections and activated brain areas in rodents[291,361,513] andin humans.[514] In addition to neurophysiological approaches,computational studies propose answers to some questions. Theexploration of the controversial existence of organization at theglomerular level[515,516] and the implementation of large-scaleneural network modelling of the mammalian olfactory systemserve as examples; this strategy brings together ORNs in theepithelium, periglomerular cells, M/T cells, G cells in the OB, andthree types of cortical cells in the piriform cortex.[322]

Sensory integration and odour description

Sensory integration of one odour as one odour-object involvescomplex processing of olfactory signals by both the OB and thebrain. Recent development in brain imaging allows for improve-ments in our understanding of this research domain.[91,517–519]

To better understand the cognitive processes involved, the imple-mentation of sensory evaluations via research and experiments incognitive science on testing conditions, especially on attention andawareness of subjects, must be continuously enhanced.[459,520–522]

Thus, another challenge involves providing and using semanti-cally well-defined data based on the relevant descriptions ofodours. Such reliable data constitute an indispensable conditionfor effective computer processing of odour descriptions,[523–525]

even if non-conventional descriptive terms are used.[415,416]

Back to the stimuli

Nevertheless, the ultimate goal is to establish a link between onemolecule (the stimulus) and one perceived odour (the odour-object). The difficulty in providing a reliable and stable verbal de-scription of an odour has been described above. However, thenature of the stimulus constitutes another difficulty, which isthe absence of an unequivocal physical descriptor, unlike coloursand sounds. Indeed, colours correspond to reflected electromag-netic waves of the visible spectrum, and sounds are caused bythe vibrations of a compressible material, which generate audibleacoustic waves. In both cases, stimuli are easily described by theamplitude and the frequency of the waves, two plainly quantifi-able descriptors. However, attempts to create structure-odourmodels are criticized because different molecules share the sameodour, whereas minor structural modifications induce importantchanges in odour quality.[479] Nonetheless, this situation is farfrom unique to odourant molecules; in fact, it is a well-knownproblem in medicinal chemistry and drug design fields.[526–528]


A. Tromelin

Odorant molecules are similar to all other biologically active mol-ecules, except that their main biological property (i.e,, their per-ceived odourant quality) depends on the activation of severaltargets from the first step of the biological process. Structure-odour relationship studies have nonetheless been successful insome cases, especially for musk, camphor and sandalwoodmolecules.[529–533] However, these molecules possess relativelyrigid structures and consequently have only a few conformationalstates. Conversely, numerous odourant molecules encompassflexible chains and thus occupy a large conformational space,and the key role of conformation was previously addressed.[534]

In other words, such molecules adopt several shapes, whereasdifferent molecules map onto the same global shape. Interest-ingly, the molecule shape is a crucial molecular feature in deter-mining molecular interactions with biological targets,[535] whichis similarly observed for odourant molecules.[100,536] Nevertheless,knowledge of the shape is not sufficient to reflect the peculiarcharacteristics of a molecule. Often, odourant molecules are de-scribed using too simple features, such as the number of carbons,the number of double bounds, the number of heteroatoms, andfunctional groups, which poorly reflect essential structural charac-teristics when considered individually. As a result, the ‘key andlock’ concept has occasionally been discredited and judged tobe unsuitable for explaining the odour of a molecule, most likelydue to a rigid understanding of the notion of ‘key’. However, the‘key’ must be regarded as a pharmacophore, as described by theIUPAC definition, and not only as a structural fragment[537–539]: ‘Apharmacophore is the ensemble of steric and electronic featuresthat is necessary to ensure the optimal supramolecular interactionswith a specific biological target structure and to trigger (or to block)its biological response’.[540] Furthermore, these features must oc-cupy specific positions in 3D space, and they most likely alsocause specific changes to these positions (i.e,, 4D space).[479]

ConclusionGiven its significant complexity, olfaction is considered an emer-gent perception from an ensemble of biological and molecularmechanisms.[98,317,541,542] At the physiological level, several charac-teristics distinguish olfaction from other sensory perceptions: themultiplicity of ORs, the processing of the olfactory signal in theOB, the direct projection to the cortex, and the difficulty forhumans to provide a verbal description of odour perception.Furthermore, contrary to colours and sounds, odourant stimulicannot be reduced to a limited range of frequency and amplitudevalues of electromagnetic or mechanical waves. Indeed, odourantstimuli are created by numerous multifaceted molecules.

Significant efforts performed over a number of decades first ledto the crucial discovery of the family of genes encoding ORs,constituting a decisive turning point in this field of research. Sincethen, research in chemistry, biochemistry, molecular biology,neurobiology, functional brain imaging, cellular and molecular im-aging, psychology, and psychophysics, as well as the connectionsbetween these disciplines, has provided a significant amount ofdata. On the basis of these data and through the improvementof computing capacity, it is now possible to build computationalmodels of olfaction, allowing us to test, confirm or validate varioushypotheses in neurophysiological and the chemical fields. Thewide-spread implementation and development of computationalapproaches applied to olfaction most likely constitutes the seconddecisive turning point in understanding olfactory processes andolfactory coding.


Acknowledgements

I would like to thank Dr. Elisabeth Guichard and Dr. CharfedinneAyed for their careful rereading and their valuable comments,and I especially express my gratitude to Dr. Elisabeth Guichardfor her ongoing support. I am very grateful to Dr. Anne-Marie LeBon for her valuable help and advice on schematic drawing ofGPCR transduction pathway.

Abbreviations:AC: adenylate cyclasecAMP: cyclic adenosine monophosphateET cells: external tufted cellsGC: granule cellsGEFs: Guanine nucleotide exchange factorsGPCR: G protein-coupled receptorhOR: human olfactory receptorIP3: inositol 1,4,5-trisphosphateM cells: mitral cellsM/T cells: mitral and tufted cellsOB: olfactory bulbOE: olfactory epitheliumOR: olfactory receptorORN: olfactory receptor neuronPG cells: periglomerularPLC: phopholipase CT cells: tufted cells

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