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 intricate

signalling pathway
Anne Tromelina,b,c*
Abstract: The perception of odours is the result of the complex processing of a signal, which initiates at peripheral receptors and
ends in the brain. Along this pathway, olfactory signal processing proceeds through several steps; each step possesses its own
complexity, and all steps are also intricately connected. This review aims to describe the main intricate steps of olfactory processing in mammals, some of which remain unclear, and the close associations and overlapping nature of these steps. The causes of
both the complexity and the variability of olfactory signals are examined: the nature of olfactory receptors, involving the diversity of the genome; the spatial organization of the olfactory epithelium (OE) and the olfactory bulb (OB); connections in the OB
and from the OB to the brain; integration and processing in the brain, which leads to the final perception of odours; and odour
recognition and odour identification, which is associated with the difficulty to verbalize a reliable description of the perception in
humans. Finally, the last part of this review encompasses recent progress made to decipher and understand olfactory coding and
focuses on computational approaches. Copyright 2015 John Wiley & Sons, Ltd.
Keywords: odourant molecules; odours; odour perception; olfaction; olfactory system; review
Introduction
Olfaction is most likely the oldest sensory perception common to
living creatures,[14] and it is extremely important for
communication.[5,6] Olfactory perception is one of the most complex and least understood senses,[7] constituting a fascinating research field. Several authors have highlighted the peculiar
complexity and sophistication of olfactory signalling, involving several levels from odourant receptors in the nose to brain
processing.[810] All the steps of the currently accepted olfactory
perception model have been investigated: the mechanisms involved at olfactory epithelium level[11]; the binding to the olfactory
receptors, a peculiar group of GPCRs;[1215] the common properties
and the specificities of olfactory system and olfactory genome of
vertebrates,[16] and the consequence of human olfactory genome
variability on olfactory perception;[7] the organization at olfactory
bulb level[10]; the treatment and the integration of olfactory signal
in the brain,[15,17,18] and the role that can play concentration on perceived intensity;[19] the causes of odour quality;[20] the mood
changes induced by odours.[21] In addition, the olfactory system
possesses a high capacity of regeneration,[2226] making it able to
resist to diverse aggressions,[2730] and confers a plasticity that enables it to adapt to some changes in olfactory environment and
to maintain or restore its remarkable efficiency.[3135]
To better understand olfactory perception, it is important to consider the possible number of odours that the mammalian nose is
able to identify and discriminate. S. Arctander collected and identified odours of molecules since 1935 and published the book Perfume and Flavor Chemicals (Aroma Chemicals) in 1969.[36] The
Monographs part of this book brings together the description of
3102 odorant molecules. Among the more recent databases describing odours, the Flavor-Base[37] is one one of the largest collections of flavour molecules (4226 compounds) providing odours
descriptions. Nevertheless, these databases report odorant descriptions of identified and known odourant molecules; these molecules
could represent only a small part of all the hypothetically existing
Flavour Fragr. J. 2015
odourants having discriminable odours. For example, the number

of all synthetically feasible molecule of molecular weight less than
500 Da (small molecule universe (SMU)) is estimated to reach
10[60] and any volatile molecule of this set is likely to be an
odourant.[38,39] It was first estimated that humans can discriminate
approximately 10,000 to 100,000 odourants.[40] Mombaerts refuted
the misconception that humans can smell only 10,000 odours and
suggested that the human nose can detect hundreds of thousands,
even millions, of distinct odours.[41] Mori estimated this number to
be greater than 400,000,[42,43] whereas Cleland and Linster calculated that approximately 21000 (1.07 10301) odours could be
discerned by mice based on the number of mouse olfactory receptors (ORs) and the number of states for each receptor (1,000 and 2,
respectively).[44] More recently, approximately 1012 odours were
proposed to be detectable by humans on the basis of psychophysical testing results.[45] Nevertheless, this gigantic number is controversial and has been recently questioned.[46,47] In any case, it
appears that mammals, and even humans, are able to discriminate
a huge number of odour stimuli.
At the initial stage of olfaction in the nose, the number of involved receptors implies a combinatorial coding of odours,,[48]
whereas the final stage in the brain implicates the involvement
of areas in the brain,[49,50] which play a central role in memory,[51,52]
attention,[53,54] language[55] and consciousness.[56] Between both
* Correspondence to: Anne Tromelin, INRA, UMR1324 Centre des Sciences du
Got et de lAlimentation, F-21000 Dijon, France. E-mail: Anne.Tromelin@dijon.
inra.fr
a
CNRS, UMR6265 Centre des Sciences du Got et de lAlimentation, F-21000

Dijon, France
b
INRA, UMR1324 Centre des Sciences du Got et de lAlimentation, F-21000

Dijon, France
c
Universit de Bourgogne, UMR Centre des Sciences du Got et de
lAlimentation, F-21000 Dijon, France
Copyright 2015 John Wiley & Sons, Ltd.
A. Tromelin
stages, numerous intricate events occur at each step of the olfactory process.
In mammals, the olfactory process begins in the nasal cavity[57] at
the surface of the olfactory epithelium (OE) when a molecule binds
to an OR[5863] (Figure 1). Mammalian ORs belong to the
Rhodopsin/family A of the G protein-coupled receptor (GPCR)
superfamily,[61,6467] which constitutes the largest receptor
subfamily.[68,69] ORs are expressed on olfactory cilia immersed into
the 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 for mammals that each
neuron expresses only one receptor type (or a few types at
most).[71,7479] A series of works carried out over the last decade
aims to identify the mechanims of OR gene choice underlying the
one neuron one receptor rule.[8082] The current results suggest
that the regulation of OR expression involves both enhancer elements and an OR-elicited feedback pathway.[83]
The binding of a molecule to an OR induces a transduction cascade that produces changes in the neuron membrane potential.
These changes generate an electrical signal that progresses along
the cells axon to the glomeruli, at outside of olfactory bulb
(OB)[84] (Figure 2). Each olfactory neuron projects a single axon onto
the same glomerulus,[58,85] and ORNs expressing the same OR converge onto the same glomeruli (typically one to a few glomeruli) in
the main olfactory bulb (MOB).[86] Olfactory glomeruli are spherical
neuropils that convergent axons from sensory neurons.[10,87] Complex interactions occur among synapses within the glomerular
circuit, and the resulting olfactory information is transmitted to
the brain[8892] via axons of neuronal cells of OB.[9396] In animals,
the olfactory signal is interpreted by the brain to induce responses
for vital behaviours, such as communicating,[5,6,97] reproducing,[98]
caring for young,[99] feeding and avoiding predators.[100] In
addition, 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 manner
that is clear to non-specialists in biology, neuroscience and cognitive science. It aspires to provide a general overview of the olfactory system and to describe the main intricate steps of olfactory
processing in mammals, some of which remain unclear, and the
close associations and overlapping nature of these steps.
Figure 1. Olfactory neurons in the human nasal cavity. Head anatomy

with olfactory nerve, Patrick J. Lynch, medical illustrator, Permission Creative Commons Attribution 2.5 License 2006 (http://patricklynch.net)
wileyonlinelibrary.com/journal/ffj
Moreover, this work presents current efforts and research perspectives in understanding the olfactory process.
Causes of olfactory signal variability and

complexity: the critical steps
Olfactory receptors
Genetics: inter-species diversity vs. constancy
One of the reasons for olfaction complexity is the remarkable
structural diversity of ORs, including both the large number of
ORs for each species and variability across species as well as inside
the human genome. Since the initial discovery of ORs,[64] several
studies have investigated these receptors. OR genes of numerous
vertebrate species have been isolated and sequenced,[16,103] and
the mammalian genome has been especially studied.[77,104107]
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 gene
families.[3,109111] However, depending on the species, a large number of these genes are pseudogenes (i.e., genes that do not express
proteins).[3,41,108,112,113] Between 2025% of the mouse OR genome
is composed of pseudogenes, whereas approximately 50% of OR
genes are pseudogenes in humans.[103,106108,110,113115] This result
reveals a peculiar loss in primate and more specifically human OR
genes.[58,116120] Currently, the number of functional ORs is about
390,[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 in
mammals.[119] In the human genome, some variability across populations has been reported,[104,121124] which induces variation in
olfactory perception and in the hedonic appreciation of odour
quality.[41,124126] However, this effect appears limited,[124,127] and
some commonalities emerge across species.[1,2,4,12,128131]
Mammalian olfactory receptors are G protein-coupled receptors
(GPCR)
The fact that mammalian ORs belong to the family A of GPCRs
implies that ORs potentially possess the sophisticated properties
of these versatile receptors.[132136] GPCRs are characterized by
a seven-helix hydrophobic transmembrane domain[67,136138]
coupled with a heterotrimeric G protein (composed of -, - and
-subunits). The binding of a ligand to the transmembrane domain
induces a transduction signal beginning by the GDPGTP exchange
on the G-subunit, and following by the stimulation of effectors
molecules, that depend of the nature of G-protein subunit, as illustrated in (Figure 3).[67,139]
GPCRs are multifaceted proteins.[134,137] Their ligands act either
as agonists, antagonists, or inverse agonists,[67] and they can also
bind to orthosteric or allosteric sites.[137,140145] The conformational
flexibility and the consequences of ligand binding have also been
determined,[137,146149] and multiple activation and signalling states
have been reported and have been linked to desensitization and
conformational changes.[150,151] Moreover, the seven-helix receptor
molecules can couple to various G protein subtypes,[152] which play
a key role in transforming the sophisticated modalities of the signal
transduction induced by ligand binding into an intracellular
response.[13,61,66,132,153,154]
Olfactory system and odour perception
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 protein
subunits are identified as -, - and -subunits. Diverse signalling pathways are regulated according to the nature of G-subunit, as illustrated for the main
effectors (AC, PLC, Rho GEFs)
ORs also possess some of the same properties as GPCRs. As examples, agonist-antagonist and inverse agonist effects as well as competitive interactions have been reported for ORs.[155160] At least
two binding modes are involved in hOR1G1 activation,[159,161,162]
and the nature of the G protein appears to be crucial to determining
the agonist or antagonist activity of the ligand as well as the olfactory
signal transduction cascades.[94,163168] Schematically, two signal
transductions are implicated, namely, the so-called cAMP transduction pathway and the IP3 transduction pathway (which involve cyclic
adenosine monophosphate (cAMP) and inositol 1,4,5-trisphosphate
(IP3), respectively). cAMP plays an essential role in the olfactory signal

transduction of most odourants. Not all odourants induce cAMP
responses; however, increased IP3[84,169180] and other signalling
pathways specific to neurons could also be involved.[181,182]
Role of other receptors and signalling pathways
Olfactory signals may also be associated with other signalling
pathways. Beta-adrenergic receptors,[11,183185] muscarinic
receptors,[11,186] nicotinic acetylcholine receptors,[187] ion channels
A. Tromelin
of ORNs,[188,189] adrenaline,[190] some neuropeptides,[191] and
peripheral events[192] modulate the olfactory signal and OR
expression on cell membranes.
Olfactory coding
In humans, the detection and discrimination of numerous odours
through less than 400 ORs implies a combinatorial coding of
odours, wherein one molecule can bind to several ORs and one
OR recognizes several odourants. Such olfactory coding was first
suggested in the early 1970s,[193] subsequently established at the
ORN level,[194,195] and ultimately detailed and formalized at the
OR level by B. Malnic et al.[48] (Figure 4). Therefore, odour identities
are ensured by the recognition of odourants by different combinations of ORs.[58,63,196198] However, more narrowly tuned ORNs are
noted in the OE compared with broadly tuned ORNs.[199]
Organisation in the olfactory epithelium
For ethical reasons, studies of OE of mammals were and are carried
out on laboratory animals, mostly on rodents, and not on humans.
The spatial organization of the OE was first observed in the middle
of the last century, but histological studies were initially challenging given the finesse and proximity of ORNs.[200] After discovering
the gene family encoding ORs, some progress has been
made.[42,70,201,202] It appears that the OE can be divided into four
zones, which roughly correspond to four zones in the OB.[203] ORNs
expressing a specific OR gene are typically localized to one of the
four zones within the OE, but they are dispersed across the respective zone of the OE.[71,204,205] Moreover, despite the fact that ORNs
expressing the same OR are dispersed over a large area, their
axons project to specific regions of the OB.[206,207]
Figure 4. Combinatorial olfactory coding. Molecular shapes are schematised

to the left in black. For each molecule, activated ORs are indicated in dark grey.
Adapted from Malnic et al.[48] Source: Olfactory receptors ORs (principle of
smell decoding); Author: Joanna Komider, 3 June 2011
In addition to the ORs, a second family of receptors is expressed

at the OE. These receptors were called trace amine-associated receptors (TAARs) because they are involved in traces of amines
detection.[208] TAARs belong to GPCR family, but they are distinct
to 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 olfactory coding;[70,77,84,93] however, the lack of point-to-point connections between the OE and OB suggests that the spatial
organization in the OE and in the OB constitute two distinct levels
of information processing of the olfactory system.[10,58,84,205,213]
Furthermore, the organization of ORs in the OE would explain
the differences observed between ortho- and retronasal odour
perception.[214217]
Olfactory bulb
The OB is the first site of synaptic processing in the vertebrate
olfactory pathway,[218] and it was first studied at the end of the
19th century.[219] A precise description was provided by Cajal,[220]
which was further elucidated by several works by Pinching
et al.[221,222] As for OE and also for ethical reasons, results report
experiments 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 onto
defined glomeruli in the OB has been observed in mammals,
suggesting the existence of a stereotyped bilaterally symmetric
map of glomerular organization.[42,84,86,206,223230] This glomerular
organization appears to be a general strategy for vertebrates;
nevertheless, the location of activity domains is specific to each
species.[231233]
Several studies have proposed a relationship between structural
features, odours, odourant molecule concentrations and the
glomerular-layer activity organization.[226,228,234237] Thus, the spatial organization of the glomeruli forms an olfactory map that
could possess fundamental functional meaning, likely related to
various structural features of odourants and/or perceived
quality.[238246]
Molecules that belong to the same chemical family but vary in
carbon chain length activate glomeruli that are located near each
other; nevertheless, glomeruli activity patterns partly or do not
overlap.[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 for
some molecules as observed for molecules sharing certain
functional groups and/or carbon chain length.[226,235,237,243,250]
Nevertheless, it is not the case for all molecules.[10,251] The scale
of observation is critically important, and no correspondence
emerges between the proximity of glomeruli and their odour
sensitivities with fine-scale observations. Conversely, a sparse
response of glomeruli and mitral cells is observed at moderate
concentrations of odourants (approximately 0.1 to 1% of the saturated vapour at room temperature; the number of recruited receptors depends on the odourant molecule concentration).[252256]
These works indicate that the glomeruli and associated circuits
are organized non-topographically. In addition, the data suggest
that glomeruli containing similar information regarding odour
stimuli are not necessarily neighbouring but rather connected by

the circuits in the glomerular layer and in the deep OB by
mitral/tufted cells (M/T cells).[256,257] Thus, it may appear that the
spatial organization of glomeruli does not adhere to the rule of
the anatomical principle that spatial organization, with neurons
being ordered according to their similarity in receptive field
properties.[258] Nevertheless, despite the absence of chemotopic
organization, glomeruli can exhibit a tunotopic organization, i.e.,
a hierarchical arrangement into clusters related to their odourtuning similarities, thereby respecting the organization principle
that exists in other sensory systems.[259]
The apparent map observed at a coarse scale could result
from a developmental pattern and was not necessarily formed
to play a role in olfactory coding.[260] Moreover, glomerular
organization is exclusively observed in laboratory animals and
could depend on environmental conditions.[260] Observations
performed on human OBs revealed an abnormally increased
number of glomeruli, suggesting that the convergence of axons
into the OB is not the same for humans[261] and for some other
mammals as marmoset[262] and whale.[263] These two recent
results are particularly striking. Indeed, the marmosets possess
about 400 intact OR genes, but the revealed total number of
glomeruli 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 total
number of glomeruli reaches 4 000, while whales carry only 80
intact OR genes, being a ratio of 50. This raises questions about
the number of glomeruli observed for laboratory mice, which
could be hypothetically not the same for wild mice. In this
way, laboratory mice would be a unique and peculiar
phenomenom.[260] Whatever be the case, the meaning of such
glomerular organization remains unexplained.
Axon guidance from ORNs to glomeruli
The rules governing axon guidance from ORNs to glomeruli are
currently better known; nevertheless, they are still not completely
understood.[96,260,264,265] Axons generate a structure without target
guidance, and the role of receptors expressed in the OE appears to
be crucial in the formation of glomeruli.[213,224,264,266272] Moreover, such axon guidance was also observed for the 2-adrenergic
receptor in receptor substitution experiments.[185,273,274] The role
of cAMP signalling and the nature of the G protein are also essential for suitable axonal convergence.[275277] The study of the sequential projection of ORN axons and the identification of ORglomerulus pairs were made possible using a genetic approach,
which permits the visualization of the axonal projections from
ORNs to the OB and is a very promising method. However, this
method is currently limited to some mouse ORs.[96,203,224,267,277]
difficult to elucidate.[284] Each glomerulus is innervated by the primary dendrites of M/T cells, which submit the olfactory signal to be
processed within the OB and modulate the olfactory
signal.[44,87,93,218,252,253,285291]
The traditional view of the organization of the OB divides the OB
in several layers, with each layer containing one type of
neuron.[292] A useful description of the organization of the OB
circuit was recently published that description differs from the traditional view, showing that conventionally categorized neurons
are in fact composed by heterogeneous populations, and that
OB neurons belong to very diverse neuronal types.[282,293] However, more recent studies revealed the imperfect meaning of such
a classification given neuronal diversity, which was seldom considered until recently. According to the conventional classification,
there are five types of cells, starting from the glomerular layer to
the deep OB: periglomerular (PG) cells, tufted cells (T) cells,
external tufted cells (ET) cells, mitral cells (M) cells, and granule
cells (GC). Nevertheless, several works suggest that encoding of
olfactory stimuli requires a higher neuronal complexity.[294,295]
The connections between glomeruli as well as the connections
to the glomerular layer and to the deep OB have been
investigated.[95,278,296300] PG cells most likely play a crucial role[297]
in modulating the input via an on/off mechanism.[301] Lateral inhibitory 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] Therefore, the exact function of the connections and their organization
in the OB is not yet clearly understood.
Broadly speaking, interactions in the OB can be described as a
sophisticated balance between inhibitory and excitatory interactions that are ensured by dendritic connections.[180,230,302,305310]
These interactions participate in an ensemble of normalization,
decorrelation, oscillation and synchronization of olfactory
signalling[281,311316] and have been studied as a computational
system.[44,317322] This signal processing appears to be extraordinarily
complex, involving several independent signals[323] and resulting in
temporary, dynamic modulations of olfactory signalling.[317,324331]
Moreover, the activity of neurons in the OB depends on
breathing,[332,333] awake vs anesthetized states,[334336] habituation, experience and context.[337342] The impact of the environment and odour exposure concerns not only the activity of
neurons but also the structure of the OB (i.e,, the density of cells
and their connections) due to the great plasticity of this
system.[343347] Another source of the modulation of signalling is
derived from cortical feedback projections to the OB, which
contribute to plasticity in the OB.[328,333,348356]
From olfactory bulb to brain areas
Connections in the olfactory bulb

The connections between glomeruli as well as across the OB play
key roles in olfactory signal processing.[278] The electrical activity
and the potential wave accompanying olfactory stimuli have received serious attention for many years.[279281] However, despite
all of these efforts, the functional processes of the olfactory
network are still not fully understood.[260,282] Indeed, the OB is
not just a structure where ORNs converge to glomeruli at the
surface of the OB before M/T cells convey the olfactory signal from
the glomeruli to the brain.[278] It became apparent that connections in the OB and from the OB to the brain are interlaced in a very
intricate manner,[283] and the axonal targets of M/T cells are
Encoded information by the OB is transmitted to brain areas as recently summarized (Figure 5).[278] M/T cells mainly project their
axons to the piriform cortex[357]; however, several other cortical
areas are also targeted, including the anterior olfactory nucleus,
olfactory tubercle, lateral entorhinal cortex, and the cortical
amygdala.[10,92,278,292,358361] Moreover, M/T cells project to different cortical areas.[10,260,291,362364] Axons of T cells project to areas
close to one another (e.g., anterior olfactory nucleus and olfactory
tubercle). Conversely, axons of M cells project to scattered areas
(e.g., anterior olfactory nucleus, piriform cortex, cortical region of
olfactory tubercle, tenia tecta, cortical amygdala, and lateral entorhinal cortex).[278] As a consequence, M cells and T cells possess different roles in the olfactory process that contribute to odourant
A. Tromelin
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 drawing
represents the ventrolateral view of the brain. Tufted cells project their axons to the other side of the OB (intrabulbar projection) and to the anterior olfactory
nucleus, which link to the contralateral OB, and also to the posteroventral part of anterior olfactory nucleus, ventrorostral part of anterior piriform cortex, and
cap 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 Biology
Vol. 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)
discrimination.[365,366] Moreover, all of these connections are

dynamic and exhibit great plasticity.[359,367] Temporal aspects of
transmission by M/T cells are also involved in odour identification
and discrimination.[291,364,368]
For most sensory perceptions, neurons are clustered according
the stimuli. Conversely, no clear olfactory map or at least no understandable correspondence exists for the spatial organization of
neurons activated by a given odourant. The spatial distribution of
neurons activated by a given odourant does not exhibit a reliable
pattern between the glomeruli and the cortex.[369372] Piriform
cortex neurons appear to respond cooperatively to glomerular
combinations[290]; on the other hand, only a few M/T cells are able
to activate a pyramidal cell in the cortex.[373] The possibility of the
existence of a simple map in the cortex appears to have been
eliminated; olfactory signal processing may be only understood
via improved knowledge regarding cortical microcircuits.[374379]
Another key peculiarity of the olfactory system is that olfactory
information projects directly to the cortex; other sensory systems
first project to the thalamus before information is relayed to the
cortex.[88,90,91,380385] However, a thalamic pathway is also involved
in the olfactory system; its role remains poorly understood, but it
has been proposed to concern memory and attention of olfactory
perception.[382,386390]
Integration and processing in the central nervous system
Because the cortex receives olfactory signals via direct projections
without significant thalamic relay, olfactory perception is closely
associated to brain areas related with cognitive functions.[359,391]
such as memory,[392] emotion[393,394] and language.[395,396] Unlike
as physiological studies of OE and OB, the studies knowledge in
this area concern largely humans.
The association between odour and memory was initially investigated in the early 20th century[397] and was often explored
thereafter.[51,398] Odours are excellent reminders of past emotions
and experiences, as illustrated by the Proustian effect (i.e,, Prousts
madeleine).[399] Nonetheless, these interrelations between odours
and memory evoke conscious and unconscious components,
which can disturb odour perception.[385]
Semantic aspects and episodic memory participate to the ability
to identify odours.[52,400406] It should be noted that odour recognition is often distinguished from odour identification; the first involves episodic memory,[52,406,407] whereas the latter implicates
semantic memory.[401,408] Odour identification is a very complex

process. Indeed, humans refer to objects of the environment to
provide an odour description, but the odours of these objects
result from a mixture of numerous odourant molecules.[409]
Perceived odours are encoded by the brain as odour objects or
odour images,[384,395,409414] and it appears difficult to find the
words to describe such odour objects, at least in Western
languages.[415,416]
Numerous results reported in the literature demonstrate that
humans have a poor ability to identify odours by object
names.[51,392,417420] Despite the fact that human language areas
are located in the cortex, the descriptions of odours reveal an
ambiguous link between an odour perception and verbal
description.[421,422] This is at least partially due to information
processing in the cortex as well as to the relationship between
areas related to both naming and semantic association[423426];
nevertheless, semantic aspects most likely play a key role in odour
identification.[405,420] Interestingly, although it is difficult to verbally
describe an odour, words play a role in associative memory, insofar
as the association between words, semantic knowledge, and
odours improves the odour identification.[129,427432] The difficulty
for humans to attach an appropriate word to an odourant appears
to be associated with personal memories,[401] and this emotional
factor most likely plays a key role in this difficulty.[385,433] Indeed, experience, familiarity and habituation play major roles in olfactory
perception and discrimination.[392,434] The context can improve,
modulate or even disturb learning and/or recognition.[435438] For
example, when two odourants with distinct odours (A and B,
respectively) are first presented simultaneously, the resulting
encoding encompasses the two odour qualities. If each odourant
is then smelled individually, its perception will be associated with
the other odourant with which it was originally simultaneously
encoded. As a result, the odour of odourant A will be perceived
with reminiscence of the odour of odourant B and vice versa. In
other words, for each odour, such encoding partially confers the
perceptual quality from the other odour.[385,439] On the other hand,
the link between an odour and a personal and emotional
memory[52,440,441] possibly leads to a subjective description; as a
result, different words are used by different people to describe
the same odour.[442] Moreover, even for the same person, the
capacity to name an odour is not constant over time, and the word
used to describe an odour can vary,[443] leading to lack of stability in
the verbal description of odours.

Interference with other modalities, such as pleasantness/
unpleasantness, hedonic character, or associative context (which
includes semantic context), adds to the difficulty in accurately
identifying and describing odours.[54,55,421,422,444451] It also
appears that mood, feelings, gender and cultural aspects may
contribute to odour identification and odourant quality
perception.[392,452455] In some cases, such perception disturbances may even cause perceptual illusions.[456459] Moreover,
on the basis of experiments carried out in rodents, the role of
olfactory perception appears to play a crucial role in mood
disorders,[460,461] and the bulbectomized rat is a well-known
model of depression.[462464]
ORs can be built by molecular modelling, and OR folding can be

performed by homology with the structure of rhodopsin and the
beta-adrenergic receptor.[502] Docking and mutagenesis experiments can further allow for refinement of OR structure and
localization of binding site(s) as well as virtual screening of
odourants[161,162,503509]; however, the identification of the repertoire of ORs using such approaches remains time consuming.
Chemoinformatics and chemogenomics approaches constitute an
interesting alternative for receptor deorphanization, as they have
been successfully used for several GPCRs.[510] These techniques
have been used to link odourant molecules to their ORs
targets.[508,511,512]
Other cause of variability of olfactory signalling
Olfactory bulb strategy
Additional factors may be involved in olfactory perception

variations. Aging modifies olfactory perception.[465468] Several
psychiatric or neurological disorders, such as Alzheimers
disease, schizophrenia and migraines, also induce olfactory
dysfunctions.[465,469472] In a less serious manner, metabolic status
and diet also modifies various aspects of olfactory perception. For
example, obese rats are more interested in food odour than lean
rats[473] and a similar observation was reported for humans.[474]
Moreover, experiments on humans showed that nonsatiated state
increase the olfactory sensitivity, compared to satiated state.[474]
In mice, it was observed that hyperlipidemic diet decreased
olfactory discrimination.[475] Conversely, odourant molecules
themselves may impact several psychological and/or biological
parameters[21] as well as food intake,[476] suggesting that olfactory
system plays a role in central nervous system function[477] and that
some odourants could modify autonomic nerve activity.[478]
At the OB and brain level, progress in brain imaging techniques

allows for improvements in the knowledge about neuronal
connections and activated brain areas in rodents[291,361,513] and
in humans.[514] In addition to neurophysiological approaches,
computational studies propose answers to some questions. The
exploration of the controversial existence of organization at the
glomerular level[515,516] and the implementation of large-scale
neural network modelling of the mammalian olfactory system
serve as examples; this strategy brings together ORNs in the
epithelium, periglomerular cells, M/T cells, G cells in the OB, and
three types of cortical cells in the piriform cortex.[322]
How olfactory coding will be deciphered?

Point nest besoin desprer pour entreprendre, ni de russir
pour persvrer (One need not hope in order to undertake, nor succeed in order to persevere)
William I, Prince of Orange William the Silent (15331584)
Faced with such complexity and a high level of sophistication,
understanding olfactory coding can appear as a mirage and an
unrealistic dream.[479] Nonetheless, numerous endeavours have
improved the knowledge of several aspects of olfactory processing
by addressing the successive steps in olfactory signalling.
Olfactory receptors strategy
The first step concerns the repertoire of ORs and consists of
deorphanizing ORs. Indeed, similar to other GPCRs,[480] most of
the ORs are orphan receptors, and several strategies have been
developed to identify their ligands. Several methods have been
developed,[481489] and these state of the art approaches are regularly reviewed.[168,490,491] Heterologous expression of ORs has faced
some difficulties,[492495] and the number of deorphaned ORs
remains low (approximately 10% of human ORs).[168] Nevertheless,
several works have led to the identification of ligands and signalling
pathways for mammalian ORs.[115,491,496,497] Moreover, very recent
works carried out on rodents open a very promising way to
improve the deorphanization of ORs.[498,499] Research has also
improved knowledge regarding ligand binding site(s).[500] Indeed,
in addition to in vitro approaches, computational approaches constitute a promising study path.[501] Three-dimensional models of
Sensory integration and odour description

Sensory integration of one odour as one odour-object involves
complex processing of olfactory signals by both the OB and the
brain. Recent development in brain imaging allows for improvements in our understanding of this research domain.[91,517519]
To better understand the cognitive processes involved, the implementation of sensory evaluations via research and experiments in
cognitive science on testing conditions, especially on attention and
awareness of subjects, must be continuously enhanced.[459,520522]
Thus, another challenge involves providing and using semantically well-defined data based on the relevant descriptions of
odours. Such reliable data constitute an indispensable condition
for effective computer processing of odour descriptions,[523525]
even if non-conventional descriptive terms are used.[415,416]
Back to the stimuli
Nevertheless, the ultimate goal is to establish a link between one
molecule (the stimulus) and one perceived odour (the odourobject). The difficulty in providing a reliable and stable verbal description of an odour has been described above. However, the
nature of the stimulus constitutes another difficulty, which is
the absence of an unequivocal physical descriptor, unlike colours
and sounds. Indeed, colours correspond to reflected electromagnetic waves of the visible spectrum, and sounds are caused by
the vibrations of a compressible material, which generate audible
acoustic waves. In both cases, stimuli are easily described by the
amplitude and the frequency of the waves, two plainly quantifiable descriptors. However, attempts to create structure-odour
models are criticized because different molecules share the same
odour, whereas minor structural modifications induce important
changes in odour quality.[479] Nonetheless, this situation is far
from unique to odourant molecules; in fact, it is a well-known
problem in medicinal chemistry and drug design fields.[526528]
A. Tromelin
Odorant molecules are similar to all other biologically active molecules, except that their main biological property (i.e,, their perceived odourant quality) depends on the activation of several
targets from the first step of the biological process. Structureodour relationship studies have nonetheless been successful in
some cases, especially for musk, camphor and sandalwood
molecules.[529533] However, these molecules possess relatively
rigid structures and consequently have only a few conformational
states. Conversely, numerous odourant molecules encompass
flexible 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, whereas
different molecules map onto the same global shape. Interestingly, the molecule shape is a crucial molecular feature in determining molecular interactions with biological targets,[535] which
is similarly observed for odourant molecules.[100,536] Nevertheless,
knowledge of the shape is not sufficient to reflect the peculiar
characteristics of a molecule. Often, odourant molecules are described using too simple features, such as the number of carbons,
the number of double bounds, the number of heteroatoms, and
functional groups, which poorly reflect essential structural characteristics when considered individually. As a result, the key and
lock concept has occasionally been discredited and judged to
be unsuitable for explaining the odour of a molecule, most likely
due to a rigid understanding of the notion of key. However, the
key must be regarded as a pharmacophore, as described by the
IUPAC definition, and not only as a structural fragment[537539]: A
pharmacophore is the ensemble of steric and electronic features
that is necessary to ensure the optimal supramolecular interactions
with a specific biological target structure and to trigger (or to block)
its biological response.[540] Furthermore, these features must occupy specific positions in 3D space, and they most likely also
cause specific changes to these positions (i.e,, 4D space).[479]
Conclusion
Given its significant complexity, olfaction is considered an emergent perception from an ensemble of biological and molecular
mechanisms.[98,317,541,542] At the physiological level, several characteristics distinguish olfaction from other sensory perceptions: the
multiplicity of ORs, the processing of the olfactory signal in the
OB, the direct projection to the cortex, and the difficulty for
humans to provide a verbal description of odour perception.
Furthermore, contrary to colours and sounds, odourant stimuli
cannot be reduced to a limited range of frequency and amplitude
values of electromagnetic or mechanical waves. Indeed, odourant
stimuli are created by numerous multifaceted molecules.
Significant efforts performed over a number of decades first led
to the crucial discovery of the family of genes encoding ORs,
constituting a decisive turning point in this field of research. Since
then, research in chemistry, biochemistry, molecular biology,
neurobiology, functional brain imaging, cellular and molecular imaging, psychology, and psychophysics, as well as the connections
between these disciplines, has provided a significant amount of
data. On the basis of these data and through the improvement
of computing capacity, it is now possible to build computational
models of olfaction, allowing us to test, confirm or validate various
hypotheses in neurophysiological and the chemical fields. The
wide-spread implementation and development of computational
approaches applied to olfaction most likely constitutes the second
decisive turning point in understanding olfactory processes and
olfactory coding.
Acknowledgements
I would like to thank Dr. Elisabeth Guichard and Dr. Charfedinne
Ayed for their careful rereading and their valuable comments,
and I especially express my gratitude to Dr. Elisabeth Guichard
for her ongoing support. I am very grateful to Dr. Anne-Marie Le
Bon for her valuable help and advice on schematic drawing of
GPCR transduction pathway.
Abbreviations:
AC: adenylate cyclase
cAMP: cyclic adenosine monophosphate
ET cells: external tufted cells
GC: granule cells
GEFs: Guanine nucleotide exchange factors
GPCR: G protein-coupled receptor
hOR: human olfactory receptor
IP3: inositol 1,4,5-trisphosphate
M cells: mitral cells
M/T cells: mitral and tufted cells
OB: olfactory bulb
OE: olfactory epithelium
OR: olfactory receptor
ORN: olfactory receptor neuron
PG cells: periglomerular
PLC: phopholipase C
T cells: tufted cells
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Odour Perception A Review of An Intricate Signalling Pathway

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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 intricate

Flavour Fragr. J. 2015

odourants having discriminable odours. For example, the number

CNRS, UMR6265 Centre des Sciences du Got et de lAlimentation, F-21000

INRA, UMR1324 Centre des Sciences du Got et de lAlimentation, F-21000

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Figure 1. Olfactory neurons in the human nasal cavity. Head anatomy

Causes of olfactory signal variability and

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Flavour Fragr. J. 2015

Olfactory system and odour perception

Flavour Fragr. J. 2015

(IP3), respectively). cAMP plays an essential role in the olfactory signal

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Figure 4. Combinatorial olfactory coding. Molecular shapes are schematised

In addition to the ORs, a second family of receptors is expressed

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Flavour Fragr. J. 2015

Olfactory system and odour perception

Connections in the olfactory bulb

Flavour Fragr. J. 2015

Copyright 2015 John Wiley & Sons, Ltd.

discrimination.[365,366] Moreover, all of these connections are

semantic memory.[401,408] Odour identification is a very complex

Copyright 2015 John Wiley & Sons, Ltd.

Flavour Fragr. J. 2015

Olfactory system and odour perception

ORs can be built by molecular modelling, and OR folding can be

Other cause of variability of olfactory signalling

Olfactory bulb strategy

Additional factors may be involved in olfactory perception

At the OB and brain level, progress in brain imaging techniques

How olfactory coding will be deciphered?

Flavour Fragr. J. 2015

Sensory integration and odour description

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B. C. Prasad, R. R. Reed. Trends Genet. 1999, 15, 150.

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Flavour Fragr. J. 2015

Olfactory system and odour perception

Flavour Fragr. J. 2015

R. M. Patel, J. M. Pinto. Clin. Anat. 2014, 27, 54.

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200. W. E. Le Gros Clark. Yale J. Biol. Med. 1956, 29, 83.

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Flavour Fragr. J. 2015

Olfactory system and odour perception

Flavour Fragr. J. 2015

G. Lowe. J. Neurophysiol. 2002, 88, 64.

Copyright 2015 John Wiley & Sons, Ltd.

E. Wnuk, A. Majid. Cognition 2014, 131, 125.

Copyright 2015 John Wiley & Sons, Ltd.

Flavour Fragr. J. 2015

Olfactory system and odour perception

Flavour Fragr. J. 2015

507. L. Gelis, S. Wolf, H. Hatt, E. M. Neuhaus, K. Gerwert. Angew. Chem.-Int.

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