Download Maps of Odorant Molecular Features in the Mammalian Olfactory Bulb

Physiol Rev 86: 409 – 433, 2006;
doi:10.1152/physrev.00021.2005.
Maps of Odorant Molecular Features
in the Mammalian Olfactory Bulb
KENSAKU MORI, YUJI K. TAKAHASHI, KEI M. IGARASHI, AND MASAHIRO YAMAGUCHI
Department of Physiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
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Introduction
Odorant Molecular Features and Perceived “Odor”
Two-Dimensional Representation of Odorant Receptor Maps in the Olfactory Bulb
Individual Glomeruli Represent a Specific Combination of Molecular Features
A. MRR property of individual glomeruli
B. MRR property of individual mitral/tufted cells
Clustering of Glomeruli Detecting a Similar Combination of Molecular Features
A. Cluster A
B. Cluster B
C. Cluster C
D. Cluster D
E. Cluster E
F. Cluster F
G. Cluster G
H. Cluster H
I. Cluster I
J. Comparison with maps obtained with other methods and in other species
Zones and Clusters in the Olfactory Bulb
Topographic Map of Characteristic Molecular Features
Molecular-Feature Clusters May Participate in Odor Quality Perception
A. Cluster A and odor quality
B. Cluster B and odor quality
C. Cluster C and odor quality
D. Cluster D and odor quality
E. Cluster H and odor quality
F. Cluster I and odor quality
Mapping the Natural Odor in the Molecular-Feature Maps of the Olfactory Bulb
A. Spatial representation of spoiled food smells in the odor maps
B. Spatial representation of urine odors in the mouse olfactory bulb
Conclusion
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Mori, Kensaku, Yuji K. Takahashi, Kei M. Igarashi, and Masahiro Yamaguchi. Maps of Odorant Molecular Features
in the Mammalian Olfactory Bulb. Physiol Rev 86: 409 – 433, 2006; doi:10.1152/physrev.00021.2005.—The olfactory bulb
(OB) is the first relay station of the central olfactory system in the mammalian brain and contains a few thousand
glomeruli on its surface. Because individual glomeruli represent a single odorant receptor, the glomerular sheet of the OB
forms odorant receptor maps. This review summarizes the emerging view of the spatial organization of the odorant
receptor maps. Recent studies suggest that individual odorant receptors are molecular-feature detecting units, and so are
individual glomeruli in the OB. How are the molecular-feature detecting units spatially arranged in the glomerular sheet?
To characterize the molecular-feature specificity of an individual glomerulus, it is necessary to determine the molecular
receptive range (MRR) of the glomerulus and to compare the molecular structure of odorants within the MRR. Studies
of the MRR mapping show that 1) individual glomeruli typically respond to a range of odorants that share a specific
combination of molecular features, 2) each glomerulus appears to be unique in its MRR property, and 3) glomeruli with
similar MRR properties gather together in proximity and form molecular-feature clusters. The molecular-feature clusters
are located at stereotypical positions in the OB and might be part of the neural representation of basic odor quality.
Detailed studies suggest that the glomerular sheet represents the characteristic molecular features in a systematic,
gradual, and multidimensional fashion. The molecular-feature maps provide a basis for understanding how the olfactory
cortex reads the odor maps of the OB.
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I. INTRODUCTION
FIG. 1. A schematic diagram illustrating the axonal connectivity pattern between the olfactory epithelium and the olfactory bulb. Olfactory epithelium in rats
and mice is divided into four zones (zones
1– 4). A given odorant receptor is expressed by sensory neurons located within
one zone. Individual olfactory sensory neurons express a single odorant receptor. Olfactory sensory neurons expressing a given
odorant receptor are distributed widely in
the epithelial zone and converge their axons onto a few topographically fixed glomeruli that are located within a corresponding zone of the olfactory bulb. Each
glomerulus represents a single odorant
receptor.
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The olfactory system plays a key role in the daily life
of mammals. Major roles of the olfactory system include
identification of foods; judging the edibility; detection of
impending danger such as predator; recognition of their
mate, parents, and offspring; and detecting signals for a
variety of social behaviors including the maintenance of
territories.
The olfactory information is carried in a vast variety
of odor molecules (odorants), small volatile compounds
with molecular mass ⬍300 Da. Each object, an apple for
example, typically emits hundreds of different odorants. It
has been estimated that more than 400,000 different compounds are odorous to the human nose (31). More surprisingly, no two compounds have ever been found to
have exactly the same odor quality (9), suggesting that the
olfactory system can detect and discriminate more than
400,000 different compounds. How does the olfactory
system recognize and discriminate numerous different
odorants? This is one of the basic and challenging questions in the field of olfactory research.
In addition to the question of odorant discrimination,
olfactory research has been challenging the difficult puzzle of the molecular structure-odor relationship (85).
Since the discovery of the methods for determining the
molecular structure of odorants, chemists, especially fragrance/flavor chemists, have noted a variety of correlations between the molecular structure of odorants and
their perceived “odor.” In addition, psychophysical studies of olfaction were pursued to elucidate the rules for
odorant structure-odor relationships (3, 9, 63, 81). It is
surprising that there exist relationships between the molecular structure and “odor,” in spite of the large gap
between the two. The structure of odorants is at the
molecular level in the range of nanometers, whereas the
perceived odor of the odorants is the subjective description of human olfactory sense.
The knowledge of the structure-odor relationship is
fragmental and far from complete. Furthermore, postulated relationship rules contain many exceptions. Nonetheless, studies on the structure-odor relationship have
accumulated a large number of specific examples and
provided theoretical frameworks of individual specific
examples that can be tested experimentally in the olfactory system of both human and animals. These studies
thus raised a notion that the information of molecular
features detected and processed at the levels of olfactory
sensory neurons and olfactory bulb (OB) may play a key
role in the perception of odor quality of odorants in the
brain. Thus olfactory research faces another important
question: What is the neural basis for the molecular structure-odor relationship? To this end, the use of panels of
odorants with systematic variation of molecular structure
for sensory stimulation is crucial.
The OB is the first relay station of the central olfactory system in the mammalian brain (Fig. 1) and has a
cortical structure with distinct layers and numerous glomerular modules (66, 100). Individual sensory neurons in
the olfactory epithelium project a single axon to a single
glomerulus in the OB. The glomerular sheet of the OB
thus forms a map of olfactory axon terminals. The axonal
projection of olfactory sensory neurons to the glomeruli is
precisely organized in such a way that olfactory sensory
neurons expressing a given odorant receptor (OR) converge their axons to a few topographically fixed glomeruli
(Fig. 1) (13, 62, 68, 83, 122). Since individual glomeruli
represent a single OR, the glomerular sheet of the OB
forms a map of ORs.
ODOR MAPS IN THE OLFACTORY BULB
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ual odorants are represented in the space of entire glomerular sheet of the OB. For many different odorants,
these studies revealed the odorant-specific spatial pattern
of glomerular activities in the OB. These studies showed
also that the odorant-induced activity maps are arranged
in a symmetric fashion; one map (lateral map) in the
rostro-dorso-lateral hemisphere of the OB and the other
(medial map) in the caudo-medial hemisphere. However,
except for the fMRI method, these methods map the
response only to a single odorant in each animal.
The second group of methods can map responses to
many different odorants in the same OB of an animal.
These methods include optical imaging of intrinsic signals, optical imaging with Ca2⫹-sensitive dyes or voltagesensitive dye, imaging with pHluorin, and fMRI. With the
use of these methods, it is possible to determine the range
of odorants that activate an individual glomerulus [molecular receptive range (MRR) of the glomerulus] (68) and
to examine the spatial representation of the MRR property in the glomerular sheet of the OB. However, again
except for the fMRI method, these methods allow us to
map only the exposed surface of the OB. Because of this
technical difficulty, we have been successful, so far, to
image only the dorsal and postero-lateral surfaces of
the OB.
The two groups of methods complement each other
and have begun to reveal the basic spatial organization of
the odor map in the OB. For the extensive knowledge of
the spatial representation of individual odorants, see
the recent reviews by Leon and Johnson (41, 52), Xu et
al. (127), and Shepherd et al. (100). Detailed data of the
spatial representation of individual odorants in the OB
can be seen at the websites of the Leon laboratory
(http://leonlab.bio.uci.edu/index.html), the Restrepo laboratory (http://www.uchsc.edu/rmtsc/restrepo/), and the OdorMapDB(http://senselab.med.yale.edu/senselab/OdorMapDB/
default.asp).
Instead of reviewing the whole knowledge about the
spatial representation of individual odorants, this review
focuses on the question about the spatial arrangement of
represented ORs in the OB. We review the emerging ideas
regarding the spatial representation of MRR properties in
the glomerular sheet of the mammalian OB. Recent studies with the optical imaging method have accumulated
information on the MRR map, although the regions that
are explored with this method cover only a half of the
lateral hemisphere of the OB. The results so far obtained
suggest that the mammalian OB represents systematically
the characteristic molecular features of odorants, which
reflect the systematic spatial representation of ORs. We
suggest that the systematic representation of characteristic molecular features may participate in the initial grouping and processing of odorant molecular information at
the level of the OB. The information carried by neuronal
activities in the molecular-feature map of the OB may be
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How are individual odorants encoded in the glomerular OR map in the OB? To address this question, it is
necessary to record and map the odorant-evoked activity
in the glomerular sheet of the OB. Because individual
mitral/tufted cells in the OB send a single primary dendrite to a single glomerulus, the glomerular OR map can
be studied also by examining odorant-evoked responses
of mitral/tufted cells. In the 1950s, Adrian (1) recorded
odorant-evoked neuronal activity in the mammalian OB,
and first demonstrated the odorant selectivity of responses of individual mitral/tufted cells. Spatial mapping
of the odorant-evoked activity was first performed by the
Shepherd’s group using the 2-deoxyglucose (2-DG) uptake method (97, 114). These pioneering 2-DG studies
demonstrated that each odorant elicits a characteristic
spatial pattern of glomerular activities in the OB and
provided the first information regarding the relationship
between molecular structure of odorants and the spatial
pattern of glomerular activities. In addition, the 2-DG
studies showed a first hint that the odorant-induced activity is represented symmetrically between lateral and
medial hemispheres of the OB (100).
Since then, a variety of methods have been used to
spatially map the odorant-induced activities of glomeruli
or mitral/tufted cells in the vertebrate OB. The mapping
methods include 2-DG uptake (39, 41, 42, 52, 97, 111, 114);
optical imaging with voltage-sensitive dyes (23, 45, 46,
112); electrophysiological recording from individual mitral/tufted cells (37, 44, 65); expression of immediate early
genes such as c-fos (29, 78, 91), c-jun (7), zif268 (38), and
activity-regulated cytoskeleton-associated (ARC) genes
(56, 57); optical imaging of intrinsic signals (10, 36, 59, 88,
116, 120); expression of phosphorylated ERK (61); imaging with calcium-sensitive dyes (24, 124); imaging using
pHluorin (11); and fMRI (128, 129).
The results clearly showed that a given odorant activates a specific combination of glomeruli that are located and distributed at stereotypical positions in the OB.
Different odorants activate a distinct combination of glomeruli. The odorant-specific spatial positions of activated
glomeruli are conserved across different animals of the
same species. The principle of odor mapping is expressed
widely by different vertebrate species (25, 76) and by
invertebrates such as honeybees (26, 90), moths (32, 51),
and flies (49, 125). Thus, either in the OB or in the antennal lobe, the insect analog of the vertebrate OB, the
principle of odor mapping is conserved.
The mapping methods can be classified into two
groups in terms of advantages and disadvantages in the
mapping of odorant-induced activities in the OB. The first
group of methods has the advantage of the ability to map
the responses over the entire OB and includes the methods using 2-DG uptake, immediate early gene expression,
phosphorylated ERK expression, and fMRI. Studies with
these methods addressed the question about how individ-
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utilized and processed at higher levels in the central olfactory system to form the neuronal representation of the
olfactory image of objects and to perceive the odor quality
of objects.
II. ODORANT MOLECULAR FEATURES AND
PERCEIVED “ODOR”
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The relationship between the molecular structure of
odorants and their subjectively perceived “odor” has been
one of the central questions of the fragrance/flavor chemists and organic chemists. Based on the assessment of
odor similarity in relation to the molecular structure, they
noted two different but overlapping categories of odorant
molecular features (3, 9, 63, 81, 85). One category of
odorant molecular feature that has been studied is a polar
functional group that contains an oxygen, or a nitrogen, or
a sulfur atom. The other category of odorant molecular
feature is the molecular profile that is formed mainly by
the overall molecular shape.
The polar functional groups are known as “osmophores” (63) and strongly influence the perceived odor
quality. As shown in Figure 2A, a homologous series of
aliphatic acids share the same functional group (carboxyl
group, -COOH) and have similar odor quality (pungent,
sour, fatty, and rancid). A homologous series of aliphatic
alcohols share the hydroxyl group (-OH) and have similar
“fresh and sweet” note. However, odors of aliphatic acids
are distinct from those of aliphatic alcohols. Thus the
comparison of odors between the two homologous series
suggests a major role of polar functional groups for the
odor quality perception.
Polar functional groups that have a strong influence
on the perceived odor include carboxyl group (-COOH),
aldehyde group (-CHO), hydroxyl group (-OH), ketone
group (⬎C⫽O), ester group (-COO-), amino group (-NH2),
isothiocyanate group (-N⫽C⫽S), and thiol group (-SH)
among others (Fig. 2B).
The molecular profile is equivalent to molecular
shape or three-dimensional structure and is known to
have a strong influence on perceived odor. The benzene
ring (Fig. 2C) is one of the characteristic molecular profiles shared by many benzene-family odorants. The similarity of perceived odor of benzene-family hydrocarbon
odorants (e.g., benzene, o-, m-, and p-xylenes, toluene,
etc.) suggests the importance of the benzene-ring profile
in odor quality perception. Cyclic terpene hydrocarbons
(e.g., limonene and pinene) share a molecular profile (Fig.
2C) and have citrusy or woody odor in common. Because
hydrocarbons lack any polar functional group, the molecular profile may play a critical role for perception of the
odor of hydrocarbon odorants.
In odor molecules, polar functional groups and molecular profiles overlap each other. A specific combina-
tion of polar functional groups and molecular profiles may
determine the basic framework of molecular features of
odorants that are critical for their perceived odor. For
example, furan and its derivatives have a specific combination of polar functional groups and molecular profiles,
as shown in Figure 3. The furans share the caramellic
odor (Fig. 3).
What is the molecular origin of the molecular featureodor relationship? One plausible explanation is the following. The polar functional groups and molecular profiles are essential for odorants to bind ORs and thus to
activate olfactory sensory neurons (4, 43, 54, 103, 133).
ORs are seven-transmembrane G protein-coupled receptors (12). Knowledge of the three-dimensional structure
of other G protein-coupled receptors such as rhodopsin
(77, 79) has provided a template for constructing computational models of ORs to investigate interactions between features of odorants and specific amino acid residues (odorant receptive sites) within transmembrane domains (20, 43, 55, 80, 103–106, 121). The distinct structure
of the odorant-receptive site in each OR recognizes a
specific combination of polar functional groups, molecular profiles, and other molecular features and appears
to determine the range of ligand odorants that are
effective in activating the OR (4, 103). Because of the
critical role of the molecular features in the odorant-OR
binding, they are also named “molecular determinants”
or “odotopes” (99).
Recent studies show that individual ORs bind to a
range of odorants having similar molecular features (54,
133). The range of odorants that bind to an OR is called
the MRR (67, 68) of the OR. We define the characteristic
molecular features of an OR as those molecular features
shared by the odorants effective in activating the OR.
Thus, at the molecular level, an individual OR presumably
functions as a molecular-feature detecting unit. Because
mice have a repertoire of ⬃1,000 OR genes, odorants are
thought to be initially probed by ⬃1,000 different molecular-feature detecting units.
The logic of molecular-feature detection at the OR
level (molecular level) is converted to the cellular and
neuronal network levels such that signals of distinct combinations of odorant molecule features are processed in
parallel by a large number of molecular-feature detecting
cells and modules (6, 66, 98).
At the cellular level, an individual sensory neuron in
the olfactory epithelium may function as a molecularfeature detecting unit. Because each olfactory sensory
neuron expresses a single OR, it may respond to a range
of odorants having similar combinations of molecular
features (4). Therefore, the characteristic molecular features of an olfactory sensory neuron can be determined
by examining the MRR and molecular features shared by
the odorants within the MRR.
ODOR MAPS IN THE OLFACTORY BULB
At the neuronal circuit level, an individual glomerulus in the OB may function as a molecular-feature detecting unit. Because individual glomeruli represent a single
OR, it is possible to determine the MRR and characteristic
molecular features of each glomerulus by the same token.
In summary, initial olfactory processing at the levels
of ORs, olfactory sensory neurons, and olfactory glomeruli is characteristic in such a way that odorant molecular
features are processed in parallel by a large number of
molecular-feature detecting units. The information regarding the molecular-features may be utilized by the
higher olfactory systems to form the conscious perception of odor quality.
The topographic arrangement of columnar modules in
the sensory maps of the neocortex provided a basis for
understanding the function of sensory systems in the brain
(33, 34, 70). The mammalian OB has a cortical structure and
contains a large number of glomerular modules (66, 68, 100).
The estimated number of glomeruli in each OB is ⬃1,800 in
the mouse (87), ⬃2,400 – 4,200 in the rat (58, 86), and ⬃6,300
in the rabbit (86). An individual glomerular module consists
of several thousands converging olfactory axons, ⬃10 –20
mitral cells, and ⬃50 –70 tufted cells (2, 86). Individual glomeruli represent a single OR (62, 83, 122). The glomerular
sheet of the OB forms OR maps.
The mouse has a repertoire of ⬃1,000 types of ORs.
Each OB contains ⬃1,800 glomeruli (87). Individual ORs are
represented by a few (typically two) glomeruli. In rats and
mice, each OB contains two mirror-image maps of ORs, the
lateral and medial maps (62, 72, 83, 122). For a majority of
ORs, each OR is represented by two sites: one site in the
lateral map and a corresponding site in the medial map. For
a small group of ORs, however, each OR is represented by a
single glomerulus in one site (115). These glomeruli are
located at the ventral midline of the OB.
To illustrate the spatial arrangement of the glomerular
sheet that covers the oval OB, it is convenient to transform
the three-dimensional glomerular sheet to a two-dimensional plane map with a defined scale and a coordinate
reference system. Such a flattened map is useful for comparing and compiling data obtained by different mapping
methods and in different individual animals. The map
proved to be useful also for detecting the distortion of odor
maps in Semaphorin 3A-deficient mice (118). Several methods have been proposed for the two-dimensional representation of odor maps in the mammalian OB, each having
advantages and disadvantages (40, 50, 114, 129) (see also the
websites of Restrepo’s lab and OdorMapDB). For the readers who are not familiar with the three-dimensional anatomy
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of the mammalian OB, however, we recommend first to
refer to the three-dimensional representation of odor maps,
as shown, for example, by Leon’s group (41).
We have generated the two-dimensional glomerular
maps of rat and mouse OB as follows (Fig. 4) (38, 72, 118).
Consecutive frontal sections of the OB are Nissl-stained or
immunohistochemically labeled for NCAM to clearly see the
glomeruli. In each section, we first define as reference points
the dorsomedial edge (arrow heads) of the mitral cell layer.
The glomeruli are then traced. The trace of the ring of
glomeruli is flattened by opening it along its ventral edge.
The traces are then aligned from anterior (top) to posterior
(bottom) using the dorsomedial edge as a reference line to
make an overall unrolled map of glomeruli.
The constructed map has a dorsal center view. The
flattened map indicates symmetrical mirror-image arrangement of glomeruli into the lateral and medial maps
(Fig. 4). A flattened map with ventral center view can also
be formed by cutting the glomerular trace at the dorsomedial edge and using the ventral edge as a marker for the
alignment of the glomerular traces.
IV. INDIVIDUAL GLOMERULI REPRESENT
A SPECIFIC COMBINATION OF
MOLECULAR FEATURES
A. MRR Property of Individual Glomeruli
To examine whether individual glomeruli in the OB
function as molecular-feature detecting units, it is necessary
to determine the MRR of individual glomeruli and to compare the molecular structure of odorants that are effective in
activating the glomeruli. For this purpose, it is essential to
use a large panel of stimulus odorants with a systematic
variation of molecular features. It is also critical to select
those methods that enable us to examine the response of
individual glomeruli in the same OB of an animal to numerous odorants in the panel.
Optical imaging of intrinsic signals is one of the useful
methods to examine the MRR property of individual glomeruli (10, 36, 59, 88, 116, 120). It has been shown with this
method that some glomeruli can discriminate even between
enantiomers (89). Although the intrinsic signal-imaging
method has several weak points that include small signalto-noise ratio and the lack of histological correlation of the
signal with glomeruli, the method provides a convenient way
of recording the glomerular responses in the same OB to
many different odorants (typically ⬃70). Using the intrinsic
signal-imaging method and a panel of systematically changing odorants, we thus examined the MRR property of a large
number of glomeruli that were located in the dorsal, dorsolateral, and postero-ventrolateral surfaces of the rat OB (36,
116, 117, 120). Comparison of MRR properties among the
imaged glomeruli revealed the following.
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III. TWO-DIMENSIONAL REPRESENTATION
OF ODORANT RECEPTOR MAPS IN THE
OLFACTORY BULB
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ODOR MAPS IN THE OLFACTORY BULB
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1) Individual glomeruli typically respond to a range
of odorants that share a specific combination of molecular features.
2) Each glomerulus in the lateral map appears to be
unique in its MRR property.
3) Glomeruli with similar MRR properties are located
in proximity and form molecular-feature clusters.
Results 1 and 2 are consistent with the notion that
individual glomeruli represent a single OR and that different
glomeruli in each map of the OB may represent different
ORs. These results suggest that each glomerulus can be
characterized by its MRR property and by its characteristic
molecular features. In other words, individual glomeruli represent the glomerulus-specific combination of molecular
features. Result 3 will be discussed in detail in section V.
B. MRR Property of Individual Mitral/Tufted Cells
Mitral/tufted cells are principal neurons in the OB and
project their axons to the olfactory cortex. Individual mitral/
tufted cells extend a single primary dendrite to a single
glomerulus and within the glomerulus receive excitatory
synaptic inputs from many olfactory axons. Thus the MRR
property of an individual mitral/tufted cell may strongly
reflect the MRR property of its own glomerulus. Studies with
single-unit recording from mitral/tufted cells basically support this hypothesis, although the MRR property of individual mitral/tufted cells is determined not solely by the MRR
property of its own glomerulus but is modified by synaptic
interactions within the local circuit of the OB (67, 68, 130).
Odorant-response specificity of individual mitral/tufted
cells was examined using the systematic panel of odorants
and extracellular single-unit recording in the rabbit OB (37,
44, 65) and in the rat OB (73, 117). Although there are many
reports on the odorant-response specificity of mitral/tufted
cells, it is critical to use a large panel of systematically
changing odorants and to have the knowledge of odor maps
in the OB (as described in sects. V–VII) to examine the MRR
property of recorded mitral/tufted cells. Our results show
that individual mitral/tufted cells in the dorsomedial region
of the OB respond to a subset of aliphatic acids and aliphatic
aldehydes with a similar hydrocarbon chain length. Mitral/
tufted cells in the ventromedial region of rabbit OB respond
to a range of aliphatic and aromatic compounds with similar
molecular structures. Thus individual mitral/tufted cells typically respond to a range of odorants that share a specific
FIG. 2. Molecular structure and perceived “odor” of odorants. A: aliphatic acids and alcohols. A homologous series of aliphatic acids share a
carboxyl group (-COOH) and have “pungent,” “sour,” “rancid,” and “fatty” odor quality. A homologous series of aliphatic alcohols share the hydroxyl
group (-OH) and have “fresh” and “sweet” odor. B: examples of polar functional groups present in odorants. Odorants with each group have distinct
odor quality. C: examples of molecular profiles present in odorants. Molecular structure of odorants is shown by ball-and-stick models. Gray ball
indicates carbon atom; white ball, hydrogen atom; red ball, oxygen atom; blue ball, nitrogen atom; yellow ball, sulfur atom. This representation
convention applies to Figs. 2, 3, 7, 9, 10, and 12.
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FIG. 3. Molecular structure of furan and its
derivatives that have caramellic-sweet odor. Furan (1,4-epoxy-1,3-butadiene) and its derivatives
(furfural, furfuryl mercaptan, furaneol, maltol,
5-methyl furfural) have similar caramellic-sweet
notes in common.
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MORI, TAKAHASHI, IGARASHI, AND YAMAGUCHI
combination of molecular features. These studies indicate
that individual mitral/tufted cells are tuned to a specific
combination of molecular features.
A recent study by Lin et al. (53) supports the idea that
individual mitral cells in the mouse OB function as a
molecular-feature detector. Urine contains numerous
odorous compounds with a variety of molecular structures. Using the gas chromatography single-unit recording
method, they demonstrated that individual urine-responsive mitral cells respond selectively to only one (or two)
compound among many components of urine.
V. CLUSTERING OF GLOMERULI DETECTING
A SIMILAR COMBINATION OF
MOLECULAR FEATURES
As stated in section I, this review focuses on the
question about the spatial arrangement of MRR representation in the glomerular sheet of the mammalian OB. We
think that our recent studies (36, 116, 117, 120) provide
the most extensive mapping to date of the relation between molecular structure and its neural representation
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at the level of individual glomeruli in the mammalian OB.
We thus summarize these studies in this section.
Figure 5A shows examples of MRR properties of
glomeruli at the dorsal surface of the rat OB. For the
detailed MRR properties of individual glomeruli, readers
may refer to the data in Takahashi et al. (116) for the
dorsal and dorsolateral surfaces and in Igarashi and Mori
(36) for the postero-ventro-lateral surface of the OB. Examination of the relationship between the spatial position
of glomeruli and their MRRs clearly indicates that glomeruli with similar MRR tend to locate in a close proximity
and form clusters (Fig. 5, A and B). The clusters of glomeruli can be seen more clearly by the spatial mapping of
characteristic molecular features using the method of
superimposing three-dimensional structures of effective
odorants, as shown in section VII. We tentatively classify
four clusters of glomeruli (clusters A–D) in the dorsal
surface, three clusters (clusters E–G) in the dorsolateral
surface, and two clusters (clusters H and I ) in the postero-ventrolateral surface of the rat OB (Fig. 6). The MRR
property of glomeruli in each cluster will be described in
detail below. These descriptions form the basis for the
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FIG. 4. An unrolled map of the glomerular layer in
the mouse olfactory bulb (OB). The flattened glomerular layer of a mouse OB (a dorsal center view) is shown.
Each circle represents an individual glomerulus. Solid
circles indicate OCAM-positive glomeruli, while open
circles indicate OCAM-negative glomeruli. Note that
OCAM-negative glomeruli (zone 1) are segregated from
OCAM-positive glomeruli (zones 2– 4). An open arrow
indicates a tonguelike region composed of OCAM-positive glomeruli in the rostromedial part of the OB. A red
dashed line indicates the presumed boundary between
the lateral map and medial map. Black dashed lines
indicate the boundary between OCAM-negative zone
(zone 1) and OCAM-positive zones (zones 2– 4). Arrowheads indicate dorsomedial edge. [Modified from Nagao
et al. (72).]
ODOR MAPS IN THE OLFACTORY BULB
spatial mapping of the MRR property in the glomerular
sheet of the OB. The molecular structure of stimulus
odorants is shown in Figure 2A and Figure 7.
A. Cluster A
Glomeruli in cluster A are located at the anteromedial part of the dorsal surface (Fig. 6). Because it is
relatively easy to image the dorsal surface, the MRR property of glomeruli in cluster A has been most thoroughly
studied among the nine clusters.
Glomeruli in cluster A respond to aliphatic acids and
aliphatic aldehydes. When examined with a homologous
series of aliphatic acids and aldehydes, individual glomeruli respond to subsets of these odorants with a similar
carbon chain length. These glomeruli respond also to
aliphatic acids and aldehydes with a branched hydrocarbon structure or with one or more double bonds in the
carbon chain.
The cluster A glomeruli respond also to a subset of
esters with a relatively long carbon chain of acid-part.
Glomeruli in the most posterior part of cluster A respond
also to diketones. A subset of cluster A glomeruli responds also to benzaldehyde and benzoic acid. Thus the
molecular features of odorants that are effective in activating the cluster A glomeruli share either a carboxyl
group (-COOH), a diketone group [-(CO)(CO)-], or an
ester group (-COO-). These are functional groups that
have two oxygen atoms located in proximity. In addition,
odorants having a single carbonyl group (⬎C⫽O) at the
end of the molecule are effective in activating the cluster
A glomeruli.
2. Nitrogen-containing functional groups
A large subset of cluster A glomeruli responds also to
alkylamines that contain an amino group (-NH2) (117).
These results suggest that ORs represented by the subset
of cluster A glomeruli respond to both fatty acids with
carboxyl group (-COOH) and alkylamines with amino
group (-NH2). Because it is difficult to conceive that a
single part in the odorant receptive site of OR binds to
both carboxyl and amino groups, we speculate that the
represented ORs can recognize both carboxyl and amino
groups at different parts of their odorant-receptive site. If
that is the case, these ORs resemble fish ORs that detect
amino acids [H2N-CH(R)-COOH] (15, 22, 24). This raises
the possibility that the alkylamine-responsive glomeruli in
cluster A represent fishlike class I ORs (see sect. VI)
(17, 132).
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3. Molecular profiles
Based on the carbon chain length of the effective
aliphatic acids, we tentatively classify the cluster A glomeruli into three subclusters: A-1, A-2, and A-3 (Fig. 5B).
Glomeruli in A-1 respond selectively to aliphatic acids
and aldehydes with a long carbon chain, those in A-2 to
acid and aldehydes with a carbon chain of middle size,
and those in A-3 selectively to acids and aldehydes with a
short carbon chain. However, this is not the case for the
carbon chain length of the homologous series of alkylamines (117).
Benzoic acid and benzaldehyde (Fig. 12B) have a
molecular profile of a benzene ring and an oxygen-containing functional group (carboxyl group or aldehyde
group) in their molecular structure. These odorants activate several glomeruli in the subclusters A-2 and A-3.
B. Cluster B
Cluster B is located in the anterior region of the
lateral part of the dorsal surface of the OB (Fig. 6).
1. Oxygen-containing functional groups and
molecular profiles
Glomeruli in cluster B respond to aliphatic alcohols
with a relatively long carbon chain and to a wide range of
aliphatic ketones. The cluster B glomeruli also respond to
a subset of esters. Whereas cluster A glomeruli respond to
a subset of esters with a relatively long carbon chain of
acid part, cluster B glomeruli preferentially respond to a
different subset of esters with a relatively long carbon
chain of alcohol-part. A majority of cluster B glomeruli
respond also to anisole and its derivatives that have a
methoxy group (-O-CH3) and a carbon side chain arranged
at the para-position of the benzene ring.
Thus the molecular features of odorants that are
effective in activating the cluster B glomeruli are a combination of elongated carbon chain structures with a hydroxyl group (-OH), an alkoxyl group (-O-R), or a carbonyl
group (⬎C⫽O) attached at one side of the molecule.
The glomeruli in the posterior part of the cluster B
respond to a wider range of aliphatic ketones and aliphatic alcohols than those in the anteromedial part. We
thus tentatively classify cluster B glomeruli into two subclusters: B-1 (the anteromedial glomeruli) and B-2 (the
posterolateral glomeruli) (Fig. 5B).
C. Cluster C
Glomeruli in cluster C are located at the central
region of the lateral part of the dorsal surface (Fig. 6).
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1. Oxygen-containing functional groups
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ODOR MAPS IN THE OLFACTORY BULB
419
(4OH-6OH). C-2 glomeruli invariably respond to salicylaldehyde (Fig. 12B), a phenol derivative with a carbonyl
group attached to the ortho-position. Glomeruli in subcluster C-3 respond relatively selectively to phenols and
phenyl ethers. Glomeruli in subcluster C-4 respond also
to short aliphatic ketones and aliphatic ethers.
D. Cluster D
Cluster D is located at the caudal region of the lateral
part of the dorsal surface (Fig. 6).
1. Functional groups and molecular profiles
1. Oxygen-containing functional groups and
molecular profiles
E. Cluster E
Glomeruli in cluster C respond to phenol family odorants, molecules having a hydroxyl group attached to the
benzene ring. Many of the cluster C glomeruli respond
also to phenyl ethers. Thus odorants effective in activating cluster C glomeruli share the molecular features composed of a benzene ring with a hydroxyl group, a methoxy
group, or an ethoxy group (-O-CH2-CH3). Thus the characteristic molecular features of those glomeruli include
the combination of the benzene-like hydrocarbon profile
and the hydroxyl or alkoxyl group.
Based on the detailed MRR properties and the positions of glomeruli, we tentatively divide the cluster C into
four subclusters: C-1, C-2, C-3, and C-4 (Fig. 5B). In
addition to phenol family odorants, C-1 glomeruli respond
to aliphatic alcohols with a relatively short carbon chain
Cluster E glomeruli are located at the dorsal-most
part of the lateral surface of the OB (Fig. 6). We could not
characterize the odorant-response specificity of cluster E
glomeruli because these glomeruli did not systematically
respond to any classes of odorants in our panel.
F. Cluster F
Cluster F is located at the rostroventral part of the
dorsolateral surface of the OB (Fig. 6).
1. Oxygen-containing functional groups
Glomeruli in cluster F are activated by aliphatic ketones. A subset of glomeruli responds also to secondary
FIG. 5. Molecular receptive range property of glomeruli in clusters A, B, C, and D in the dorsal surface of an olfactory bulb. A: top row indicates
12 structural classes of odorants. Abbreviated names of odorants are shown in the second row. See Figs. 2 and 7 for the name and structure of these
odorants. The left column indicates glomerular number. The glomerular number corresponds to that shown in B. The magnitude of glomerular
responses to each odorant is classified into 4 levels: very strong (the largest circle), strong (a large circle), moderate (a small circle), and weak (the
smallest circle) and are shown in each box. Open boxes indicate no response. B: spatial arrangement of glomeruli in the imaged region of the dorsal
and dorsolateral surfaces of the OB. The molecular receptive range (MRR) of individual glomeruli is shown in A. Glomeruli with similar MRR
properties locate in a close proximity. Cluster A (pink) is located at the most dorsal part of the imaged region. Cluster B (yellow and blue), cluster
C (green), and cluster D (blue and pale blue) are arranged from anterior to posterior in the dorsolateral OB.
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FIG. 6. Molecular feature clusters of glomeruli in the dorsal and
posterolateral surfaces of the olfactory bulb. In the dorsal surface, 7
clusters (clusters A–G) are defined from the anteromedial to posterolateral direction. In the lateral surface, 2 clusters (clusters H and I) are
defined. Anterolateral and medial surfaces of the OB are yet to be
explored by the optical imaging method.
Glomeruli in cluster D tend to respond to wide structural classes of odorants. Most notable are their responses to a variety of ketones: aliphatic ketones, aliphatic-aromatic ketones, diketones, and cyclic ketones.
Compared with glomeruli in cluster B, the cluster D glomeruli tend to respond to a subset of aliphatic ketones
with relatively short carbon side chains (Fig. 5B). We
tentatively classify the cluster D glomeruli into two subclusters: D-1 and D-2. Medially located subcluster D-1
glomeruli respond to creosol and eugenol, phenol derivatives with a methoxy group attached at the ortho-position and a carbon side chain at the para-position. Laterally located subcluster D-2 glomeruli respond to aldehydes, alcohols, and ethers in addition to ketones.
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ODOR MAPS IN THE OLFACTORY BULB
alcohols, phenyl ethers, diketones, aliphatic-aromatic ketones, and cyclic ketones. We tentatively divide cluster F
glomeruli into two subclusters: anteriorly located F-1 and
posteriorly located F-2 (116). Compared with F-1 glomeruli, F-2 glomeruli tend to respond to a wide range of
aliphatic ketones and cyclic ketones.
2. Molecular profiles
421
1. Molecular profiles
Individual glomeruli in cluster H respond to one or
more of the benzene-family odorants. However, these
glomeruli show no or only a weak response to cyclic
terpene hydrocarbons. In addition, some of the cluster H
glomeruli respond also to open-chain hydrocarbons.
2. Oxygen-containing functional groups
Most of the glomeruli in cluster H respond also to
one or more of the benzene derivatives with a polar
functional group, such as anisole (which has a methoxy
group on the benzene ring), phenol (a hydroxyl group),
benzaldehyde (an aldehyde group), or acetophenone (a
carbonyl group) (Fig. 7).
Thus the characteristic molecular features of odorants effective in activating glomeruli in cluster H appear
to be benzene-related hydrocarbon skeleton.
G. Cluster G
Cluster G is located at the ventrocaudal part of the
dorsolateral surface of the OB (Fig. 6).
1. Oxygen-containing functional groups
I. Cluster I
Cluster I is located at the anteroventral region of the
postero-ventrolateral surface of the OB (Fig. 6).
Many glomeruli in cluster G respond to phenyl
ethers, diketones, aliphatic ketones with relatively short
side chains, aliphatic-aromatic ketones, cyclic ketones,
and ethers. The cluster G glomeruli are tentatively parceled into two subclusters: G-1 and G-2. Ventrally located
G-1 glomeruli respond to aliphatic alcohols, while dorsally located G-2 does not respond to them.
1. Molecular profiles
2. Molecular profiles
2. Oxygen-containing functional groups
Glomeruli in cluster G invariably respond to hydrocarbons as well as odorants with oxygen-containing functional groups. Interestingly, cluster G glomeruli preferentially respond to benzene family hydrocarbon odorants
rather than to terpene hydrocarbons. Thus the benzene
ring structure (Fig. 2C) could be one of the main determinants for the activation of cluster G glomeruli.
Several glomeruli in the ventral part of cluster I
respond also to the cyclic terpene ketones (for example,
d-pulegone or d-carvone) or cyclic terpene alcohols (for
example, d-menthol).
Thus the characteristic molecular features of odorants in cluster I contain the hydrocarbon skeleton shared
by terpene hydrocarbons, terpene ketones, and terpene
alcohols.
Figure 8 summarizes the response specificity of clusters A–G in terms of chemical classes of odorants. The
glomeruli responsive to a similar combination of chemical
classes are located in close proximity and form molecular-feature clusters. The results shown in this section
suggest that ORs represented in a same molecular-feature
H. Cluster H
Cluster H glomeruli extend from the posterocentral
region to the posterodorsal region of the postero-ventrolateral surface of the OB (Fig. 6).
Glomeruli in cluster I respond to at least one of the
cyclic terpene hydrocarbons. Many of the cyclic terpene
hydrocarbon-responsive glomeruli in cluster I respond
also to a subset of benzene-family odorants and openchain hydrocarbons.
FIG. 7. Molecular structures of odorants that were used for the optical imaging of the dorsal surface of the olfactory bulb. Based on the
molecular structure, the odorants are categorized into 12 chemical classes. For aliphatic acids and primary aliphatic alcohols, see Fig. 2A. This figure
shows 4 aldehydes (pink), 4 aliphatic alcohols (yellow), 3 cyclic alcohols (light brown), 7 phenol and its derivatives (green), 5 phenyl ethers (yellow
green), 2 diketones (dark brown), 15 aliphatic ketones (blue), 3 aliphatic-aromatic ketones (dark blue), 10 cyclic ketones (pale blue), 3 ethers
(purple), and 5 hydrocarbons (gray). The abbreviated name for each odorant is shown with color codes and applies to Figs. 5 and 11.
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In addition to odorants with oxygen-containing functional groups, odorants effective in activating cluster F
glomeruli include hydrocarbon odorants that do not have
any polar functional group. Among the hydrocarbon odorants, the cluster F glomeruli preferentially respond to
terpene hydrocarbons. Thus the terpene hydrocarbon
structure (Fig. 2C) may be one of the main determinants
for the activation of the cluster F glomeruli.
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MORI, TAKAHASHI, IGARASHI, AND YAMAGUCHI
FIG. 8. Response selectivity of clusters A–G to structural classes of odorants. The top row indicates structural
classes of stimulus odorants. The left column indicates molecular feature clusters.
Response magnitude and selectivity of
individual clusters for each odorant class
are shown by gray scale. Open box indicates very weak or no response. Note
that individual clusters selectively respond to a specific combination of odorant classes. A-A ketones, aliphatic-aromatic ketones.
J. Comparison With Maps Obtained With Other
Methods and in Other Species
With regard to the idea of molecular-feature clusters,
it is interesting to compare our maps with the intrinsic
signal imaging maps reported by other laboratories (10,
59, 88). Because the latter studies are designed to address
questions other than the molecular-feature clusters, it is
difficult to compare the reported maps of odorant-in-
duced glomerular activity with our maps of MRR. Nevertheless, the reported maps at the dorsal surface of the rat
and mouse OB are consistent with the idea of cluster
organization, especially with regard to the position and
odorant specificity of cluster A.
Using the 2-DG method, Johnson et al. (40) collected
a huge number of measurements of glomerular activities
in response to a large panel of odorants with systematic
variation of the molecular structure. With the 2-DG
method, it is possible to map the glomerular response
only to a single odorant in each animal. Therefore, they
compiled the maps from many different rats and found
that almost the entire glomerular sheet is covered by
glomerular “modules” (clusters of nearby glomeruli) and
that each module responds to a particular molecular feature. Because of the difference in the measurement
method and the definition of glomerular clusters, it is
difficult to compare our maps of molecular-feature clusters with the maps of the glomerular “modules,” especially in terms of the shape and boundary of each cluster.
However, the overall comparison in terms of odorant
specificity and spatial position suggests that the glomerular “modules” in the 2-DG studies are similar in general
FIG. 9. Examples of odorants that are not examined yet
for the MRR mapping. Molecular structure of examples of
lactones, pyridines, pyrazines, and musks. These classes of
odorants have specific odor quality.
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cluster or subcluster may selectively respond to odorants
that have similar combination of molecular features. The
molecular-feature clusters A–I are located at stereotypical positions in the glomerular sheet.
Although the panel of odorants we used is relatively
large and covers several chemical classes, it nevertheless
contains only a small subset of odorants in each class. In
addition, the panel lacks important classes of odorants
that include thiols, sulfides, lactones, pyridines, pirazines,
and musks (Fig. 9). By expanding the panel of stimulus
odorants, it is therefore necessary to refine the description of MRR properties of individual glomeruli and individual clusters.
ODOR MAPS IN THE OLFACTORY BULB
VI. ZONES AND CLUSTERS IN THE
OLFACTORY BULB
Most ORs are classified into four zonal subsets (84,
123). Because individual glomeruli in the OB represent a
single OR, glomeruli can be classified into zonal subsets
(66, 68). With the use of an antibody that recognizes a cell
adhesion molecule OCAM, it is possible to immunohistochemically distinguish glomeruli that receive input from
zone 1 ORs (OCAM-negative glomeruli) from those that
receive input from zones 2– 4 ORs (OCAM-positive glomeruli) (131). In the flattened glomerular sheet of the OB
(Fig. 4), OCAM-negative glomeruli are largely segregated
from OCAM-positive glomeruli (64, 72, 95, 131). OCAMnegative glomeruli are located at the rostro-dorsal part of
the OB (zone 1 of the OB), while OCAM-positive glomeruli
are distributed at the latero-ventral and postero-medioventral parts of the OB (zones 2– 4 in the OB, Figs. 1
and 4).
By combining the optical imaging method and the
OCAM immunohistochemistry, we examined the spatial
relationship between bulbar zones and the molecularfeature clusters in the rat OB (Fig. 10) (36, 116). Most
glomeruli in clusters A-D are in the OCAM-negative zone
1, whereas those in clusters F-I are in the OCAM-positive
zones 2– 4. The boundary between zone 1 and zones 2– 4
is located near the lateral margin of clusters B, C, and D.
Figure 10 shows a schematic diagram illustrating the
spatial map of the glomerular sheet of the OB. In each
cluster, one or two representative examples of the MRR
of individual glomeruli are shown by the structural formulas of the odorants (indicated by an arrow and surrounding line). Thick color lines on the structural formulas indicate the common and characteristic molecular
Physiol Rev • VOL
features that are shared by effective odorants for individual glomeruli.
Comparison of the MRR property indicates a clear
difference in the characteristic molecular features of individual glomeruli between the group of clusters A-D (in
zone 1) and that of clusters F-I (in zones 2– 4). Odorants
effective in activating glomeruli in clusters A-D (in zone 1)
have one or more polar functional group(s) in common.
Thus the presence of a specific polar functional group
tends to be of primary importance to activate glomeruli in
zone 1. In contrast, odorants effective in activating glomeruli in clusters F-I (in zones 2– 4) have one or more
molecular profile(s) in common, suggesting that the overall molecular shape tends to be critical in activating glomeruli in zones 2– 4. For example, characteristic molecular features of glomeruli in clusters H and I are the
hydrocarbon profiles or relatively nonpolar parts of odorants (Fig. 10).
OR genes are classified into two broad families, class
I and class II (27, 132). Class I ORs (fish type, present in
both fish and tetrapods) tend to recognize relatively hydrophilic compounds with one or more polar functional
group(s), whereas tetrapod-specific class II ORs tend to
recognize more hydrophobic compounds (48, 54, 60).
Class I ORs are expressed in zone 1 of the olfactory
epithelium, while class II ORs are expressed in all the four
zones (14, 17, 54). Thus glomeruli in zone 1 represent both
class I ORs and class II ORs, while glomeruli in zones 2– 4
are most likely to represent class II ORs. Thus the difference in the characteristic molecular features between the
groups of clusters A-D (in zone 1) and F-I (in zones 2– 4)
might correlate in part to the zonal difference in the
expression of class I and class II ORs. Further studies are
necessary to examine the spatial relationships among the
clusters, zones, and OR classes in the glomerular OR
maps of the OB.
VII. TOPOGRAPHIC MAP OF CHARACTERISTIC
MOLECULAR FEATURES
As described in sections IV, V, and VI, comparison of
the MRR property among many glomeruli in the dorsal
and lateral surfaces of rat OB reveals the following results.
1) Individual glomeruli typically respond to a range
of odorants that share a specific combination of molecular features.
2) Each glomerulus (in the lateral map) appears to be
unique in its MRR property.
3) Glomeruli with a similar MRR property locate in
proximity and form molecular-feature clusters.
Results 1 and 2 suggest that each glomerulus represents a specific combination of molecular features. They
thus raise the possibility that each glomerulus can be
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to the molecular-feature clusters in our study. For example,
glomerular “modules” a and c (40) may correspond to clusters A and D in our study, respectively. The assembly of
glomerular “modules” d, e, f, h, j, k, and l may roughly
correspond to the assembly of clusters H and I. Thus the
two different methods presumably shed light on the same
basic spatial arrangement of glomeruli from different angles.
The idea of molecular-feature clusters is consistent
with the evidence that olfactory sensory neurons expressing homologous odorant receptor genes project their axons to neighboring glomeruli (119). The molecular-feature
clusters are found also in the fish OB (25, 47, 76). Furthermore, recent studies indicate that a primitive form of
molecular-feature clusters is present also in the larval and
adult antenna lobe of insects (16, 49, 51, 90). These results
suggest that the clustering of glomeruli that detect similar
molecular features is the basic spatial organization of the
OB (and antennal lobe) and is conserved across a wide
variety of species.
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MORI, TAKAHASHI, IGARASHI, AND YAMAGUCHI
characterized by determining the specific combination of
molecular features that are shared by the odorants that
are effective in activating the glomerulus. We define the
term characteristic molecular features of a glomerulus as
the specific combination of molecular features that are
shared by odorants that are effective in activating the
glomerulus (116).
One of the practically feasible methods for deducing
the characteristic molecular features of an individual glomerulus is to superimpose the three-dimensional structure of odorants that are effective in activating the glomerulus and to determine the combination of molecular
features that the effective odorants share. Figure 11
shows two examples of this method. It should be noted
that the superposition of effective odorants is not intended to describe the odorant receptive site structure,
but to effectively examine the spatial representation of
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MRR properties. Mapping the deduced characteristic molecular features on the glomerular sheet will make it
easier to see the spatial arrangement of MRR maps.
Odorant molecular features include overall molecular profiles. Because open-chain aliphatic compounds are
very flexible and can have many different molecular conformations, it is difficult to deduce the three-dimensional
structure of these compounds. In contrast, aromatic compounds have at least one benzene ring or benzene-like
ring that assumes a fixed disklike conformation and thus
has a semirigid molecular structure. Therefore, aromatic
compounds are more suitable for superimposition of the
three-dimensional structure than the open-chain aliphatic
compounds. We focused our analysis of determining the
characteristic molecular features of individual glomeruli
first in cluster C and its neighboring clusters because
cluster C glomeruli respond to phenol, its derivatives,
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FIG. 10. Zonal difference in the MRR property. Clusters A–I (dashed lines) are shown on the unrolled map of the OB with zonal boundary.
Yellow regions indicate OCAM-positive zones (zones 2– 4), while the white region indicates the OCAM-negative zone (zone 1). Clusters A–D are
located in zone 1. Clusters H and I are in zones 2– 4. MRR properties of representative glomeruli in the clusters A, B, C, D, H, and I are indicated
in rectangles with the molecular structure of effective odorants. The shared molecular features are indicated with green or red surroundings. The
common and characteristic molecular features of glomeruli in zone 1 appear to be the polar parts of odorants (green), whereas those of glomeruli
in zones 2– 4 may be the hydrocarbon part or relatively nonpolar parts of odorants (red). A, anterior; P, posterior; D, dorsal; V, ventral; L, lateral;
M, medial. Scale bars, 1 mm. [Modified from Igarashi and Mori (36).]
ODOR MAPS IN THE OLFACTORY BULB
425
phenylethers, and methoxybenzenes, all having a rigid
benzene ring.
Figure 12 shows a map of the characteristic molecular features in the cluster C and neighboring clusters in
the rat OB. To facilitate the analysis, the presumed critical
parts of the combination of characteristic molecular features are labeled by color in this figure. For example, blue
shadows indicate a combination of molecular features
composed of a single methoxy (-O-CH3) group or a single
ethoxy group (-O-CH2CH3) attached to a benzene ring
profile. Yellow shadows show a combination of molecular
features composed of a single hydroxyl group (-OH) attached to a benzene ring. Red surroundings indicate a
combination of molecular features composed of a single
hydroxyl group and a single alkoxyl group (-O-R) arranged at the ortho-position around a benzene ring. The
combination of molecular features composed of a single
hydroxyl group and a single carbonyl group (⬎C⫽O)
arranged at the ortho-position around a benzene ring is
shown by pink surroundings.
By the comparison of the characteristic molecular
features of individual glomeruli (Fig. 12A), we noted a
systematic and gradual change in the represented characteristic molecular features along the axes of the glomerular sensory maps of the OB. This idea originated from
the observation that two neighboring clusters or subclusters show a similarity in terms of the characteristic molecular features of constituent glomeruli. For example, as
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indicated by pink surroundings, subcluster C-2 glomeruli
selectively respond to salicyl aldehyde that has a hydroxyl
group and a carbonyl group arranged at the ortho-position
(Fig. 12B). Thus the characteristic molecular features of
the subcluster C-2 glomeruli include two oxygen atoms in
proximity. At the region medial to the subcluster C-2,
there are many glomeruli in cluster A that respond to
aliphatic acids (-COOH), diketones [-(CO)(CO)-], and esters (-COO-). Because these odorants also have two oxygen atoms in proximity, the results suggest that the characteristic molecular features of C-2 glomeruli partially
resemble those of neighboring cluster A glomeruli.
In terms of the combination of molecular profile and
functional group, salicyl aldehyde closely resembles benzoic acid and benzaldehyde (Fig. 12B). In accordance
with this observation, several glomeruli in subclusters A-2
and A-3 respond to benzoic acid and benzaldehyde, and
subclusters A-2 and A-3 directly appose the salicyl aldehyde-responsive subcluster C-2. This observation also
suggests a similarity of the characteristic molecular features among neighboring subclusters C-2, A-2, and A-3.
The systematic and gradual change in the represented characteristic molecular features is also seen
among subclusters within cluster C. As indicated by red
surroundings, many glomeruli in subcluster C-2 respond
to methoxyphenols (e.g., guaiacol, creosol, eugenol; see
Fig. 7) as well as salicyl aldehyde. The area occupied by
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FIG. 11. Superimposition of the 3-dimensional structures of the odorants effective in activating individual glomeruli.
A and E: abbreviated name and molecular formula of odorants that activated
glom #51 in subcluster C-2 (A) and glom
#19 in cluster B (E). The magnitude of
glomerular response to each odorants is
shown by symbols: the largest circle
(very strong), a large circle (strong), a
small circle (modest), and the smallest
circle (weak). The superposition of the
3-dimensional structures of the compounds was performed by least-squarefitting using the atoms, 1–7 numbered in
A or 1– 6 in E, respectively. B and F:
superimposed 3-dimensional structures
of the effective odorants. C and G: a total
van der Waals (VDW) volume of the superimposed structures. D and H: 2-dimensional representation of the VDW
volume. Slc-CHO, salicyl aldehyde; o-Chp,
ortho-chlorophenol; 4-Eanle, 4-ethylanisole; 4-Aanle, 4-allylanisole. [Modified from
Takahashi et al. (116).]
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MORI, TAKAHASHI, IGARASHI, AND YAMAGUCHI
the methoxyphenol-responsive glomeruli extend anterolaterally from subcluster C-2 to the medial part of subcluster C-3 and even to a part of the subcluster C-1. Thus
the neighboring glomeruli in subclusters C-2, C-3, and C-1
share the molecular features.
The similarity of the characteristic molecular features can be seen further along the axis that crosses the
boundary between cluster C and anteriorly adjacent cluster B. As indicated by yellow shadows, the common characteristic molecular features in the cluster C glomeruli
include a hydroxyl group attached to a benzene ring profile (phenols in Fig. 7). In addition, the subcluster C-1
Physiol Rev • VOL
glomeruli invariably respond to relatively short aliphatic
alcohols such as butanol and hexanol. At the region more
anterior to subcluster C-1, there are many glomeruli in
cluster B that strongly respond to aliphatic alcohols with
a relatively long carbon chain. Furthermore, a few C-1
glomeruli respond also to phenyl ethers that have
methoxy group and a carbon side chain attached at the
para-position (shown by blue shadows). A majority of the
cluster B glomeruli also respond to phenyl ethers (Fig.
11E). These results suggest that the C-1 glomeruli and
neighboring cluster B glomeruli partially share the characteristic molecular features.
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FIG. 12. A map of the characteristic molecular features in the dorsal surface of an olfactory bulb. A: positions of individual glomeruli are shown
by gray interrupted circles. The presumed critical parts of the characteristic molecular features are labeled by colors. Blue shadows indicate the
molecular features composed of a methoxy group (-O-CH3) or an ethoxy group (-O-CH2-CH3) attached to a benzene ring. Yellow shadows indicate
the molecular features composed of a single hydroxyl group (-OH) attached to a benzene ring. Red surroundings indicate the molecular features
composed of a combination of a hydroxyl group and an alkoxyl group (-O-R) arranged at ortho-position around a benzene ring. Pink surroundings
indicate the molecular features composed of a combination of a hydroxyl group and a carbonyl group (-C⫽O) arranged at the ortho-position around
a benzene ring. Scale bar, 200 ␮m. [Modified from Takahashi et al. (116).] B: molecular structures of salicyl aldehyde, benzoic acid, and
benzaldehyde.
ODOR MAPS IN THE OLFACTORY BULB
VIII. MOLECULAR-FEATURE CLUSTERS
MAY PARTICIPATE IN ODOR
QUALITY PERCEPTION
A. Cluster A and Odor Quality
Odorants effective in activating the cluster A glomeruli include aliphatic acids, diketones, and aldehydes.
These odorants contain “fatty, rancid, sour, and pungent”
note in common (Fig. 2). Aliphatic acids with a relatively
short carbon chain (C2-C3) tend to have “pungent” and
“sour” notes, those with a middle size carbon chain (C4C5) have “sour” and “rancid” notes, and those with a
relatively long carbon chain (C6-C10) have “rancid” and
“fatty” notes in common. Because the carbon chain length
of aliphatic acids is represented in part by overlapping
glomeruli whose position shifts gradually from subcluster
A-3 through A-2 to A-1 as their carbon number increases,
a correlation is noted among the molecular structure of
aliphatic acids, their perceived odor quality, and spatial
position of their activated glomeruli within cluster A. The
carbon chain length of aliphatic aldehydes is also systematically represented along the posteromedial-to-anterolateral axis within the cluster A. In accordance with this,
aliphatic aldehydes with a relatively short carbon chain
tend to have “pungent” note, whereas those with a long
carbon chain tend to have “fatty” note in common. In
addition, diketones that have “pungent” note in common
activate many glomeruli within subcluster A-3. These results suggest that cluster A might be part of the representation of the basic odor quality that participates in the
“pungent, sour, rancid, fatty” odor quality.
Alkylamines activate a large subset of glomeruli in
cluster A and have a fatty, fishy, disagreeable odor. As will
be discussed in section IX, this part of cluster A might
participate in the representation of fatty, fishy off-flavor
(117).
B. Cluster B and Odor Quality
As described in sections V–VII, glomeruli in the OB
form molecular-feature clusters and subclusters. Glomeruli in a same cluster or subcluster tend to represent a
similar combination of molecular features. The molecular
feature clusters are located at stereotypical positions in
the glomerular sheet, and their overall spatial arrangement is conserved across individual animals. Because
odorants having a similar combination of molecular features tend to have similar “odor quality” to the human
Physiol Rev • VOL
nose, the above observations raise the possibility that the
molecular-feature clusters of glomeruli might be part of
the representation of basic odor quality. Under this supposition, we summarized the possible relationship between the molecular-feature clusters and basic odor quality. It should be noted, however, that the basic odor
quality is described in subjective words and is difficult to
define precisely.
Odorants effective in activating glomeruli in cluster B
are aliphatic alcohols with a relatively long carbon chain
and a wide range of aliphatic ketones. The odor quality
shared by these odorants is “floral and fruity” note. Some
aliphatic alcohols and aliphatic ketones also contain
“green and grassy” note in common. In addition, many
cluster B glomeruli respond to anisole family odorants
which share “anisic” note. Thus cluster B may be part of
the representation of the basic odor quality that partici-
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Thus the characteristic molecular features change
gradually and systematically in the chains of subclusters
A-2, A-3, and C-2; in the medial part of C-3 and C-1; and
in cluster B. Because a systematic and gradual change in
the characteristic molecular features occurs also along
the chains of subclusters C-4, D-1, and D-2, we speculate
that the systematic and gradual representation of characteristic molecular features is the property that is not
unique to cluster C and neighboring clusters but is shared
by many different clusters.
As described above, we observed multidimensional
change in the represented characteristic molecular features along the axis across clusters A, C-2, C-3, C-1, and
B. In one segment along this axis, we observed a change
of a particular molecular feature, but in the other segment
we noted a change of different molecular features. In
other words, a specific axis in the glomerular sheet does
not appear to represent a particular molecular feature.
This is consistent with the observation that the change in
the carbon chain length in homologous series of aliphatic
compounds causes a gradual shift of the positions of
activated glomeruli only in a particular segment along an
axis in the glomerular sheet. In the different segments of
the same axis, carbon chain length does not appear to be
systematically represented.
In a wide variety of species, olfactory sensory neurons with related functional specificity map to related
spatial positions in the OB or in the antennal lobe (47, 49,
51, 90, 119). The hypothesis that the glomerular sheet of
the rat OB topographically represents the characteristic
molecular features in a systematic, gradual, and multidimensional fashion is consistent with the above finding.
This raises the possibility that the topographic representation of characteristic molecular features might be conserved across different species. In addition, the hypothesis of topographic representation raises the issue whether
there are boundaries between different molecular-feature
clusters. Clustering of glomeruli with a similar MRR property does not necessarily indicate that different clusters
are segregated by specific boundaries.
427
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MORI, TAKAHASHI, IGARASHI, AND YAMAGUCHI
pates in the “floral, fruity, and anisic” and “green and
grassy” odor quality.
C. Cluster C and Odor Quality
D. Cluster D and Odor Quality
The cluster D glomeruli respond to a relatively wide
range of structural classes of odorants in our panel. Odorants effective in activating subcluster D-1 glomeruli are
mainly cyclic ketones and methoxyphenols, while those
of subcluster D-2 glomeruli are cyclic ketones. Because
these odorants tend to have “spicy” and “minty” notes in
common, the representation of basic odor quality by the
cluster D glomeruli may be part of the representation of
“spicy” and “minty” odor quality.
E. Cluster H and Odor Quality
The cluster H glomeruli tend to respond to benzene
derivatives that have no, one, or two side chain(s) at
ortho- or meta-position around the benzene ring. Because
these odorants have gassy and kerosene-like odor in common, the cluster H glomeruli might participate in the
representation of “gassy” and “kerosene-like” odor quality.
F. Cluster I and Odor Quality
The cluster I glomeruli tend to respond to cyclic
terpene hydrocarbons in addition to the benzene derivatives. Because cyclic terpene hydrocarbons have “citrusy”
or “woody” odor in common, these glomeruli in cluster I
may participate in the representation of “citrusy” or
Physiol Rev • VOL
1
Cluster AB is composed of a small number of glomeruli that are
located at the boundary between cluster A and cluster B (see Figs. 6, 10,
and 12). Glomeruli in cluster AB selectively respond to aliphatic acids
and aliphatic alcohols with relatively long carbon chains.
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Glomeruli in cluster C invariably respond to phenol
family odorants. Phenol family odorants contain “phenolic and medicinal” note in common, suggesting that
cluster C may represent part of the “phenolic and medicinal” odor quality. Further analysis suggests that individual subclusters might differ in the basic odor quality
representations. The subcluster C-1 glomeruli respond
not only to phenols but also to aliphatic alcohols with a
relatively short carbon chain (mainly C4-C6). These short
aliphatic alcohols have “chemical” note in common. Subcluster C-2 glomeruli are strongly activated by salicylaldehyde, which have “almondlike” note in addition to
“phenolic” note. Many subcluster C-3 glomeruli respond
to methoxyphenols, which have “spicy” note as well as
“phenolic and medicinal” note. Subcluster C-4 glomeruli
are activated by aliphatic ketones with relatively short
side chains and ethers in addition to phenols. Short aliphatic ketones and ethers tend to have “ethereal” note in
common.
“woody” odor quality, in addition to the “gassy” or “kerosene-like” odor quality.
The above results suggest a working hypothesis that
a specific molecular-feature cluster (or subcluster) might
represent a cluster-specific basic odor quality. Because a
given odorant typically activates more than one cluster
(or subcluster) in the OB, the quality of the odorant may
be ascribed to the complex combination of more than one
cluster-specific basic odor quality. The results obtained by
optical imaging studies fit well to this notion. For example, odor quality of hexanol is composed of “fruity,”
“chemical,” and “fatty” notes. Optical imaging data
showed that hexanol activated glomeruli within cluster B,
cluster AB, and subcluster C-1.1 Cluster B represents in
part “fruity and floral,” cluster AB “fatty” and subcluster
C-1 “phenolic, medicinal, and chemical” notes. Thus the
map of the molecular-feature clusters in the OB might
provide the neuronal basis for the relationship between
the odorant molecular structure and the subjectively perceived odor quality.
It should be noted, however, that behavioral studies
showed almost no change in the discrimination among
odorants (e.g., a homologous series of fatty acids) even
after a lesion of a large part of the OB (108 –110). These
studies underscore the notion that individual odorants are
typically coded by two or more clusters and that the
activated clusters are arranged both in the lateral and
medial maps of the OB. Animals with the OB lesion may
be able to perform odorant discrimination based on the
information only from the remaining clusters. Because of
the difficulty in assessing the odor quality perception in
animals, we think that it is not yet known whether or not
the animals with the OB lesion perceive the same odor
quality. The present hypothesis that different clusters are
involved in coding particular odor quality predicts that
the animals with the OB lesion show the change in odor
quality perception. Further studies are necessary to understand the neuronal systems and the logic responsible
for odor quality perception.
Studies of axonal projection of mitral/tufted cells to
the olfactory cortex indicate that a given region of the
olfactory cortex receives converging inputs from several
different clusters of glomeruli (19, 30, 94, 96, 107, 134).
Thus olfactory cortex may integrate signals arising from
different clusters (74, 126, 135). The knowledge of the
molecular-feature clusters and their possible relationship
to the basic odor quality may be indispensable for understanding the way of integrating signals from different
clusters at the level of the olfactory cortex.
ODOR MAPS IN THE OLFACTORY BULB
IX. MAPPING THE NATURAL ODOR IN THE
MOLECULAR-FEATURE MAPS OF THE
OLFACTORY BULB
A. Spatial Representation of Spoiled Food Smells
in the Odor Maps
One of the important roles of the olfactory system in
animal life is to recognize and discriminate between safe,
nutritious foods and spoiled foods that contain microorganisms or bacterial toxins. How are spoiled food smells
encoded in the odor maps of the OB? Amine odorants are
produced by the bacterial decarboxylation of free amino
acids in meat and fish (5, 18, 28, 82, 102) and are one of the
major causes of the unpleasant fatty, fishy off-flavors of
spoiled foods. Amines thus signal the presence of bacterial toxins in the foods, and detection of amine odors
leads to the avoidance of spoiled foods. Other major
ingredients of the fatty, fishy off-flavors of spoiled foods
are aliphatic acids and aliphatic aldehydes that are generated by lipid oxidation of meat and dairy products (5, 8,
8a, 21, 35, 69, 75, 113).
We mapped glomerular responses to amine odorants
in the dorsal and dorsolateral surfaces of the rat OB using
the intrinsic signal-imaging method and found that the
amine-responsive glomeruli were clustered in the anteromedial region (cluster A) of the dorsal OB. Glomeruli in
the anteromedial part are known to respond to aliphatic
acids and aliphatic aldehydes. Thus we performed detailed analysis of the MRRs of these glomeruli using a
systematic panel of stimulus odorants containing a homologous series of aliphatic acids, aliphatic aldehydes,
and amines (117). The results show that many glomeruli
in the anteromedial region respond not only to amines but
also to aliphatic acids and aldehydes. In agreement with
the result of imaging study, the single-unit recording study
shows that individual mitral/tufted cells in the anteromedial region respond to amines in addition to aliphatic
acids and aliphatic aldehydes (117). Since amines, aliphatic acids, and aliphatic aldehydes are major causes of
fatty, fishy off-flavors emitted by spoiled foods, the results
suggest that the antero-medial amine-responsive glomerPhysiol Rev • VOL
ular cluster may be involved in detecting the spoiled food
smells and participate in the representation of fatty, fishy
off-flavor.
In cooking, a variety of spices (e.g., fennel and clove)
are commonly used to add flavor and reduce any unpleasant fatty, fishy off-flavor. Optical imaging shows that
odors of fennel and clove activate clusters of glomeruli
that are located near the alkylamine-responsive cluster
(117). Single-unit recording shows that spike discharges
of about half of alkylamine-responsive neurons are clearly
suppressed by fennel and clove. These results suggest
that the masking of spoiled food smells is mediated, in
part, by lateral inhibitory connections in the odor maps of
the OB.
B. Spatial Representation of Urine Odors in the
Mouse Olfactory Bulb
Another important role of the olfactory system is
conspecific recognition including olfactory recognition of
their mate, parents, and offspring. Mapping studies using
immediate early gene expression revealed that urine odor
activates clusters of glomeruli in the ventro-lateral region
of the mouse OB (92, 93). Recently, Katz and colleagues
(53) addressed the issue of how volatile compounds in
urine were encoded by individual mitral/tufted cells in the
mouse OB. They fractionated the volatile compounds in
urine using gas chromatography and recorded the singleunit responses of mitral/tufted cells to the fractionated
components. The results show that urine-responsive mitral/tufted cells are clustered in two restricted regions of
the OB. These two urine-responsive clusters might reflect
the mirror-imaged symmetric maps of ORs in the OB.
More importantly, urine-responsive mitral/tufted cells
show high odorant selectivity. Most urine-responsive neurons in the cluster selectively respond to a single eluted
volatile component among more than 100 different components. Thus individual mitral/tufted cells may function
as a molecular-feature detector and, in most cases, do not
combine information of more than two different component odorants of urine.
X. CONCLUSION
This review summarizes the emerging view of the
spatial organization of the odor maps in the mammalian
OB. Individual glomeruli and mitral/tufted cells can be
viewed as molecular-feature detectors and selectively respond to a specific combination of molecular features.
Thus information carried by individual odorants is fractionated according to the ORs that they bind and is handled by a specific combination of molecular-feature detectors in the OB. Even a complex combination of many
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What is the functional significance of the systematic
molecular-feature maps in the OB? It is conceivable that
the olfactory nervous system has evolved to detect and
discriminate odors that are important for the animal’s life
such as food odors and predator odors. Therefore, a key
step to investigate the functional significance of the molecular feature maps is to examine how the behaviorally
significant odors are spatially represented in the sensory
maps of the OB. In this section, we review two examples
of the mapping of behaviorally significant odors: spoiled
food smells and urine odors.
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MORI, TAKAHASHI, IGARASHI, AND YAMAGUCHI
Physiol Rev • VOL
relatively unexplored region in terms of processing of
odorant molecular information. We think that future researches seek to understand the specific functional roles
of the olfactory cortex and higher olfactory centers for
perception, learning and memory of food odors, social
odors, and predator odors. The basic knowledge of the
molecular-feature maps of the OB would be indispensable
for the future research of the central olfactory system.
ACKNOWLEDGMENTS
We thank the members of the Department of Physiology in
the University of Tokyo for discussion and anonymous referees
for helpful suggestions.
Address for reprint requests and other correspondence: K.
Mori, Dept. of Physiology, Graduate School of Medicine, Univ. of
Tokyo, 7–3-1 Hongo, Bunkyo-ku, Tokyo 113– 0033, Japan (email: [email protected]).
GRANTS
This work was supported by Grants-in-Aid for Creative
Scientific Research (to K. Mori) from the Japanese Society for
the Promotion of Science (JSPS). Y. K. Takahashi and K. M.
Igarashi were supported by JSPS Research Fellowships for
Young Scientists.
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