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C H A P T E R
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The Olfactory System
Tim J van Hartevelt 1, 2, Morten L Kringelbach 1, 2, 3
1
2
University of Oxford, Department of Psychiatry, Warneford Hospital, Oxford, UK,
Aarhus University, Centre for Functionally Integrative Neuroscience (CFIN), Denmark,
3
Nuffield Department of Surgery, John Radcliffe Hospital, Oxford, UK
O U T L I N E
Introduction
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Rostral, “Olfactory” Entorhinal Cortex
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The Olfactory System
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Olfactory Mucosa
Location
Structure
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Accessory Olfactory Cortical Areas
Centrifugal Projections to the Olfactory Bulb
Intracortical Associational Fiber System
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The Vomeronasal Organ
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Olfactory Bulb
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Primary Olfactory Cortex
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Cortical Structure and Projections of the Olfactory
Bulb
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Anterior Olfactory Nucleus
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Olfactory Tubercle
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Piriform Cortex
Anterior Cortical Nucleus of the Amygdala
and Periamygdaloid Cortex (PAC)
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Human Imaging of Olfactory Sensory Activity
Olfaction as a Multimodal System
Olfactory Dysfunction and Anhedonia
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INTRODUCTION
In order to survive both as individuals and as a species,
we need to eat and procreate. Our sensory systems have
developed to allow us to identify, evaluate, and predict
stimuli in the environment such that we make sensible
decisions about them (Kringelbach and Stein, 2010).
Olfaction, or as it is more commonly known, the sense
of smell, is of great importance for both food selection
and reproduction, especially when taken together with
the sense of taste (gustation). In fact, taste and smell
are so closely linked that when most people talk about
The Human Nervous System, Third Edition DOI: 10.1016/B978-0-12-374236-0.10034-3
Olfactory Projections Beyond the Primary
Olfactory Cortex
Olfactory Projections to the Amygdala and
Hippocampus
Olfactory Projections to the Hypothalamus
Olfactory Projections to the Striatum, Pallidum,
and Thalamus
Olfactory Projections to Neocortical Areas
the taste of something, they are usually referring to the
multimodal experience of taste and smell. Studies on,
amongst others, single-cell organisms indicate that the
combined chemical sense of taste and smell is possibly
the oldest of the senses and the most universally
employed (Kovács, 2004; Hoover, 2010). Taste and smell
has since diverged such that gustation is foremost
a proximal sense allowing us to identify nearby stimuli,
while more distal stimuli can be identified by olfaction.
We and other animals rely strongly on olfaction to
locate and identify food sources. Most animals also
rely heavily on olfaction for mate selection and to
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Copyright Ó 2012 Elsevier Inc. All rights reserved.
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34. THE OLFACTORY SYSTEM
identify their offspring. In addition, animals use olfaction to navigate not only to food sources, but also to their
homes or in some cases to their birth places to lay eggs
(e.g. sea turtles and salmon). Further evidence for the
importance of olfaction can be found in the size of the
olfactory organ and system in a vast majority of species.
For example, dogs have about 100 times more olfactory
receptor cells compared to humans.
Some researchers have argued that compared to other
animals, humans depend less on olfactory functions and
more on other senses such as vision and hearing (Jacobs,
2009). Such arguments have some truth to them but are
difficult to uphold given the evidence for how we rely
heavily on our sense of smell to identify spoiled or toxic
food, or our ability to identify sources of potential
danger such as fire or gas leaks. The function of olfaction
with regard to food selection is not, however, limited to
identifying potentially dangerous food sources. Deficits
in olfactory function can sometimes lead to malnutrition
(Warner et al., 1986). The lack of olfaction is a strong
predictor of anhedonia, the lack of pleasure in eating
or smelling and tasting food, and as such may contribute
to the malnutrition.
In addition to the function of smell in food selection,
olfaction is also important in sex. Although humans do
not use olfaction for mate selection to the extent of other
animals such as dogs, olfaction is still related to sex drive.
Studies using smell for attractiveness ratings show that
men and women are susceptible to pheromones and
rate the opposite sex as more or less attractive, depending on their hormonal state and the hormonal state of
the opposite sex (Mostafa et al., 2011). Smells from family
members are readily identified as such (and generally
rated as less attractive), which may indicate a mechanism
to select genetically different partners and avoid
inbreeding. Mothers are able to recognize the smell of
their newborn babies (and vice versa) after prior exposure of as little as one hour (Porter, 1998).
Furthermore, olfactory dysfunction is associated with
apathy, depression, and a lower quality of life (Smeets
et al., 2009; Cramer et al., 2010). These observations
combined with the fact that olfactory neurons project
directly to the amygdala and hippocampus without
a thalamic relay, suggest a prominent role for olfaction
in mediating hedonic experience.
In addition to its role in food, sex, and pleasure, olfactory cues have a remarkable ability to evoke extremely
vivid memories, as noted for example by Proust in his
novel À la recherche du temps perdu. Taken together, the
weight of the evidence shows that olfaction is a very
important sensory system in humans which needs to
be fully functioning to support not only our survival
but very much our sense of well-being in general.
This chapter outlines the human olfactory system,
beginning with the peripheral receptor neurons in the
nasal cavity and the first relay in the olfactory bulb.
The projections of the olfactory bulb to the primary
olfactory cortical areas are described using evidence
from macaque monkeys, and the comparable olfactory
areas in the human brain are also described. Finally,
olfactory projections to the hypothalamus, thalamus,
and frontal cortex are discussed, based on experimental
work in monkeys and in particular using new evidence
from functional imaging studies in humans.
THE OLFACTORY SYSTEM
Similar to other sensory systems, olfactory information must be transmitted from peripheral structures
(the olfactory epithelium) to more central structures
(the olfactory bulb and cortex), integrated to detect
and discriminate specific stimuli, and then transferred
to other parts of the brain in order to reach sensory
awareness and affect behavior. Similar to other sensory
systems, the olfactory system is able to identify objects
by its emitted odorants and locate the source. However,
the olfactory system is different from the other sensory
systems in three fundamental ways.
Firstly, as mentioned before, olfaction is the only
sensory modality that is directly connected into the cerebral hemisphere (in a sense, the telencephalon developed in relation to olfactory input). Possibly because of
this phylogenetic relationship, olfactory sensory activity
is transferred directly from the olfactory bulb to the
olfactory cortex, without a thalamic relay. Although
there is a subsequent projection from the olfactory cortex
to the mediodorsal thalamic nucleus and from there to
the posterior orbitofrontal/agranular insular cortex,
this transthalamic pathway is less substantial (in terms
of the number of neurons involved) than a direct, monosynaptic projection from the olfactory cortex to the same
orbitofrontal/insular areas. The transthalamic projection is therefore not essential for relay of sensory information to the neocortex.
Secondly, the neural integration and analysis of olfactory stimuli may not involve a topographic organization
beyond the olfactory bulb. Olfactory stimuli are not
intrinsically ordered along spatial axes, like vision and
somatic sensation, or along a frequency axis, like audition. Although an organization has been found in the
projection from the olfactory epithelium to the olfactory
bulb (e.g. Mombaerts, et al., 1996), there is little if any
solid evidence for a topographic organization from the
bulb to the olfactory cortex. While it is possible that
a more complex organization may eventually be discovered, on the present evidence it is more likely that
spatio-temporal patterns across large regions of the
olfactory cortex may be the critical factor in detecting
and discriminating different odors.
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OLFACTORY MUCOSA
Thirdly, olfactory receptor neurons exhibit significant
turnover throughout life. Olfactory neurons have a short
life span averaging approximately 30–60 days. They are
constantly replaced by mitotic division of the basal stem
cell population in the olfactory epithelium. The olfactory
receptors are the only neurons that are inserted in the
surface epithelium of the body and are, therefore,
directly exposed to the environment. It is likely that
this makes them more vulnerable to insult and necessitates their regenerative capacity. Although other
receptor-related cells also have a turnover, such as the
taste buds, these are not true neurons that make
synapses within the central nervous system.
As noted in the introduction, humans are generally
considered “microsmatic,” with a relatively poorly
developed olfactory system compared to that of “macrosmatic” mammals. Indeed, the structure and lamination
of the olfactory bulb and primary olfactory cortex (POC)
are not as well-defined in humans as in rodents and
carnivores. Furthermore, the olfactory structures
certainly do not make up as large a fraction of the forebrain in humans as in rats and cats. However, almost all
of the major olfactory structures found in rats are also
present in humans, and in absolute terms the human
structures are far from rudimentary. For example, the
volume of the olfactory bulb in a young adult human
is reported to be 50–60 mm3 (per side) (Turetsky et al.,
2000), while it is only 15–20 mm3 in rats (Hinds and
McNelly, 1977). Similarly, the primary olfactory cortical
areas such as the anterior olfactory nucleus (AON), piriform cortex, and periamygdaloid cortex are readily
recognizable around the junction of the frontal and
temporal lobes of human brains. What is more, humans
are able to discriminate between odors differing by only
one carbon atom (Laska and Teubner, 1999).
The vomeronasal organ is another interesting potential
difference between humans and other animals. Although
some researchers have argued that humans do not
possess a vomeronasal organ and an accessory olfactory
bulb, which represent the peripheral receptors and first
relay of the “accessory olfactory system” in other animals,
this structure has been found in humans (Jacob et al.,
2000). What is not clear is whether its functions are intact
in humans. Substantial debate has been raised over this
matter and on balance the evidence suggests that this
system is inactive in humans (Mast and Samuelsen,
2009; Frasnelli et al., 2011). The major axonal target of
the accessory olfactory bulb in rodents, the medial amygdaloid nucleus, is present in adult humans, but may have
come to mediate non-olfactory functions. It should be
noted that the accessory olfactory system is anatomically
and functionally distinct from the main olfactory system,
and has been implicated in perception of odors important
for species-specific functions, including aspects of reproduction (Wysocki and Meredith, 1987).
OLFACTORY MUCOSA
Location
The peripheral olfactory receptor neurons in the
humans are situated within the olfactory epithelium, in
the posterodorsal recess of the nasal cavity (e.g. see
Lovell et al., 1982; Jafek, 1983; Nakashima et al., 1984)
(see Figure 34.1). This specialized epithelium occupies
an area of approximately 1 cm2 in each nasal cavity
(covering the cribriform plate of the ethmoid bone),
located in the dorsal posterior recess on the dorsal
aspects of the nasal vault, the septum, and the superior
turbinate. It is, however, important to note that olfactory
epithelium is replaced by respiratory epithelium during
aging, meaning that the surface area of olfactory epithelium decreases considerably. The remainder of the nasal
cavity (60 cm2 per side) is occupied by respiratory epithelium, which serves the major function of conditioning the
air that passes through the nose and at the end of
the nasal cavity, air is 31–34 degrees Celsius and has
a Relative Humidity of 90–95% to match the conditions
in the lungs (Elad et al., 2008). The inaccessibility of the
olfactory epithelium serves an important role in protecting the receptor neurons, which are the only sensory
neurons that are directly exposed to the external environment in the surface epithelium of the body. Although the
access of odorants through the nostrils is seemingly
straightforward, a phenomenon called the nasal cycle
influences the intake of air into the nasal cavity by
diluting and restricting the left and right nasal airways
in a switching manner. The switching occurs periodically
with (large) individual differences. This non-conscious
mechanism allows for odorant molecules with different
sorption quality (i.e. whether molecules are readily
absorbed by the nasal mucosa or not) to have an optimal
possibility for binding to olfactory mucosa when inhaled
(e.g. see Sobel et al., 1999; Gottfried, 2009).
Structure
The human olfactory epithelium is considerably
thicker than the respiratory epithelium (70 versus
45 mm), and is generally described as containing bipolar
receptor neurons, supporting or sustentacular cells, and
basal cells. In addition, microvillar cells have been found
near the surface, and Bowman’s glands extend deep to
the epithelium into the lamina propria. The epithelium
is pseudostratified, and both the bipolar receptor cells
and the sustentacular cells span the full thickness. Cilia
or microvillae extend from the apical surface of the cells
into a layer of mucus that covers the epithelium and
separates it from the air of the nasal cavity (Figure 34.2).
The Bowman’s glands are tubuloalveolar in nature,
with ducts extending through the epithelium to the
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34. THE OLFACTORY SYSTEM
(A)
(B)
FIGURE 34.1
Schematic representation of olfactory system neuroanatomy. (A) Odors are delivered to the olfactory epithelium both
orthonasally and retronasally. Receptors in the olfactory epithelium project to the olfactory bulb, which in turn sends signals to primary olfactory
cortical areas. (B) Olfactory receptor neurons merge with identical receptor neurons and connect to mitral (M) and tufted (T) cells in the
glomerular layer. Mitral and tufted cells are modulated by granule cells (G) from the granular layer. Mitral and tufted cells project to
both the anterior olfactory nucleus located in the olfactory bulb as well as to primary olfactory cortical areas through the lateral olfactory tract.
(A) modified from Lafreniere and Mann (2009) and (B) modified from Duda (2009).
surface. In humans, they apparently secrete a serous
fluid that contributes to the mucous layer overlying
the epithelium (Jafek, 1983). Because of the number of
these glands and their restricted distribution in the olfactory region, it has been suggested that the secretion of
Bowman’s glands may play a role in olfactory transduction, but this has not been well established.
The bipolar receptor neurons have a superficial
“dendrite” that extends to the surface of the epithelium,
and a thin (0.2–0.3 mm) axon which runs into the lamina
propria. The axons then group together into small
bundles or “fila” and run through the cribriform plate
to the olfactory bulb. The cell bodies of the receptors
occupy a broad band in the middle of the olfactory
epithelium, deep to the nuclei of the supporting cells
and superficial to the basal cells. Counts of the receptors
in humans indicate that their density is about 30 000 per
mm2, or 6 million per nose (Moran et al., 1982a). As in
other mammals, the human receptor neurons and their
processes show selective immunoreactivity for the olfactory marker protein (Nakashima et al., 1985). Evidence
from rats and other animals indicates that the transmitter
used by the receptor neurons is glutamate (Berkowicz,
et al., 1994; Aroniadou-Anderjasska et al., 1997).
Superficially, the receptor dendrite terminates in the
knoblike olfactory vesicle, which protrudes above the
surface of the epithelium. Ten to 30 non-motile cilia arise
from basal bodies in each olfactory vesicle and protrude
into the mucous layer (Jafek, 1983). The cilia generally
have the typical 9 pairs þ2 microtubule structure,
without dynein arms between the microtubule pairs.
The ciliary membranes carry molecular odorant receptors, which mediate sensory transduction from odorant
molecules to neural signals.
There are believed to be about 950 odorant receptors,
each of which binds a specific chemical moiety. The
receptors are coded for by the largest known gene
family in mammals (Buck and Axel, 1991; Glusman
et al., 2000). In humans, odorant receptor genes are
distributed over at least 16 chromosomes, but as
many as 63–70% of them are reported to have accumulated mutations that make them dysfunctional pseudogenes (Gaillard et al., 2004). Studies in rodents have
indicated that olfactory receptor neurons (ORN) are
organized into four zones within the olfactory epithelium, which express different groups of molecular
odorant receptors (Ressler et al., 1993; Vassar et al.,
1993; Mori et al., 1999). Within each zone, neurons
expressing specific odorant receptors are intermingled
with neurons expressing other receptors.
The microvillar cells are flask-shaped cells in the
superficial zone of the epithelium with a rapidly
tapering neck that ends in a tuft of microvilli which
extends out into the mucous layer (Moran et al., 1982b;
VI. SYSTEMS
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OLFACTORY MUCOSA
Food
Sensory input
Decoding
Evaluation - Expectation - Experience
Decision - Selection
Environment
Body
Brain
OM
Smell
OB
Sensory cortices
PIR
The orbitofrontal cortex
Agranular insula/
posterior OFC
Medial OFC
lateral OFC
Evaluation leading to change
Thalamus
Taste
Cingulate cortex
INS/OP
mid anterior OFC
Touch
Nucleus Accumbens
S1..S2
Correlates of hedonic experience
V1..V4
IT
Vision
A1..A2
Hearing
Reinforcer
identity
medial OFC
Multi-modal
representations
Reward value
representations
Hypothalamus
Amygdala
Ventral Pallidum
Monitoring / learning / memory
Cortical structures
Hippocampus
Sub-cortical structures
Brainstem
Receptors
Autonomic
Gastro-intestinal tract / liver / pancreas / muscle / adipose
FIGURE 34.2 Schematic representation of the sensory pathways involved in food intake. The figure summarizes the interactions with
environment to procure suitable food sources with a special focus on olfaction. Potential food sources are identified on the basis of the sensory
input, which through the appropriate receptors are relayed to the orbitofrontal cortex (only one hemisphere shown), where processing is taking
place of evaluation, expectation, experience as well as decision and selection. Here the input is processed in the primary sensory cortices via the
thalamus (except for olfaction) and made available for pattern-association between primary (e.g. taste) and secondary (e.g. visual) reinforcers.
Stimulus sensory identities are then processed for multimodal perceptual integration in the posterior orbitofrontal cortex. Hedonic reward value
is represented in more anterior parts of orbitofrontal cortex, from where it can then be used to influence subsequent behavior (in lateral parts of
the anterior orbitofrontal cortex with connections to anterior cingulate cortex), stored for valence learning/memory (in medial parts of the
anterior orbitofrontal cortex) and made available for subjective hedonic experience (in mid-anterior orbitofrontal cortex). There are multiple
modulatory brain-loops with other important structures such as the nucleus accumbens, ventral pallidum, hippocampus, amygdala, and
hypothalamus, as well as modulation with autonomic input from the gut (Batterham et al., 2007). Abbreviations: V1, V2, V4, primary and
secondary visual areas; SS, somatosensory cortex (3,1,2); A1.A2, auditory cortex; INS/OP, insular cortex/frontal operculum; IT, inferior temporal
visual cortex; PIR, piriform cortex; OB, olfactory bulb; OFC, orbitofrontal cortex. Modified from Kringelbach and Stein (2010).
Jafek, 1983). Although the neuronal nature of these cells
is not established, they have a thin, axon-like process
that extends toward the deepest layer of the epithelium
toward the olfactory bulb.
The supporting cells in the olfactory epithelium are
columnar cells, with a microvillous border at their apex.
Unlike similar cells in the adjacent respiratory epithelium,
those in the olfactory epithelium do not show morphological specializations characteristic of mucous secretion. The
function of the supporting cells is not clear but several
functions have been suggested, including secretion of
a non-mucous substance, phagocytotic removal of
substances from the mucous, or provision of glia-like
support for the receptor neurons (e.g. Jafek, 1983).
The basal cells are situated in the deepest zone of the
olfactory epithelium. As in other vertebrates, the basal
cells in humans are apparently stem cells, undergoing
mitotic division and differentiation into receptor neurons
lost to turnover or injury (Moran et al., 1982a). Such
replacement cannot keep up with degeneration over
a human lifetime, however. In adults substantial areas
of the olfactory epithelium are found to have degenerated or been replaced with respiratory epithelium (Nakashima et al., 1984, 1985; Morrison and Costanzo, 1992). In
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34. THE OLFACTORY SYSTEM
addition, contrary to olfactory epithelium in (young)
adults, olfactory epithelium in elderly is found to be
thinner than respiratory epithelium.
THE VOMERONASAL ORGAN
The vomeronasal organ (also known as Jacobson’s
organ) is located in the anterior third of the epithelium
of the nasal septum at the base of the nasal cavity. Prevalence studies of the vomeronasal organ in humans vary
widely from 25% to 100%. Moreover, repeated observation shows us that the vomeronasal organ changes in
visibility from being absent to being well defined and
vice versa (Frasnelli et al., 2011).
The vomeronasal organ is believed to be involved in
species-specific behavior, such as reproduction, in
many animals. The observation of synchronization of
the menstrual cycle in women living together suggested
a similar function of the vomeronasal system in humans.
However, recent evidence refutes this hypothesis. The
human vomeronasal organ contains very few neurons.
Most cells express keratin proteins, specific markers for
epithelial cells and no cells in fact express olfactory
marker protein (Mast and Samuelsen, 2009). Additionally, no evidence has been found for a neural connection
between the vomeronasal organ and the accessory olfactory bulb, a specific region of the olfactory bulb. In fact,
the presence of an accessory olfactory bulb in humans
is doubtful. Studies investigating the role of the vomeronasal organ in pheromone detection have shown that
androstadienone is in fact detected by the olfactory
epithelium and not the vomeronasal organ. Subjects
with functional occlusion of the vomeronasal organ or
without a visible vomeronasal organ showed no difference in perception or detection of androstadienone
compared to controls. Further investigation using PET
imaging confirmed that the vomeronasal organ in
humans has no function. The notion that the human
vomeronasal organ is not functional does not imply
humans are unable to detect pheromones or social chemical signals. Detection of pheromones could be achieved
through the olfactory epithelium in a similar way as in
the olfactory system in mice (Mast and Samuelsen, 2009).
OLFACTORY BULB
In most primates, including humans, the olfactory
bulb is pulled forward from its point of attachment to
the cerebral hemisphere, remaining connected by a relatively long olfactory stalk or peduncle. The olfactory
bulb in young adult humans is 50–60 mm3 (per side)
(Turetsky et al., 2000). The intrinsic structural features
of the human olfactory bulb are similar to those in other
species, but they are somewhat less sharply defined. As
in all mammals, in humans the bulb has a concentric
laminar structure with distinct neuronal somata and
synaptic neuropil separated into layers. Although our
understanding of the synaptic organization of the olfactory bulb depends on observations made in rats and
other animals (see Macrides et al., 1985; Scott and Harrison, 1987; Mori et al., 1999 for reviews), it is very likely
that the human bulb has the same basic organization.
The olfactory nerve fibers ramify in the most superficial layer (olfactory nerve layer), after passing through
the cribriform plate from the nasal cavity. Where the
nerves first reach the olfactory bulb, rostrally and
ventrally, the olfactory nerve layer is thick. It becomes
progressively thinner in the more caudal and dorsal
part of the bulb. Deep to the olfactory nerve layer, the
fibers terminate in the characteristic glomerular formations both on the primary dendritic tufts of the “mitral”
and “tufted” relay cells and on other cell types. In rats,
the transmitter used at this synapse has been shown to
be glutamate, which acts on both NMDA and nonNMDA receptors (Aroniadou-Anderjaska et al., 1997).
In rodents, the organization of the olfactory epithelium
into zones appears to be more or less preserved in the
olfactory bulb, based on the distribution of zone-specific
molecular markers (Mori et al., 1999). Within each zone in
the epithelium, axons from the several thousand receptor
neurons that express a given molecular odorant receptor
converge onto one or two glomeruli in the corresponding
zone of the olfactory bulb (Ressler et al., 1994; Vassar
et al., 1994). In humans the ratio from olfactory receptor
neurons to glomeruli is 16:1 with a total of approximately
5500 glomeruli (Maresh et al., 2008). This suggests that
the glomeruli are the unit structures for olfactory discrimination (e.g. Mori et al., 1999). That is, the initial distinction between different odors is based on hard-wired
connections between specific receptor neurons and
specific glomeruli. Studies with 2-deoxyglucose as a functional imaging method have also shown that specific
odorants activate a small, consistent portion of the olfactory bulb, again suggesting that initial olfactory discrimination depends on a spatial code in the olfactory bulb
(e.g. Johnson and Leon, 2000; Xu et al., 2000).
The synaptic neuropil of the glomeruli is outlined by
somata of small “periglomerular cells”. These interneurons send dendrites and axons into adjacent glomeruli
and receive synapses from the olfactory nerves. Like
the granule cells in the deeper part of the bulb, the
periglomerular cell dendrites form “reciprocal” or bidirectional synapses with mitral and tufted dendrites.
In humans as in other animals, most (at least) of the periglomerular cells are GABAergic and also contain one of
the calcium-regulating proteins, parvalbumin or calbindin (Kosaka et al., 1987; Ohm et al., 1990, 1991). In addition, many are dopaminergic (Smith et al., 1991). In rats
VI. SYSTEMS
PRIMARY OLFACTORY CORTEX
it has been shown that GABA and dopamine colocalize
within periglomerular cells (Kosaka et al., 1985; Gall
et al., 1987). There are also a number of superficial “short
axon cells” in the glomerular region.
Deep to the glomeruli is the external plexiform layer,
with dendrites of mitral, tufted, and granule cells. The
tufted cell somata are also scattered through this layer,
but the mitral cell somata are located in a thin layer at
the border between the external plexiform layer and
the deeper granule cell layer. One or occasionally two
“primary” dendrites of the mitral and tufted cells arise
from the superficial aspect of the somata and extend
through the external plexiform layer to the glomeruli.
Several “secondary” dendrites ramify in the external
plexiform layer.
The small granule cells are by far the most numerous
neuron type in the olfactory bulb and the granule cell layer
makes up approximately half of the volume of the bulb
(Bhatnagar et al., 1987). These interneurons lack an axon
and instead send a superficial “dendritic” process into
the external plexiform layer, where they form reciprocal
synapses with mitral and tufted cell dendrites. Other
dendrites ramify within the granule cell layer and are
solely post-synaptic. There are also short axon cells in
the granule cell layer, which synapse on the granule cells.
Studies in rats and other animals indicate that the
mitral to granule cell component of the reciprocal
synapse uses glutamate, acting on both NMDA and
non-NMDA receptors (Chen et al., 2000). The granule
to mitral cell component of the synapse is GABAergic,
acting on GABA-A receptors. The reciprocal synapses
appear to allow for spatial and temporal modulation
of activity in the relay cells, both on a local (at individual
synapses) and on a more global level (through conduction along granule and mitral/tufted cell dendrites). It
has been reported in non-human primates, including
chimpanzees, that the somata and dendrites of many
cells in the olfactory bulb may be ensheathed by
compact myelin (Tigges and Tigges, 1980). Since many,
at least, of these cells have presynaptic dendrites, it is
possible that the myelin will affect conduction between
different segments of the neuron.
In humans, approximately 5500 glomeruli and 40 000
mitral cells have been counted in young adults (Maresh
et al., 2008; Meisami et al., 1998). There is a progressive
decrease with age in the number and structural integrity
of the glomeruli, and in the thickness of the glomerular/
periglomerular layer (Bhatnagar et al., 1987; Meisami
et al., 1998; although see Maresh et al., 2008). In olfactory
bulbs from very old individuals (>90 years old) less than
30% of the glomeruli and mitral cells were recognized.
Together with the degeneration of the olfactory epithelium mentioned above, this presumably is related to the
decline in olfactory function with age (e.g. Murphy
et al., 2000).
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PRIMARY OLFACTORY CORTEX
Cortical Structure and Projections of the
Olfactory Bulb
The axons of mitral and tufted cells run through the
granule cell layer and emerge from the caudolateral
aspect of the olfactory bulb to form the lateral olfactory
tract (LOT). This tract forms the bulk of the olfactory
peduncle in humans and other primates. Although
a “medial olfactory tract” has been described in the
past, a large body of experimental studies in several
mammalian species, including primates, has shown
that all of the axons from the olfactory bulb pass through
the LOT. There is no medial olfactory tract in mammals.
The LOT can be visualized readily in human brain
sections stained for fibers or myelin. It runs just deep
to the pial surface, from the olfactory peduncle onto
the posterior ventral surface of the frontal lobe and
then laterally around the junction between the frontal
and temporal lobes (the limen insulae) and onto the
anteromedial part of the temporal lobe. Most of the
primary olfactory cortical (POC) areas have a relatively
simple structure, with a broad plexiform layer
composed of dendrites of neurons in deeper layers (I),
a well-defined, compact layer of pyramidal-like cell
somata (II) and a deeper layer(s) of pyramidal and
non-pyramidal cells (III and higher).
The full efferent projection of the olfactory bulb can
only be mapped with experimental methods, so the
description of this projection is based on data from
non-human primates (Heimer et al., 1977; Turner et al.,
1978; Carmichael et al., 1994). As in lower animals, axons
from the olfactory bulb in monkeys run caudally
through the LOT and give off collaterals that extend
medially, laterally, and deep to the tract to contact
dendrites in the superficial part of layer I of the olfactory
cortex. In addition, in primates a few axons from the
olfactory bulb are found in and deep to layer II. In
contrast to the olfactory bulb, there is very little evidence
for a spatial organization in the olfactory cortex that
could support a spatial code. That is, small areas of the
olfactory bulb project to virtually the entire olfactory
cortex, and small areas of the cortex receive fibers from
virtually the entire olfactory bulb (e.g. Haberly and
Price, 1977; Luskin and Price, 1982; Haberly 1985). There
may be a more “fine-grain” organization within this (e.g.
Ojima et al., 1984), but it has not yet been recognized.
Anterior Olfactory Nucleus
The anterior olfactory nucleus (AON) is the most
rostral of the primary olfactory structures. In primates,
including humans, there is a “bulbar” part of this
nucleus located in the rostral part of the olfactory
VI. SYSTEMS
1226
34. THE OLFACTORY SYSTEM
peduncle, including several groups of pyramidal-like
cells in the caudolateral part of the olfactory bulb. As
in other olfactory cortical areas, axons of the mitral
and tufted cells synapse on the distal segments of
dendrites that extend into the plexiform layer around
the neuron clusters. More caudal “medial” and “lateral”
subdivisions of the AON are situated on either side of
the LOT where it joins the orbitofrontal cortex, at the
posterior end of the olfactory peduncle. In monkeys
and other animals, “external” and “dorsal” subdivisions
are also recognizable, but these are not readily distinguishable in humans.
As described earlier, olfactory perception can be
influenced by alternating air intake through the nostrils.
Recently, Kikuta and colleagues (Kikuta et al., 2010)
found that rodents can localize the source of an odor
by comparing the inputs to the left and right nostril.
This is achieved by neurons in the AON pars externa,
which showed different response levels to ipsi- versus
contranostril odor stimulation. Although humans do
exhibit a similar mechanism of source location in the
auditory system (Chapter 36), whether this is also true
for olfaction is unknown. The lack of readily distinguishable subdivision of the AON does make generalization
of animal models problematic.
Olfactory Tubercle
More caudally on the ventral surface of the frontal
lobe, the LOT runs at the junction of the olfactory tubercle
(OTu), medially, and the piriform cortex, dorsal and laterally (Figures 34.3, 34.4, 34.5). The OTu is a prominent
structure in rodents and birds with a well-developed
laminar structure similar to that in other olfactory cortical
areas. It is much less distinct in primates, but still has
a laminar arrangement of cell bodies and afferent fibers.
In all mammals, collaterals of axons in the LOT leave the
medial side of the tract and run through the superficial
part of layer I of the OTu to contact apical dendrites of
cells with somata in layers II and III. Although this
laminar structure is clearly cortical, other features of
the OTu resemble the underlying corpus striatum, and
it has often been included with the nucleus accumbens
(NAcc) in the “ventral striatum” (Chapter 20). For
example, the OTu has a high concentration of acetylcholinesterase, apparently related to intrinsic cholinergic
neurons, and it receives a prominent dopaminergic input
from the ventral midbrain. Its major output is to the
“ventral pallidum”, which is similar to and dorsally
continuous with the globus pallidus.
The primary neurons of the OTu closely resemble the
“medium spiny” cells of other parts of the striatum in
their dendritic structure and appearance. Between and
deep to these cells are clusters of small neurons that
constitute the islands of Calleja. In monkeys, ventral
pallidal elements are distributed somewhat loosely
within the deep part of the OTu rostrally, although
more distinct components of the ventral pallidum are
found further caudally and dorsally.
Both in humans and non-human primates the OTu is
less readily identifiable due to the small size of the basal
forebrain bulge, which houses the OTu (Wesson and Wilson, 2011). In human imaging studies the OTu has been
identified between the uncus and the medial forebrain
bundle. Furthermore, besides the direct inputs from
the olfactory bulb, the OTu also receives minor input
from the olfactory amygdala (Martinez-Marcos, 2009).
PIRIFORM CORTEX
The piriform cortex is the largest and most distinctive
olfactory cortical area. The area was previously referred
to as the prepiriform or prepyriform cortex, apparently
because it is partially situated rostral to the “pyriform
lobule” in carnivores. This designation is not descriptive
in most animals, however, and the suffix “pre” has been
dropped. Furthermore, the piriform lobule in turn
received its name thanks to its pear-shaped anatomy.
In both monkeys and humans, the piriform cortex is situated deep and lateral to the LOT, from the caudolateral
aspect of the frontal lobe, around the limen insulae, to
the rostral dorsomedial aspect of the temporal lobe.
The piriform cortex is characterized by a densely packed
layer II composed of moderately large pyramidal cell
somata, and a less dense layer III of slightly larger pyramidal cells and other neurons. Layer II is found
throughout the piriform cortex but layer III is only
well developed in the caudal part of the cortex. In
monkeys, layer II is thick and prominent, but in humans
layer II is relatively thin and the boundaries of the cortex
are not as distinct. Deep to the piriform cortex, a ventral
continuation of the claustrum forms the endopiriform
nucleus. There are little data on this nucleus in primates,
but in rodents it is closely interconnected with the overlying piriform cortex.
Axon collaterals leave the deep and lateral aspects of
the LOT and terminate primarily on apical dendrites in
the superficial part of layer I. In monkeys, although
not in rodents or carnivores, a few fibers from the olfactory bulb also ramify in deeper layers. As discussed
below, the piriform cortex gives rise to a substantial
association fiber system that extends throughout all
parts of the POC.
Evidence from anatomical, physiological, and functional differences suggests that the piriform cortex can
actually be divided into two different sections, the anterior piriform cortex (APC) and the posterior piriform
cortex (PPC) (Gottfried, 2010). However, input from
the olfactory bulb does not appear to exhibit spatial
VI. SYSTEMS
1227
PIRIFORM CORTEX
RS
10m
24b
11l
14r
32
25
Visual
12m 12l
13b
14c
13m
13l
13a
47/12r
11m
Visceral
11l
10r
46
24b
13m
14r
Olfaction
IOS
9
Somato
sensory
12o
PrCO
Iam
Ial
AON Iapm Iai Iapl G
45
13l
TOS
47/12l
13b
32m
14c
47/12m
13a
9
24b
11l
14c
25
13m
13l
13a
Iapm
Olfaction
Visceral
Gustation
10o
12r
11m
9
11l
14r
32
25
13m
13a
12o
11m
46
24b
13m
14r
Gustation
25
45
13l
14c
Lateral
hypothalamus
vlPAG
Visual
47/12l
13b
32m
Visceral
11l
10r
Somato
sensory
PrCO
Iam
Ial
AON Iapm Iai Iapl G
Olfaction
Medial and lateral
hypothalamus
dlPAG
13l
47/12r
9
Visual
12m 12l
13b
14c
Dorsal
hypothalamus
lPAG
Gustation
Visceral
10o
10m
10m
Ial
Iai
Somato
sensory
12o
PrCO
Iam
Ial
AON Iapm Iai Iapl G
Olfaction
24b
Iam
AON
Visual
12m 12l
13b
Somato
sensory
47/12s
12r
14r
32
Visual
LOS
10o
11m
HR
Gustation
25
10m
10o
MOS
12r
11m
9
FMS
OS
10m
10o
Somato
sensory
47/12m
13a
47/12s
Iam
AON
Iapm
Olfaction
Ial
Iai
Gustation
Visceral
10o
10m
47/12r
9
11m
11l
10r
46
24b
13m
14r
25
45
13l
14c
47/12s
Iam
AON
Iapm
Olfaction
Medial and lateral
hypothalamus
dlPAG
Somato
sensory
47/12m
13a
Dorsal
hypothalamus
lPAG
Visual
47/12l
13b
32m
Visceral
Iai
Ial
Gustation
Lateral
hypothalamus
vlPAG
FIGURE 34.3 Olfaction and comparative networks in the orbitofrontal cortex of macaques and humans. Left-hand images show areas on the
medial and orbitofrontal surfaces, a cortico-cortical network and projections from the primary olfactory cortices in macaque monkeys (Öngür
and Price, 2000). Right-hand images show areas on the medial and orbitofrontal surfaces, a cortico-cortical network and projections from the
primary olfactory cortices in humans (Kringelbach and Rolls, 2004).
patterning across the piriform cortex. Additionally,
contrary to the olfactory bulb, the piriform cortex has
not been shown to have a spatial organization.
Anterior Cortical Nucleus of the Amygdala and
Periamygdaloid Cortex (PAC)
Caudal and lateral to the piriform cortex the axons
from the olfactory bulb continue into several small areas
on the medial surface of the amygdala. The anterior
cortical amygdaloid nucleus is directly caudal to the
piriform cortex and is characterized by a relatively
loosely packed layer II and even more diffuse layer III.
The periamygdaloid cortex is a larger area located
ventrolateral to the piriform cortex. It is markedly
heterogeneous, and in monkeys and humans can be
divided into five subdivisions, PACO, PAC1, PAC2,
PAC3, and PACS, based on architectonic differences
VI. SYSTEMS
1228
34. THE OLFACTORY SYSTEM
(A)
Signal change (%)
0.8
*
0.4
0
-0.4
APC
0
4
8
12 16 20 24 26
Time (s)
(B)
0
4
8
12 16 20 24 26
Time (s)
*
Signal change (%)
0.8
0.4
0
-0.4
-0.8
PPC
0
4
8
12 16 20 24 26
Time (s)
0
4
8
12 16 20 24 26
Time (s)
Different group
Different quality
Same group
Similar quality
(C)
6.5
Signal change (%)
0.8
0.6
0.4
0.2
0
0.0
-0.2
-2
1
-1
0
Subjective pleasantness of smell
FIGURE 34.4 Olfactory processing in humans measured with neuroimaging. A dissociation has been found between the anterior and
posterior parts of the piriform cortex with the anterior part encoding difference between group of odors but not their perceptual quality, while
the posterior part encodes perceptual quality but not between group of odors (Gottfried, 2010). (A) Specifically, the presentation of odorants from
the same functional group leads to significantly reduced activity in the anterior piriform cortex (circled in red), as shown in the left-most plot,
while the right-most graph shows no significant differences for perceptual quality. (B) This is different from the presentation of odorants
containing similar perceptual qualities which leads to reduced activity in the posterior piriform cortex (circled in red). Here, the left-most plot
shows no effect for functional group, while the right-most graph shows a significant difference between perceptual qualities. Following this
perceptual processing, the affective valence is processed in the orbitofrontal cortex. (C) Region of the medial orbitofrontal (circled in white) and
medial prefrontal cortices correlate significantly with the subjective pleasantness ratings of odors, as demonstrated by the correlation between
signal change and pleasantness ratings (shown on the right). (Rolls et al., 2003).
VI. SYSTEMS
ACCESSORY OLFACTORY CORTICAL AREAS
FIGURE 34.5 Representations of odor
Odour object
Stimulus A
Identification and categorization of
odor object
N1
Stimulus B
N2
N1
N2
0
1
2
3
4
5
Time point
Stimulus A Stimulus B
0
1,1
1,1
1
0,3
4,2
2
1,4
3,3
3
3,2
2,2
4
3,4
3,1
5
1,2
0.3
2
Third dimension
Time point
4,3
Citral
Geraniol
0.3
1
0.6
B
0.9
0
0.6
1.2
–1
2
4
2
1.2
0.9
Number of spikes of neuron 2
1229
1
0
1
0
Second dimension
–1
First dimension
–1
3
object in the brain. Odor objects are difficult to
decode in terms of their temporal and spatial
properties. Here we describe a potential model
for how this information might be encoded in
brain networks. The top image show the spatio-temporal patterns in the olfactory system
for two different hypothetical odor stimuli
depicted in blue and red. This firing pattern is
divided into five time bins. Visualization of the
network activity for these two different stimuli
results in two different neural trajectories
(shown in the lower left plot). The points in the
trajectory hold information about which stimulus was present, as well as when it was
present, thus including both temporal and
spatial information (Buonomano and Maass,
2009). Compare this with real data taken from
recordings of 87 projection neurons from the
locust antennal lobe (right-most plot). These
projection neurons from the locust were
recorded during multiple presentations of two
odors (citral and geraniol). This three-dimensional plot (reduced from the 87 vectors)
reveals that each odor produces a different
trajectory, and thus different spatiotemporal
patterns of activity. The numbers along the
trajectory indicate time points (seconds), and
the point marked B indicates the resting state
of the neuronal population.
2
1
0
1
2
3
4
Number of spikes of neuron 1
Valence of
odor object
(Price et al., 1987; Amaral et al., 1992; Carmichael et al.,
1994). All but the most caudal of these (PACS) receive
input from the olfactory bulb in monkeys, although
the layer of axons is thick only in PACO, and is quite
thin in PAC1, PAC2, and PAC3.
superficial lamina in layer I in which the fibers end. EOl
is characterized by a distinct but thin layer II, which is
broken up into cell islands, as in other parts of the entorhinal cortex. The deeper layers are thicker and more
complex than in other olfactory cortical areas, but less
well developed than in other regions of the entorhinal
cortex.
Rostral, “Olfactory” Entorhinal Cortex
In rodents and carnivores, a large fraction of the entorhinal cortex receives fibers directly from the olfactory
bulb (e.g. Price, 1973; Boeijinga and Van Groen, 1984).
In monkeys, however, olfactory bulb input is limited to
a small “olfactory” zone at the rostral edge of the entorhinal cortex (Amaral et al., 1987; Carmichael et al.,
1994). Even in this region, the olfactory projection is relatively slight, both in density, and in the thickness of the
ACCESSORY OLFACTORY CORTICAL
AREAS
Although humans lack an accessory olfactory bulb,
the major target of the accessory olfactory tract in other
animals, the medial amygdaloid nucleus, is present in
humans. The medial nucleus is situated immediately
VI. SYSTEMS
1230
34. THE OLFACTORY SYSTEM
caudal to the anterior cortical amygdaloid nucleus, but
has a slightly denser cellular layer II. In rodents, this
nucleus has been shown to be involved in mating
behavior and a variety of other, related functions.
Presumably, the medial amygdaloid nucleus may have
similar functions in humans, but these may not be as
strongly modulated by olfactory stimuli.
Centrifugal Projections to the Olfactory Bulb
All of the olfactory cortical areas except the OTu send
fibers back to the olfactory bulb (Haberly, 1985; Price,
1987; Carmichael et al., 1994). These fibers arise from
cells in layers II and III of the cortex and end primarily
in the granule cell layer of the olfactory bulb. The projection from the anterior olfactory nucleus and (in
monkeys) the anterior part of the piriform cortex is bilateral, with fibers crossing in the anterior commissure. In
addition, a thin “external” part of the anterior olfactory
nucleus just deep to the most rostral part of the LOT
projects solely or (in monkeys) primarily to the contralateral olfactory bulb.
There is also a substantial fiber projection from the
nucleus of the diagonal band to the olfactory bulb
(Mesulam et al., 1983; Carmichael and Price, 1994).
Although this fiber system is partially cholinergic, only
about 10% of the cells stain for acetylcholinesterase
(Mesulam et al., 1983). In rats, other cells in the nucleus
that project to the olfactory bulb have been shown to be
GABAergic (Zaborsky et al., 1985).
Intracortical Associational Fiber System
Experimental studies in many mammals, including
monkeys, have indicated that the primary olfactory
cortex is organized in a very different way than other
primary sensory cortices. In particular, there is an extensive system of intracortical connections with the POC
(e.g. Price, 1973; Luskin and Price, 1983; Haberly, 1985;
Carmichael et al., 1994; Johnson et al., 2000). This system
suggests that the olfactory cortex functions as a correlative region, comparable to higher-order “association”
cortex in other sensory systems.
The greatest number of association fibers arises in the
piriform cortex, but fibers originate in all of the olfactory
cortical areas except the OTu. The fibers are distributed
throughout the olfactory cortex and to adjacent orbitofrontal and agranular insular areas. In rats, at least, individual neurons in the piriform cortex have axons that
extend into all or most of these areas (Johnson et al.,
2000). Within the olfactory cortex itself, the association
fibers terminate primarily in the deep part of layer
I and in layer III. This laminar pattern of termination is
complementary to the termination of the fibers from
the olfactory bulb in the superficial part of layer I. In
the tangential dimension of the cortex, there is a broad
and relatively complex organization within the association fibers, which has been best defined in rats. While
cortical regions near the LOT project to other parts of
the olfactory cortex near the tract, regions distant to
the tract tend to project to regions at the edges of the
olfactory cortex (Luskin and Price, 1983; Carmichael
et al., 1994).
The association projections from the AON and the
anterior part of the piriform cortex also extend to the
contralateral olfactory cortex, crossing in the anterior
commissure (Luskin and Price, 1983; Carmichael and
Price, 1994). The laminar and areal patterns of termination in the contralateral cortex are approximately the
same as on the ipsilateral side.
Presumably, the association system interacts with the
sensory activity being input to the cortex from the olfactory bulb to support olfactory discrimination. In
contrast to the olfactory bulb, neither of these fiber
systems has the sort of detailed topographic organization that would be expected if odors were represented
in a spatial code. It is possible that cells related to
different odors are dispersed in many parts of the
cortex, and appropriate bulbar and association fibers
synapse on them in a selective manner. It may be
more likely, however, that olfactory discrimination
depends on a system of spatio-temporal patterning
across the cortex, in which adjustments in synaptic
strength are built up from sensory experience.
OLFACTORY PROJECTIONS BEYOND THE
PRIMARY OLFACTORY CORTEX
Olfactory information is transmitted from the POC to
several other parts of the forebrain, including the orbitofrontal cortex, amygdala, hippocampus, ventral striatum, hypothalamus, and mediodorsal thalamus (Price,
1987; Russchen et al., 1987; Carmichael et al., 1994), areas
that are associated with affective learning and memory.
Although these connections have been best studied in
rodents, there are also some experimental data from
monkeys, and functional imaging studies have recently
provided data on humans.
Olfactory Projections to the Amygdala and
Hippocampus
Both the amygdala and hippocampus have often
been considered to be closely associated with olfaction,
especially in lower animals. In primates, these limbic
structures have become dominated by other sensory
inputs, especially vision, but they still have direct
olfactory connections. These arise primarily in the
VI. SYSTEMS
OLFACTORY PROJECTIONS BEYOND THE PRIMARY OLFACTORY CORTEX
periamygdaloid cortex and the olfactory part of entorhinal cortex, which projects both to deep amygdaloid
nuclei and to several parts of the hippocampus (Price
et al., 1987; Jolkkonen et al., 2001; Chapter 24).
Olfactory Projections to the Hypothalamus
In rats, both electrophysiological recordings and
axonal tracer experiments indicate that there are olfactory inputs to several parts of the hypothalamus. The
most direct projection arises from cells in the deepest
layer of the piriform cortex and other olfactory cortical
areas. Although the fibers run through the full rostrocaudal extent of the hypothalamus, in the medial forebrain bundle, they terminate predominantly in the
caudal half of the lateral hypothalamic area. Axons
from the anterior cortical nucleus and medial nucleus
of the amygdala end in more rostral and medial parts
of the hypothalamus.
The olfactory inputs to the hypothalamus have not
been as well defined in monkeys. Experiments with
retrograde tracer injections in the lateral hypothalamus,
however, label neurons in most of the olfactory cortical
areas, as well as in related orbitofrontal/insular cortical
areas (Öngür et al., 1998). Electrophysiological
responses to olfactory stimuli have also been recorded
in the lateral hypothalamic area in monkeys (Tazawa
et al., 1987; Karadi et al., 1989).
Olfactory Projections to the Striatum, Pallidum,
and Thalamus
Along with the amygdala, the olfactory cortex projects
to the ventral part of the striatum, including the NAcc
and the OTu. The olfactory projections are largely
restricted to the OTu and the caudal, ventrolateral part
of the NAcc (Price, 1973; Luskin and Price, 1983; Fuller
et al., 1986). These areas project out to the ventral pallidum, a continuation of the globus pallidus ventral to
the anterior commissure. The major output of the ventral
pallidum, in turn, is to the mediodorsal thalamic
nucleus. As with the dorsal striato-pallidal-thalamic
system, the inputs to the ventral striatum are glutamatergic, but the striato-pallidal and pallido-thalamic projections are GABAergic (Fuller et al., 1986; Kuroda and
Price, 1991).
As in other mammals, both electrophysiological
recording and axonal tracing in monkeys also indicate
excitatory olfactory input to the mediodorsal thalamic
nucleus (MD) from the olfactory cortex (Yarita et al.,
1980; Russchen et al., 1987). The neurons that project to
MD are primarily located in the deep layers of the piriform cortex and other olfactory cortical areas. There
are relatively small numbers of these neurons, and it
1231
appears that they may relay convergent activity from
a relatively large portion of the olfactory cortex. Within
MD in monkeys, fibers from small areas of the olfactory
cortex or the amygdala end in small “patches”, suggesting that inputs from restricted regions converge onto
a few thalamic neurons (Russchen et al., 1987; Ray and
Price, 1993). Similarly, olfactory-responsive units are
restricted to a relatively small region of the medial, magnocellular part of MD. Compared to the hypothalamus,
the olfactory-related units in MD appear to be relatively
broadly tuned and respond to many different odors
(Yarita et al., 1980).
In addition to MD, anatomical and electrophysiological studies in both rats and monkeys indicate that there
is an olfactory projection to the anteroventral portion of
the submedial thalamic nucleus (SM; Price and Slotnick,
1987; Russchen et al., 1987). SM is separated from MD
only by the internal medullary lamina, and it may represent a portion of the same nucleus functionally. In rats,
the projection to SM arises in a relatively restricted
zone at the junction of the piriform cortex and OTu
(Price and Slotnick, 1987).
The portion of medial MD that receives olfactory
input is reciprocally connected with several areas in
the posterior orbitofrontal cortex and rostral agranular
insular cortex (Russchen et al., 1987). The cortical
connections of SM are to a more restricted area near
the junction of the olfactory peduncle and the frontal
lobe (especially area 13a). It might be presumed, therefore, that MD would relay olfactory information to the
orbitofrontal cortex. As discussed below, however, these
same cortical areas receive more numerous, monosynaptic projections directly from the POC. These corticocortical projections appear to be better suited to relay
detailed sensory information. It is likely, therefore, that
the trans-thalamic projection does not represent
a sensory relay as such.
Olfactory Projections to Neocortical Areas
In the 1970s and 1980s Takagi and colleagues reported
that odorant stimuli or electrical stimulation of the olfactory bulb could evoke neuronal responses in the orbitofrontal cortex (Tanabe et al., 1975a, 1975b; Yarita et al.,
1980; Takagi, 1986). Two areas in the lateral and central
parts of the posterior orbitofrontal cortex were identified. In the lateral area the units were relatively specific,
responding to only one or two odorants, while in the
more central area units responded to several odorants.
These studies suggested that the sensory information
reached the orbitofrontal cortex from the POC through
the hypothalamus and thalamus. There is now clear
anatomical evidence in monkeys and other animals,
however, that the principal pathway is directly from
the POC to the orbitofrontal cortex.
VI. SYSTEMS
1232
34. THE OLFACTORY SYSTEM
Injections of anterograde axonal tracers in the piriform cortex of monkeys label axons in several areas of
the agranular insula/posterior orbitofrontal cortex
(areas Iam, Iapm, Iai, Ial, 13a, 13m, and 14c; Carmichael
et al., 1994). All of these cortical areas are agranular or
dysgranular, and the areas nearest to the POC have
sometimes been referred to as periallocortex. The projection is different from more usual sensory inputs to cortex
that are relayed through the thalamus, because the label
is heaviest in layer I. Retrograde axonal tracer injections
into the same agranular insula/posterior orbitofrontal
areas label neurons in many parts of the POC, including
the AON, piriform cortex, anterior cortical amygdaloid
nucleus, PAC, and olfactory part of the entorhinal
cortex. The labeled cells are located in both layer II
and layer III. Electrical stimulation of the olfactory
bulb also evokes unit and field potential responses in
most of the areas where there is anatomical evidence
of olfactory input (Carmichael et al., 1994).
The projections from the POC are largely reciprocated
by fibers from agranular insula/posterior orbitofrontal
areas. Anterograde axonal tracer injections into several
of the agranular insular areas label axons in the rostral
parts of the POC (Carmichael et al., 1994). These include
the OTu, which is the only olfactory cortical area that
does not project to the orbitofrontal cortex.
The agranular insula/orbitofrontal cortical areas that
receive olfactory input interact with other areas on the
orbital surface through cortico-cortical connections to
integrate olfactory sensory information with other
sensory modalities (Carmichael and Price, 1995, 1996).
Taste information reaches the orbitofrontal cortex
through the thalamic gustatory relay and the primary
gustatory cortex (Chapter 33). The orbitofrontal cortex
is the first place where olfactory information and taste
information converge, so it presumably underlies the
sensation of flavor, which depends on both of the
primary modalities. In addition, there are corticocortical somatosensory and visual inputs to the orbitofrontal cortex from the parietal and inferior temporal
cortex. The somatosensory inputs appear to be related
to the hand and mouth (Carmichael and Price, 1995).
The cortico-cortical connections between orbitofrontal
areas form an “orbitofrontal network” that appears to
function in the integration and analysis of food-related
sensory information (Carmichael and Price, 1996).
Recordings in the orbitofrontal cortex in monkeys
show neuronal responses to food and food-related
stimuli, including visual stimuli that are associated
with food (Rolls, 2000). Importantly, the responses
reflect the affective or reward significance of the stimuli
as well as their sensory properties. For example, the
neuronal response to a particular visual stimulus (e.g.
a triangle) will change markedly if the association of
the stimulus with a food reward changed. In addition,
if the animal is fed to satiety with a food stimulus, the
neuronal response to that food will decrease.
HUMAN IMAGING OF OLFACTORY
SENSORY ACTIVITY
Several studies have used functional imaging
methods to identify the human cortical areas activated
by olfactory stimuli (see Zald and Pardo, 2000).
Odorant-induced responses were first obtained in the
region of primary cortex by Zatorre et al. (1992), and
have been confirmed by subsequent reports from the
same research group (Small et al., 1997; Dade et al.,
1998). Other studies have failed to find substantial activation of primary olfactory areas, however (e.g. Zald
and Pardo, 1997; Yousem et al., 1997; Sobel et al.,
1998). Several factors may explain the inconsistency.
Technical factors such as the “susceptability” artefact
related to nearby bone and air sinuses make it difficult
to image this region with fMRI. Neuronal responses to
odorants in the piriform cortex are also rapidly adapting
and may be coded for by temporal or spatial patterns of
activity instead of response amplitude. Further, sniffrelated activity may mask odorant-related activity
(Sobel et al., 1998). When these are taken into account
odorant-related activation can be visualized in the
POC (Sobel et al., 2000).
Olfactory-related activity has consistently been
detected in the orbitofrontal cortex (e.g. Zatorre et al.,
1992; Small et al., 1997; Zald and Pardo 1997; Sobel
et al., 2000; Royet et al., 2001; Rolls et al., 2003). All of
these studies found an area of activation in the central
orbitofrontal cortex, in some cases through the rostral
to caudal extent (Sobel et al., 2000). It has also been
demonstrated that there was a correlation between the
subjective pleasantness ratings of the odors with activity
of a medial region of the rostral orbitofrontal cortex
(Anderson et al., 2003; Rolls et al., 2003). In contrast,
a correlation between the subjective unpleasantness
ratings of odors was found in regions of the left and
more lateral orbitofrontal cortex (Anderson et al., 2003;
Rolls et al., 2003).
It is not yet possible to identify these areas in terms of
the architectonic subdivisions of the orbitofrontal cortex,
but they appear to correspond to the “orbitofrontal
network” defined in monkeys (see above; Carmichael
and Price, 1996). Zald and Pardo (1997) also identified
an area in the lateral orbitofrontal/anterior insular
cortex with activity following stimulation with aversive
odors; the region of the amygdala was also activated to
the same odors.
Imaging studies have shown activation in the piriform cortex during olfactory learning and memory tasks
as well as olfactory tasks related to motivational and
VI. SYSTEMS
HUMAN IMAGING OF OLFACTORY SENSORY ACTIVITY
cognitive states. This indicates a higher or more elaborate function of the piriform cortex than solely the function of a relay to olfactory cortical areas beyond the POC
(Gottfried, 2010).
A more recent fMRI study has found activity in the
central posterior orbitofrontal cortex related to the detection of discrepant olfactory events (Sabri et al., 2005).
Although this study also found activation in the subgenual cingulate cortex, this activity may be attributed to
selective attention. These areas were only activated if
there was no attention paid to the olfactory stimuli.
However, when attention was being paid to the olfactory
stimulation, activation was found in a small part of the
right and lateral OFC region.
The OFC has been shown to be activated during
a multitude of tasks, ranging from odor discrimination
learning to multisensory integration. In addition,
patients with orbitofrontal lesions (e.g. head trauma)
have difficulties with odor identification, memory, and
discrimination while having little difficulties with odor
detection. More specifically, a case-study showed that
an injury in the right OFC led to anosmia while activation in the left OFC and bilateral piriform cortex still
allowed for odor-evoked autonomic responses to
unpleasant smells. This lateralization of olfactory functioning finds support from an early PET study by
Zatorre and colleagues (1992), who found greater activation in right OFC compared to the contralateral homologous OFC after odorant stimulation. Meanwhile
olfaction areas in the temporal lobes were symmetrically
active. Although some have suggested that the right
OFC is necessary for conscious olfactory processing (Li
et al., 2010), lesion studies in patients with medically
refractory epilepsy showed a similar impairment on all
olfactory tasks after unilateral temporal lobectomy,
leaving detection thresholds intact (Eskenazi et al.,
1983). This would seem to indicate a more complex
system with regard to olfactory tasks.
In favor of a lateralization of olfactory function is an
MRI study measuring gray matter loss using voxelbased morphometry in people suffering from anosmia
(Bitter et al., 2010). This study showed a greater atrophy
on the right side. This controlled study furthermore
showed that anosmia leads to reduced gray matter in
the anterior cingulate cortex, the middle cingulate
cortex, the dorsolateral prefrontal cortex, the subcallosal
gyrus, and the NAcc. Further analysis in this study
showed volume loss in the right piriform cortex the right
insular cortex and the right OFC. Direct comparison of
these results with fMRI data from the same participants
showed an overlap of areas activated in healthy participants with gray matter loss areas in anosmic
participants.
It has long been thought that orthonasal and retronasal olfactory stimulation are similar to each other.
1233
Reported activation in piriform cortex, insula, OFC,
hippocampus and entorhinal cortex after retronasal
stimulation by Cerf-Ducastel and Murphy (2001)
contributed to this belief, as the reported areas are
similar to those active after orthonasal olfactory stimulation. No direct comparisons were made, however,
between the two different types of olfactory stimulation.
More recently it has been found that there are fundamental differences in both odor perception as well as
neural activation. According to Small and colleagues
(2005) the insula, opercula, thalamus, hippocampus,
amygdala/piriform, and caudolateral OFC show greater
activation after orthonasal stimulation whereas the perigenual cingulate, posterior cingulate, medial OFC, and
superior temporal gyrus extending into the temporal
operculum show greater activation after retronasal
olfactory stimulation. A very important note is that
this difference was only found in food related odors.
Non-food odors did not result in a similar dissociation.
This finding supports one of the first theories of
orthonasal versus retronasal differences coined by Rozin
(1982), stating that there are different behavioral consequences depending on the two types of information. In
short, orthonasal stimulation represents information
from odor sources in the environment ranging from
animals to plants to fire. Retronasal stimulation signals
information from odor sources in the oral cavity, which
is generally an object that has been previously selected
as food.
Olfaction as a Multimodal System
Food selection is one of the most important functions
of olfaction, and there are close connection between
olfaction and gustation. Ultrasound imaging has shown
that retronasal stimulation (compared with orthonasal
stimulation) increases the speed of swallowing
(Welge-Lüssen et al., 2009). However, only food-related
odors were used in this study, so whether this is specifically related to food intake or also to non-food-related
odors requires further investigation.
The central orbitofrontal cortical region that responds
to odorants also is active by taste stimuli (Small et al.,
1999). This corresponds well with the anatomical
evidence in monkeys that cortico-cortical interconnections within the orbitofrontal cortex relate olfactory
and gustatory systems. The responses to simultaneous,
matched taste and olfactory stimuli appear to be quantitatively different from both unimodal stimuli alone, suggesting that flavor is not a simple convergence of its
component senses (Small et al., 1997). As suggested by
recordings in monkeys (see above), the olfaction- and
taste-related responses in the orbitofrontal cortex also
depend on hedonic properties of the stimuli. For
example, fMRI responses to food-related olfactory
VI. SYSTEMS
1234
34. THE OLFACTORY SYSTEM
stimuli show specific decreases after feeding to satiety
with that food (O’Doherty et al., 2000). Also, in addition
to areas with activity following either olfactory stimulation or taste stimulation, such as parts of the orbitofrontal cortex, amygdala, insular cortex, and anterior
cingulate cortex, some parts of the orbitofrontal cortex
are active only when both taste and olfactory stimuli
were combined (De Araujo et al., 2003).
Taken together, the evidence indicates that the orbitofrontal cortex must be considered as a key node in the
brain networks available for the analysis of food and
food-related stimuli. More generally, it has been
proposed that the orbitofrontal cortex plays a central
role for the analysis of reward and hedonic processing
(Kringelbach, 2005) (see Figure 34.6).
(A)
This view is further supported by how olfactory
dysfunction has been shown to influence malnutrition
(Mesholam et al., 1998; Lafreniere and Mann, 2009).
Both Parkinson disease and Alzheimer disease are
accompanied by malnutrition and weight loss without
clear evidence for changes in metabolism (Warner
et al., 1986; Korczyn and Gurevich, 2009). Also, the
loss of smell (and taste) in elderly is believed to negatively influence appetite and pleasure of food intake,
which in turn lead to malnutrition.
Besides the gustatory system, the trigeminal system
(see Chapter 31) also plays a prominent role in olfaction.
The free nerve endings of the trigeminal nerve are stimulated by a majority of odorants. Additionally, the
trigeminal nerve is also stimulated by odorless vapors
(B)
Monitoring / learning / memory
10o
anterior
47/12r
11m
11l
13m
14r
lateral
Reward value
representations
Evaluations leading
to change
lateral
Correlates of hedonic
experience
Increase in complexity
medial
anterior
45
13l
47/12l
13b
posterior
medial
14c
Multi-modal
representations
46
47/12m
13a
47/12s
Iam
am
m
AON
posterior
Iapm
Ia
Iap
Iai
Ial
Primary sensory cortices
Reinforcer identity
Olfaction Somatosensory Autonomic Visual Auditory
Gustatory
FIGURE 34.6 General model of interaction between sensory and hedonic processing in the OFC. The proposed model shows the interactions
between sensory and hedonic systems in the orbitofrontal cortex using as an example one hemisphere of the orbitofrontal cortex (Kringelbach,
2004). Information is flowing from bottom to top on the figure. Sensory information arrives from the periphery to the primary sensory cortices,
where the stimulus identity is decoded into stable cortical representations. This information is then conveyed for further multimodal integration
in brain structures in the posterior parts of the orbitofrontal cortex. The reward value of the reinforcer is assigned in more anterior parts of the
orbitofrontal cortex from where it can then be used to influence subsequent behavior (in lateral parts of the anterior orbitofrontal cortex with
connections to anterior cingulate cortex), stored for learning/memory (in medial parts of the anterior orbitofrontal cortex) and made available for
subjective hedonic experience (in mid-anterior orbitofrontal cortex). The reward value and the subjective hedonic experience can be modulated
by hunger and other internal states. In addition, there is important reciprocal information flowing between the various regions of the orbitofrontal cortex and other brain regions involved in hedonic processing.
VI. SYSTEMS
REFERENCES
such as carbon dioxide, which induces a sensation of
pain (Kobal, 1985; Hummel et al., 2003). The stimulation
of the trigeminal system by odorants is known to influence the perception of odorants. Animal studies have
shown that, whereas trigeminal stimuli have an inhibitory effect on olfactory afferent nerves, blockage of
trigeminal activity enhances activity in, for example,
the olfactory bulb (Stone et al., 1968; Brand, 2006). It is
furthermore believed that pungency, as tested with
carbon dioxide, can diminish or suppress certain odors.
However, olfactory sensitivity for both purely olfactory
as well as olfactory/trigeminal odorants increases after
previous trigeminal stimulation. The effect of trigeminal
activity on olfactory perception is believed to be both
central as well as peripheral, e.g. interaction may take
place in parts of the thalamus and fibers of the trigeminal nerve innervate the olfactory epithelium (Brand,
2006).
Contrary to the olfactory system, the trigeminal
system has a limited amount of sensations (e.g. pain,
temperature, humidity) compared to the vast amount
of odors detected by the olfactory system and is more
involved in protective reflexes than the olfactory system.
So, although most odorants stimulate both systems, they
are separate systems and can indeed be affected separately, e.g. most patients with Parkinson disease suffer
from olfactory dysfunction while the trigeminal system
appears to be unaffected (Barz et al., 1997).
Olfactory Dysfunction and Anhedonia
There is a vast amount of literature on olfactory
dysfunction, ranging from nasal fractures and head
trauma to toxic exposure, depression, and neurodegenerative disorders. Head trauma can cause olfactory
dysfunction by severing the neurons from the olfactory
epithelium to the olfactory bulb through the cribriform
plate, where scar tissue is subsequently blocking the
growth of new neurons. Olfactory dysfunction due to
neurodegenerative disorders could perhaps tell us
more about the nature of the olfactory system.
Although the literature on olfactory dysfunction in for
example Parkinson disease or Alzheimer disease kept
growing steadily for the past 30 years, the exact underlying mechanisms for olfactory dysfunction in these
disorders is still largely unknown (Hawkes, 2003;
Murphy et al., 2005; Doty, 2007). Whereas both apathy
and olfactory dysfunction are common symptoms in
Parkinson disease, Cramer and colleagues (2010) found
a correlation between olfactory impairment and apathy
where non-apathetic patients performed better on
olfactory tasks. Also, humans suffering from olfactory
dysfunction are found to report a lower quality of life,
in particular with respect to enjoying food and drinks,
socializing, and intimate relationships (Frasnelli and
1235
Hummel, 2005; Smeets et al., 2009). Furthermore, the
olfactory bulb is significantly reduced in patients
suffering from acute major depression (Negoias et al.,
2010).
These studies, however, only show a correlation
between olfactory dysfunction and anhedonia. A wellknown and often-used model for depression in rats is
the creation of anhedonia through olfactory bulbectomy
(Song and Leonard, 2005; Romeas et al., 2009). Peripherally induced loss of olfaction does, however, not induce
the same behavioral changes. In other words, the induction of anhedonia relies not solely on olfaction, but is
caused by the disruption of a more complex system,
the cortical–hippocampal–amygdala circuit. Olfactory
bulbectomy in rats also means that input from the vomeronasal organ is removed, which is important for the
behavior of rats.
In humans, Bitter and colleagues (2010) showed that
a loss of the sense of smell leads to loss of gray matter
cortical areas, including the OFC, medial prefrontal
cortex, anterior cingulate cortex, insular cortex and
NAcc, associated with pleasure or hedonic experience
(Berridge and Kringelbach, 2008; Kringelbach and Berridge, 2010). While the differences in olfactory functioning (especially the influence of the vomeronasal
organ) in rats make it difficult to extrapolate the results
to humans, converging evidence from imaging and
lesioning studies in humans do seem to indicate a major
role of the olfactory system in anhedonia, which should
be further investigated in the coming years.
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