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Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010.

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The Neurobiology of Olfaction.

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Chapter 14Cortical Activity Evoked by Odors

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14.1. INTRODUCTION

It has been hypothesized (Lynch 1986; Aboitiz et al. 2002; Montagnini and Treves 2003) that the mammalian cortex initially evolved as an associative structure, allowing features of the sensory world extracted by more peripheral circuits to be merged both within and between sensory modalities into objects capable of driving behavior. Associative cortical circuits generally have broadly distributed, overlapping inputs, allowing convergence of different pieces of information. This is in contrast to classic topographic, hierarchical cortical circuits, where information flow is more restricted to narrow, specialized channels, with much less cross-talk between disparate inputs.

The early mammalian cortex, like the modern reptilian cortex, was dominated by olfaction (lateral cortex) and hippocampus (medial cortex), with a multimodal interface (dorsal cortex) between the two. The olfactory cortex and hippocampus are characterized by nontopographic, associative networks capable of merging distributed, diverse, collections of inputs into everything from rich memories of specific life events, to maps of the visuospatial world, to single olfactory percepts derived from complex molecular mixtures. Only with continued evolutionary expansion of the cortex through the emergence of the neocortex did regional specialization and topographic, unimodal sensory processing come to be expressed, as seen, for example, in the mammalian primary visual or auditory cortex (Lynch 1986; Montagnini and Treves 2003).

Thus, the strongly associative nature of the primitive cortex—i.e., trilaminar cortices like the piriform cortex or hippocampus—promotes synthetic object processing, as opposed to analytical processing of features from complex mixtures. The processing of complex stimulus patterns as objects by associative circuits leads to robust stimulus recognition in the face of degraded inputs and enhanced discrimination of overlapping patterns (Whitfield 1979). It also leads to several testable predictions about cortical activity evoked by odors and the resulting sensory perceptions. Although there is great evolutionary conservation of peripheral features of odor processing across phyla (Hildebrand and Shepherd 1997), mammals have invested a substantial metabolic commitment to paleo- and neocortical olfactory circuits. This chapter will review the structure and function of the olfactory cortex, and describe data on the associative, multimodal, state- and expectation-dependent nature of cortical odor processing. This chapter will also attempt to outline issues that need to be addressed before we can answer how the olfactory cortex contributes to odor perception (Figure 14.1).

FIGURE 14.1. Illustration of the major connections with the piriform cortex.

FIGURE 14.1

Illustration of the major connections with the piriform cortex. In addition to afferent input from the olfactory bulb and anterior olfactory nucleus, the piriform cortex receives input from neuromodulatory as well as higher order processing centers. These (more...)

14.2. THE OLFACTORY CORTEX

The olfactory cortex is typically defined as those areas receiving direct input from the olfactory bulb. This includes wide regions of the olfactory peduncle and ventrolateral forebrain in rodents, and more ventromedial regions in humans. Specific target structures include the anterior olfactory nucleus, the olfactory tubercle, the cortical nucleus of the amygdala, the piriform cortex, and even lateral regions of the entorhinal cortex, though direct input to the entorhinal cortex from the olfactory bulb is minor. Beyond these primary olfactory cortical regions, neocortical areas with substantial olfactory input (e.g., via the primary olfactory cortex) include the lateral entorhinal cortex and the orbitofrontal cortex. This chapter will focus primarily on the piriform cortex and the orbitofrontal cortex, given that the majority of recent work on odor-evoked cortical activity has emphasized these regions (though see, anterior olfactory nucleus: [Lei et al. 2006; Yan et al. 2008]; olfactory tubercle: [Zelano et al. 2007]).

In addition to olfactory bulb input, the olfactory cortex has strong, often reciprocal relationships with limbic areas, such as the amygdala (Majak et al. 2004), the hypothalamus (Price et al. 1991), and the perirhinal cortex (Luskin and Price 1983). There is also heavy innervation by modulatory inputs from the horizontal limb of the diagonal band of Broca (acetylcholine), the raphe nucleus (serotonin), and the locus coeruleus (norepinephrine) (Shipley and Ennis 1996). Together, these limbic and modulatory connections allow behavioral state, hedonic valence, arousal, and attention to shape cortical responses to odor.

14.3. AUTOASSOCIATIVE CIRCUITS WITHIN THE PRIMARY OLFACTORY CORTEX

As opposed to primary sensory regions of the neocortex (somatosensory, visual, and auditory), there is no apparent spatial organization of afferent projections or sensory-evoked activity within the olfactory cortex. In the olfactory bulb, olfactory sensory neurons expressing the same olfactory receptor distributed across the olfactory epithelium converge onto a small number of individual glomeruli. Given that different receptors impart different ligand-binding characteristics to the sensory neurons (Malnic et al. 1999; Araneda et al. 2000, see also Chapter 7), the homogenous sensory neuron convergence to different glomeruli creates odor-specific spatial patterns of activity within the olfactory bulb (Stewart et al. 1979; Rubin and Katz 1999; Wachowiak et al. 2000; Johnson and Leon 2007, see also Chapters 12 and 13). The associated second-order neurons and local interneurons appear to form columns aligned with the glomeruli (Guthrie et al. 1993; Willhite et al. 2006). Thus, different spatial patterns of glomeruli and their associated mitral cells are activated in response to different odorants. Furthermore, there may be spatial organization within these patterns, with for example, glomeruli and associated neurons tuned to aldehydes clustering together, while those tuned to alcohols clustering together in a different region of the bulb (Imamura et al. 1992; Johnson and Leon 2007). Similarly, within the primary sensory neocortex, neurons within a given cortical column display similar tuning characteristics to stimulus features such as auditory wavelength, orientation of visual stimuli, or location of touch on the body surface. Columns near to each other tend to contain neurons expressing similar, though not identical receptive fields (Figure 14.2).

FIGURE 14.2. A highly simplified illustration of network connections between PCX, OB, and AON.

FIGURE 14.2

A highly simplified illustration of network connections between PCX, OB, and AON. The blue lines represent forward projecting axons. Green lines represent feedback connections. The intracortical association fibers are shown in black. The association fibers (more...)

In both the olfactory bulb and the sensory neocortex, these organized tuning characteristics emerge through precise patterns of afferent input from sensory receptors. In the sensory neocortex, these highly organized patterns of activity form topographical maps that are preserved as information is transmitted through the thalamus to the neocortex. Opportunities for interaction between neocortical columns exist through lateral and association connections, which allow for higher order feature detection. Similarly, olfactory sensory receptor neurons converge onto specific olfactory glomeruli; however, this topographic map does not appear to be conserved beyond the olfactory bulb. The basic spatial organization seen in most sensory systems is absent in the piriform cortex.

Afferents to the piriform cortex and the hippocampus are organized entirely differently (Neville and Haberly 2004). In contrast to the tight spatial patterning of sensory neuron input to the olfactory bulb and mitral cells, mitral cell projections to the piriform cortex terminate in broad patches (Ojima et al. 1984; Buonviso et al. 1991). There may be some regional difference in termination between anterior and posterior subregions, but there does not appear to be any clear topographic pattern of input from the spatially organized olfactory bulb to the piriform cortex. These broad afferent patches allow for extensive overlap and convergence of input from different mitral cells conveying information from different olfactory sensory receptor neurons.

Furthermore, in addition to the convergence afforded by afferent fiber overlap, there is an extensive excitatory association fiber system within the piriform cortex. This system is recurrent and autoassociative. That is, individual pyramidal cells receiving input from a specific pattern of mitral cells can feedback onto themselves and their neighbors (which may receive a different random combination of afferent inputs) to enhance convergence and potential associations between different patterns of mitral cell input. A single pyramidal cell may terminate on over one thousand other pyramidal cells in widely disparate regions of the piriform cortex (Johnson et al. 2000). Importantly, the association fiber system expresses activity-dependent associative synaptic plasticity (Kanter and Haberly 1990; Poo and Isaacson 2007; Stripling and Galupo 2008). Thus, as particular input patterns (odors) become familiar, the association fiber system records them through changes in synaptic weight. As discussed below, this allows the system to complete degraded or noisy patterns, which allows perceptual stability (Hasselmo et al. 1990; Granger and Lynch 1991; Hopfield 1991; Haberly 2001), and is a classic characteristic of autoassociative networks.

14.4. ODOR-EVOKED ACTIVITY IN THE PRIMARY OLFACTORY CORTEX

Based on the structure of the piriform cortex, it does not appear to be purely a primary sensory area, but a multimodal association cortex. As a result, there are predictions that can be made. First, activity evoked by a particular odorant should be distributed across the piriform cortex, given the distributed afferent input and the widespread associational connections. Second, there should be minimal spatial organization of odor-response patterns of individual neurons, with, for example, neighboring cells potentially responding to very different odorants depending on the specific set of afferent and association connections on those individual neurons. Third, mixtures of odorants should be processed more synthetically and distinct from their components in the piriform cortex than in the olfactory bulb, based on the extensive convergence within the cortex and the columnar organization and limited afferent convergence within the olfactory bulb. Fourth, experience should strongly influence odor processing within the cortex, given the hypothesized role of association fiber plasticity in cortical circuit function. Fifth, piriform cortical activity should reflect not only odor stimulation, but also odor associations, given the extensive reciprocal connections with limbic and neocortical areas. Each of these predictions is supported by the following findings.

14.4.1. Global Spatial Patterns

Data from 14C-2-deoxyglucose metabolic imaging (Cattarelli et al. 1988), c-fos and other immediate-early gene mapping (Illig and Haberly 2003; Zou and Buck 2006), voltage-sensitive dye mapping (Litaudon et al. 1997), and ensemble unit recording (Rennaker et al. 2007), all show no evidence of strong spatial topography in odor-evoked or olfactory bulb-evoked activity within the piriform cortex. There may be regional variations in sensitivity to given odorants (Illig and Haberly 2003; Zou and Buck 2006), for example, between the dorsal and ventral regions of the anterior piriform cortex (Illig and Haberly 2003). There are also differences between the anterior and posterior piriform cortex, with the posterior piriform cortex neurons, having lower spontaneous activity, being more selective (narrowly tuned) to unfamiliar odors than the anterior piriform cortex neurons in anesthetized rats (Litaudon et al. 2003). However, as predicted from the distributed patterns of afferent and intracortical association fibers, the precise odor-specific spatial patterning evident in the olfactory bulb is largely lost in the piriform cortex.

14.4.2. Local Spatial Patterns

The loss of global odor-specific spatial activity patterns in the piriform cortex is also evident at the single neuron level. Single-unit pairs recorded in the anterior piriform cortex with a single electrode, and thus assumed to be near neighbors, showed differences in both spontaneous and odor-evoked activity. Thus, for example, spontaneous activity of neighboring neurons was poorly correlated across the respiratory cycle, with neurons often completely out of phase (Rennaker et al. 2007). Furthermore, neighboring neurons display different odor tuning, with one of the pair responsive to a particular odor and the other not (Rennaker et al. 2007). Again, this is consistent with a highly distributed afferent input amplified by a highly distributed intracortical association fiber system.

14.4.3. Odor Mixture Processing

Olfactory cortical neurons appear to respond to mixtures differently than olfactory bulb mitral cells, in accord with the convergence of multiple inputs to cortical neurons. However, the difference can be subtle. For example, a mitral cell may respond to a variety of odor mixtures, as long as they include a component that activates olfactory sensory neurons modulating that cell’s activity. Similarly, cortical neurons may also respond to multiple mixtures either because of the strength of single afferent inputs (Franks and Isaacson 2006), or because of activity in specific combinations of afferent and association fiber inputs to that cell. Furthermore, responses to odor mixtures can be affected at all levels of the olfactory pathway by ligand interactions at the olfactory receptor, local circuit effects within the olfactory bulb, and larger circuit interactions within olfactory cortical areas. For example, mixture suppression effects have been observed at all levels of the olfactory pathway where it has been looked for (Derby et al. 1991; Kadohisa and Wilson 2006b). Thus, comparison of mitral cell and piriform cortical responses to novel, random odor mixtures may not tell the whole story about how the cortex responds to mixtures (see below).

Nonetheless, mixture responses in two olfactory cortical areas, the anterior olfactory nucleus (Lei et al. 2006) and the piriform cortex (Wilson 2000b; Barnes et al. 2008), have been compared to responses to the same odors by mitral cells. Mitral cells responding to a mixture of molecularly dissimilar components generally respond to only a single or small number of the components, while olfactory cortical neurons may respond to many of the components (Lei et al. 2006). This fits with the idea that mitral cells respond to a mixture due to the presence of a particular component, while cortical neurons respond to a convergence of multiple components. In fact, a subset of cortical neurons may require convergent input from different afferent populations in order to be activated (Lei et al. 2006; Zou and Buck 2006). Furthermore, cross-adaptation studies of familiar binary mixtures and their molecularly dissimilar components demonstrate that mitral cells that have adapted to a mixture also cross-adapt to the components (Wilson 2000a). In contrast, anterior piriform cortex neurons showed minimal cross-adaptation between familiar mixtures and their components (Wilson 2000a). These results suggest that cortical neurons treat mixtures as distinct objects, different from their components.

Recordings of cortical single-unit ensembles further demonstrate that cortical circuits allow completion of degraded input patterns evoked by complex odor mixtures. As noted above, pattern completion is a defining feature of autoassociative networks. Most natural odors are combinations of many odorants. While each may contribute differentially to the overall mixture quality, there can be natural variation in the presence or strength of individual components, yet the percept remains stable. For example, the aroma of a chardonnay wine may include dozens of individual components, each detectable when presented alone. However, when presented together, their individual qualities are lost perceptually to allow a single percept of chardonnay (Jinks and Laing 2001). In many cases, the complete percept can be recreated, even if some of the individual components are missing, i.e., the olfactory system can fill in the missing gaps and complete the chardonnay pattern. In contrast, inclusion of a single abnormal component, such as mold on a cork, may completely alter the chardonnay percept—even if the abnormal component cannot be explicitly identified. Autoassociative networks are ideal for solving such pattern completion and pattern separation (discrimination) problems.

Complex odor mixtures evoke complex spatiotemporal patterns in the olfactory bulb glomerular layer and mitral cell output (Lin et al. 2006). Even very subtle changes in the sensory input, e.g., loss of a component within the mixture, can be detected by mitral cell ensembles and thus are reflected in olfactory bulb output patterns (Barnes et al. 2008). However, piriform cortex single-unit ensembles fail to decorrelate these very subtle losses from their response to the complete mixture, thus allowing a completion of the full pattern from the degraded pattern (Barnes et al. 2008). This pattern completion should result in difficulty in behavioral discrimination of the complete mixture from its degraded version, and it does (Barnes et al. 2008). However, continued degradation of the mixture with loss of additional components rapidly produces a pattern completion process in piriform cortical ensembles, enhancing decorrelation of the complete mixture from its morphed version. This enhanced pattern separation corresponds to excellent behavioral discrimination. Similarly, inclusion of a single abnormal component within a complex mixture (similar to the cork taint in wine), leads to marked cortical decorrelation, pattern separation, and behavioral discrimination (Barnes et al. 2008).

14.4.4. Odor Experience Effects

Cortical responses to odors are highly dynamic, reflecting past experience over both short and long time courses. This means that cortical odor responses not only reflect sensory neuron input, but also past experience and previous odor associations.

The piriform cortex rapidly adapts to stable odor input in rats (Wilson 1998), mice (Kadohisa and Wilson 2006b), and humans (Sobel et al. 2000). The cortical adaptation occurs despite relatively stable responses of olfactory bulb mitral cells (Wilson, 1998). In rats, short-term cortical odor adaptation is induced by metabotropic glutamate receptor-mediated synaptic depression of mitral cell input to the cortex (Best and Wilson 2004). Blockade of these receptors prevents both cortical adaptation (Best and Wilson 2004) and habituation of simple odor-evoked behaviors (Best et al. 2005; McNamara et al. 2008). Increases in noradrenergic input to the piriform cortex, as might occur with an increase in arousal or vigilance, can induce dishabituation and return of odor-evoked responses (Smith et al. submitted). The cortical odor adaptation is highly odor-specific, especially to familiar odors (Wilson 2003). This odor specificity allows the piriform cortex to use adaptation to segment new odors from an odorous background (Kadohisa and Wilson 2006b; Linster et al. 2007).

Associative conditioning also modifies cortical odor responses (Litaudon et al. 1997; Zinyuk et al. 2001; Moriceau and Sullivan 2004; Li et al. 2008). In general, learned familiar odors evoke enhanced activation of the piriform cortex as measured with c-fos immunohistochemistry or metabolic activity (Moriceau and Sullivan, 2004; Li et al. 2008), though specific effects may differ between anterior and posterior subregions (Litaudon et al. 2003; Kadohisa and Wilson, 2006a). At the global (fMRI; Li et al. 2008) and cortical ensemble (Kadohisa and Wilson 2006a) levels, associative conditioning also enhances decorrelation of encoding between similar odors within the anterior piriform cortex. In the posterior piriform cortex, which has been implicated in encoding higher order odor quality or category (e.g., “fruity”; Gottfried et al. 2006), associative conditioning can lead to a decrease in decorrelation of similar odors or odors experienced within mixtures (Kadohisa and Wilson 2006a). These changes in the posterior piriform cortex may underlie the observed merging of odor quality perceptions of odors experienced in binary mixtures (Stevenson 2001).

Some of this cortical modification reflects changes that occur as early as the olfactory bulb (Sullivan and Leon 1986; Fletcher and Wilson 2003; Martin et al. 2004b; Harley et al. 2006; Mandairon et al. 2006; Doucette and Restrepo 2008), although odor learning also modifies synaptic physiology and cellular biophysics within the piriform cortex itself (Roman et al. 1993; Saar et al. 2002; Saar and Barkai 2003; Cohen et al. 2008). Nonetheless, these findings suggest that odor processing is linked very early in the sensory pathway to odor associations and hedonics. The piriform cortex is strongly, reciprocally linked to the amygdala and orbitofrontal cortex, thus, odor “meaning” extracted by those regions may feedback to the piriform cortex and shape processing (see below).

Recent work in the gustatory cortex suggest that single-unit ensembles within this primary sensory cortex go through several stages reflecting different network states encoding not only stimulus identity, but also hedonic valence or palatability (Jones et al. 2007). The ensemble encoding is also modulated by behavioral state or attention (Fontanini and Katz 2006). The changes in network activity may reflect not only local circuit interactions, but also larger scale interactions between the gustatory cortex and other areas such as the amygdala (Grossman et al. 2008). These kinds of single-unit ensemble analyses need to be applied to the olfactory cortex in the future.

14.4.5. Descending Control and Multimodal Convergence

Odor responses in the primary olfactory cortex reflect not only olfactory sensory neuron activity, but also behavioral state, context, and current and past associations with the odor. Information regarding these diverse nonolfactory features comes from descending inputs from neocortical and limbic areas, as well as modulatory inputs from the basal forebrain and brainstem.

In recordings from awake animals performing odor-guide behaviors, piriform cortical activity reflects not only odor stimulus quality, but also other aspects of the animal’s behavior, such as approach to the odor sampling port, movement from the sample port to the reward port, and consummation of the reward (Schoenbaum and Eichenbaum 1995; Zinyuk et al. 2001). This nonolfactory activity may reflect the fact that even olfactory bulb neurons respond to multiple aspects of the behavioral task (Kay and Laurent 1999; Rinberg and Gelperin 2006), and the broader circuit context within which the piriform cortical activity rests.

For example, both cholinergic inputs from the basal forebrain horizontal nucleus of the diagonal band of Broca (Linster et al. 1999) and noradrenergic input from the brainstem nucleus locus coeruleus (Bouret and Sara 2002) modulate spontaneous and evoked piriform cortical activity. For example, activation of the locus coeruleus enhances entrainment of piriform cortical single-unit spontaneous activity to the respiratory cycle, and enhances (primarily) odor-evoked activity (Bouret and Sara 2002). Given that locus coeruleus activity is affected by novel or intense stimuli (such as unconditioned stimuli) and behavioral state (Sara et al. 1994), odors temporally associated with these conditions should impinge on a hyperexcitable piriform cortex, enhancing the probability that the odor input will be memorized by cortical circuits (Linster and Hasselmo 2001). Interestingly, as noted above, norepinephrine can also induce dishabituation of habituated odor responses (Smith et al. submitted), further enhancing the probability of learning odors associated with significant, nonolfactory events.

These same modulatory inputs may also be important for decreasing sensory-evoked activity within the piriform cortex during down states. During slow-wave sleeplike states in urethane-anesthetized rats, piriform cortical single-units become less responsive to the olfactory bulb and odor input (Fontanini and Bower 2005; Murakami et al. 2005). This state-dependent gating of sensory throughput is similar to the role the thalamus plays in thalamocortical sensory systems.

In addition to changes in intrinsic piriform cortical activity, state, context, and task demands can also affect coupling of cortical activity to that in other regions. Such changes in coupling, usually measured with coherence of local field potential oscillations, can reflect the varying strength of functional connectivity between local or distant brain regions. For example, beta frequency oscillations in local field potentials (around 15–40 Hz, though this varies between laboratories) generally reflect the information flow between two regions at some distance, for example, between the olfactory bulb and piriform cortex, or between the hippocampus and olfactory bulb. Activity can be recorded in different brain regions within these frequency ranges, and under specific conditions, the activity in the different regions can become entrained, or coherent. This increase in coherence suggests an increased functional coupling between areas, and a potential enhancement in transfer or linking of information.

During odor conditioning or in response to a biologically significant odor, beta frequency oscillations are enhanced in several discrete olfactory regions, such as the olfactory bulb (Ravel et al. 2003), the piriform cortex (Martin et al. 2004a), and the entorhinal cortex (Chabaud et al. 2000). However, in addition to the increase in these oscillations in specific areas, there is also an increase in coherence within beta frequency between, for example, the hippocampus and olfactory bulb (Martin et al. 2007). Beta frequency oscillations may also be indicative of feedback input to the olfactory bulb from the entorhinal cortex, perhaps enhancing identification or recognition of learned odor features (Kay et al. 1996). Thus, as odors gain significance, or even have their significance modulated by behavioral state (e.g., hunger; Chabaud et al. 2000), large-scale circuits begin to act coherently, linking odor representations to their meaning, and to expectations or context.

14.5. BEYOND THE PRIMARY OLFACTORY CORTEX

Odorant stimulation evokes activity in a variety of regions beyond the primary olfactory cortex. In humans, many neocortical areas are activated by odor stimulation, with the specific contribution of individual areas influenced by the route of odor stimulation (ortho- or retronasal; Small et al. 2005), stimulus intensity (Bensafi et al. 2008), stimulus hedonics (Bensafi et al. 2007; Grabenhorst et al. 2007), attention (Zelano et al. 2005; Plailly et al. 2008), expectation and/or multimodal context (Gottfried and Dolan 2003), stimulus familiarity (Plailly et al. 2005), and imagery of odors (Djordjevic et al. 2005). As described below, in many cases, functional imaging in humans has led the way in mapping these larger circuit olfactory processes, though important observations in animals add to the overall understanding (Figure 14.3).

FIGURE 14.3. Illustration of the major connections with the orbital frontal cortex.

FIGURE 14.3

Illustration of the major connections with the orbital frontal cortex. The multimodal sensory input, along with connections to emotional areas, memory, and higher order processing, suggests a complex modulation of olfactory responses in the piriform cortex (more...)

Of particular note as an olfactory processing area is the neocortical orbitofrontal cortex. The dorsomedial nucleus of the thalamus projection to the orbitofrontal cortex is the olfactory thalamocortical pathway most comparable to other sensory systems. However, the olfactory orbitofrontal cortex receives odor input not only from the thalamus, but also directly from the piriform cortex (Johnson et al. 2000). This piriform cortex-orbitofrontal cortex connection is reciprocal (Illig 2005), allowing descending neocortical control over piriform cortex activity. Furthermore, the orbitofrontal cortex is highly multimodal, with single neurons responsive to olfactory, gustatory, somatosensory, and visual stimuli (Rolls 2001, 2004). Finally, in addition to multimodal convergence, activity within the orbitofrontal cortex reflects affective response to, or incentive value of, odors (Schoenbaum et al. 2003a), and is strongly modified by past odor associations (Rolls et al. 1996; Schoenbaum et al. 1999) and current motivational state (Critchley and Rolls, 1996b; O’Doherty et al. 2000).

As expected in an olfactory region, single-units in the orbitofrontal cortex can respond to odor stimulation, and can discriminate between different odors, potentially having more narrow odor receptive fields than mitral cells (Tanabe et al. 1975). As in the piriform cortex, there does not appear to be any detectable spatial topography in odor-evoked activity within the orbitofrontal cortex, though this has not been closely examined. In primates, there is a lateralization in odor-evoked activity, with the right orbitofrontal cortex showing the dominant response (Zatorre et al. 1992).

As mentioned above, orbitofrontal cortex activity reflects odor-reward associations in rats (Schoenbaum et al. 2003b; van Duuren et al. 2007, 2008), humans (Gottfried et al. 2002), and non-human primates (Critchley and Rolls 1996a). Thus, for example, in a task wherein different odors predicted different sized rewards, single-units and single-unit ensembles responded differentially to the predicted reward size as signaled by the learned odors (van Duuren et al. 2007, 2008). Such associative learning is also correlated with the enhanced strength of orbitofrontal synaptic projections to the anterior piriform cortex (Cohen et al. 2008), providing a learning-induced top-down modulation of piriform odor processing.

As with piriform cortex activity described above, recent work has examined orbitofrontal cortex functional connectivity with other components of large-scale brain networks. Again, these analyses examine not only odor-evoked activity within a specific brain region, but also how that activity is correlated with or entrained to activity in other brain regions. For example, as noted above, the two primary sources of odor information to the orbitofrontal cortex come from the piriform cortex and the dorsomedial nucleus of the thalamus. However, both the dorsomedial nucleus of the thalamus (Amaral et al. 2003) and the piriform cortex (Majak et al. 2004) receive input from the basolateral amygdala, a region critical for emotional memory and hedonic reactions (LeDoux 2003).

Thus, a large-scale network exists involving (at least) the orbitofrontal cortex, the piriform cortex, the amygdala, and the dorsomedial nucleus of the thalamus. Functional connectivity between several of these circuit nodes has been examined during odor learning and attention. For example, activity within both the basolateral amygdala and orbitofrontal cortex increase during reward expectation in an odor-learning task (Schoenbaum et al. 1998). Lesions of the amygdala reduce these reward-based responses in the orbitofrontal cortex, leaving cortical responses more restricted to odor quality coding alone (Schoenbaum et al. 2003b). This suggests a potential convergence within the orbitofrontal cortex of odor information driven from the piriform cortex and perhaps the dorsomedial nucleus of the thalamus, and hedonic or value information from the amygdala via the dorsomedial nucleus of the thalamus.

Furthermore, attention plays an important role in functional connectivity within this circuit. For example, attention to odors enhances the functional connectivity between the dorsomedial nucleus and the orbitofrontal cortex in humans, compared to attention to tones (Plailly et al. 2008). There was no effect of attention on piriform cortex functional connectivity to the orbitofrontal cortex (Plailly et al. 2008). In addition, selective attention to odor pleasantness enhances activation of the orbitofrontal cortex relative to conditions where attention was directed to odor intensity (Rolls et al. 2008). Given that this hedonic information appears to be derived from the amygdala-dorsomedial nucleus-orbitofrontal cortex pathway, both studies suggest an attentional modulation of thalamic input to the orbitofrontal cortex. A similar role for the thalamus in attention has been described in other sensory systems (McAlonan et al. 2008).

Finally, in addition to the orbitofrontal cortex, odor-evoked activity has been described in the entorhinal cortex in rats (Kay, 2005; Petrulis et al. 2005) and humans (Cerf-Ducastel and Murphy, 2003; Bensafi et al. 2008), and the cingulate cortex (Grabenhorst et al. 2007). Entorhinal cortex damage in Alzheimer disease is associated with impaired odor identification (Wilson et al. 2007). Cingulate cortical activity may reflect hedonic valence, especially negative valence of odors (Grabenhorst et al. 2007). Further mapping of odor-evoked neocortical activity is warranted.

14.6. SUMMARY

The neuroanatomy of the olfactory bulb-piriform cortex circuit is highly conserved in vertebrates, and thus might be thought to play a basic, critical role in odor perception. The piriform cortex neural architecture is that of an autoassociative array, and it seems to serve in a pattern recognition capacity to deal with complex spatiotemporal patterns of olfactory bulb output in response to complex natural odors. Plasticity of intrinsic intracortical connections permits memorization of familiar patterns, which promotes both completion of slightly degraded patterns to allow perceptual stability, and separation/decorrelation of more distinct patterns to allow perceptual discrimination. Given the diverse limbic and neocortical inputs to the piriform cortex, the odor representations can also include, perhaps inextricably, nonolfactory components such as learned associations. Thus, odor-evoked activity within the piriform cortex is spatially diffuse (nontopographic) and modulated by behavioral state, expectations, and past experience.

The piriform cortex, in turn, projects both directly and indirectly to the orbitofrontal cortex. In addition to olfaction, the orbitofrontal cortex receives multimodal sensory inputs. Through network interactions with the piriform cortex, the thalamus, and the amygdala (among other areas), the orbitofrontal cortex appears to encode learned or intrinsic value together with odor quality. Thus, learned or state-dependent changes in hedonic valence or value of the odor can affect odor-evoked activity within the orbitofrontal cortex.

Based on these and other findings, it is the cortex that drives what is commonly experienced as our conscious sense of smell. While olfactory sensory neuron activity places constraints on odor perception, it is cortical processing that allows the perception of synthetic odor objects, reactions of pleasure or disgust, and memories of home.

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