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. 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. 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.

14.5. 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. 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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