Cortical Processing of Odorants
Summary and Keywords
Odorants, inhaled through the nose or exhaled from the mouth through the nose, bind to receptors on olfactory sensory neurons. Olfactory sensory neurons project in a highly stereotyped fashion into the forebrain to a structure called the olfactory bulb, where odorant-specific spatial patterns of neural activity are evoked. These patterns appear to reflect the molecular features of the inhaled stimulus. The olfactory bulb, in turn, projects to the olfactory cortex, which is composed of multiple sub-units including the anterior olfactory nucleus, the olfactory tubercle, the cortical nucleus of the amygdala, the anterior and posterior piriform cortex, and the lateral entorhinal cortex. Due to differences in olfactory bulb inputs, local circuitry and other factors, each of these cortical sub-regions appears to contribute to different aspects of the overall odor percept. For example, there appears to be some spatial organization of olfactory bulb inputs to the cortical nucleus of the amygdala, and this region may be involved in the expression of innate odor hedonic preferences. In contrast, the olfactory bulb projection to the piriform cortex is highly distributed and not spatially organized, allowing the piriform to function as a combinatorial, associative array, producing the emergence of experience-dependent odor-objects (e.g., strawberry) from the molecular features extracted in the periphery. Thus, the full perceptual experience of an odor requires involvement of a large, highly dynamic cortical network.
Olfactory Cortical Anatomy
The olfactory cortex is defined as those regions that receive direct input from the olfactory bulb. In mammals this includes, but is not limited to, the anterior olfactory nucleus (aka anterior olfactory cortex), the olfactory tubercle, the cortical nucleus of the amygdala, the anterior and posterior piriform cortex, and the lateral entorhinal cortex (Cleland & Linster, 2003). These cortical regions are heavily interconnected and also project back to the olfactory bulb (see Figure 1). Traditionally, the piriform cortex is considered the primary olfactory cortex and has received the most experimental attention. While the entorhinal cortex is a neocortical structure containing five–six layers, the other olfactory cortical regions are considered paleocortical, generally containing three layers.
The nature of olfactory bulb inputs to olfactory cortical sub-regions varies (Igarashi et al., 2012). For example, olfactory bulb mitral cells send widely distributed projections throughout the anterior olfactory nucleus, piriform cortex, and entorhinal cortex, with no clear spatial patterning. In contrast, olfactory bulb tufted cell axons terminate in small dense clusters, primarily in anterior olfactory nucleus and olfactory tubercle, and much less so in piriform cortex. Given the known differences in odor response characteristics between these two output cell types, these different projection patterns may contribute to differences in odor processing in different cortical targets.
In addition to input from the olfactory bulb, the olfactory cortex also receives extensive multi-sensory, higher-order, and modulatory inputs. The nature and density of these inputs varies between olfactory cortical regions. For example, for the piriform cortex, there is both a direct and indirect cortico-thalamo-cortical connection with the orbitofrontal cortex (Cohen, Reuveni, Barkai, & Maroun, 2008; Courtiol & Wilson, 2015; Johnson, Illig, Behan, & Haberly, 2000). In addition, there are direct inputs to the piriform cortex from the insular (gustatory) cortex (Maier, Wachowiak, & Katz, 2012). While the posterior piriform cortex receives a strong input from the basolateral nucleus of the amygdala, this input is much less dense in the anterior piriform cortex (Majak, Ronkko, Kemppainen, & Pitkanen, 2004). The olfactory tubercle receives auditory and visual inputs, as well as strong inputs from classical reward circuits such as ventral tegmental area and nucleus accumbens (Wesson & Wilson, 2011). The entorhinal cortex receives multi-sensory input from a variety of areas, as well as feedback from the hippocampal formation. Cholinergic input from the horizontal limb of the diagonal band of Broca, serotonerigic input from the dorsal raphe nucleus, and noradrenergic inputs from the nucleus locus coeruleus also project broadly throughout the olfactory cortex (Cleland & Linster, 2003).
Finally, in addition to variation in inter-regional connectivity, local circuitry and cell types also vary between olfactory cortical sub-regions (Bekkers & Suzuki, 2013). For example, there appears to be an anterior to posterior gradation in the relative density of intra-cortical, auto-associative connections (Haberly, 2001). Thus, while axonal connections between pyramidal cells within the anterior olfactory nucleus are light, they dominate apical dendrites of pyramidal cells in the posterior piriform cortex, being much more dense than input from the olfactory bulb. The structure of the olfactory tubercle is even more distinct from other olfactory cortical regions, displaying a pyramidal cell layer combined with dense granule cell clusters forming the Islands of Calleja.
This superficial overview of olfactory cortical structure emphasizes that while all regions of the olfactory cortex receive input from the olfactory bulb, they vary in (1) the olfactory bulb projection neuron cell type that dominates that input, (2) the source and extent of non-olfactory bulb inputs they receive, and (3) the local neural architecture onto which those inputs terminate. In addition to these factors, each olfactory cortical region also differs in its output projections. For example, while some neurons in the anterior piriform cortex project directly to the orbitofrontal cortex, neurons in the anterior olfactory nucleus and olfactory tubercle do not. Thus, cortical odorant processing displays both serial and parallel processing characteristics. Some cortical areas function iteratively, potentially building on processing occurring in earlier stages (e.g., anterior olfactory nucleus—anterior piriform cortex—posterior piriform cortex). Simultaneously, odorant information is distributed to different cortical areas directly from different classes of olfactory bulb output neurons (e.g., tufted cells to olfactory tubercle and mitral cells to lateral entorhinal cortex). Together, these characteristics suggest that odorant-evoked activity in a specific neuron or neural ensemble reflects not only what odorant was inhaled, but also the specific context in which that neuron or ensemble functions.
Distributed Odor Processing
Odorants, like other sensory stimuli, are processed to extract different kinds of information. One basic distinction is between odorants inhaled in an orthonasal manner, with the stimulus in the air, and retronasal olfaction, where the volatiles come from objects (food) in the mouth that then pass the olfactory receptor sheet on exhalation. Odorants sampled retronasally are perceptually referred to the mouth, and are experienced as flavor. Beyond this stimulus sampling distinction, odorants convey information that can be used to judge intensity, quality (e.g., this odor is different from that), hedonic valence (e.g., like, do not like), identity (e.g., strawberry or vanilla), and category (e.g., fruity or floral). It is important to also note that most natural odors are composed of mixtures of different volatile molecules, in some cases with components that individually smell nothing like the mixture. Thus, the olfactory system must also be capable of configural processing, merging odorant components into perceptual odor objects.
While activity in many olfactory cortical regions reflects these diverse characteristics, both the known neuroanatomy and increasing physiological data suggest specialization of function across the olfactory cortical network. That is, the activity within different olfactory regions contributes to different features of the overall percept. While some aspects of processing within this network appear to be sequential, with downstream sites building on processing of earlier stages, there also appears to be extensive parallel processing. Finally, as in other sensory systems, there is increasing evidence in both humans and animals models of hemispheric specialization, with an asymmetry in activation of left and right cortical structures depending on the nature of the olfactory task and the familiarity of the odor (Cohen, Putrino, & Wilson, 2015; Royet & Plailly, 2004).
The piriform cortex serves several roles in the cortical processing of odorants. First, it is a major component of the configural odor processing network (Wilson & Sullivan, 2011). In contrast to the precise spatial patterns of sensory afferent input to the olfactory bulb, the olfactory bulb input to the piriform cortex is non-topographic and highly convergent. In this manner, individual cortical pyramidal cells can receive input from a population of mitral cells conveying information from a variety of sensory neurons expressing different receptors. This convergence allows synthesis of extracted and refined odorant features into odor “wholes” or odor perceptual objects.
In addition to the convergence of mitral cell input, the piriform cortex also includes a substantial intra-cortical association fiber system that enhances the possibility for convergence of different features. In fact, selective pharmacological suppression of intra-cortical fiber synapses substantially reduces odor responses by piriform cortical single-units, especially in those cells that are normally broadly tuned (Franks et al., 2011; Poo & Isaacson, 2011). Suppression of these synapses can also impair behavioral odor discrimination in humans and animal models. Furthermore, the association fiber system displays associative synaptic plasticity, which allows the cortex to learn and remember previously experienced patterns of input, a process known to contribute to perceptual stability when the precise make-up of complex input patterns (e.g., complex mixtures of many odorants) varies (Chapuis & Wilson, 2011). Thus, when a distributed ensemble of piriform cortical neurons is activated by an odor (Stettler & Axel, 2009), the inter-connections between those neurons can become strengthened through experience-dependent synaptic plasticity. This strengthens the cohesiveness of the ensemble such that association fibers alone could drive members of the ensemble if the input pattern is degraded (Chapuis & Wilson, 2011; Haberly, 2001). This process of filling in missing components of a familiar perceptual object is known as pattern completion, and has been best described in the visual system.
In addition to the synthesis of odor objects from their molecular features, the olfactory cortex also receives input about behavioral state (e.g., hungry or sated), emotion, expectation, and even multimodal information. For example, input to the piriform cortex from the basolateral amygdala modulates single-unit and ensemble odor responses (Sadrian & Wilson, 2015). This could allow emotional state or emotionally evocative stimuli to influence piriform cortical odor processing, and potentially perceived odor quality or intensity. In fact, in rodents odor fear conditioning modifies piriform cortex single-unit odor receptive fields and olfactory perceptual acuity (Chen, Barnes, & Wilson, 2011). Thus, learned changes in the piriform cortex could contribute to both odor-associative memory and to odor perceptual learning. Furthermore, in both humans and animal models, the anterior and posterior components of the piriform contribute different aspects of quality coding (Howard, Plailly, Grueschow, Haynes, & Gottfried, 2009; Kadohisa & Wilson, 2006). Coding in the anterior piriform predicts precise odor quality, for example, ester or banana, while coding in the posterior piriform is more closely tied to odor category, for example, floral or fruity.
The piriform cortex also plays a critical role in short-term odor habituation and our ability to filter background odors (Linster, Henry, Kadohisa, & Wilson, 2007). Synaptic depression of mitral cell input to the piriform cortex is both necessary and sufficient for short-term odor habituation. Adaptation and habituation are critical features of stimulus processing in all sensory systems. Reducing responses to stable or repetitive sensory inputs allows activity in the sensory system to more accurately reflect biologically important or dynamic stimuli. In olfaction, this short-term adaptation process occurs within the piriform cortex. A central mechanism for odor habituation, as opposed to peripheral receptor adaptation, allows for dis-habituation if contingencies change and the odor becomes relevant. In fact, the short-term depression at the mitral cell–piriform cortical pyramidal cell synapse that underlies short-term habituation can be reversed by norepinephrine beta receptor activation, and blockade of those receptors in vivo prevents behavioral odor dis-habituation (Smith, Shionoya, Sullivan, & Wilson, 2009).
Recent work in both humans and animal models shows that sleep plays an important role in odor memory and that the piriform cortex is one site of sleep-dependent memory consolidation (Arzi et al., 2012; Barnes & Wilson, 2014; Shanahan & Gottfried, 2014). Post-training sleep, especially slow-wave or non–rapid eye movement (REM) sleep provides an opportunity for the olfactory cortex to replay recently learned odor patterns and strengthen connections within ensembles that process those odors. During slow-wave sleep the piriform cortex is hypo-responsive to odors compared to during waking or REM sleep (Murakami, Kashiwadani, Kirino, & Mori, 2005). At the same time, functional connectivity between the piriform cortex and other regions such as basolateral amygdala, lateral entorhinal cortex, and hippocampus is enhanced (Wilson & Yan, 2010). This could allow replay of odor memories, similar to that which occurs in the hippocampal formation, during a time of reduced interference from environmental odors and a time of enhanced links to contextual, emotional, and other associative information. Most recent studies suggest that exposing humans or animal models to recently learned odors or odor-related neural activity during post-training slow-wave sleep enhances memory strength and acuity for those odors, and/or for information acquired in that odor context.
In general, odor quality coding, for example, coffee or almond, that is most closely predictive of behavioral perception occurs in the piriform cortex. While many regions are involved and required for the complete percept, computations occurring in the piriform cortex are more strongly linked to the perception.
The amygdala is a complex of distinct nuclei, some of which receive direct input from the main and accessory olfactory bulbs in mammals. The medial nucleus of the amygdala receives input from the accessory olfactory bulb, and the cortical nucleus of the amygdala receives input from the main olfactory bulb. In addition, the basolateral nucleus of the amygdala has a reciprocal connection with the piriform cortex. Neurons in each of these three areas respond to odors. In accord with the role of the amygdala in perception, expression, and memory of emotional information, these amygdala odor responses can be modified by learned associations between the odors and aversive or appetitive stimuli (Perry, Al Ain, Raineki, Sullivan, & Wilson, 2016; Raineki, Shionoya, Sander, & Sullivan, 2009). This plasticity has been most thoroughly explored in the basolateral amygdala, which is known to be involved in hedonic memory for other sensory modalities.
The role of the cortical nucleus of the amygdala in odor perception has only very recently received experimental attention. As opposed to all other regions of the olfactory cortex, olfactory bulb inputs to the cortical amygdala show some spatial patterning (Root, Denny, Hen, & Axel, 2014). For example, rather than the highly distributed and overlapping inputs from specific olfactory bulb glomeruli to the piriform cortex, there is spatial organization in the cortical amygdala, with some glomeruli reliably projecting to more rostral regions and some to more caudal regions. More important, this stereotyped spatial organization appears to play a role in innate odor preferences and aversions. For example, odors that trigger approach responses more strongly activate caudal regions of the cortical nucleus of the amygdala, and optogenetic activation of those neurons, in the absence of odor, also drives odor approach responses. On the contrary, innately aversive odors, such as 2,3,5-trimethyl-3-thiazoline (TMT), activate the cortical amygdala more broadly. This rostral-caudal axis for hedonic valence in the cortical amygdala is similar to a rostral-caudal spatial patterning for odor hedonic valence recently described in the olfactory bulb.
Together, these different amygdala nuclei may contribute to olfaction by adding important hedonic valence to the percept, with some aspects of this valence due to innate wiring in the cortical nucleus and some due to learned associations in basolateral amygdala. As noted, this link between odors and hedonic valence is bidirectional, with the basolateral amygdala exerting a strong influence over piriform cortical odor processing.
As with other regions of the olfactory cortex, olfactory bulb output neurons directly target the olfactory tubercle. The olfactory tubercle is unique among olfactory cortical regions in that it is also anatomically and embryologically a component of the ventral striatum. As such, it is a region rich in dopamine receptors, and strongly tied to circuits driving motivated behaviors. Though research into its olfactory functions has been neglected, recent work has begun to clarify the contributions of the olfactory tubercle to odor perception and odor-driven behavior. For example, olfactory tubercle single-units in behaving animals appear to encode odor valence in preference to odor identity (Gadziola, Tylicki, Christian, & Wesson, 2015). This encoding varies with learned changes in odor valence. There may be a spatial component to this encoding, with medial sites more strongly driven by odors with positive valence (approach-inducing odors) and lateral sites more strongly driven by odors with negative valence (aversion-inducing odors). Again, this valence-specific spatial response pattern is odor-identity independent, with, for example, the same odor quality evoking medial or lateral olfactory tubercle activity depending on the learned association.
Importantly, the odor-evoked, valence-sensitive neural activity emerges before the onset of the behavioral response. This suggests that olfactory tubercle activity may be involved in driving the appropriate behavior, rather than simply reflecting the behavioral state.
Finally, recent evidence suggests that the olfactory tubercle is multi-sensory (Wesson & Wilson, 2011). For example, single neurons in the olfactory tubercle can respond to both odors and sounds. The anatomical basis for this multi-sensory input, that is, the site of multi-sensory convergence, is not known, but these results further emphasize the access of rich contextual information to early olfactory cortical sites.
Lateral Entorhinal Cortex
The entorhinal cortex is increasingly believed to have an important role in sensory perception, in addition to its role in the medial temporal lobe memory system. The lateral entorhinal cortex is a component of the olfactory cortex, receiving input from both the main olfactory bulb and piriform cortex. In rodents, afferent fibers from olfactory areas are the dominant input to the lateral entorhinal cortex. This input terminates in Layer I on the apical dendrites of Layer II pyramidal and stellate cells. In addition to the input from the olfactory bulb and piriform cortex, the lateral entorhinal cortex projects directly back to both areas. This feedback originates from Layer II neurons just as do the cells that form the perforant path projection to the hippocampal formation, although the two pathways come from separate cell populations with different odor response properties (Leitner et al., 2016). Thus, layer II neurons that express reelin are located in the superficial Layer IIa, project to the hippocampal formation, and are narrowly tuned to odors. In contrast, Layer IIb odor-responsive neurons are calbindin-positive (reelin-negative), project to the piriform cortex and olfactory bulb (not the hippocampal formation), and are more broadly tuned.
Entorhinal cortex output to other, non-olfactory areas is predominantly from layer V pyramidal neurons. The lateral entorhinal cortex is responsive to objects (perhaps odorous) in an open field, and to odors. Furthermore, local field potential analyses reveal that in odor discrimination-trained animals the entorhinal cortex can signal the olfactory bulb prior to odor onset, potentially preparing the system for odor sampling. Together, these features suggest the potential for the lateral entorhinal cortex to provide odor-specific, memory, and expectation-dependent feedback to the olfactory bulb and olfactory cortex.
Aspiration lesions of the entorhinal cortex appear to release piriform cortical activity from suppression and can even enhance some forms of olfactory learning and memory (Ferry, Oberling, Jarrard, & Di Scala, 1996). More selective reversible suppression of lateral entorhinal cortex activity reversibly impairs discrimination of a well-learned, but difficult, discrimination requiring high olfactory acuity but leaves discrimination of a well-learned but relatively easy discrimination intact (Chapuis et al., 2013). These results argue for an important role of the lateral entorhinal cortex not only in odor learning but also in odor perception and discrimination of familiar odors. The early appearance of olfactory deficits in Alzheimer’s disease, prior to major cognitive impairment, may in part reflect the early emergence of neuropathology in the entorhinal cortex and a consequent loss of top-down control over more peripheral regions of the olfactory pathway.
Higher Order Cortical Contributions
In addition to the olfactory cortical regions that receive direct olfactory bulb input already outlined, the orbitofrontal cortex also plays a role in odor perception. Olfactory inputs to the orbitofrontal cortex in rodents can come either directly via its reciprocal connections with the piriform cortex (Johnson, Illig, Behan, & Haberly, 2000) or indirectly via the piriform cortical projection to the mediodorsal thalamic nucleus, which in turn is heavily reciprocally connected with the orbitofrontal cortex (Courtiol & Wilson, 2015). The piriform projection to the orbitofrontal cortex originates primarily from the anterior piriform. The cells of origin of this projection show a topography, with piriform cortical cells projecting to either the agranular insula or the lateral portions of the orbitofrontal cortex, but no cells projecting to both (Chen et al., 2014). This suggests, similar to the organization of the lateral entorhinal layer II neurons described, a segregation of projection neuron outputs (Diodato et al., 2016).
Orbitofrontal cortical neurons are commonly multi-sensory, with, for example, individual neurons responding to the smell, the taste, and even the mouth feel of foods (Critchley & Rolls, 1996). Thus, the orbitofrontal cortex is important in the perception of flavor. In addition, this region plays an important role in tying odor representations to their associated reward value. Learning that an odor signals reward, and even reward of a specific value, is encoded by orbitofrontal cortex neurons. Recent evidence has demonstrated that as animals learn difficult odor discriminations, during the acquisition phase, there is a concomitant plasticity of orbitofrontal cortex top-down synaptic input to the piriform cortex, with a depression of left orbitofrontal cortex input to left piriform cortex (Cohen, Wilson, & Barkai, 2015). Once the discrimination is well learned, the strength of this connection returns to baseline levels. In contrast to this depression in the left hemisphere, the synaptic input from the right orbitofrontal cortex to the right piriform cortex is enhanced during the post-learning phase (Cohen, Reuveni, Barkai, & Maroun, 2008). Thus, there is asymmetry in the plasticity of top-down pathways in the olfactory system, and this plasticity is dependent on the phase of the olfactory learning (acquisition vs post-learning).
These neurons’ activity is also shaped by spatial orientation of the animal (Feierstein, Quirk, Uchida, Sosulski, & Mainen, 2006). Thus, the orbitofrontal cortex places odor input into a representation of spatial location and expected reward. One important output of the orbitofrontal cortex is the striatum, a region important in motor control and goal-oriented behavior, perhaps thus contributing to odor-guided behavior.
It should be noted that much of this basic information is also available in the activity of neurons afferent to the orbitofrontal cortex, in the mediodorsal thalamic nucleus (Courtiol & Wilson, 2016). In fact, this thalamic nucleus receives inputs from diverse olfactory regions comprising the piriform cortex, and its neurons can present odorant selectivity. Moreover, single neurons in the mediodorsal thalamic nucleus can also encode the associated reward value of an odorant and spatial location or orientation variables (Courtiol & Wilson, 2016; Kawagoe et al., 2007). The mediodorsal thalamic nucleus has also been proposed to be involved in attention to odors with a specific and dynamic involvement of the piriform cortex–mediodorsal thalamus–orbitofrontal cortex pathway (Plailly, Howard, Gitelman, & Gottfried, 2008). Those recent findings corroborate earlier studies of mediodorsal thalamic lesions where the animals were not impaired in odorant detection or easy discriminations but in performing more complicated odor discrimination tasks.
Thus, in addition to the primary olfactory cortical regions that receive direct input from the olfactory bulb, the cortical network contributing to the rich experience of odor perception includes higher order prefrontal cortex. This places olfactory perceptual network astride both the most primitive cortical regions and the most evolutionarily advanced cortex. Given the differences in ontogeny of these diverse cortical regions, this also means that networks activated by biologically meaningful odors expand during early development, with, for example, involvement of prefrontal cortical areas emerging substantially later than the primary olfactory cortex.
Cortical Pathology and Odor Processing
Olfactory perception appears uniquely sensitive to a wide range of disorders including Alzheimer’s disease, Parkinson’s disease, depression and schizophrenia. In fact, onset of olfactory perceptual impairment often occurs prior to the onset of the canonical symptoms of these disorders. For example, individuals who have genetic risk factors for dementia, such as expression of the apolipoprotein E (ApoE) epsilon 4 allele, but do not have dementia yet, are more likely to express olfactory impairments than those expressing non-risk factor ApoE alleles (Olofsson et al., 2016). Similarly, olfactory dysfunction often emerges prior to motor control or movement problems in Parkinson’s disease (Doty, 2012).
Olfactory impairments can range from anosmia or hyposmia (decreased sensitivity to odors) to odor identification difficulty where the subject can detect the odor and distinguish it from other odors, but cannot correctly identify it by name. While damage to the nasal passage and olfactory sensory neurons can lead to olfactory problems, more central brain functions are believed to underlie the perceptual deficits associated with Alzheimer’s disease, Parkinson’s disease, and depression. For example, there is some evidence for association of odor identification deficits in Alzheimer’s disease with piriform cortex dysfunction in humans and some animal models (Li, Howard, & Gottfried, 2010; Wesson et al., 2011). In Parkinson’s disease it has been hypothesized that damage to brain circuits underlying control of sniffing, such as the cerebellum, may contribute to olfactory perceptual deficits (Sobel et al., 2001). However, there is very little direct evidence for mechanisms of olfactory disturbances tied to these disorders, and this is thus currently an area of intensive research.
Odor perception involves a large, highly interconnected cortical network that includes both the evolutionarily oldest cortex (e.g., piriform cortex) and the most recently evoked neocortical (e.g., orbitofrontal cortex). Both serial and parallel processing appear to occur based on the broad distribution of olfactory bulb outputs. There is increasing evidence of specialization of function across the different cortical subunits, with, for example, extraction of specific odor qualities (e.g., banana) and odor categories (e.g., fruity) occurring in different cortical regions. Learned and innate odor hedonic information is partially encoded by amygdala nuclei, which can directly modulate odor coding in piriform cortex. Finally, very recent work has demonstrated in rodents that these broad cortical networks develop postnatally, with relatively simple networks activated by biologically meaningful odors in neonates and the addition of new cortical components as the animals mature (Perry, Al Ain, Raineki, Sullivan, & Wilson, 2016).
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