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Sniffing Out Smell: Odorant Detection, Coding, and Perception
Department of Neuroscience
Lake Forest College
Lake Forest, Illinois 60045
Smell, the most ancient of all senses, is crucial for animal reproduction and survival. Humans can detect the most minute changes in odorant structures as a different perceived odor. Despite its significance, the mechanism of olfactory sensory perception remained unknown before 1991. Through research in my lab and others, we discovered a large multigene family containing approximately 1000 genes in mice and 500 in humans that encode seven transmembrane proteins in the olfactory epithelium (OE) responsible for odorant detection. These odorant receptors (ORs) are organized in four spatial zones. From the OE, identical ORs project to a distinct subset of glomeruli in the olfactory bulb. Genetic tracing from the olfactory bulb to the olfactory cortex (OC) demonstrated that the activation of a particular OR actives a specific region of the OC. These findings suggest odorant perception is predominantly computational coding. Additionally, three families of receptors in the vomeronasal organ have been found that are involved in pheromone detection. Although the pathway underlying olfaction is better understood, many questions remain. The mechanism by which only a single OR gene is expressed in each neuron is still unclear. Together these findings begin to elucidate one of the most important and conserved senses.
In order to perceive the world, animals are dependent upon their five senses: touch, taste, audition, sight, and smell. Our oldest evolutionary sense, smell serves a multitude of purposes. In many organisms, smell plays a crucial role in locating prey, navigating, and recognizing kin. Additionally, the detection of pheromones can determine sexual and social behaviors and neuroendricrine changes necessary for reproduction. The importance of smell can be further demonstrated in the study of anosmiacs, individuals who cannot perceive odor. The human olfactory system is immensely powerful: 10,000 to 100,000 chemicals can be detected as having a distinct odor1,2. The smallest change in an odorant’s chemical structure can result in the detection of a different smell1,2.
Small, volatile molecules, odorants are first detected in specialized olfactory neuroepithelium found in the nasal cavity, which consists of three cell types: olfactory sensory neurons, supporting cells, and basal cells, the site of olfactory neuron genesis3,4. From the olfactory epithelium (OE), olfactory neurons project along the “main” olfactory pathway to the olfactory bulb and then the olfactory cortex (OC). Specialized cilia on the dendrites reside in the mucous membrane of the nasal cavity. Research suggests odorants bind to receptors on this cilia, causing signaling transduction to occur that involves G proteins5,6. Pheromones, in contrast, are detected by sensory neurons in the neuroepithelium of the vomeronasal organ (VNO), which can be found at the base of the nasal cavity7. OE and VNO neurons are similar to one another structurally, suggesting their signal transduction mechanism is the same7. VNO neurons project along the “accessory” olfactory pathway, which leads to the accessory olfactory bulb, followed by the amygdala, then hypothalamus. Individual odorants activate seven transmembrane proteins in a specific subset of neurons found in the olfactory epithelium. These neurons project to one or two glomeruli in the olfactory bulb. From the glomeruli, neurons travel to specific clusters of neurons in the olfactory cortex. Different odorants activate partially overlapping regions of the olfactory cortex.
Although the neuroanatomy involved in olfaction was understood, prior to the 1990s, the biological mechanism of olfactory sensory perception remained unknown. My lab aimed to solve two questions: how do mammals perceive such a wide variety of chemicals, and how does the brain interpret these chemicals to produce the perception of smell and changes in behavior? As seen in figure 1, we hypothesized odorants are detected by a large family of seven transmembrane proteins restricted to the OE, leading to activation of specific glomeruli and a specific portion of a stereotyped sensory map in the OC.
The detection of individual odorants could occur through one of two possibilities. Similar to color vision, odorants could bind to one of a few odorant receptors (ORs) that are activated by a large number of chemicals. In contrast, odorants could bind to a very select number of distinct ORs. Before beginning our search for ORs, we made three postulations. First, the gene family should encode G-protein coupled receptors. Second, since odorants vary greatly in structure, there should be variation within the OR protein structure as well, suggesting ORs should be encoded on multiple chromosomes. Finally, The ORs should be found solely in the OE. Thus, our lab set out to find a large multigene family that encodes seven transmembrane proteins.
A Novel Multigene Family
By using Polymerase Chain Reaction (PCR) and restriction enzymes, my lab cloned eighteen members of a multigene family that encodes seven transmembrane domain proteins in a rat10. Gene sequencing showed high variability amongst individual proteins, specifically in regions that would be involved in ligand binding10. Northern blot analysis demonstrated these proteins were found only in the OE10. We found a similar family of genes encoding G-protein coupled receptors in the catfish11. This gene family was much smaller than that of the rat11. In situ hybridization showed individual receptors are only expressed in a small subset of OE neurons11. These findings suggest each neuron expresses only one receptor11. Years later, we discovered a secondary class of ORs responsible for the detection of volatile amines in the OE that we named trace amine-associated receptors (TAARs)12. Similar to the first class of ORs, TAARS are expressed in a small subset of OE neurons12. In contrast, however, TAARS became activated when exposed to mature male mouse urine12. These findings demonstrate some OE neurons are responsible for the detection of pheromones.
Olfactory Epithelium Organization
After finding these ORs, the next step was to determine their spatial distribution within the OE using a mouse model. We found OR subfamilies are restricted to one portion of the OE13. There are four different spatial zones that are symmetrical within the two nasal cavities13. Within an individual zone, ORs are randomly expressed13.
Since neurons that express the same ORs are found in the same OE zonal region, we wondered if these genes were located on the same locus on a chromosome. To determine whether OR gene selection occurs though a locus-independent or locus-dependent mechanism, we determined the chromosome location and expression zone location for many mouse OR genes14. This experiment showed OR genes are distributed on at least 7 different chromosomes, and there are several loci that contain clusters of OR genes14. A later study determined the mouse genome contains over 900 OR genes and nearly 300 nonfunctional genes15. These genes were found in 51 loci spread over 17 chromosomes15. Each locus encodes between 1 to 50 subfamilies; the majority of subfamilies are restricted to a single locus15. The human genome, in contrast, contains approximately 640 OR genes, of which 350 are functional16. Fifty-one loci were found across 21 chromosomes16. Most subfamilies were only found on locus, and over half of loci encode a small number of subfamilies16. Although mice and humans share a large proportion of OR subfamilies, each mouse subfamily encodes a larger number of ORs15. Furthermore, the mouse genome contains a greater number of subfamilies exclusively found in mice compared to the number of subfamilies exclusively found in the humans15. These findings make sense from an evolutionary standpoint because mice are much more dependent on their sense of smell for survival and reproduction. Humans and mice can most likely detect the same types of smells, but mice will be far more sensitive.
Odorant Signal Transduction
Previous research suggested signal transduction begins by an odorant binding to the appropriate receptor, activating Gαolf protien17. This protein stimulates adenylate cyclase to produce cAMP, which binds to a cyclic nucleotide- gated ion channel6. The resulting influx of sodium and potassium ions leads to depolarization of the neuron, and an action potential is propagated from the OE to the OB and higher cortical regions to create perception6. Although many other labs cloned various parts of the transduction pathway, the stoichiometry of the cyclic nucleotide-gated ion channel was unknown. One subunit of the channel, rOCNC1, has already been cloned, but we believe there are other units18. Through PCR, my lab identified a second subunit called rOCNC218. In situ hybridization showed rOCNC1 and rOCNC2 are both expressed in the same neurons in the olfactory epithelium. Next, we injected some oocytes with only rOCNC1 RNA and the other oocytes with both rOCNC1 RNA and rOCNC2 RNA. Then, varying concentrations of cAMP were infused in each type of cell, which should cause the cyclic nucleotide-gated ion channels to open18. The rOCNC1 and rOCNC2 channels opened more frequently compared to the rOCNC1 channels.18 These findings suggest ion channels involved in odorant transduction are composed of hetero- oligomer subunits18.
Even though the ORs had been found, we did not know which odorants bound to each individual OR. Through RT-PCR and calcium imaging, we were able to measure the activation of individual ORs to individual odorants belonging to the aliphatic alcohol, which is a family of chemicals with a similar structure19. First, we noted that each receptor became activated by multiple odorants; of the fourteen receptors tested, twelve of them detected more than one odorant19. The individual receptor seemed to be activated by odorants with a similar structure19. For example, nearly all of the ORs recognized odorants within a particular range of length19. Individual receptors also seemed to favor a small number of functional groups19. Notably, similar odorant structure does not mean similar perceived odor. Hexanoic acid and hexanol, for example, both contain six carbon molecules, but the first smells rancid while that latter smells sweet. Next, we found that one type of odorant is recognized by many ORs19. Of the 17 odorants that were used in this experiment, the majority were detected by at least two ORs19. The receptors activated by the same odorant oftentimes had a similar protein sequence19. Finally, we observed that individual odorants activate their own unique combination of receptors19. These findings suggest that olfaction occurs through a computational coding scheme rather than label-lined. Later, this study was replicated on a larger scale by testing the response of 3000 mouse receptors with over a hundred diverse odorants20. Our experiment demonstrated that olfactory neurons as a whole are more responsive to certain functional groups; yet, neurons also show great diversity when responding to individual odorants20. While most ORs will only respond to odorants with a similar structure, other ORs respond to a broad variety of odorants20. These findings help explain how mammals can perceive such a wide breadth of smells.
A Novel Multigene Family
The detection of pheromones in the VNO, a tubular structure near the nasal cavity, causes behavioral changes in animals. Two types of sensory neurons are found in the VNO that each express a different G-protein α subunit: GαO and Gαi221. Another lab identified a family of pheromone receptors found only in neurons that express Gαi221. We identified a novel multigene family that encodes receptors found exclusively in GαO + neurons called V2Rs22. Each individual pheromone receptor was expressed in a small percentage of scattered neurons in the GαO+ zone22. Like ORs, pheromone receptors are seven transmembrane proteins, but V2Rs have an exceptionally long N-terminal22. This difference in structure could explain why pheromones would preferentially bind to one of the two types of pheromone receptors. In a later experiment, we found a third class of chemosensory receptors in the VNO belonging to the formyl peptide receptor (FPR) family23. This gene family is significantly smaller, with only 5 FPR receptors being expressed in the mouse VNO23. Although the exact function of these receptors remains elusive, we hypothesize they may play an important health role by detecting bacteria in food23. For years, scientists believed that odorants were only detected in the OE and pheromones in the VNO; this dogma is incorrect. We found that as many as 1% of VNO neurons respond to a particular type of odorant and can even differentiate between minute changes in molecule structure24. These findings propose odorants may evoke behavioral changes in mammals24.
Pheromone Sensory Transduction
The VNO was believed to have a similar signal cascade as in the OE. To determine the proteins involved in transduction, we cloned the all of the Gα subunits, adynlyl cyclases, and guanylyl cyclases in the entire VNO and then looked for those exclusively expressed in VNO neurons25. This search showed VNO neuron microvilli highly express GαO and Gαi2 rather than Gαolf25. Moreover, we found adenylyl cyclase II is the only cyclase exclusively expressed in VNO neurons and not supporting cells25. Another experiment indicates that VNO neurons do not contain oCNC1, though they do contain oCNC226. Thus, odorant sensory transduction most likely involves a cyclic nucleotide-gated ion channel, but the subunits of this channel will be different from the channel in OE neurons.
A Novel Genetic Approach
In order to fully understand the pathway of OE and VNO neurons from the epithelium, to the OB, to higher brain regions, we needed a method that would allow us to trace these neurons. By injecting a neuronal tracer into a cell, one can visualize the circuitry using a histochemical technique27. Although neuronal tracers existed, they had limitations: it was difficult to label one small subset of neurons, and neurons could not be labeled in utero27. To combat these problems, we developed a technique in which olfactory and VNO neurons would produce their own tracer, barely lectin, in a transgenic mouse27.Using this novel technique in utero, we saw that neural connections formed much faster in the main olfactory bulb than the accessory olfactory bulb27. These findings imply that only odorants can be detected in utero27.
By using the above technique, we next wanted to understand how VNO neurons communicate with other neurons to cause changes in reproduction. GnRH neurons, found predominantly in the hypothalamus, cause a release of hormones involved in sexual behavior28. We hypothesized that VNO neurons must interact with these neurons in some way28. Indeed, we found GnRH neurons form both pre and postsynaptic connection to both VNO and olfactory neurons, indicating that they regulate one another28. Moreover, some of these circuits exhibited sexual dimorphism, which could help explain differences in sexual behavior among mice28.
The Olfactory Bulb
Olfactory Bulb Organization
As mentioned previously, there are nearly a thousand ORs expressed in the mouse OE. These receptors are exclusively expressed in one of four spatial zones. However, within the spatial zone, ORs are randomly dispersed. How is the OB organized? Do olfactory neurons project onto the OB in a random or organized manner? The mouse OB is divided up into about 2,000 subunits called glomeruli; each olfactory or VNO neuron forms multiple synaptic connections with only one glomerulus, but each glomerulus is innervated by multiple neurons29.To understand the organization of the OB, we first noted that, using in situ hybridization, we could see where olfactory sensory neurons project to on the glomeruli by the appearance of OR RNA at the neuron’s axon29. We discovered neurons expressing the same OR projected to the same glomeruli29 (as seen in figure 1). Even when comparing two ORs from the same spatial zone, they projected to their own discrete glomeruli29. Moreover, each receptor type only synapses to one, or a few, glomeruli29. The activation of one particular glomeruli by a specific receptor is bilaterally symmetrical and consistent throughout individuals of the same species29. These findings indicate the OB is highly organized into a stereotyped map. These results have been confirmed in another lab30. Years after our experiment, a different lab studied OB organization in the Drosophila brain using a combination of two-photon microscopy and a calcium-sensitive fluorescent protein31. Similar to the mouse, Drosophila olfactory neurons synapse on one of the 43 glomeruli in the antennal lobe of the fly’s brain31. These flies have been mutated so that their neurons express G-CaMP; when exposed to an odorant, certain neurons will become depolarized due to an influx of calcium, and as a result, they will strongly fluoresce31. Using two-photon microscopy, one can determine where these depolarized neurons project to in the fly brain31. This experiment supported our findings that each type of odorant neuron connects to only a distinct group of glomeruli31.
The Evolution of the OB and OE Spatial Map
Both the OE and OB possess an organized spatial map, but it was unknown whether the development of one map was dependent on the other. By observing the development of the olfactory system in a mouse embryo, we hoped to address this question32. We compared normally developing mice to mice that lacked olfactory bulbs, and we found that the OE spatial map is the same31. Our results lead us to believe the OB does not impose organization onto the OE.
The Olfactory Cortex
Olfactory Cortex organization
The olfactory cortex is responsible for odorant perception. Yet, we did not understand how the organization of odorant input from the OB leads to the perception of thousands of distinct smells. We wondered if the cortex is as tightly organized as the OB. To find the answer, we expressed Barley Lectin in each individual mouse odorant neuron, which expresses only a single OR, and followed its projection from the epithelium, OB, to the cortex33. We noticed that neurons expressing the same OR activated a cluster of neurons in the piriform cortex, the primary olfactory cortex, suggesting a high level of organization33 (as seen in figure 1). These clusters of activation were bilaterally symmetrical in addition to being similar between individuals33. However, there is some overlap, meaning some ORs activate the same OC neuron33. Additionally, One OR can activate multiple neuron clusters that are spread out in the cortex33. As a whole, these findings suggest the OC possesses a stereotyped sensory map. A follow up study showed odorants with a similar molecular structure activate the same neurons in the OC34. We also found that altering the odorant concentration causes a change in cortical activation: increased concentration leads to the activation of more neurons, even the activation of new regions of the cortex34. In our next study, we wondered if some cortical neurons were only activated by integrating signals from multiple odorants. To test this idea, we compared the response of mouse OC neurons exposed to a mixture of odorants as well as the individual odorants35. We observed that odorant mixes activated additional OC neurons that were not activated by the individual components35.This combinatorial effect could explain why mammals posses such a wide gamut of perceived odors.
An Antidepressant Increases Longevity
Although my work has predominantly focused on the olfactory system, I have also researched other topics, such as the mechanism behind aging. My lab discovered that Caenorhabditis elegans exposed to the human antidepressant mianserin had a significant increase in lifespan36-37. This drug acts as a serotonin antagonist, and may increase longevity through inducing perceived feelings of starvation.
Other Contributions to the Field
Odor Discrimination and Adaptation
Although I have elucidated many of the queries related to olfaction, many other scientists have made significant contributions to the field. One lab has tried to determine the mechanism by which mice become sensitized to a smell38. It is believed odorant neurons adapt to smell by becoming less sensitive to cAMP; as a result, the cyclic nucleotide-gated channel does not open, there is no influx of calcium, the neuron does not become depolarized, and odorant detection does not occur38. Mice that do not have all of the subunits of the cyclic nucleotide-gated channel, like CNGA4 knockout mice, show a decreased ability to adapt. Mice without a normal channel show an inability to discriminate between an odorant if a background odor is present, suggesting adaptation is dependent on the ability to control calcium levels.
Another lab researched whether the olfactory system requires activity-dependent competition, similar to the visual system39. One particular subunit of the cyclic nucleotide-gated channel, oCNC1, is coded by the X chromosome, and is critical for odorant detection39. Thus, in heterozygous females, two cell types can be found in the same mouse. Over time, oCNC1 deficient neurons are irradiated, unless the mouse is deprived of odorants39. These findings suggest competition among neurons could lead to pruning in the OE.
Gene Selection Mechanism
How does each olfactory neuron select only one from hundreds of receptors to express? How are the other receptors silenced? These questions have been the focus of many scientists. One lab proposes that expression of a functioning OR protein forms a feedback loop that enforces monoallelic expression40. In this experiment, they inserted an OR-promoter- driven reporter to an insertion site that was surrounded by multiple OR genes40. They found that the expression of one functional receptor was able to stop the restriction of other receptors within the same cell40. Some olfactory sensory neurons, at a low frequency, will switch from expressing one receptor to another41. One lab believed that the expression of a functional receptor stops the neuron from switching expression41. To test this hypothesis, they mutated a receptor gene, so the protein was abnormal41. At first, half of the mouse olfactory sensory neurons in the epithelium expressed the mutant receptor; after several weeks, however, almost none of the cells expressed the original receptor41. The researchers found these cells switch to express a different receptor and project to new glomeruli41. Research done in another lab suggests the expression selection in every olfactory sensory neuron is controlled by one regulatory enhancer DNA sequence42. Using fluorescence in situ hybridization, researchers were able to capture the interaction between the H-enhancer on chromosome 14 with single OR alleles of other chromosomes42. Furthermore, they demonstrated that this colocalization leads to a monoallelic expression because in transgenic mice with multiple H elements, some sensory neurons expressed additional receptors42. Together, these findings help elucidate this complex and mysterious mechanism of gene silencing, as seen in figure 2.
Over the past twenty years or so, my lab and others have ‘sniffed out’ many of the mysteries surrounding the sense of smell. Before the 1990s, we were unsure of many aspects of olfaction, including odorant receptors, a coding scheme, and signal transduction, to name a few. Now, we know there are at least two types of OE receptors, which are both seven transmembrane proteins, encoded by the largest multigene family in mammals. Similarly, there are three types of VNO receptors responsible for the detection of pheromones. Although they use some different proteins, pheromone and odorant signaling transduction both involve the activation of a G protein, leading to an increase in cAMP, and the opening of a cyclic nucleotide-gated ion channel. My research also suggests the olfactory system uses a computational coding scheme, meaning one odorant is detected by multiple ORs and one OR detects multiple odorants. We also now have a greater understanding of the odorant pathway, which is illustrated in figure 1. Individual odorants activate a different combination of ORs, which are arranged into four zones in the epithelium. Each neuron expresses only one OR, and these neurons synapse to the same few glomeruli, the anatomical subunits of the OB. From the glomeruli, sensory neurons project to the cortex; each sensory neuron activates disperse clusters of cortical neurons, showing that the OC is organized into a stereotyped map.
Many questions, however, still remain. The field is currently unsure how olfactory sensory neurons are able to express only one receptor. Figure 2 illustrates some of the current hypotheses explored by others labs, involving the importance of functional OR expression and a regulatory enhancer DNA sequence.
Understanding the molecular mechanism behind olfaction gives us a better appreciation for this ancient and critical sense. Although humans do not think about olfaction as their most important sense, it plays an important role in the perception of food, reproductive functions, and the recognition between mother and child. In fact, a decrease in odor detecting abilities is seen in some disorders, including Alzheimer’s disease43. With continued research, we hope to solve the remaining mysteries surrounding olfaction.
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