# Sensory Systems/Olfactory System

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## Introduction

Probably the oldest sensory system in nature, the olfactory system concerns the sense of smell. The olfactory system is physiologically strongly related to the gustatory system, so that the two are often examined together. Complex flavors require both taste and smell sensation to be recognized. Consequently, food may taste “different” if the sense of smell does not work properly (e.g. head cold).
Generally the two systems are classified as visceral sense because of their close association with gastrointestinal function. They are also of central importance while speaking of emotional and sexual functions.
Both taste and smell receptors are chemoreceptors that are stimulated by molecules soluted respectively in mucus or saliva. However these two senses are anatomically quite different. While smell receptors are distance receptors that do not have any connection to the thalamus, taste receptors pass up the brainstem to the thalamus and project to the postcentral gyrus along with those for touch and pressure sensibility for the mouth.
In this article we will first focus on the organs composing the olfactory system, then we will characterize them in order to understand their functionality and we will end explaining the transduction of the signal and the commercial application such as the eNose.

## Sensory Organs

In vertebrates the main olfactory system detects odorants that are inhaled through the nose where they come to contact with the olfactory epithelium, which contains the olfactory receptors.
Olfactory sensitivity is directly proportional to the area in the nasal cavity near the septum reserved to the olfactory mucous membrane, which is the region where the olfactory receptor cells are located. The extent of this area is a specific between animals species. In dogs, for example, the sense of smell is highly developed and the area covered by this membrane is about 75 – 150 cm$^2$; these animals are called macrosmatic animals. Differently in humans the olfactory mucous membrane cover an area about 3 – 5 cm$^2$, thus they are known as microsmatic animals.
In humans there are about 10 million olfactory cells, each of which have 350 different receptor types composing the olfactory mucous membrane. The 350 different receptors are characteristic for only one odorant type. The bond with one odorant molecule starts a molecular chain reaction, which transforms the chemical perception into an electrical signal.
The electrical signal proceeds through the olfactory nerve’s axons to the olfactory bulbs. In this region there are between 1000 and 2000 glomerular cells which combine and interpret the potentials coming from different receptors. This way it is possible to unequivocally characterise e.g. the coffee aroma, which is composed by about 650 different odorants. Humans can distinguish between about 10.000 odors.
The signal then goes forth to the olfactory cortex where it will be recognized and compared with known odorants (i.e. olfactory memory) involving also an emotional response to the olfactory stimuli.
It is also interesting to note that the human genome has about 600 – 700 genes (~2% of the complete genome) specialized in characterizing the olfactory receptors, but only 350 are still used to build the olfactory system. This is a proof of the evolution change in the necessity of humans in using the olfaction.

## Sensory Organ Components

Similar to other sensory modalities, olfactory information must be transmitted from peripheral olfactory structures, like the olfactory epithelium, to more central structures, meaning the olfactory bulb and cortex. The specific stimuli have to be integrated, detected and transmitted to the brain in order to reach sensory consciousness. However the olfactory system is different from other sensory systems in three fundamental ways:
* Olfactory receptor neurons are continuously replaced by mitotic division of the basal cells of the olfactory epithelium. This is necessary due to the high vulnerability of the neurons, which are directly exposed to the environment.
* Due to phylogeny, olfactory sensory activity is transferred directly from the olfactory bulb to the olfactory cortex, without a thalamic relay.
* Neural integration and analysis of olfactory stimuli may not involve topographic organization beyond the olfactory bulb, meaning that spatial or frequency axis are not needed to project the signal.

### Olfactory Mucous Membrane

The olfactory mucous membrane contains the olfactory receptor cells and in humans it covers an area about 3 – 5 cm^2 in the roof of the nasal cavity near the septum. Because the receptors are continuously regenerated it contains both the supporting cells and progenitors cells of the olfactory receptors. Interspersed between these cells are 10 – 20 millions receptor cells.
Olfactory receptors are neurons with short and thick dendrites. Their extended end is called an olfactory rod, from which cilia project to the surface of the mucus. These neurons have a length of 2 micrometers and have between 10 and 20 cilia of diameter about 0.1 micrometers.
The axons of the olfactory receptor neurons go through the cribriform plate of the ethmoid bone and enter the olfactory bulb. This passage is in absolute the most sensitive of the olfactory system; the damage of the cribriform plate (e.g. breaking the nasal septum) can imply the destruction of the axons compromising the sense of smell.
A further particularity of the mucous membrane is that with a period of a few weeks it is completely renewed.

### Olfactory Bulbs

In humans, the olfactory bulb is located anteriorly with respect to the cerebral hemisphere and remain connected to it only by a long olfactory stalk. Furthermore in mammals it is separated into layers and consists of a concentric lamina structure with well-defined neuronal somata and synaptic neuropil.
After passing the cribriform plate the olfactory nerve fibers ramify in the most superficial layer (olfactory nerve layer). When these axons reach the olfactory bulb the layer gets thicker and they terminate in the primary dendrites of the mitral cells and tufted cells. Both these cells send other axons to the olfactory cortex and appear to have the same functionality but in fact tufted cells are smaller and consequently have also smaller axons.
The axons from several thousand receptor neurons converge on one or two glomeruli in a corresponding zone of the olfactory bulb; this suggests that the glomeruli are the unit structures for the olfactory discrimination.
In order to avoid threshold problems in addition to mitral and tufted cells, the olfactory bulb contains also two types of cells with inhibitory properties: periglomerular cells and granule cells. The first will connect two different glomeruli, the second, without using any axons, build a reciprocal synapse with the lateral dendrites of the mitral and tufted cells. By releasing GABA the granule cell on the one side of these synapse are able to inhibits the mitral (or tufted) cells, while on the other side of the synapses the mitral (or tufted) cells are able to excite the granule cells by releasing glutamate. Nowadays about 8.000 glomeruli and 40.000 mitral cells have been counted in young adults. Unfortunately this huge number of cells decrease progressively with the age compromising the structural integrity of the different layers.

### Olfactory Cortex

The axons of the mitral and tufted cells pass through the granule layer, the intermediate olfactory stria and the lateral olfactory stria to the olfactory cortex. This tract forms in humans the bulk of the olfactory peduncle. The primary olfactory cortical areas can be easily described by a simple structure composed of three layers: a broad plexiform layer (first layer); a compact pyramidal cell somata layer (second layer) and a deeper layer composed by both pyramidal and nonpyramidal cells (third layer). Furthermore, in contrast to the olfactory bulb, only a little spatial encoding can be observed; “that is, small areas of the olfactory bulb virtually project the entire olfactory cortex, and small areas of the cortex receive fibers from virtually the entire olfactory bulb”.
In general the olfactory tract can be divided in five major regions of the cerebrum: The anterior olfactory nucleus, the olfactory tubercle, the piriform cortex, the anterior cortical nucleus of the amygdala and the entorhinal cortex. Olfactory information is transmitted from primary olfactory cortex to several other parts of the forebrain, including orbital cortex, amygdala, hippocampus, central striatum, hypothalamus and mediodorsal thalamus.
Interesting is also to note that in humans, the piriform cortex can be activated by sniffing, whereas to activate the lateral and the anterior orbitofrontal gyri of the frontal lobe only the smell is required. This is possible because in general the orbitofrontal activation is greater on the right side than on the left side, this directly implies an asymmetry in the cortical representation of olfaction.

## Signal Processing

Examples of olfactory thresholds. :
| Substance | mg/L of Ari |
| Ethyl ether | 5.83 |
| Chloroform | 3.30 |
| Pyridine | 0.03 |
| Oil of peppermint | 0.02 |
| lodoform | 0.02 |
| Butyric acid | 0.009 |
| Propyl mercaptan | 0.006 |
| Artificial musk | 0.00004 |
| Methyl mercaptan | 0.0000004 |
Only substances which come in contact with the olfactory epithelium can excite the olfactory receptors. The right table shows thresholds for some representative substances. These values give an impression of the huge sensitivity of the olfactory receptors.
It is remarkable that humans can recognize more than 10,000 different odors. Many odorant molecules differ only slightly in their chemical structure (e.g. stereoisomers) but can nevertheless be distinguished.

### Signal Transduction

An interesting feature of the olfactory system is that a simple sense organ which apparently lacks a high degree of complexity can mediate discrimination of more than 10'000 different odors. On the one hand this is made possible by the huge number of different odorant receptor. The gene family of the olfactory receptor is in fact the largest family studied so far in mammals. On the other hand, the neural net of the olfactory system provides with its 1800 glomeruli a large two dimensional map in the olfactory bulb that is unique to each odorant. In addition, the extracellular field potential in each glomerulus oscillates, and the granule cells appear to regulate the frequency of the oscillation. The exact function of the oscillation is unknown, but it probably also helps to focus the olfactory signal reaching the cortex

### Smell measurement

Olfaction consists of a set of transformations from physical space of odorant molecules (olfactory physicochemical space), through a neural space of information processing (olfactory neural space), into a perceptual space of smell (olfactory perceptual space). The rules of these transforms depend on obtaining valid metrics for each of those spaces.

#### Olfactory perceptual space

As the perceptual space represents the “input” of the smell measurement, its aim is to describe the odors in the most simple possible way. Odors are ordered so that their reciprocal distance in space confers them similarity. This means that the closer two odors are to each other in this space the more are they expected to be similar. This space is thus defined by so called perceptual axes characterized by some arbitrarily chosen “unit” odors.

#### Olfactory neural space

As suggested by its name the neural space is generated from neural responses. This gives rise to an extensive database of odorant-induced activity, which can be used to formulate an olfactory space where the concept of similarity serves as a guiding principle. Using this procedure different odorants are expected to be similar if they generate a similar neuronal response. This database can be navigated at the Glomerular Activity Response Archive.

#### Olfactory physicochemical space

The need to identify the molecular encryption of the biological interaction, makes the physicochemical space the most complex one of the olfactory space described so far. R. Haddad suggest that one possibility is to span this space would to represent each odorant by a very large number of molecular descriptors by use either a variance metric or a distance metric. In his first description single odorants may have many physicochemical features and one expects these features to present themselves at various probabilities within the world of molecules that have a smell. In such metric the orthogonal basis generated from the description of the odorant leads to represent each odorant by a single value. While in the second, the metric represents each odorant with a vector of 1664 values, on the basis of Euclidean distances between odorants in the 1664 physicochemical space. Whereas the first metric enabled the prediction of perceptual attributes, the second enabled the prediction of odorant-induced neuronal response patterns.

## Pheromones and Vomeronasal System
### Pheromones

Pheromones are a distinct class of species and gender specific chemical cues that provide information about sexual and social status. These airborne chemical signals are released by individuals into the environment. Pheromones can influence the physiology and behavior of other members of the same species, and play a crucial role in various biological processes, including communication, reproduction, territorial marking, and social organization. Indeed, there are alarm pheromones, food trail pheromones and sex pheromones.
For example, in adult male silkmoth (Bombyx mori), the antennae act as a sensing organ both for odors and sex pheromones. When the latter bind, it evokes courtship behaviour..
It is important to note that while pheromones can have significant effects on individuals within a species, they generally do not cross species boundaries. Each species has its own unique set of pheromones that are specific to their reproductive and behavioral needs.

### Vomeronasal System

The system allowing the perception of pheromones in mammals is called the vomeronasal system or Jacobson-organ. The sensory neurons found in the vomeronasal organ (VNO) contain cell bodies that house receptors capable of detecting pheromones from the surrounding environment. Although very close and similar, this system is independent from the olfactory system. In fact, it projects to a separate bulb, called the accessory olfactory bulb, and from there to the hypothalamus via the vomeronasal amygdala. It also has a distinct class of genes, the vomeronasal receptors (V1R and V2R), along with Trp receptors. Those genes sustain the production and maintenance of the vomeronasal system receptors and proteins, allowing its functioning as a whole system.
For example, it has been shown that Trp2 knockout mice males do not present the territorial behaviour (urine marking), a normal behavior provoked by pheromones contained in the urine of other males: by inactivating the vomeronasal organ, the mice changed behavior. In addition, this shows that Trp2 channel is required in the vomeronasal organ to detect male specific pheromones and elicit an aggressive, territorial behavior in mice.
In humans it is yet still unclear if the behaviour is affected by pheromones. There is an extensive ongoing debate between experts. There are VR genes in human genome, but they seem to be non-functional. We even have an embryonic structure that resembles the vomeronasal organ and a foetal accessory olfactory bulb (AOB) but it regresses with growth. In addition, primates have responses that can be attributed to pheromone or pheromone-like-hormones. As of today, these issues are still unresolved.

## References

* 1 2 3 4 Paxinos, G., & Mai, J. K. (2004). The human nervous system. Academic Press.
* ↑ Ganong, W. F., & Barrett, K. E. (2005). Review of medical physiology (Vol. 22). New York: McGraw-Hill Medical.
* 1 2 Haddad, R.; Lapid, H.; Harel, D.; Sobel, N. (2008). "Measuring smells". Current Opinion in Neurobiology. 18 (4): 438–444. doi:10.1016/j.conb.2008.09.007.
* ↑ Glomerular Activity Response Archive
* ↑ KARLSON, P.; LÜSCHER, M. (1959). "'Pheromones': A New Term for a Class of Biologically Active Substances". Nature. 183 (4653): 55–56. doi:10.1038/183055a0.
* 1 2 3 Savic, Ivanka (2014). "Pheromone Processing in Relation to Sex and Sexual Orientation.". In CRC Press/Taylor & Francis (ed.). Neurobiology of Chemical Communication. Boca Raton (FL).
* ↑ Vogt, R. G.; Riddiford, L. M. (1981). "Pheromone binding and inactivation by moth antennae". Nature. 293: 161–163. doi:10.1038/293161a0.
* ↑ Dulac, C.; Torello, A. T. (2003). "Molecular detection of pheromone signals in mammals: from genes to behaviour". Nature Reviews Neuroscience. 4 (7): 561–562. doi:10.1038/nrn1140.
* ↑ Leypold, B. G.; Yu, C. R.; Leinders-Zufall, T.; Kim, M. M.; Zufall, F.; Axel, R. (2002). "Altered sexual and social behaviors in trp2 mutant mice". Proceedings of the National Academy of Sciences of the United States of America. 99 (9): 6376–6381. doi:10.1073/pnas.082127599.
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