Molecular and cellular basis of human olfaction

The human olfactory systems recognize and discriminate a large number of different odorant molecules. The detection of chemically distinct odorants begins with the binding of an odorant ligand to a specific receptor protein in the ciliary membrane of olfactory neurons. To address the problem of olfactory perception at a molecular level, we have cloned, functionally expressed, and characterized some of the human olfactory receptors from chromosome 17. Our results show that a receptor protein is capable of recognizing the particular chemical substructure of an odor molecule and, therefore, is able to respond only to odorants that have a defined molecular structure. These findings represent the beginning of the molecular understanding of odorant recognition in humans. In the future, this knowledge could be used for the design of synthetic ideal receptors for specific odors (biosensors), or the perfect odor molecule for a given receptor.     

Cell suspensions from porcine olfactory mucosa. Changes in membrane potential and membrane fluidity in response to various odorants

A suspension of olfactory epithelial cells was prepared from porcine olfactory mucosa and the physiological functions of the suspension were examined. The membrane potential of the cell suspension, which was monitored by measuring the fluorescence changes of rhodamine 6G, was depolarized by an increase in the K+ concentration in the external medium. Various odorants depolarized the cell suspension in a dose-dependent fashion. The magnitude of depolarization by odorants was either unchanged or slightly increased by a reduction of the concentration of Na+, Ca2+, and Cl- in the external medium, which suggests that changes in the permeabilities of specific ions are not involved in depolarization by odorants. The application of various odorants to the cell suspension induced changes in the membrane fluidity at different sites of the membrane that were monitored with various fluorescent dyes [8-anilino-1-naphthalene sulfonate, n-(9-anthroyloxy) stearic acids, 12-(9-anthroyloxy) oleic acid, and (1,6-diphenyl-1,3,5-hexatriene)], which suggests that the odorants having different odors are adsorbed on different sites in the membrane. On the basis of these results, a possible mechanism of odor discrimination is discussed.     

Olfactory discrimination of aliphatic odorants at 1 ppm: too easy for CD-1 mice to show odor structure–activity relationships?

Using an operant conditioning paradigm we tested the ability of CD-1 mice to discriminate between 25 odorants comprising members of five homologous series of aliphatic odorants (C4-C8) presented at a gas phase concentration of 1 ppm. We found (a) that all mice significantly discriminated between all 50 stimulus pairs that involved odorants sharing the same functional group, but differing in carbon chain length, as well as between all 50 stimulus pairs that involved odorants sharing the same carbon chain length but differing in functional group, (b) a significant negative correlation between discrimination performance and structural similarity of odorants in terms of differences in carbon chain length with the acetic esters and the 2-ketones, but not with the 1-alcohols, n-aldehydes, and n-carboxylic acids tested, and (c) that odorant pairs differing in functional group were significantly better discriminated than odorant pairs differing in carbon chain length. These findings demonstrate that CD-1 mice have excellent discrimination ability for structurally related aliphatic odorants, that correlations between discrimination performance and structural similarity of odorants are odorant class-specific rather than a general phenomenon, and that both carbon chain length and type of functional group play an important role for odor quality coding in mice.     

'Sniffin' Sticks': Olfactory Performance Assessed by the Combined Testing of Odour Identification, Odor Discrimination and Olfactory Threshold

‘Sniffin’ Sticks' is a new test of nasal chemosensoryperformance based on pen-like odor dispensing devices. It comprisesthree tests of olfactory function, namely tests for odor threshold(n-butanol, testing by means of a single staircase), odor discrimination(15 pairs of odorants, triple forced choice) and odor identification(16 common odorants, multiple forced choice from four verbalitems per test odorant). After extensive preliminary investigationsthe tests were applied to a group of 104 healthy volunteers(52 female, 52 male, mean age 49.5 years, range 18–84years) in order to establish test-retest reliability and tocompare them with an established measure of olfactory performance(the Connecticut Chemosensory Clinical Research Center Test,CCCRC). Performance decreased with increasing age of the subjects(     

Olfaction and odor discrimination are mediated by the C. elegans guanylyl cyclase ODR-1

Animals in complex environments must discriminate between salient and uninformative sensory cues. Caenorhabditis elegans uses one pair of olfactory neurons called AWC to sense many different odorants, yet the animal can distinguish each odorant from the others in discrimination assays. We demonstrate that the transmembrane guanylyl cyclase ODR-1 is essential for responses to all AWC-sensed odorants. ODR-1 appears to be a shared signaling component downstream of odorant receptors. Overexpression of ODR-1 protein indicates that ODR-1 can influence odor discrimination and adaptation as well as olfaction. Adaptation to one odorant, butanone, is disrupted by ODR-1 overexpression. Olfactory discrimination is also disrupted by ODR-1 overexpression, probably by overproduction of the shared second messenger cGMP. We propose that AWC odorant signaling pathways are insulated to permit odor discrimination.     

Combinatorial receptor codes for odors

The discriminatory capacity of the mammalian olfactory system is such that thousands of volatile chemicals are perceived as having distinct odors. Here we used a combination of calcium imaging and single-cell RT-PCR to identify odorant receptors (ORs) for odorants with related structures but varied odors. We found that one OR recognizes multiple odorants and that one odorant is recognized by multiple ORs, but that different odorants are recognized by different combinations of ORs. Thus, the olfactory system uses a combinatorial receptor coding scheme to encode odor identities. Our studies also indicate that slight alterations in an odorant, or a change in its concentration, can change its "code," potentially explaining how such changes can alter perceived odor quality.     

Learned odor discrimination in Drosophila without combinatorial odor maps in the antennal lobe

A unifying feature of mammalian and insect olfactory systems is that olfactory sensory neurons (OSNs) expressing the same unique odorant-receptor gene converge onto the same glomeruli in the brain [1-7]. Most odorants activate a combination of receptors and thus distinct patterns of glomeruli, forming a proposed combinatorial spatial code that could support discrimination between a large number of odorants [8-11]. OSNs also exhibit odor-evoked responses with complex temporal dynamics [11], but the contribution of this activity to behavioral odor discrimination has received little attention [12]. Here, we investigated the importance of spatial encoding in the relatively simple Drosophila antennal lobe. We show that Drosophila can learn to discriminate between two odorants with one functional class of Or83b-expressing OSNs. Furthermore, these flies encode one odorant from a mixture and cross-adapt to odorants that activate the relevant OSN class, demonstrating that they discriminate odorants by using the same OSNs. Lastly, flies with a single class of Or83b-expressing OSNs recognize a specific odorant across a range of concentration, indicating that they encode odorant identity. Therefore, flies can distinguish odorants without discrete spatial codes in the antennal lobe, implying an important role for odorant-evoked temporal dynamics in behavioral odorant discrimination.     

Dissociable codes of odor quality and odorant structure in human piriform cortex

The relationship between odorant structure and odor quality has been a focus of olfactory research for 100 years, although no systematic correlations are yet apparent. Animal studies suggest that topographical representations of odorant structure in olfactory bulb form the perceptual basis of odor quality. Whether central olfactory regions are similarly organized is unclear. Using an olfactory version of fMRI cross-adaptation, we measured neural responses in primary olfactory (piriform) cortex as subjects smelled pairs of odorants systematically differing in quality and molecular functional group (as one critical attribute of odorant structure). Our results indicate a double dissociation in piriform cortex, whereby posterior regions encode quality (but not structure) and anterior regions encode structure (but not quality). The presence of structure-based codes suggests fidelity of sensory information arising from olfactory bulb. In turn, quality-based codes are independent of any simple structural configuration, implying that synthetic mechanisms may underlie our experience of smell.     

An artificial neural network approach for glomerular activity pattern prediction using the graph kernel method and the gaussian mixture functions

This paper proposes a neural network model for prediction of olfactory glomerular activity aimed at future application to the evaluation of odor qualities. The model's input is the structure of an odorant molecule expressed as a labeled graph, and it employs the graph kernel method to quantify structural similarities between odorants and the function of olfactory receptor neurons. An artificial neural network then converts odorant molecules into glomerular activity expressed in Gaussian mixture functions. The authors also propose a learning algorithm that allows adjustment of the parameters included in the model using a learning data set composed of pairs of odorants and measured glomerular activity patterns. We observed that the defined similarity between odorant structure has correlation of 0.3-0.9 with that of glomerular activity. Glomerular activity prediction simulation showed a certain level of prediction ability where the predicted glomerular activity patterns also correlate the measured ones with middle to high correlation in average for data sets containing 363 odorants.     

A large contribution of a cyclic AMP-independent pathway to turtle olfactory transduction

Although multiple pathways are involved in the olfactory transduction mechanism, cAMP-dependent pathway has been considered to contribute mainly to the transduction. We examined the degree of contribution of cAMP-independent pathway to the turtle olfactory response by recording inward currents from isolated cells, nerve impulses from cilia and olfactory bulbar responses. The results obtained by the three recordings were essentially consistent with each other, but detail studies were carried out by recording the bulbar response to obtain quantitative data. Application of an odorant cocktail to the isolated olfactory neuron after injection of 1 mM cAMP from the patch pipette elicited a large inward current. Mean amplitude of inward currents evoked by the cocktail with 1 mM cAMP in the patch pipette was similar to that without cAMP in the pipette. Application of the cocktail after the response to 50 microM forskolin was adapted also induced a large inward current. Application of the odorant cocktail to the olfactory epithelium, after the response to 50 microM forskolin was adapted, brought about an appreciable increase in the impulse frequency. The bulbar response to forskolin alone reached a saturation level around 10 microM. After the response to 50 microM forskolin was adapted, 11 species of odorants were applied to the olfactory epithelium. The magnitudes of responses to the odorants after forskolin were 45-80% of those of the control responses. There was no essential difference in the degree of the suppression by forskolin between cAMP- and IP3- producing odorants classified in the rat, suggesting that certain part of the forskolin-suppressive component was brought about by nonspecific action of forskolin. Application of a membrane permeant cAMP analogue, cpt-cAMP elicited a large response, and 0.1 mM citralva after 3 mM cpt- cAMP elicited 51% of the control response which was close to the response to citralva after 50 microM forskolin. A membrane permeant cGMP analogue, db-cGMP elicited a small response and the response to 0.1 mM citralva was unaffected by db-cGMP. It was concluded that cAMP- independent (probably IP3-independent) pathway greatly contributes to the turtle olfactory transduction.