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ScienceWeek
NEUROSCIENCE: ON THE HUMAN OLFACTORY SYSTEM
The following points are made by A. Keller and L.B. Vosshall (Current Biology 2004 14:R875):
1) Of all the senses, smell is the least understood. Despite centuries of investigation, science can still offer no satisfying theory for why a particular substance smells the way it does. Nor do we understand in any detail how we are able to distinguish the smell of a peach from that of an apricot, or how a particular smell can trigger long-forgotten memories of a distant time or place.
2) Human olfactory psychophysics, the study of how humans perceive odors, is possible because humans have acquired language. Human subjects can report directly if something smells, characterize the smell, or decide if two smells are distinguishable. Answers to the following simple questions have the potential to provide insight into important questions: What (if any) is the relationship between the chemical structure of an odor and its perceived smell? What types of olfactory stimuli can be discriminated, and how is this accomplished in the nose and the brain? How does experience modulate our perception of odorants? There are of course many things that cannot be done in humans, for instance genetic manipulation and electrophysiology, but these types of approaches are successfully used in animal models.
3) The olfactory system of humans consists of several million olfactory sensory neurons arrayed in a sensory epithelium located inside the nasal cavity. Each of these sensory neurons expresses one of approximately 350 odorant receptor genes, which confers upon that neuron a specific sensitivity to the set of odor molecules that will bind and activate the respective odorant receptor. It is widely believed that only a small region of the odor molecule is recognized by a given odorant receptor. Therefore, unlike hearing or seeing, olfaction is not a spectral sense, but rather consists of a large number of sensors with different specificities and affinities. Any given odor may activate only a single receptor or many different receptors. On the other hand an odorant receptor can be very specific and only be activated by very few odor molecules or be more promiscuous and recognize a variety of odor molecules.
4) We are far from a complete understanding of which odors activate which odorant receptors; however, the available data support the notion that the combinatorial activation of olfactory neurons has the potential to account for the extremely large number of different odors that can be detected. How the activation of populations of olfactory sensory neurons is translated in the brain into a discretely perceived odor quality is still completely mysterious, despite vigorous investigation in model systems as disparate as nematodes, fruit flies, fish, mice, and humans. No clear models have emerged to account for the various psychophysical observations surrounding smell and we do not yet know how different odors are represented in higher brain regions.(1-5)
References (abridged):
1. Araneda, R.C., Kini, A.D. and Firestein, S. (2000). The molecular receptive range of an odorant receptor. Nat. Neurosci. 3, 1248-1255.
2. Buck, L. and Axel, R. (1991). A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell 65, 175-187
3. Doty, R.L. and Laing, D.G. (2003). Psychophysical Measurement of Human Olfactory Function, Including Odorant Mixture Assessment. In Handbook of Olfaction and Gustation 2nd Edition. In Doty, R.L. ed. (New York: Marcel Dekker)
4. Dravnieks, A. (1982). Odor quality: semantically generated multidimensional profiles are stable. Science 218, 799-801
5. Laska, M., Seibt, A. and Weber, A. (2000). ôMicrosmaticö primates revisited: Olfactory sensitivity in the squirrel monkey. Chem. Senses 25, 47-53
Current Biology http://www.current-biology.com
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NEUROBIOLOGY: ON MAMMALIAN PHEROMONES
The following points are made by P.A. Brennan and E.B. Keverne (Current Biology 2004 14:R81):
1) Chemical signals that convey information between members of the same species are commonly termed "pheromones". This term was first used by Karlson and Loescher [1] and defined as "substances secreted to the outside of an individual and received by a second individual of the same species in which they release a specific reaction, for example, a definite behavior or developmental process" [1]. However, there are problems with defining mammalian pheromones in this way, as it is difficult to define what constitutes a "specific reaction" [2]. Mammals are subject to more complex influences on their behavior than insects. For instance, odors that convey information about individuality may bias the behavior of other individuals of the same species [3], but because they do not elicit a specific behavior they would not qualify as pheromones according to the original definition.
2) The meaning of the term is further muddled by many investigators adding their own criteria for what constitutes a pheromone. For example, some investigators have stated that a substance should be airborne and not be consciously perceived in order for it to be defined as a pheromone [4]. An easy way out would be to redefine the term pheromone to encompass all chemical substances that convey information among individuals of the same species. Nevertheless, there are many mammalian examples of single molecules or cocktails of a few molecules that elicit dramatic behavioral effects. Such substances are often referred to as "releaser pheromones", whereas chemosignals that cause longer term changes in neuroendocrine or developmental states are usually referred to as "primer pheromones".
3) One of the best characterized mammalian pheromone is the rabbit nipple "search pheromone". Sensed by rabbit pups via their main olfactory system, it elicits a characteristic nipple search behavior that quickly results in the location of a nipple [5]. This guidance cue is particularly important for rabbits, as a doe only nurses her pups for around four minutes once a day and the quick location of a nipple in the face of sibling competition is vital for survival. This pheromone has recently been shown to be a single molecule, 2-methylbut-2-enal, which is produced in rabbit milk and is sufficient to elicit full nipple search and grasping behavior when presented on its own. Whereas the rabbit nipple search pheromone is a single molecule, many pheromones consist of blends of two or more molecules, which can elicit a greater response than any individual component. For example, the androgen derivatives 5a-androst-16-en-3-one and 5a-androst-16-en-3-ol are present at high concentrations in boar saliva. Each component elicits pheromonal effects to attract estrus sows and cause them to adopt a characteristic mating stance known as standing.
4) In summary: Olfaction is the dominant sensory modality for most animals and chemosensory communication is particularly well developed in many mammals. Our understanding of this form of communication has grown rapidly over the last 10 years since the identification of the first olfactory receptor genes. The subsequent cloning of genes for rodent vomeronasal receptors, which are important in pheromone detection, has revealed an unexpected diversity of around 250 receptors belonging to two structurally different classes. Recent studies using genetically modified mice and electrophysiological recordings have highlighted the complexities of chemosensory communication via the vomeronasal system and the role of this system in handling information about sex and genetic identity. Although the vomeronasal organ is often regarded as only a pheromone detector, evidence is emerging that suggests it might respond to a much broader variety of chemosignals.
References (abridged):
1. Karlson, P. and Loescher, M. (1959). Pheromones: a new term for a class of biologically active substances. Nature 183, 55-56
2. Doty, R.L. (2003). Mammalian pheromones: fact or fantasy?. In Handbook of Olfaction and Gustation. Doty, R.L. ed. (: Marcel Dekker Inc)
3. Beauchamp, G.K. and Yamazaki, K. (2003). Chemical signalling in mice. Biochem. Soc. Trans. 31, 147-151
4. Stern, K. and McClintock, M.K. (1998). Regulation of ovulation by human pheromones. Nature 392, 177-179
5. Distel, H. and Hudson, R. (1985). The contribution of the olfactory and tactile modalities to the performance of nipple-search behavior in newborn rabbits. J. Comp. Physiol. [A] 157, 599-605
Current Biology http://www.current-biology.com
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MECHANISMS OF OLFACTION
The following points are made by Stuart Firestein (Nature 2001 413:211):
1) The sensitivity and range of olfactory systems is remarkable, enabling organisms to detect and discriminate between thousands of low molecular mass, mostly organic compounds, which we commonly call "odors". Represented in the olfactory repertoire are aliphatic and aromatic molecules with varied carbon backbones and diverse functional groups, including aldehydes, esters, ketones, alcohols, alkenes, carboxylic acids, amines, imines, thiols, halides, nitriles, sulfides and ethers. This remarkable chemical-detecting system, developed over eons of evolutionary time, has received considerable attention in the past decade, revealing sensing and signaling mechanisms common to other areas of the brain, but developed here to unusual sophistication.
2) How does the olfactory system manage this sophisticated discriminatory task? Beginning with the identification of a large family of G-protein-coupled receptors (GPCRs) in the nose, the foundations of a comprehensive understanding have emerged in surprisingly short order. The advent of advanced molecular and physiological techniques, as well as the publication of eukaryotic genomes from Caenorhabditis elegans to Homo sapiens, has provided the critical tools for unveiling some of the secrets. We now possess a detailed description of the transduction mechanism responsible for generating the stimulus-induced signal in primary sensory neurons, and also an explicit picture of the neural wiring, at least in the early parts of the system. From this body of work a view of molecular coding in the olfactory system has arisen that is surely incomplete, but nonetheless compelling in its simplicity and power.
3) Among higher eukaryotes, from flies through to mammals, there is a striking evolutionary convergence towards a conserved organization of signaling pathways in olfactory systems(1). Two olfactory systems have developed in most animals. The common or main olfactory system is the sensor of the environment, the primary sense used by animals to find food, detect predators and prey, and mark territory. It is noteworthy for its breadth and discriminatory power. Like the immune complex, it is an open system built on the condition that it is not possible to predict, a priori, what molecules it (that is, you) might run into. Therefore, it is necessary to maintain an indeterminate but nonetheless precise sensory array.
4) A second, or accessory, olfactory system has developed for the specific task of finding a receptive mate -- a task of sufficient complexity that evolution has recognized the need for an independent and dedicated system. Known as the vomeronasal system, it specializes in recognizing species-specific olfactory signals produced by one sex and perceived by the other, and which contain information not only about location but also reproductive state and availability. In addition to its role in sexual behaviors, it is important in influencing other social behaviors such as territoriality, aggression and suckling.
5) In summary: The human nose is often considered something of a luxury, but in the rest of the animal world, from bacteria to mammals, detecting chemicals in the environment has been critical to the successful organism. An indication of the importance of olfactory systems is the significant proportion -- as much as 4% -- of the genomes of many higher eukaryotes that is devoted to encoding the proteins of smell. Growing interest in the detection of diverse compounds at single-molecule levels has made the olfactory system an important system for biological modeling.(2-5)
References (abridged):
1. Hildebrand, J. G. & Shepherd, G. M. Mechanisms of olfactory discrimination: converging evidence for common principles across phyla. Annu. Rev. Neurosci. 20, 595-631 (1997)
2. Buck, L. B. The molecular architecture of odor and pheromone sensing in mammals. Cell 100, 611-618 (2000)
3. Mombaerts, P. Seven-transmembrane proteins as odorant and chemosensory receptors. Science 286, 707-711 (1999)
4. Mombaerts, P. et al. Visualizing an olfactory sensory map. Cell 87, 675-686 (1996)
5. Buck, L. & Axel, R. A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell 65, 175-187 (1991)
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