(1) Walter Freeman and his colleagues have shown that every neuron in the olfactory bulbs participates in the generation of olfactory perception (Freeman, Scientific American 1991; 264(2): 78-85). In other words, the salient information about the stimulus is carried in some distinctive pattern of bulbwide activity and not in a subset of specific neurons. In the absence of a stimulus, the pattern of activity across the olfactory bulb has "chaotic" characteristics. However, upon receiving a stimulus the chaotic behavour rapidly assumes a cross-bulbar pattern. This pattern need not be the same each time for the same odour, but may change its characteristics depending upon the previous stimulus. This system allows for odorant conditioning, and also explains how we can be sensitive to odours we have never previously experienced.
(2) Another prevalent view is that the chemical features of the odour are encoded by the glomeruli in the olfactory bulb (see Bozza & Mombaerts, Current Biology 2001; 11: R687-R690 for a good summary). This view is compatible with that of Freeman explained above. Each glomeruli of the olfactory bulb receives the input from only those ORNs expressing the same receptor. Thus each glomerulus responds to one, and only one, chemical feature of the odour. Neighboring glomeruli respond optimally to slightly different features, e.g. increasing carbon chain length or different side groups. The odour is thus represented by bulb-wide activity - glomerular activation - representing those receptors to which the odour binds, as well as the binding affinity - a kind of 3-D bar code.
The pattern of activation of the different glomeruli is then relayed to the primary olfactory cortex - the piriform cortex. The cells in the olfactory (piriform) cortex should each respond to a different glomerulus becoming active. However, Linda Buck has shown (Zhou & Buck, Science; 311, 1477-81, 2006) that there are cells in the olfactory cortex that only respond when two odorants are present and not when each component odour is present on its own. This could explain why odour mixtures can have different odour percepts to the smell of their individual ingredients. In fact, we are rather bad at picking out individual odours in a mixture.
Taste & Smell
What we refer to as taste is actually flavour. Flavour is a combination of taste and smell sensory information.
"As much as 80% of what we call "taste" actually is aroma" (Dr Susan Schiffman quoted in Chicago Tribune, 3 May 1990)
"Ninety percent of what is perceived as taste is actually smell" (Dr Alan Hirsch of the Taste Treatment and Research Foundation in Chicago, quoted in MX, Melbourne, Australia, 28 Jan 2003).
Smell is more sensitive than taste: threshold for sucrose (taste) is between 12 and 30mM (millimolar) depending upon test used. Strychnine is a very powerful taste (apparently), and can be tasted at 10-6M (one micromolar). As for smell, mercaptan can be detected at 7x10-13Molar. Taking into account the relative volumes needed for taste and smell (you sniff a greater volume of air than you taste a liquid), smell is 10,000 times more sensitive than taste (Moncrieff, R.W. "The Chemical Senses", 3rd ed., Leonard Hill, London, 1967).
Who said "A rose by any other name would smell as sweet"?
Smell and memory are closely linked. Smell evokes memories. Damage to the temporal cortical region of the brain - the site of memory - does not affect the ability to detect smell, but, rather, prevents the identification of the odour. We must first remember a smell before identifying it.
What we know about smell and memory:
- Memory - odour memory falls off less rapidly that other sensory memory (Miles & Jenkins, 2000)
- Odour memory lasts a long time.
- The "Proust effect" - odour associated with experience and a smell can recall the memory; smell is better at this memory cue effect than other senses (Chu and Downes, 2000)
If we smell (or taste something) before a negative experience, that smell (or taste) is linked to that experience. The memory is very robust. This can be a problem for unpleasant medical treaments, or surgery when the last meal is often associated with the pain or trauma. But this very effect could, in the future, be put to therapeutic advantage; if smell were to be associated with a positive, healing treatment then the smell itself can substitute for the treatment once the link has been reinforced. It works in rats!
Some very interesting research was published recently - insulin was injected into healthy male volunteers once a day for four days and their blood glucose was measured (it fell). At the same time, they were exposed to a smell. On the fifth day they were just given the smell, and, their blood glucose fell (Stockhorst & Gritzmann, (1999) Psychosomatic Medicine 61, 424-435).
Women, particularly women of reproductive age, have a more acute sense of smell than men. The smell sensitivity of most women varies across the menstrual cycle, peaking at ovulation (approx. day 14 of cycle where the beginning of menstruation is day 0). This peak in smell sensitivity coincides with a surge in plasma estradiol (an oestrogen). Estradiol also increases during pregnancy, perhaps explaining why some women report an increase in smell (and taste) sensitivity during pregnancy.
Smell declines with age but postmenopausal decreases in smell sensitivity are not reversed by hormone replacement therapy (HRT)1.
In Kallmann's syndrome there is an impaired sense of smell. Affected individuals have deficient gonadotropin levels (hormones that stimulate the function of the testes and the ovaries). Recent studies demonstrate that GnRH neurons originate in olfactory tissues and migrate to the hypothalamus but fail to do so in Kallman's syndrome. In addition the olfactory bulbs fail to develop.
1Hughes et al. Climacteric. 2002 Jun;5(2):140-50
Smell and dreams - A recent study in Germany has shown that smell can influence the quality and emotional tone of dreams. Researchers wafted the smell of roses under the noses of sleeping volunteers in the REM phase of their sleep (dreaming phase). They then woke them up and asked them to report on the content and quality of their dreams. While the subjects did not report actually smelling anything during their dreams, the emotional tone of their dream did change depending upon the stimulation. The smell of roses evoked pleasant emotions and the smell of rotting eggs had the opposite effect. BBC News online Sept 2008
|moths can smell a single|
molecule (of the moth pheromone
|insect antennae attached to electronic circuits are being used as odour sensors|
|FACT - taste is mostly (~75%) smell||FACT - we can smell happiness|
|dogs can distinguish non-identical twins by smell - but not identical twins!||some people can't smell skunks - and some can't smell freesias|
|all smells are small molecules (less than 350 molecular mass)||bloodhounds can pick up a 24 h old trail and identify the person.|
If a bloodhound comes across a 20 minute-old trail at right angles,
sniffing for 2-5 steps will give the direction of the trail.
|"sniffer rats" have been used to detect|
expolosives - but they haven't
replaced their canine cousins!
|FACT - everyone has a unique smell (except identical twins)|
In the roof of each nostril is a region called the nasal mucosa. This region contains the sensory epithelium - the olfactory epithelium - covered by mucus. The area of this olfactory region is 5cm2 in humans and 25cm2 in cats. The epithelium contains, as well as the sensory cells, Bowman's glands producing the secretion that bathes the surface of the receptors. This is an aqueous secretion containing mucopolysaccharides, immunoglobulins, proteins (e.g. lysozyme) and various enzymes (e.g. peptidases). Also found in the nasal mucosa is a pigmented-type of epithelial cell: the depth of colour is often correlated with olfactory sensitivity, being light yellow in humans and dark yellow or brown in dogs. Pigment may play a part in olfaction, perhaps absorbing some kind of radiation, like infrared. Finally the nasal epithelium contains the receptor cells - some 10 million in humans (more in rats and cats). They possess a terminal enlargement (a "knob") that projects above the epithelial surface, from which extend about 8-20 olfactory cilia. These cilia do not beat (being non-motile) but they contain the smell receptors.
The olfactory receptor neurone
Olfactory receptor neuron (ORN) is shown in yellow. It has cilia that project from the dendritic knob into the mucus and on which the receptors for odorants are located.
ORNs are embedded in the olfactory epithelium which has a number of other cell types; basal cells are stem cells for ORNs and other epithelial cells and supporting cells provide a glial-like function and may be involved in detemining the composition of the mucus. The ORN has an axon that terminates in the olfactory bulb.
Proteins, found in the olfactory mucus, have recently been discovered that bind to odorants. These have been termed the Odorant Binding Proteins (OBPs). Odorants dissolve in the aqueous/lipid environment of the mucus and then bind to an OBP. It is thought that these proteins facilitate the transfer of lipophilic ligands (odorants) across the mucus layer to the receptors, and also increase the concentration of the odorants in the layer, relative to air. There are two other proposed roles for these proteins as, (1) a transporter, in which they would bind to a receptor with the ligand and accompany it across the membrane and (2) as a terminator, causing "used" odorants to be taken away for degradation, allowing another molecule to interact with the receptor. The protein could also be acting as a kind of protector for the receptor, preventing excessive amounts of odorant from reaching the receptor.
Odorant receptors (ORs)It appears that there may be hundreds of odorant receptors, but only one (or at most a few) expressed in each olfactory receptor neuron. A large family of odorant receptors was cloned in 1991 by Linda Buck and Richard Axel (Buck and Axel, 1991) and the mRNA encoding these proteins has been found in olfactory tissue. These families may be encoded by as many as 1000 different genes. This is a huge amount and accounts for about 2% of the human genome. In humans, however, most are inactive pseudogenes and only around 350 code for functional receptors. There are many more functional genes in macrosmatic animals like rats. These receptor proteins are members of a well known receptor family called the 7-transmembrane domain G-protein coupled receptors (GPCRs - see Fig. below). The hydrophobic regions (the transmembrane parts) contain maximum sequence homology to other members of the G-protein linked receptor family. There are some notable features of these olfactory receptors, like the divergence in sequence in the 3rd, 4th and 5th transmembrane domains, that suggest a how a large number of different odorants may be discriminated.
Vomeronasal-like receptors (V1RL1) have been found in the human olfactory epithelium (Rodriguez et al. Nat. Genet; 26, 18-19, 2000). This, in theory, could give humans sensitivity to pheromones although it yet to been proved that V1r proteins are involved in pheromone detection - but it's a thought!
TAARs - a new type of receptor has been discovered (Liberles & Buck, 2006) in the mouse that detects volatile amines. These are found in mouse urine and convey information about stress and gender. One has been reported to be a pheromone. Are they found in humans??? Wait and see!
An odorant receptor (7-transmembrane G-protein-coupled receptor)
|Odorant receptor. A G-protein-coupled receptor with 7 transmembrane domains. Domains 3-5 are highly variable between the 350 or so human isoforms of this gene and are probably the odorant binding site. The C-terminus and the intracellular loops I2 and I3function as G-protein binding domains.|
The receptor cells are bipolar neurones in the nasal epithelium (see figure "Olfactory Receptor Neuron" above). It is thought that each ORN expresses only one type of receptor (out of the total of about 350). The ORNs are unique to the extent that they are capable of regenerating. They possess cilia which project into the mucus (these contain the receptor proteins) and, at the other end, axons that project to the olfactory bulb. 10-100 axons form up into bundles that penetrate the ethmoidal cribriform plate and terminate in the olfactory bulb, converging on synaptic glomeruli. ORNs expressing the same receptor protein synapse onto the same glomerulus in the olfactory bulb. There are two olfactory bulbs, one in each nasal cavity. In humans there are about 6M receptor cells in each nostril and this rises to 50M olfactory receptor neurons in the rat. The diagram below shows the incoming axons from ORNs (in green) synapsing with glomeruli in the olfactory bulb.
Olfactory ensheathing cells are like glial cells. They are the non-myelinating cells that wrap around (ensheath) olfactory axons within both the peripheral and and central nervous system portions of the primary olfactory pathway. In vivo these glial cells express a mixture of astrocyte-specific and Schwann cell-specific phenotypic features with the former cellular phenotype predominating, but in vitro can assemble a myelin sheath when co-cultured with dorsal root ganglion neurons. Thus, certain in vitro conditions induce ensheathing cells to express a phenotype more like that of a myelinating Schwann cell.
Foetal olfactory ensheathing glial cells (OECs) are thought to have the capacity to regenerate damaged nerve fibers. NeurosurgeonHuang Hongyun, of Chaoyang Hospital, Beijing is using these cells in the hope of repairing neurological damage. Over the past 3 years he has used foetal tissue transplants to treat more than 450 patients. He now has 1000 Chinese and foreign patients on a waiting list, including about 100 Americans, who find him via the Internet or word of mouth. He has also used the procedure to treat strokes, multiple sclerosis, cerebral palsy, and brain injuries with, he says, "equally positive results".
The bulk of his Huang's patients are people suffering from spinal cord injury, followed by ALS, a distant second. He has only treated a few patients with Parkinson disease.
Sour grapes? Hongyun's work is criticised by the West (see Nature 437, pp. 810-811 (6 October 2005) Fetal-cell therapy: Paper chase by David Cyranoski) because he doesn't publish carefully controlled trials. He has however published in Chinese journals but his work has been rejected by the leading medical and scientific journals. He now says he is going to give up trying to convince the Western scientific community. This is our loss and shows a disturbing arrogance and prejudice on behalf of Western scientists.
The olfactory bulb
- Mitral cells are the principal neurons in the olfactory bulb. There are about 45,000 of these cells in each bulb in the rat and around 50,000 in the adult human. They have a primary apical dendrite which extends into a spherical bundle of neuropil called a glomerulus (see below) which receives the input from the olfactory receptor neurons. Their axons merge together to form the lateral olfactory tract. They possess colaterals, involved in negative feedback and positive feed-forward.
- Glomeruli are roughly spherical bundles of dendritic processes - some 25 mitral cells may send their primary dendrites to a single glomerulus - and it is here that they make contact with incoming olfactory nerves (in rodents the branches of 17,000-25,000 olfactory axons). In the rabbit there are about 2000 glomeruli per olfactory bulb.
- Periglomerular cells are involved in lateral inhibition at the level of the glomeruli
- Granule cells are inhibitory interneurones. They receive both contra- and ipsi-lateral input.
- The lateral olfactory tract terminates in the pyriform and prepyriform areas (primary olfactory cortex) from where the primary projection goes to the thalamus (medialis dorsalis). Axons project from here to the neocortex (orbito-frontal). In addition, primates have a pathway that runs via the limbic brain to the hypothalamus and is involved with mood (and memory) and neuroendocrine regulation. This latter pathway is responsible for the so-called "affective" component of smell.
- Centrifugal pathways have a "wipe clean" function to reset the system ready for the next input and also with dis-inhibition. When hungry smells have a greater effect!
- The architecture of the bulb results in 1:1000 convergence of olfactory receptor neurons to mitral cells. Thus a lot of information about individual receptors is thrown away but this increases sensitivity since contributions from many receptors are added together.
|Olfactory receptor neurons (ORNs) express one (or a few) type of receptor per cell. Each ORN expressing the same receptor project to the same glomerulus in the olfactory bulb. There is a symmetry in the two bulbs with glomeruli in similar positions receiving input from ORNs expressing the same receptor.|
Simon O'Connor and I have just published a review on the Pharmacology of the Olfactory bulb.
Neuropharmacology of the Olfactory Bulb. O'Connor, S. and Jacob, T.J.C. Current Molecular Pharmacology, 2008, 1, 181-190.
Glutamate has been proposed as the olfactory cell neurotransmitter in turtle, toad and in rat – mediating transmission at the first synapse in the pathway (olfactory receptor neuron (ORN)-mitral cell). There is evidence that noradrenaline is a neurotransmitter in the rat olfactory bulb . There is considerable clinical interest in this system because of the number of conditions associated with diminuished noradrenaline activity in which olfactory discrimination is also impaired, including Korsakoff’s disease, normal ageing, Parkinson’s disease and Alzheimer’s disease.
Both behavioral and molecular studies point to a potentially important role of dopamine in olfaction. Parkinson’s patients, who have reduced dopamine levels, also have impaired odour recognition. Injection of dopamine analogues reduces olfactory sensitivity in rats. Dopamine may play an important neuormodulatory role in olfaction by reducing transmitter release from ORNs . Dopaminereceptors of the D2 sub-type have been found to modulate input to the olfactory bulb from the olfactory receptor cells in rats and some periglomerular and mitral cells are dopaminergic . D1 receptors are only sparsely expressed in the rat olfactory bulb (glomerular layer, external plexiform, mitral and granule cell layers) stimulate cAMP and are excitatory, whereas D2 receptors which are more prominent in the bulb (ORNs and glomerular layer) reduce cAMP and are inhibitory.
Inhibitory circuits in the bulb have been found to be mediated by GABA and in vitro studies have shown interactions betweenGABA and glycine.
Various drugs have been demonstrated to have an effect on the sense of smell, in particular drugs that affect calcium channels, nifedipine and diltiazem. These are thought to have their effect by blocking olfactory nerve transmission.
There are no reports in the literature of the effects of glutamate antagonists or GABA or glycine agonists on human olfactory acuity.
1. Berkowicz, D.A. and Trombley, P.Q. (2000) Dopaminergic modulation at the olfactory nerve synapse. Brain Res. 855, 90-99.
2. Berkowicz, D.A., Trombley, P.Q. and Shepherd, G.M. (1994) Evidence for glutamate as the olfactory receptor cell neurotransmitter. J. Neurophysiol. 71, 2557-61.
3 . Mair, R.G. and Harrison, L.M (1991) Influence of drugs on smell function. Chapter 16 in “The Human Sense of Smell “eds. D.G. Laing, R.L. Doty and W. Breipohl, Springer-Verlag, Berlin, pp. 335-359.
4. Hawkes, C.H. and Shephard, B.C. (1998) Olfactory evoked responses and identification tests in neurological disease. Ann. N.Y. Acad. Sci. 855, 608-615.
5. Kratskin, I.L. and Belluzzi, O. (2003) Anatomy and neurochemistry of the olfactory bulb. In "Handbook of Olfaction and Gustation" 2nd edition, ed. R.L. Doty, Marcel Dekker, New York, pp. 139-164
The rostral migratory stream (RMS) is a pathway where newborn neurons are produced in the subventricular region of the brain and then migrate to the olfactory bulb. Curtis et al in Peter S. Eriksson's collaboration have convincingly shown that it does exists in spite of a recent paper claiming that it did not exist in humans (more later....).
Curtis, M.A. et al (2007) Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science315, 1243 49
Neurons from the lateral olfactory tract project to; (1) the amygdala, septal nuclei, pre-pyriform cortex, the entorhinal cortex, hippocampus and the subiculum. Many of these structures form the limbic system, an ancient region of the brain concerned with motivation, emotion and certain kinds of memory. The septal nuclei and amygdala contain regions known as the "pleasure centres". The hippocampus is concerned with motivational memory (the association of certain stimuli with food). (2) Projections are also sent to the thalamus and thence to the frontal cortex for recognition. There are many forward and backward connections between each of these brain centres.
We respond in an involuntary way to smell – this is due to the wiring of the olfactory pathway. The olfactory nerves go first to a primitive region of the brain called the limbic system (Figure below). The limbic system is a collection of brain structures situated beneath the cerebral cortex that deal with emotion, motivation, and association of emotions with memory. Only after this relay has occurred does the information arrive in the higher cortical brain regions for perception and interpretation. Smell is unique among the senses in its privileged access to the subconscious.
The brain - showing the limbic system (coloured)
The limbic system includes such brain areas as the amygdala, hippocampus, pyriform cortex and hypothalamus (see coloured areas in above diagram). This complex set of structures lies on both sides and underneath the thalamus, just under the cerebrum. The limbic system is increasingly recognised to be crucial in determining and regulating the entire emotional 'tone'. Excitation of this, by whatever means, produces heightened emotionalism and an intensification of the senses. It also has a lot to do with the formation of memories and this is the reason that smell and memory are so intimately linked.
Olfactory hallucinations coupled with feelings of deja vu occur in "uncinate seizures", a form of temporal lobe epilepsy, and sometimes there is a generalised intensification of smell. The uncus, phylogenetically part of the "smell-brain" (or rhinencephalon), is functionally associated with the whole limbic system (which includes such brain areas as the amygdala, hippocampus, pyriforn cortex and hypothalamus - the cooloured bits in the figure above), which is increasingly recognised to be crucial in determining and regulating the entire emotional 'tone'. Excitation of this, by whatever means, produces heightened emotionalism and an intensification of the senses.
Preliminary work has demonstrated that smell can be used to reduce the occurrence of seizures in epilepsy. One possible explanation is that because olfactory centres (primary olfactory cortex, entorhinal cortex) are next door to regions where seizures begin in temporal lobe epilepsy, activity generated in these areas by the presentation of a smell prevents the spread of the synchronous activity from the epileptic focus.