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OLFACTORY EPITHELIUM AND OLFACTORY BULBS
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Olfactory sensory neurons are located in a specialized portion of the nasal mucosa, the yellowish pigmented olfactory epithelium. In dogs and other animals in which the sense of smell is highly developed (macrosmatic animals), the area covered by this membrane is large; in microsmatic animals, such as humans, it is small. In humans, it covers an area of 10 cm2 in the roof of the nasal cavity near the septum (Figure 11–1). The olfactory epithelium is said to be the place in the body where the nervous system is closest to the external world.
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The human olfactory epithelium contains about 50 million bipolar olfactory sensory neurons interspersed with glia-like supporting (sustentacular) cells and basal stem cells. New olfactory sensory neurons are generated by basal stem cells as needed to replace those damaged by exposure to the environment. The olfactory epithelium is covered by a thin layer of mucus secreted by the supporting cells and Bowman glands, which lie beneath the epithelium.
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Each olfactory sensory neuron has a short, thick dendrite that projects into the nasal cavity where it terminates in a knob containing 6–12 cilia (Figure 11–1). In humans, the cilia are unmyelinated processes, about 5–10 μm long and 0.1–2 μm in diameter that protrude into the mucus overlying the epithelium. Odorant molecules (chemicals) dissolve in the mucus and bind to odorant receptors on the cilia of olfactory sensory neurons. The mucus provides the appropriate molecular and ionic environment for odor detection.
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The axons of the olfactory sensory neurons (first cranial nerve) pass through the cribriform plate of the ethmoid bone and enter the olfactory bulbs (Figure 11–1). In the olfactory bulbs, the axons of the olfactory sensory neurons contact the primary dendrites of the mitral cells and tufted cells (Figure 11–2) to form anatomically discrete synaptic units called olfactory glomeruli. The olfactory bulbs also contain periglomerular cells, which are inhibitory neurons connecting one glomerulus to another, and granule cells, which have no axons and make reciprocal synapses with the lateral dendrites of the mitral and tufted cells (Figure 11–2). At these synapses, the mitral or tufted cells excite the granule cell by releasing glutamate, and the granule cells in turn inhibit the mitral or tufted cell by releasing GABA.
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Free endings of many trigeminal pain fibers are found in the olfactory epithelium. They are stimulated by irritating substances, which leads to the characteristic “odor” of such substances as peppermint, menthol, and chlorine. Activation of these endings by nasal irritants also initiates sneezing, lacrimation, respiratory inhibition, and other reflexes.
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The tufted cells are smaller than the mitral cells and they have thinner axons, but they are similar from a functional point of view. The axons of the mitral and tufted cells pass posteriorly through the lateral olfactory stria to terminate on apical dendrites of pyramidal cells in five regions of the olfactory cortex: anterior olfactory nucleus, olfactory tubercle, piriform cortex, amygdala, and entorhinal cortex (Figure 11–3). From these regions, information travels directly to the frontal cortex or via the thalamus to the orbitofrontal cortex. Conscious discrimination of odors is dependent on the pathway to the orbitofrontal cortex. The orbitofrontal activation is generally greater on the right side than on the left; thus, cortical representation of olfaction is asymmetric. The pathway to the amygdala is probably involved with the emotional responses to olfactory stimuli, and the pathway to the entorhinal cortex is concerned with olfactory memories.
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In rodents and various other mammals, the nasal cavity contains another patch of olfactory epithelium located along the nasal septum in a well-developed vomeronasal organ. This structure is concerned with the perception of odors that act as pheromones. Vomeronasal sensory neurons project to the accessory olfactory bulb (Figure 11–3) and from there to the amygdala and hypothalamus that are concerned with reproduction and ingestive behavior. Vomeronasal input has major effects on these functions. An example is pregnancy block in mice; the pheromones of a male from a different strain prevent pregnancy as a result of mating with that male, but mating with a mouse of the same strain does not produce blockade. The vomeronasal organ has about 100 G-protein-coupled odorant receptors that differ in structure from those in the rest of the olfactory epithelium.
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The organ is not well developed in humans, but an anatomically separate and biochemically unique area of olfactory epithelium occurs in a pit in the anterior third of the nasal septum, which appears to be a homologous structure. There is evidence for the existence of pheromones in humans, and there is a close relationship between smell and sexual function. Perfume advertisements bear witness to this. The sense of smell is said to be more acute in women than in men, and in women it is most acute at the time of ovulation. Smell and, to a lesser extent, taste have a unique ability to trigger long-term memories, a fact noted by novelists and documented by experimental psychologists.
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ODORANT RECEPTORS & SIGNAL TRANSDUCTION
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The olfactory system has received considerable attention in recent years because of the intriguing biologic question of how a simple sense organ such as the olfactory epithelium and its brain representation, which apparently lacks a high degree of complexity, can mediate discrimination of more than 10,000 different odors. One part of the answer to this question is that there are many different odorant receptors.
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There are approximately 500 functional olfactory genes in humans, accounting for about 2% of the human genome. The amino acid sequences of odorant receptors are very diverse, but all the odorant receptors are G-protein-coupled receptors (GPCRs). When an odorant molecule binds to its receptor, the G-protein subunits (α, β, γ) dissociate (Figure 11–4). The α-subunit activates adenylyl cyclase to catalyze the production of cAMP, which acts as a second messenger to open cation channels, increasing the permeability to Na+, K–, and Ca2+. The net effect is an inward-directed Ca2+ current which produces the graded receptor potential. This then opens Ca2+-activated Cl– channels, further depolarizing the cell due to the high intracellular Cl– levels in olfactory sensory neurons. If the stimulus is sufficient for the receptor potential to exceed its threshold, an action potential in the olfactory nerve (first cranial nerve) is triggered.
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A second part of the answer to the question of how 10,000 different odors can be detected lies in the neural organization of the olfactory pathway. Although there are millions of olfactory sensory neurons, each expresses only one of the 500 olfactory genes. Each neuron projects to one or two glomeruli (Figure 11–2). This provides a distinct two-dimensional map in the olfactory bulb that is unique to the odorant. The mitral cells with their glomeruli project to different parts of the olfactory cortex.
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The olfactory glomeruli demonstrate lateral inhibition mediated by periglomerular cells and granule cells. This sharpens and focuses olfactory signals. 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 focus the olfactory signals reaching the cortex.
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ODOR DETECTION THRESHOLD
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Odor-producing molecules (odorants) are generally small, containing from 3 to 20 carbon atoms; and molecules with the same number of carbon atoms but different structural configurations have different odors. Relatively high water and lipid solubility is characteristic of substances with strong odors. Some common abnormalities in odor detection are described in Clinical Box 11–1.
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The odor detection thresholds are the lowest concentration of a chemical that can be detected. The wide range of thresholds illustrates the remarkable sensitivity of the odorant receptors. Some examples of substances detected at very low concentrations include hydrogen sulfide (0.0005 parts per million, ppm), acetic acid (0.016 ppm), kerosene (0.1 ppm), and gasoline (0.3 ppm). On the other end of the spectrum, some toxic substances are essentially odorless; they have odor detection thresholds higher than lethal concentrations. An example is carbon dioxide, which is detected at 74,000 ppm but is lethal at 50,000 ppm. Not all individuals have the same odor detection threshold for a given odorant. While one person may detect and recognize an odorant at a particular concentration, another person may barely notice it.
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Olfactory discrimination is remarkable. On the other hand, determination of differences in the intensity of any given odor is poor. The concentration of an odor-producing substance must be changed by about 30% before a difference can be detected. The comparable visual discrimination threshold is a 1% change in light intensity. The direction from which a smell comes may be indicated by the slight difference in the time of arrival of odorant molecules in the two nostrils.
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CLINICAL BOX 11–1 Abnormalities in Odor Detection
Anosmia (inability to smell) and hyposmia or hypesthesia (diminished olfactory sensitivity) can result from simple nasal congestion or nasal polyps. It may also be a sign of a more serious problem such as damage to the olfactory nerves due to fractures of the cribriform plate or head trauma, tumors such as neuroblastomas or meningiomas, and respiratory tract infections (such as abscesses). Congenital anosmia is a rare disorder in which an individual is born without the ability to smell. Prolonged use of nasal decongestants can also lead to anosmia and damage to the olfactory nerves is often seen in patients with Alzheimer disease. According to the National Institutes of Health, 1–2% of the North American population under the age of 65 experiences a significant degree of loss of smell. However, aging is associated with abnormalities in smell sensation; 50% of individuals between the ages of 65 and 80 and >75% of those over the age of 80 have an impaired ability to identify smells. Because of the close relationship between taste and smell, anosmia is associated with a reduction in taste sensitivity (hypogeusia). Anosmia is generally permanent in cases in which the olfactory nerve or other neural elements in the olfactory neural pathway are damaged. In addition to not being able to experience the enjoyment of pleasant aromas and a full spectrum of tastes, individuals with anosmia are at risk because they are not able to detect the odor from dangers such as gas leaks, fire, and spoiled food. Hyperosmia (enhanced olfactory sensitivity) is less common than loss of smell, but pregnant women commonly become oversensitive to smell. Dysosmia (distorted sense of smell) can be caused by several disorders including sinus infections, partial damage to the olfactory nerves, and poor dental hygiene.
THERAPEUTIC HIGHLIGHTS Quite often anosmia is a temporary condition due to sinus infection or a common cold, but it can be permanent if caused by nasal polyps or trauma. Antibiotics can be prescribed to reduce the inflammation caused by polyps and improve the ability to smell. In some cases, surgery is performed to remove the nasal polyps. Topical corticosteroids have also been shown to be effective in reversing the loss of smell due to nasal and sinus diseases.
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ODORANT-BINDING PROTEINS
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The olfactory epithelium contains one or more odorant-binding proteins (OBP) that are produced by support cells and released onto the extracellular space. An 18-kDa OBP that is unique to the nasal cavity has been isolated, and other related proteins probably exist. The protein has considerable homology to other proteins in the body that are known to be carriers for small lipophilic molecules. A similar binding protein appears to be associated with taste. These OBP may function in several ways. One, they may concentrate the odorants and transfer them to the receptors. Two, they may partition hydrophobic ligands from the air to an aqueous phase. Three, they may sequester odorants away from the site of odor recognition to allow for odor clearance.
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It is common knowledge that when one is continuously exposed to even the most disagreeable odor, perception of the odor decreases and eventually ceases. This sometimes beneficent phenomenon is due to the fairly rapid adaptation, or desensitization, that occurs in the olfactory system. Adaptation in the olfactory system occurs in several stages. The first step may be mediated by a calcium-binding protein (calcium/calmodulin) that binds to the receptor channel protein to lower its affinity for cyclic nucleotides. The next step is called short-term adaptation, which occurs in response to cAMP and implicates a feedback pathway involving calcium/calmodulin-dependent protein kinase II acting on adenylyl cyclase. The next step is called long-term adaptation, which includes activation of guanylyl cyclase and cGMP production. A Na+/Ca2+ exchanger to restore ion balance also contributes to long-term adaptation.