Chapter 9: Chemical Senses: Taste and Smell

Clinical Case

CLINICAL CASE | Central Tegmental Tract Lesion and Unilateral Taste Loss

A 25-year-old woman suddenly complained of diplopia (double vision) and impaired sense of taste. On examination, taste was probed carefully by applying solutions of different qualities (salty, sweet, acidic, and bitter) to the tongue. The results indicated a loss of all tested qualities of taste on the right side of the tongue. A taste researcher in the Otolaryngology Department was contacted, and the patient was subsequently examined using an electronic device to examine taste thresholds. This confirmed loss of taste on the right half of the tongue and soft palate.

A T1-weighted MRI with gadolinium enhancement (Figure 9–1A) revealed a focal lesion in pontine tegmentum. Figure 9–1B is a closely corresponding myelin-stained section. An MRI from a healthy person (Figure 9–1C) shows the location of the pons in parts A and B, in relation to the brain in the skull. Note that the dorsal brain surface is down in all of these images. The lesion in A corresponds to the region of the central tegmental tract. The lesion also includes parts of the superior cerebellar peduncle, which transmits mostly the output of part of the cerebellum for movement control, and the medial longitudinal fasciculus, which contains axons that coordinate eye movements. Here we will only consider the loss of taste and the central tegmental tract lesion. The ocular control impairments will be considered in another case in Chapter 12. On the basis of the MRI and additional tests, the patient was diagnosed with multiple sclerosis, a demyelinating disease.

Answer the following questions.

1. Why is unilateral taste loss more likely a result of a peripheral than central lesion?

2. Why is loss of taste ipsilateral to the lesion?

3. What key pontine gustatory structure is likely to be damaged in the patient?

Key neurological signs and corresponding damaged brain structures Peripheral versus central

First consider that the three nerves that supply taste buds each have a limited distribution on the tongue (see Figure 9–4). Damage to a single nerve likely would result in partial taste loss, such as only on the anterior two thirds of the tongue with damage to a branch of the facial nerve. Thus, a peripheral lesion is unlikely. Next consider that central sensory systems receive convergent input from their various peripheral components, so that a system on each side will represent completely the peripheral receptive sheet from which it receives information (eg, the homunculus, Figure 4–9; indicates a complete contralateral body representation for mechanosensations). The three nerves supplying taste buds converge upon the rostral solitary nucleus.

Ipsilateral taste loss

The gustatory pathway, unlike the other sensory pathways, is ipsilateral. Thus, the loss of taste likely involves lesion somewhere along this central path.

Critical structures

The projection from the solitary nucleus ascends in the central tegmental tract, and terminates in the parvocellular division of the ipsilateral ventral posterior medial nucleus of the thalamus. The pontine lesion is also likely to damage the parabrachial nucleus, which could contribute to the impairment. However, we learned in Chapter 6 that the parabrachial nucleus is more important for visceral sensations. Further, other studies in the human reveal taste loss with small vascular lesions that are more selective to the central tegmental tract, demonstrating, at least, the importance of the tract.

References

Shikama Y, Kato T, Nagaoka U, et al. Localization of the gustatory pathway in the human midbrain. Neurosci Lett. 1996;218(3):198-200.

Uesaka Y, Nose H, Ida M. The pathway of gustatory fibers in the human ascends ipsilaterally. Neurology. 1998;50:827.

FIGURE 9–1

Lesion of the gustatory pathway. A. MRI of patient with multiple sclerosis showing a region of demyelination (or plaque) in the pontine tegmentum. The arrow points to the plaque. B. Myelin-stained section through the rostral pons, close to the levels of the MRIs in A and C. C. MRI from a healthy person showing the location of the regions in A and B. (A, Reproduced with permission from Uesaka Y, Nose H, Ida M. The pathway of gustatory fibers in the human ascends ipsilaterally. Neurology. 1998;50:827. B, Courtesy of Dr. Joy Hirsch, Columbia University.)

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Two distinct neural systems are used to sense the molecular environment of the world around us: the gustatory system, which mediates taste, and the olfactory system, which serves smell. These systems are among the phylogenetically oldest neural systems of the brain. Compared with those of the other sensory systems, the neural systems for processing chemical stimuli are remarkably different. For example, both taste and smell have ipsilateral ascending projections, whereas those of the other sensory systems are either contralateral or bilateral. Moreover, the primary cortical areas for taste and smell are within limbic system regions, where emotions and their associated behaviors are formed. Information from the other sensory modalities reaches the limbic system only after additional processing stages. Smells and tastes have a particular knack for evocative recall of our dearest memories. Recall Marcel Proust's vivid description of how a spoonful of tea-soaked madeleine brought back childhood memories.

The gustatory and olfactory systems work jointly in perceiving chemicals in the oral and nasal cavities, a more essential collaboration than that which occurs between the other sensory modalities. For example, even though the gustatory system is concerned with the primary taste sensations—such as sweet or sour—the perception of richer and more complex flavors such as those present in wine or chocolate is dependent on a properly functioning sense of smell. Chewing and swallowing cause chemicals to be released from food that waft into the nasal cavity from the orapharynx, where they stimulate the olfactory system. Damage to the olfactory system, as a result of head trauma—or even the common cold, which temporarily impairs conduction of airborne molecules in the nasal passages—can dull the perception of flavor even though basic taste sensations are preserved. Although taste and smell work together and share similarities in their neural substrates, the anatomical organization of these systems is sufficiently different to be considered separately.

The Gustatory System: Taste

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There are classically four taste qualities—sweet, sour, bitter, and salty—and there are corresponding taste receptor cells for each of these modalities. A fifth quality has been proposed, termed savory, which is best associated with a meaty broth because a fifth class of taste receptor cell has been identified, umami (Japanese, flavor). Whereas we may think our gustatory system's primary function is to identify foods, this is more a role of sights and smells. Rather, the system is exquisitely organized to identify nutrients or harmful agents in what we ingest, in relation to particular physiological processes: sweet and savory are key to maintaining proper energy stores, salty for electrolyte balance, bitter and sour for maintaining pH, and bitter also for avoiding toxins.

Taste is mediated by three cranial nerves, through their innervation of oral structures: facial (VII), glossopharyngeal (IX), and vagus (X). As discussed in Chapter 6, the glossopharyngeal and vagus nerves also provide much of the afferent innervation of the gut, cardiovascular system, and lungs. This visceral afferent innervation provides the central nervous system with information about the internal state of the body.

The Ascending Gustatory Pathway Projects to the Ipsilateral Insular Cortex

Taste receptor cells are clustered in the taste buds, located on the tongue and at various intraoral sites. Chemicals from food, termed tastants, either bind to surface membrane receptors or pass directly through membrane channels, depending on the particular chemical, to activate taste cells. Taste cells are innervated by the distal branches of the primary afferent fibers in the facial, glossopharyngeal, and vagus nerves (Figure 9–2). These afferent fibers have a pseudounipolar morphology, similar to that of the dorsal root ganglion neurons. In contrast to the nerves of the skin and mucous membranes, where generally the terminal portion of the afferent fiber is sensitive to stimulus energy, taste receptor cells are separate from the primary afferent fibers. For taste, the role of the primary afferent fiber is to receive information from particular classes of taste receptor cells and to transmit this sensory information to the central nervous system, encoded as action potentials. For touch, the role of the primary afferent fiber is both to transduce stimulus energy into action potentials and to transmit this information to the central nervous system.

FIGURE 9–2

General organization of the gustatory system. A. Ascending gustatory pathway. B. Approximate location of the gustatory cortex in the insular cortex. The frontal operculum has been removed to show the insular cortex. C. MRI showing insular cortex and approximate region of the gustatory cortex in the insular cortex.

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The central branches of the afferent fibers, after entering the brain stem, collect into the solitary tract (Figure 9–2) of the dorsal medulla and terminate in the rostral portion of the solitary nucleus (Figure 9–2, lower inset). Recall that the caudal solitary nucleus is a viscerosensory nucleus, critically involved in regulating body functions and transmitting information to the cortex for perception of visceral information as well as the emotional and behavioral aspects of visceral sensations.

The axons of second-order neurons in the rostral solitary nucleus ascend ipsilaterally in the brain stem, in the central tegmental tract, and terminate in the parvocellular division of the ventral posterior medial nucleus (Figure 9–2). From the thalamus, third-order neurons project to the insular cortex and the nearby operculum, where the primary gustatory cortical areas are located (Figure 9–2). This pathway is thought to mediate the discriminative aspects of taste, which enable us to distinguish one quality from another. The insular cortex projects to several brain structures for further processing of taste stimuli. Projections to the orbitofrontal cortex (see Figure 9–11), as well as the insular and cingulate cortical areas, are thought to be integrated with olfactory information, for the awareness of flavors. In addition, these cortical areas may be important for the behavioral and affective significance of tastes, such as the pleasure experienced with a fine meal or the dissatisfaction after one poorly prepared. A component of the processing of painful stimuli also involves the limbic system cortex, and pain in humans is not without emotional significance.

Although taste and visceral afferent information (see Chapter 6) are distinct modalities and have separate central pathways, the two modalities interact. In fact, linking information about the taste of a food and its effect on body functions upon ingestion is key to an individual's survival. One of the most robust forms of learning, called conditioned taste aversion, associates the taste of spoiled food with the nausea that it causes when eaten. Another name for this learning is bait shyness, referring to a method used by ranchers to discourage predators from attacking their livestock. In this technique, ranchers contaminate livestock meat with an emetic, such as lithium chloride, which causes nausea and vomiting after ingestion. After eating the bait, the predator develops an aversion for the contaminated meat and will not attack the livestock. People can experience a phenomenon related to conditioned taste aversion, in which they develop an intense aversion to food they ate before becoming nauseated and vomiting, even if the food was not spoiled and the illness resulted from a viral infection. Experimental studies in rats have shown that such interactions between the gustatory and viscerosensory systems, leading to conditioned taste aversion, may occur in the insular cortex.

Regional Anatomy of the Gustatory System

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Branches of the Facial, Glossopharyngeal, and Vagus Nerves Innervate Different Parts of the Oral Cavity

Taste receptor cells are epithelial cells that transduce soluble chemical stimuli within the oral cavity into neural signals. They are present in complex microscopic sensory organs, called taste buds (Figure 9–3A). Taste receptor cells are short lived; they are regenerated approximately every 10 days. Taste receptor cells are responsive to a single taste quality. In addition to the taste receptor cells, taste buds contain two additional types of cells: basal cells, which are thought to be stem cells that differentiate to become receptor cells, and supporting cells, which provide structural and possibly trophic support (Figure 9–3A). Taste receptor cells have a synaptic contact with the distal processes of primary afferent fibers. A single afferent fiber terminal branches many times, both within a single taste bud and between different taste buds, so that it forms synapses with many taste cells. However, each sensory fiber will contact taste receptor cells that are responsive to a single taste modality.

FIGURE 9–3

Taste receptors (A) and tongue (B). Taste buds (A) consist of taste receptor cells, supporting cells, and basal cells. The colors show particular afferent nerve fibers innervating corresponding taste receptor cells. The three types of papillae—circumvallate, foliate, and fungiform—are shown in B. Taste buds in papillae are shown in light purple.

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Taste buds are present on the tongue, soft palate, epiglottis, pharynx, and larynx. Taste buds on the tongue are clustered on papillae (Figure 9–3B), whereas those at the other sites are located in pseudostratified columnar epithelium or stratified squamous epithelium rather than distinct papillae. Taste receptor cells that are located on the anterior two thirds of the tongue are innervated by the chorda tympani nerve, a branch of the facial (VII) nerve. (The facial nerve consists of two separate roots [Figure 9–4], a motor root commonly known as the facial nerve and a combined sensory and autonomic root called the intermediate nerve.)

FIGURE 9–4

Oropharynx and brain stem. Gustatory innervation of the oral cavity by the facial, glossopharyngeal, and vagus nerves. In the periphery the chorda tympani nerve (a branch of cranial nerve VII) supplies taste buds on the anterior two thirds of the tongue, the lingual branches of the glossopharyngeal (IX) nerve supply taste buds on the posterior third, and the superior laryngeal (X) nerve supplies taste buds on the epiglottis. The greater petrosal nerve (another branch of cranial nerve VII) supplies taste buds on the palate. The olfactory epithelium in the nasal cavity is also shown. Volatile molecules from the oral cavity waft into the nasal cavity during chewing to activate olfactory receptors by retronasal olfaction (arrow).

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Taste buds on the posterior third of the tongue, which are located primarily in the circumvallate and foliate papillae (Figure 9–3B), are innervated by the glossopharyngeal (IX) nerve (Figure 9–4). Taste buds on the palate are innervated by a branch of the intermediate nerve. Taste buds on the epiglottis and larynx are innervated by the vagus (X) nerve, whereas those on the pharynx are innervated by the glossopharyngeal nerve. The familiar taste map of the tongue—showing that sweet and salty are sensed in the front of the tongue, sour laterally, and bitter at the back of the tongue—is wrong. Taste buds in all regions are sensitive to the five basic taste attributes.

The cell bodies of the afferent fibers innervating taste cells are located in peripheral sensory ganglia. The cell bodies of afferent fibers in the intermediate branch of the facial nerve are found in the geniculate ganglion. Those of the vagus and glossopharyngeal nerves are located in their respective inferior ganglia. As discussed in Chapter 6, the glossopharyngeal and vagus nerves also contain afferent fibers that innervate cranial skin and mucous membranes; the cell bodies of these afferent fibers are found in the superior ganglia. The afferent fibers of the intermediate branch of the facial nerve enter the brain stem at the pontomedullary junction, immediately lateral to the root that contains somatic motor axons (Figure 9–4). The taste fibers of the glossopharyngeal and vagus nerves enter the brain stem in the rostral medulla.

The Solitary Nucleus Is the First Central Nervous System Relay for Taste

Gustatory fibers innervating the taste buds enter the brain stem and collect in the solitary tract, located in the dorsal medulla. The axons of the facial nerve enter the tract rostral to those of the glossopharyngeal and vagus nerves. After entering, however, the fibers send branches that ascend and descend within the tract, similar to the terminals of afferent fibers in Lissauer's tract of the spinal cord. The axon terminals leave the tract and synapse on neurons in the surrounding rostral solitary nucleus where second-order neurons (Figures 9–2, 9–5A, and 9–6B) project their axons into the ipsilateral central tegmental tract (Figures 9–5A and 9–6A) and ascend to the thalamus. The trigeminal and medial lemnisci, which carry the ascending somatic sensory projection from the main trigeminal and dorsal column nuclei, are ventral to the central tegmental tract (Figure 9–6A). Recall that the caudal solitary nucleus is important for visceral sensory function. It has a projection to the parabrachial nucleus, a pontine nucleus that is critical for relaying interoceptive information to the hypothalamus and amygdala for controlling various bodily functions, such as autonomic nervous system regulation. Brain stem centers that respond to tastants can be imaged using fMRI. The active region is the rostral pons, where the rostral solitary nucleus is located.

FIGURE 9–5

Brain stem and thalamic components of the gustatory system. A. Dorsal view of the brain stem, illustrating the rostral solitary nucleus receiving input from the taste buds (unilaterally) and the ascending projection of the rostral, or gustatory division, of the nucleus to the ipsilateral ventral posterior medial nucleus (parvocellular division). This path travels within the central tegmental tract. The caudal solitary nucleus is shown by the hatched lines. B. Coronal MRI, slicing the brain stem along its long axis, showing the approximate locations of the rostral solitary nuclei (blue).

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FIGURE 9–6

Myelin-stained transverse sections through the rostral pons (A) and medulla (B), with corresponding MRIs shown to the right. Note, the dorsal surfaces of both the sections and the MRIs are up. The locations of the structures indicated can only be approximated to the circled areas on the MRIs. Note that dorsal is up and ventral is down in the sections and images in this figure. The inset shows the planes of section.

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The Parvocellular Portion of the Ventral Posterior Medial Nucleus Relays Gustatory Information to the Insular Cortex and Operculum

Similar to somatic sensations, vision, and hearing, a thalamic relay nucleus receives taste information and projects this information to a circumscribed area of the cerebral cortex. The ascending projection from the rostral solitary nucleus terminates in the parvocellular division of the ventral posterior medial nucleus. This nucleus has a characteristic pale appearance on myelin-stained sections (Figure 9–7A). The axons of thalamocortical projection neurons in the thalamic gustatory nucleus project into the posterior limb of the internal capsule (Figure 9–7A, B) and ascend to the insular cortex and the nearby operculum (Figure 9–8B, C). These are the locations of the primary gustatory cortex. A PET scan of the human brain when sucrose is used as a tastant (Figure 9–8D) reveals activation in the insular and opercular regions. Different nuclei in the ventromedial thalamus receive different inputs and project to different cortical areas. Viscerosensory inputs are processed in adjacent but slightly separated thalamic regions and project to adjoining areas of the insular cortex. Touch and pain also engage different thalamic nuclei and nearby cortical areas in the postcentral gyrus and parietal operculum.

FIGURE 9–7

A. Myelin-stained coronal section through the thalamic taste nucleus, the parvocellular portion of the ventral posterior medial nucleus. The medial dorsal nucleus is also shown on this section; a portion of this nucleus may play a role in olfactory perception. B. MRI at a level close to that of the myelin-stained section in A. The inset shows the plane of section.

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FIGURE 9–8

Cortical taste areas (A) and structural and functional MRIs (B, C). Cortical gustatory areax. A. Lateral view of human cerebral hemisphere; the blue-tinted field on the insular cortex corresponds approximately to insular gustatory area. In addition, there is a region of the frontal operculum, shown on the MRI in B, that represents taste. The primary somatic sensory cortex is also highlighted. B. MRI through the frontal operculum. C. H₂¹⁵ O positron emission tomography scan shows bilateral areas of cortical activation in response to tasting a 5% sucrose solution. The color scale indicates that intensity of activation, measured as cerebral blood flow, which correlates with neural activity. White indicates maximal blood flow (or high neural activity), whereas blue indicates low blood flow (or activity). Note that two distinct taste areas are distinguished in the subject's right cortex (left side of image). The single zone on the other side is probably due to blurring of the PET signal. The planes of section are shown in A. (C, Courtesy of Dr. Stephen Trey, McGill University; Frey S, Petrides M. Re-examination of the human taste region: a positron emission tomography study. Eur J Neurosci. 1999;11:2985-2988.)

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The Olfactory System: Smell

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The sense of smell is mediated by the olfactory (I) nerve. There are two major differences between smell and the other sensory modalities, including taste. First, information about airborne chemicals impinging on the nasal mucosa is relayed directly to a part of the cerebral cortex without first relaying in the thalamus. The thalamic nucleus that processes olfactory information receives input from the cortical olfactory areas. Second, these cortical olfactory areas are phylogenetically older (allocortex) than the primary cortical regions (neocortex) that process other stimuli (see Chapter 16).

The Olfactory Projection to the Cerebral Cortex Does Not Relay Through the Thalamus

Primary olfactory neurons are found in the olfactory epithelium, a portion of the nasal cavity (Figure 9–9A). The primary olfactory neurons have a bipolar morphology (see Figure 6–3). The peripheral portion of the primary olfactory neuron is chemosensitive, and the central process is an unmyelinated axon that projects to the central nervous system. Recall that taste receptor cells, which transduce chemical stimuli on the tongue, and the primary taste fibers, which transmit information to the brain stem, are separate cells. Primary olfactory neurons are sensitive to airborne chemicals, or odorants; they have transmembrane olfactory receptors on their chemosensitive membranes in the olfactory epithelium. Each primary olfactory neuron has one type of olfactory receptor, which determines the spectrum of odorants to which the neuron is sensitive. Although most odorant molecules are carried into the olfactory epithelium with inhaled air, some travel from the oral cavity during chewing and swallowing.

FIGURE 9–9

Organization of the olfactory system. A. Olfactory epithelium (red shading) on the superior nasal concha. The nasal septum is not shown. The inset shows a cutaway view of the cribriform plate, through which the olfactory nerve fibers course, the olfactory epithelium, and olfactory bulb. B. Schematic of medial surface of cerebral hemisphere, illustrating the five main termination sites of olfactory tract fibers. C. Similar to B, but showing the main olfactory tract termination sites on the inferior brain surface.

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The unmyelinated axons of the primary olfactory neurons collect into numerous small fascicles, which together form the olfactory nerve. Olfactory nerve fascicles pass through foramina in a portion of the ethmoid bone termed the cribriform plate (Figure 9–9A) and synapse on second-order neurons in the olfactory bulb (Figures 9–9A, inset and 9–10). Head trauma can shear off these delicate fascicles as they traverse the bone, resulting in anosmia, the inability to.

FIGURE 9–10

Projection of primary olfactory sensory neurons to the olfactory bulb. A. The axons of olfactory bipolar cells synapse on the projection neurons of the olfactory bulb, the mitral cells and the tufted cells, as well as the periglomerular cells, a type of inhibitory interneuron. B. In situ hybridization of olfactory receptor mRNA in the axon terminals of primary olfactory sensory neurons in a single glomerulus in the olfactory bulb of the rat. The two bright spots on the ventral surface of the bulb (arrows) correspond to the two labeled glomeruli. (A, Reproduced with permission from Yoshihara Y. Basic principles and molecular mechanisms of olfactory axon pathfinding. Cell & Tissue Research. Oct:290(2):457-463, 1997. B, Courtesy of Dr. Robert Vassar, Columbia University; Vassar R, Chao SK, Sticheran R, Nuñez JM, Vosshall LB, Axel R. Topographic organization of sensory projections to the olfactory bulb. Cell. 1994;79:981-991.)

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Neurons that have a particular olfactory receptor are scattered randomly within a portion of the olfactory epithelium. The axons of these olfactory neurons all converge onto a glomerulus (Figure 9–9A, inset), which contains projection neurons and interneurons. The glomerulus is the basic processing unit of the olfactory bulb. The next link in the olfactory pathway is the projection of second-order neurons in the olfactory bulb through the olfactory tract, directly to the primitive allocortex (see Figure 16–16) on the ventral surface of the cerebral hemispheres. Five separate areas of the cerebral hemisphere receive a direct projection from the olfactory bulb (Figure 9–9B, C): (1) the anterior olfactory nucleus, which modulates information processing in the olfactory bulb, (2) the amygdala and (3) the olfactory tubercle, which together are thought to be important in the emotional, endocrine, and visceral consequences of odors, (4) the adjacent piriform cortex, which may be important for olfactory perception, and (5) the rostral entorhinal cortex, which is thought to be important in olfactory memories. Several higher-order projections arise from the primary areas. The projection from the piriform cortex to the orbitofrontal cortex is thought to be particularly critical for perception. Surprisingly, the medial dorsal nucleus of the thalamus receives olfactory information from the primary areas.

Animals, and likely humans, have additional olfactory organs in and around the nose that complement the principal olfactory organ that originates from the main portion of the olfactory epithelium, which was discussed earlier. One of these is the vomeronasal organ, which is discussed later. The various olfactory organs—together with the targets of their cortical projections—form a network that is the basis of olfactory discriminations, memory, emotions, and the diversity of olfactory-regulated behaviors, such as feeding and mating and sexual behaviors in animals. The trigeminal nerve also innervates the nasal mucosa and has a protective function. These trigeminal sensory fibers respond to the inhalation of noxious or irritating chemical stimuli and trigger protective reflexes, such as apnea or sneezing.

Regional Anatomy of the Olfactory System

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The Primary Olfactory Neurons Are Located in the Nasal Mucosa

Most of the lining of the nasal cavity is part of the respiratory epithelium, which warms and humidifies inspired air. The olfactory epithelium is a specialized portion of the nasal epithelial surface that contains the primary olfactory neurons. It is located on the superior nasal concha on each side as well as the midline septum and roof. Primary olfactory neurons, of which there are approximately several million, are short lived, similar to taste cells. Regenerated olfactory neurons also must regenerate their axon and form synaptic connections with their appropriate target neurons in the olfactory bulb. These bipolar sensory neurons have an apical portion with hairlike structures (olfactory cilia) that contain the molecular machinery for receiving chemical stimuli (Figure 9–10A). In addition to the olfactory neurons, the olfactory epithelium contains two other cell types: (1) glial-like supporting cells and (2) basal cells, which are stem cells that differentiate into primary olfactory neurons as the mature sensory neurons die.

The initial step in olfactory perception is the interaction of an odorant molecule with an olfactory receptor protein, a complex transmembrane protein located in the apical membrane of primary olfactory neurons. Olfactory receptor proteins are encoded by a large family of olfactory genes, which number up to approximately 1000 in many animals. Remarkably, individual primary olfactory sensory neurons each contain only one olfactory receptor protein type. How a neuron comes to express one particular olfactory receptor is not known. Olfactory sensory neurons that express the same receptor are scattered about within the olfactory epithelium. Olfactory receptors bind multiple odorants, indicating that individual primary olfactory neurons are sensitive to multiple odorants. Different odorants therefore appear to be initially processed by sensory neurons that are distributed widely and randomly throughout the olfactory epithelium. The scattering of olfactory receptor types within the olfactory epithelium is similar to the distribution of taste cells in the oral cavity. There are fewer olfactory receptor genes in primates, including humans. Despite having fewer olfactory genes, primates have a well-developed sense of smell. It is thought that the decline in olfactory genes is compensated by having larger and more complex brains.

Another component of the olfactory system, the vomeronasal organ, comprises a portion of the olfactory epithelium separate from the main olfactory epithelium (Figure 9–9). Whereas olfactory sensory neurons in the main olfactory epithelium can sense pheromones, in animals the vomeronasal organ is also important in detecting pheromones that have important effects on the individual animal's social and sexual behavior. Rather than project to the olfactory bulb, virtually all the neurons of the vomeronasal organ project to a different structure, the accessory olfactory bulb, which projects only to the amygdala. Whereas humans have a vomeronasal organ, whether it is a functioning olfactory sensing organ is in dispute.

The Olfactory Bulb Is the First Central Nervous System Relay for Olfactory Input

Primary olfactory neurons synapse on neurons in the olfactory bulb (Figure 9–10), which is actually a portion of the cerebral hemispheres. This is because the olfactory bulb develops as a small outpouching on the ventral surface of the telencephalon. The olfactory bulb has a very small, vestigial, ventricular space (see Figure 9–13B). Compared with rodents and carnivores, the olfactory bulb is reduced in size in monkeys, apes, and humans. Similar to most other components of the cerebral hemisphere, neurons in the olfactory bulb are organized into discrete laminae. Surprisingly, the olfactory bulb is the recipient of migrating neurons that are born in maturity within specialized regions of the wall of the lateral ventricle. These neurons migrate along the ventricular wall and into the bulb, where they become incorporated into local olfactory circuits (see Box 9–1).

Box 9–1 Adult Neurogenesis in the Olfactory Bulb

Surprisingly, neurons are continuously born, a process termed neurogenesis, and incorporated into local neural circuits in the mature mammalian brain. Whereas there is evidence for and against neurogenesis in multiple brain regions, including the cerebral neocortex, there is clear and well-documented evidence for adult neurogenesis in only two locations: a specialized region of the wall of the lateral ventricle, the subventricular zone (SVZ), and a portion of the hippocampal formation, the dentate gyrus. Neurogenesis in other brain regions is controversial.

Adult neurogenesis occurs anteriorly in the SVZ, just under the walls of the lateral ventricle, and posteriorly in the dentate gyrus of the hippocampal formation, in a region termed the subgranular zone (SGZ) (Figure 9–13A). Neurons born in the SVZ migrate a long distance farther anteriorly to reach the olfactory bulb. There, they become one of two classes of inhibitory interneuron: periglomerular cells and granule cells (Figures 9–10 and 9–13A). Neurons born in the posterior region migrate only a short distance to become granule cells within the dentate gyrus of the hippocampal formation. This will be discussed in Chapter 16. Here we focus on the SVZ and olfactory bulb.

Along the ventricular wall, embryonic stem cells divide to generate an intermediate cell type (termed transit amplifying cell) that, in turn, gives rise to neuroblasts, which are cells that develop into neurons (Figure 9–13A3). These adult-born neuroblasts migrate along a predefined path, termed the rostral migratory stream (RMS), to reach the olfactory bulb (Figure 9–13A). The rostral migratory stream has recently been described in the human brain (Figure 9–13C). The parasagittal myelin-stained section (C1) shows the general location of the rostral migratory stream (red line). On the Nissl-stained sagittal section (C2), a line of cells can be seen that can be stained for a protein that marks proliferating cells (C3), proliferating cell nuclear antigen (PCNA). It is estimated that about 100,000 cells comprise the RMS in the human brain. Once neuroblasts from the RMS arrive at the olfactory bulb, they migrate into their appropriate layers (Figure 9–13A1). Interestingly, animal studies reveal that only about 50% of the migrating neuroblasts that arrive at the olfactory bulb and mature to become neurons survive for more than a month. We think that there is a balance between potential benefits of adult-born neurons and the disadvantages to adding more cells to the brain; which, of course, is located within the confined cranial cavity.

Not surprisingly, the process of adult neurogenesis has a complex regulation. Intrinsic factors local to the sites of neurogenesis (A3) and migration (A2) are important, including neurotransmitters, guidance molecules, and signaling molecules. Extrinsic factors, such as the animal's physical activity level and environmental enrichments, are also important. Much ongoing research is aimed at determining the extent to which these adult-born neurons, which incorporate into the correct locations in the olfactory bulb, form functioning circuits and what role these neurons serve in olfaction. The minority of long-term surviving adult-born neurons is apt to be playing an important role, but exactly what that role is, is not yet understood. We do know that reduced neurogenesis in the olfactory bulb can impair discrimination and other olfactory-related behaviors. Why are we so fascinated by adult neurogenesis? In addition to the continued mystery of their function, further knowledge of adult neurogenesis may lead to devising cell-replacement therapies for such degenerative neurological disorders as Alzheimer and Parkinson disease.

The central processes of olfactory receptor cells synapse on three types of neurons in the olfactory bulb (Figure 9–10A): on mitral cells and tufted cells, which are the two projection neurons of the olfactory bulb, and on interneurons called periglomerular cells. The terminals of the olfactory receptor cells and the dendrites of mitral, tufted, and periglomerular cells form a morphological unit called the glomerulus (Figure 9–10). Within a glomerulus, certain presynaptic and postsynaptic elements are ensheathed by glial cells. This sheath ensures specificity of action, limiting the spread of neurotransmitter released by the presynaptic terminal. Whereas structures called glomeruli are located in other central nervous system locations, including the cerebellar cortex (see Chapter 13), those in the olfactory bulb are among the largest and most distinct.

Mitral and tufted cells are the projection neurons of the olfactory bulb. Their axons project from the olfactory bulb through the olfactory tract to the primary olfactory cortical areas (Figures 9–11 and 9–12). The granule cell (Figure 9–10A) is an inhibitory interneuron that receives excitatory synaptic input from mitral cells to which it feeds back inhibition. Another inhibitory interneuron in the olfactory bulb is the periglomerular cell, which receives a direct input from the primary olfactory neurons. This neuron inhibits mitral cells in the same and adjacent glomeruli. One function of these inhibitory interneurons is to make the neural responses to different odorants more distinct, thereby facilitating discrimination.

FIGURE 9–11

Ventral surface of the cerebral hemisphere showing regional anatomy and key olfactory areas. The parahippocampal gyrus contains numerous anatomical and functional divisions, two of which are the entorhinal cortex and piriform cortex. Allocortex is located medial to the collateral sulcus and rhinal fissure. The approximate location of the amygdala is indicated. The inset shows the location of the olfactory tubercle within the region of the anterior perforated substance (red). Primary olfactory regions of the temporal lobe and the medial orbital surfaces of the frontal lobe (bottom) are shown. The orbitofrontal cortex receives a projection from the primary olfactory areas, as well as the medial dorsal nucleus of the thalamus.

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FIGURE 9–12

Olfactory areas shown on myelin-stained coronal sections (A, C) and corresponding MRIs (B, D). The inset shows the approximate planes of section.

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A remarkable specificity exists in the projections of olfactory sensory neurons to the glomeruli. Even though primary olfactory neurons that contain a particular type of olfactory receptor are widely distributed throughout part of the olfactory epithelium, they project to one or a small number of glomeruli in the olfactory bulb (Figure 9–10B). Because there are up to about 1000 different olfactory receptor genes, and double the number of glomeruli on each side, researchers have suggested that each glomerulus may receive projections from olfactory sensory neurons that have a single type of receptor. This finding suggests that the neuronal processes within the glomerulus—the dendrites of mitral, tufted, and periglomerular cells—comprise a functional unit for processing a particular set of odorants.

The Olfactory Bulb Projects to Structures on the Ventral Brain Surface Through the Olfactory Tract

The olfactory bulb and tract lie in the olfactory sulcus on the ventral surface of the frontal lobe (Figure 9–11). The gyrus rectus (or straight gyrus) is located medial to the olfactory bulb and tract (Figure 9–11). As the olfactory tract approaches the region where it fuses with the cerebral hemispheres, it bifurcates into a prominent lateral olfactory stria and a small medial olfactory stria (Figure 9–11). The lateral olfactory stria contains the axons from the olfactory bulb, whereas the medial olfactory stria contains axons from other brain regions that are projecting to the olfactory bulb.

The anterior perforated substance is located caudal to the olfactory striae (Figure 9–11, inset). Tiny branches of the anterior cerebral artery perforate the ventral brain surface in this region. These branches provide the arterial supply for parts of the basal ganglia and internal capsule. The anterior perforated substance is gray matter (see below), whereas the olfactory striae are pathways on the brain surface. The olfactory tubercle, one of the gray matter regions to which the olfactory bulb projects, is located in the anterior perforated substance (Figure 9–11, inset). The tubercle and other parts of the anterior perforated substance are part of the basal forebrain. One nucleus of the basal forebrain is the basal nucleus of Meynert, which comprises neurons containing acetylcholine that project diffusely throughout the cortex and regulate cortical excitability (see Chapter 2; Figure 2–3A).

The Primary Olfactory Cortex Receives a Direct Input From the Olfactory Bulb

The projection neurons of the olfactory bulb (tufted and mitral cells) send their axons directly to five spatially disparate regions on the ventral and medial surfaces of the cerebral hemispheres. These areas are collectively termed the primary olfactory cortex (Figure 9–9B): (1) anterior olfactory nucleus, (2) amygdala, (3) olfactory tubercle, (4) piriform cortex, and (5) rostral entorhinal cortex.

Primary olfactory areas are allocortex

Most of the primary olfactory areas on the ventral and medial surfaces of the cerebral hemispheres (Figure 9–9B, C) have a cytoarchitecture that is characteristically different from the nonolfactory cortical regions located lateral to them. Recall that most of the cerebral cortex is neocortex, with at least six cell layers (see Chapter 2, Figure 2-19; also Figure 16–16). Somatic sensory, visual, auditory, and gustatory cortical areas are all part of the neocortex. In contrast, the olfactory cortex has fewer than six layers, termed allocortex (see Figure 16–16). With fewer layers, allocortex is more limited than neocortex in its processing capabilities. Allocortical areas also receive little direct input from the thalamus. There are two major kinds of allocortex: archicortex and paleocortex. Archicortex is located primarily in the hippocampal formation (see Chapter 16). Paleocortex is located on the basal surface of the cerebral hemispheres, in part of the insular cortex, and caudally along the parahippocampal gyrus and retrosplenial cortex (the area of cortex located caudal to the splenium of the corpus callosum; see Figure AI–4). In addition to archicortex and paleocortex, there are various forms of transitional cortex with characteristics of both neocortex and allocortex. On the ventral brain surface, allocortex and transitional cortex remain medial to the rhinal sulcus and its caudal extension, the collateral sulcus (Figure 9–11). The paleocortical olfactory areas each have three morphologically distinct layers. Axons of the olfactory tract course in the most superficial layer before synapsing on neurons in the deeper layers.

Neurons in the anterior olfactory nucleus modulate information transmission in the olfactory bulb bilaterally

The anterior olfactory nucleus is located caudal to the olfactory bulb, near where the olfactory tract fuses with the cerebral hemispheres (Figure 9–11A). It contains many neurons that use acetylcholine as their neurotransmitter. Neurons of the anterior olfactory nucleus are also scattered along the olfactory tract. Many neurons in this nucleus project their axons back to the olfactory bulb, both ipsilaterally and contralaterally. Because of these connections, the anterior olfactory nucleus is well positioned to regulate early olfactory processing. In Alzheimer disease, a progressive neurological degenerative disease in which individuals become severely demented, the anterior olfactory nucleus undergoes characteristic structural changes. Early in Alzheimer's patients, there is a loss of cholinergic neurons in the anterior olfactory nucleus, as well as another cholinergic cell group, the basal nucleus of Meynert. Interestingly, there is also a reduction in adult neurogenesis in Alzheimer's patients. Damage of the anterior olfactory nucleus, and possibly the reduction in neurogenesis, may underlie the impaired sense of smell in Alzheimer's patients.

Projections of the olfactory bulb to the amygdala and olfactory tubercle play a role in olfactory regulation of behavior

A major projection of the olfactory bulb is to the amygdala, a heterogeneous structure located in the anterior temporal lobe (Figures 9–11 and 9–12C, D). The amygdala has three major nuclear divisions: the corticomedial nuclear group, the basolateral nuclear group, and the central nucleus. The olfactory bulb projects to a portion of the corticomedial nuclear group (Figure 9–12C). This olfactory projection is thought to be important in behavior regulation rather than in odor perception and discrimination. For example, neurons in the corticomedial nuclear group are part of a circuit transmitting olfactory information to the hypothalamus (Figure 9–12C), for the regulation of food intake. Also, in certain animals the corticomedial nuclear group plays an essential role in the olfactory regulation of reproductive behaviors. The organization of the amygdala is considered in detail in Chapter 16.

The olfactory tubercle is a part of the basal forebrain located medial to the olfactory tract (Figure 9–12A). Compared with the amygdala, which receives a major olfactory projection in most animal species, the olfactory projections to the olfactory tubercle are fewer in number in primates. Neurons in the olfactory tubercle receive input from and project their axons to brain regions that play a role in emotions (see Chapter 16).

The olfactory areas of the temporal and frontal lobes may be important in olfactory perceptions and discriminations

The olfactory bulb also projects directly to the caudolateral frontal lobe and the rostromedial temporal lobe. These areas consist of the piriform cortex and the rostral entorhinal cortex (Figures 9–11 and 9–12). Receiving the largest projection from the olfactory bulb, the piriform cortex—named for its appearance in certain mammals, where the rostral temporal lobe is shaped like a pear (pirum is Latin for "pear")—is important in the initial processing of odors leading to perception. The piriform cortex projects directly, and indirectly via the medial dorsal nucleus (Figure 9–7), to the orbitofrontal cortex (Figure 9–13). When humans are engaged in olfactory discriminations, functional imaging studies indicate consistent activation within a consistent area near the intersection of the medial and transverse orbital sulci (Figure 9–13). Damage to the orbitofrontal cortex in humans and monkeys impairs olfactory discrimination.

FIGURE 9–13

Sites of adult neurogenesis in the rat brain (A, top) and corresponding regions in the human brain (B, bottom). In the rat brain, the site of neurogenesis is within the wall of the lateral ventricle (A3). Cells migrate anteriorly (A2) to become incorporated into olfactory bulb circuitry (A1). Neurogenesis in the human brain and the migratory path for neuroblasts from the subventricular zone to the olfactory bulb. B shows the olfactory bulb on T2-weighted MRI; the arrow points to a cavity within the olfactory bulb that is the extension of the lateral ventricle. C shows the path likely taken by newly born neurons in the human brain. The migration path is shown in C; C1 gives an overview of the migratory path (red line); C2 and C3, (expanded) show the region in a Nissl (C2) and are stained using a primary antibody to a marker of the newborn cells (proliferating cell nuclear antigen; PCNA). Adult neurogenesis is regulated by many local molecules, such as: the neurotransmitter GABA; guidance molecules and receptors, such as ephrin and Eph receptors; growth factors, such as bone morphogenic protein (BMP); and many other signaling molecules and proteins (eg, MCD24, E2F1, amyloid precursor protein [APP]). (B, C2, and C3, Reproduced with permission from Curtis MA, Kam M, Nannmark U, et al. Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science. 2007;315[5816]:1243-1249.)

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The rostral entorhinal cortex is located on the parahippocampal gyrus (Figure 9–13). This area is thought to be important in allowing a particular smell to evoke memories of a place or event. This cortex projects to the hippocampal formation, which has been shown to be essential for consolidation of short-term memories into long-term memories (see Chapter 16).

Olfactory and Gustatory Information Interacts in the Insular and Orbitofrontal Cortex for Sensing Flavors

Perception of the flavor of foods and beverages we ingest not only reflects the combined sensing of the five primary taste qualities, but depends on our sense of smell; without smell, flavors become flat. Smell is actively integrated with tastes to achieve our sense of flavors. Human brain imaging studies show, not surprisingly, odors alone activate the olfactory cortical areas in the temporal and orbitofrontal cortical regions. And tastes alone activate the primary taste cortical areas in the insular and opercular regions. Interestingly, combined presentation of odorants and tastants coactivated many of these regions as well as activated new, neighboring, regions. This shows how our brain is exquisitely sensitive to combinations of chemical stimuli necessary for flavor perception.

Physical interactions between odorants and tastants occur largely through an unexpected route. As shown in Figure 9–4, the oropharynx communicates with the nasal cavity. Volatile molecules during chewing and swallowing can activate olfactory sensory neurons in the olfactory epithelium through retronasal olfaction (Figure 9–4, arrow), as opposed to orthonasal olfaction where molecules travel from the external environment through the nostrils (nares). Retronasal olfaction, when studied in the laboratory, is sensed as taste, whereas orthonasal olfaction is sensed as a smell originating in the external environment. Imaging studies have revealed different patterns of brain activation dependent on the route a molecule takes to reach the olfactory epithelium. When the same molecule, such as a component of chocolate, is delivered via the ortho- and retronasal routes, a different pattern of activated brain regions occurs. Interestingly, one difference is that the retronasal route leads to activation of the tongue area of the primary somatic sensory cortex activation. This further emphasizes how sensing the flavor of what we ingest is a multisensory experience, with intraoral texture and temperature also playing an important role.

Summary

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The Gustatory System

Sensory Receptors and Peripheral Nerves

Gustatory receptors are clustered in taste buds (Figure 9–3), which are located on the tongue, palate, pharynx, larynx, and epiglottis (Figure 9–4). The facial (VII) nerve innervates taste buds on the anterior two thirds of the tongue and the palate; the glossopharyngeal (IX) nerve innervates taste buds on the posterior one third of the tongue and pharynx; and the vagus (X) nerve innervates taste buds on the epiglottis and larynx (Figure 9–4).

Brain Stem, Thalamus, and Cerebral Cortex

Afferent fibers of the three cranial nerves serving taste enter the solitary tract and terminate principally in the rostral portion of the solitary nucleus (Figures 9–2, 9–5, and 9–6B). Projection neurons from the solitary nucleus ascend ipsilaterally, in the central tegmental tract (Figures 9–5 and 9–6A), to the parvocellular portion of the ventral posterior medial nucleus (Figure 9–7). The cortical areas to which the thalamic neurons project are located in the insular cortex and nearby operculum (Figure 9–8). These areas are separate from the representation of tactile sensation on the tongue.

The Olfactory System

Receptors and Olfactory Nerve

Primary olfactory neurons, located in the olfactory epithelium, are bipolar neurons (Figures 9–9 and 9–10). The distal process is sensitive to chemical stimuli, and the central process projects to the olfactory bulb (Figures 9–9C and 9–10) as the olfactory (I) nerve. The olfactory nerve is formed by multiple small fascicles of axons of primary olfactory neurons that pass through foramina in a portion of the ethmoid bone termed the cribriform plate (Figure 9–9). There are about 1000 olfactory receptors, but an individual olfactory neuron contains one type of receptor. The olfactory receptor type determines the odorants to which the neuron is sensitive.

Cerebral Cortex

Olfactory nerve fibers synapse on neurons in the glomeruli of the olfactory bulb (Figure 9–10). Primary olfactory neurons with a particular olfactory receptor send their axons to one or just a few glomeruli (Figure 9–10). Projection neurons in glomeruli send their axons, via the olfactory tract, to five regions of the cerebral hemisphere (Figures 9–11 and 9–12): (1) the anterior olfactory nucleus, (2) the olfactory tubercle (a portion of the anterior perforated substance), (3) the amygdala, (4) the piriform and periamygdaloid cortical areas, and (5) the rostral entorhinal cortex. The piriform cortex projects, via the medial dorsal nucleus (Figure 9–7), to the orbitofrontal cortex (Figure 9–11), which is thought to be important in olfactory discrimination.

Selected Reading

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Buck LB, Bargmann C. Smell and taste: the chemical senses. In: Kandel ER, Schwartz JH, Jessell TM, Siegelbaum SA, Hudspeth AJ, eds. Principles of Neural Science. 5th ed. New York, NY: McGraw-Hill; in press.

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FIGURE 9–1

The Ascending Gustatory Pathway Projects to the Ipsilateral Insular Cortex

FIGURE 9–2

Branches of the Facial, Glossopharyngeal, and Vagus Nerves Innervate Different Parts of the Oral Cavity

FIGURE 9–3

FIGURE 9–4

The Solitary Nucleus Is the First Central Nervous System Relay for Taste

FIGURE 9–5

FIGURE 9–6

The Parvocellular Portion of the Ventral Posterior Medial Nucleus Relays Gustatory Information to the Insular Cortex and Operculum

FIGURE 9–7

FIGURE 9–8

The Olfactory Projection to the Cerebral Cortex Does Not Relay Through the Thalamus

FIGURE 9–9

FIGURE 9–10

The Primary Olfactory Neurons Are Located in the Nasal Mucosa

The Olfactory Bulb Is the First Central Nervous System Relay for Olfactory Input

FIGURE 9–11

FIGURE 9–12

The Olfactory Bulb Projects to Structures on the Ventral Brain Surface Through the Olfactory Tract

The Primary Olfactory Cortex Receives a Direct Input From the Olfactory Bulb

Primary olfactory areas are allocortex

Neurons in the anterior olfactory nucleus modulate information transmission in the olfactory bulb bilaterally

Projections of the olfactory bulb to the amygdala and olfactory tubercle play a role in olfactory regulation of behavior

The olfactory areas of the temporal and frontal lobes may be important in olfactory perceptions and discriminations

FIGURE 9–13

Olfactory and Gustatory Information Interacts in the Insular and Orbitofrontal Cortex for Sensing Flavors

The Gustatory System

Sensory Receptors and Peripheral Nerves

Brain Stem, Thalamus, and Cerebral Cortex

The Olfactory System

Receptors and Olfactory Nerve

Cerebral Cortex

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