The olfactory system consists of the olfactory epithelium, olfactory nerves, olfactory bulbs, and olfactory tracts, together with functionally associated cerebral cortex and subcortical structures. The parts of the brain that process olfactory signals are sometimes collectively called the rhinencephalon.
Olfaction is a significant sense that conjures up memories and arouses emotions. Smell also contributes to alimentary pleasures. Those who have lost their sense of smell complain of impairment of taste, stating that everything is bland and tastes alike, and they may be unaware of their inability to smell. Much of our enjoyment of taste is, in fact, an appreciation of aromas through the olfactory system. Some chemical stimuli, notably those from foods with “hot” flavors, excite general sensory fibers of the trigeminal nerve in the nose and mouth. The olfactory, gustatory, and general sensory responses to chemical stimuli in the nose may be integrated in the insula, where the primary cortical areas for the three systems are in proximity.
Olfactory Epithelium and Olfactory Nerves
The olfactory epithelium is derived from an ectodermal thickening, the olfactory placode, at the rostral end of the embryonic head. The cells of this placode give rise to the cells of the epithelium, the glial cells of the olfactory nerves, and some of the glial cells of the most superficial layer of the olfactory bulb. In adults, the olfactory epithelium (Fig. 17-1) covers an area of 2.5 cm2 in the roof of each nasal cavity and extends for a short distance on the lateral wall of the cavity and the nasal septum. The olfactory sensory cells are contained in a pseudostratified columnar epithelium, which is thicker than that lining the respiratory passages elsewhere. Olfactory glands (Bowman's glands)
beneath the epithelium bathe the surface with a layer of mucous fluid, in which odoriferous substances dissolve. The olfactory neurosensory cells (also known as primary olfactory neurons or simply as olfactory cells) are bipolar neurons that serve as sensory receptors as well as conductors of impulses. The major modification consists of specialization of the dendrite; this process extends to the surface of the epithelium, where it ends as an exposed bulbous enlargement known as an olfactory vesicle, bearing unusually long (≤100 µm) cilia.
FIGURE 17-1 Olfactory epithelium.
Unmyelinated axons of the olfactory cells are gathered into about 20 bundles on each side, which are the olfactory nerves. These enter the cranial cavity by passing through the foramina of the cribriform plate of the ethmoid bone and then enter the olfactory bulb. The axons form a superficial fibrous layer in the olfactory bulb; continue more deeply; and terminate in specialized synaptic configurations, the glomeruli. The olfactory axon terminals release an excitatory neurotransmitter; in rodents, it is glutamate.
The few neurosensory cells shown in Figure 17-1 represent approximately 25 million of such cells in the olfactory epithelium of each side of the nose. The olfactory cells are continuously produced by mitosis and differentiation of some of the basal cells of the olfactory epithelium, and the cells are lost by desquamation. Observations in animals indicate that olfactory neurons probably are lost by wear and tear rather than because of an innately short life span. In healthy human noses, each receptor neuron probably survives for about 3 months. Consequently, new axons are always growing along the olfactory nerves and into the olfactory bulbs.
The olfactory system is exquisitely sensitive to minute amounts of excitants in the air. Direct stimulation of the receptors, convergence of many neurosensory cells on the principal neurons of the olfactory bulb, and facilitation by neuronal circuits in the bulb are among the factors responsible for the low threshold. Smell is a chemical sense, as is taste. For a substance to be smelled, it must enter the nasal cavity as a gas or as an aerosol and then dissolve in the fluid that covers the olfactory epithelium. The secretory product of Bowman's glands contains
glycoproteins that can bind odoriferous substances that are not otherwise soluble in water for presentation to receptor molecules on the surfaces of the sensory cilia.
A large range of odors can be appreciated because of the existence of approximately 3,000 different receptor proteins, each with a different chemical specificity, embedded in the surface membranes of the cilia of the olfactory neurosensory cells. Combination of an odorant with its specific receptor initiates changes that tend to depolarize the cell membrane. Individual olfactory neurons have receptors for several odorants but in different combinations, and the olfactory epithelium is a mosaic of overlapping sets of neurons whose activities encode different odors. Experiments with animals reveal that the projection from the epithelium to the olfactory bulb is topographically organized, with the specific sites of termination of the axons of neurons that possess particular combinations of odorant receptor molecules. This mode of organization is comparable to the topographic distribution of neuronal circuitry in the other sensory systems.
The olfactory system adapts rather quickly to continuous stimuli, so that the odor becomes unnoticed. The mechanisms of adaptation involve the receptor cells themselves and neuronal circuitry in the olfactory bulb. A physiological mechanism that allows the receptors to recover from continuous exposure to odors is a cyclic alternation of mucosal blood flow in the left and right sides of the nose. At any instant, the side with the higher flow of blood presents greater resistance to the flow of air because of swelling of the mucosa. The nasal cavity with lower air flow consequently receives smaller amounts of the ambient odorants. Most older people have a reduced acuity of smell, caused by a progressive reduction (about 10% per decade between 30 and 90 years of age) in the populations of olfactory neurosensory cells and of neurons in the olfactory bulb.
FIGURE 17-2 Neuronal circuitry of the olfactory bulb. Principal cells are red, interneurons are black, and afferents to the olfactory bulb are blue.
Olfactory Bulb, Tract, and Striae
The olfactory bulb is ventral to the orbital surface of the frontal lobe. It is connected by the olfactory tract to a central point of attachment in front of the anterior perforated substance. The bulb contains two types of glutamatergic principal cells (mitral and tufted cells) and at least two types of interneurons (Fig. 17-2). The five layers are irregular and indistinct in the adult human olfactory bulb, although they are obvious in the fetal stages of development. The nerve fiber layer is of interest because it continuously
admits newly growing axons from the olfactory nerves into the central nervous system (CNS). A mixture of neuroglial cells (i.e., astrocytes from the neural tube and olfactory ensheathing cells of placodal origin that surround bundles of primary olfactory axons) may account for this unique circumstance of axonal growth into the adult mammalian CNS. Olfactory ensheathing cells encourage axonal growth not only in the olfactory nerves and bulb but also in laboratory animals after transplantation to sites of injury elsewhere in the CNS, including the spinal cord.
Deep to the nerve fiber layer, the 25 million axons of the olfactory receptors terminate in some 8,000 spherical masses of neuropil known as glomeruli. Each glomerulus receives many afferent axons, which synapse with dendrites of about 5 of the 40,000 principal cells. The activity of the principal cells is modified by the predominantly inhibitory (dopaminergic and γ-aminobutyrate-ergic) interneurons of the olfactory bulb, especially the extremely numerous granule cells. The complex circuitry (see Fig. 17-2) is believed to be largely responsible for identifying different odors.
Three small groups of neurons make up the anterior olfactory nucleus. One is situated at the transition between the olfactory bulb and olfactory tract; the others are deep to the lateral and medial olfactory striae described in the next paragraph. Collateral branches of axons of mitral and tufted cells terminate in this nucleus. Fibers that originate in the anterior olfactory nucleus pass through the anterior commissure to the contralateral olfactory bulb. This is only one of the populations of centrifugal fibers that project to the olfactory bulb. Centrifugal fibers synapse principally with the dendrites of the interneurons. This arrangement probably sets the sensitivity or indifference of the olfactory system to specific odors.
The principal cells of the olfactory bulb have axons that pass through the olfactory tract and end as excitatory (glutamatergic) presynaptic terminals in primary olfactory areas for subjective appreciation of smells. The primary olfactory areas establish connections with other parts of the brain for emotional and visceral responses to olfactory stimuli. The olfactory tract expands into the olfactory trigone at the rostral margin of the anterior perforated substance. Most of the axons of the tract pass into the lateral olfactory stria (Fig. 17-3), which passes to the lateral olfactory area. Other axons of the olfactory tract leave the olfactory trigone to enter the anterior perforated substance. The name medial olfactory stria was applied to a ridge once thought to carry olfactory fibers to the septal area. It is now known that no such connection exists.
Olfactory Areas of the Cerebral Hemisphere
The “nose brain” was once thought to include more parts of the forebrain than those currently believed to be devoted to the sense of smell. The term is now restricted to the regions that receive afferent fibers from the olfactory bulbs. The primary olfactory area, believed to be the region for conscious awareness of olfactory stimuli, receives afferents through the lateral olfactory stria (Fig. 17-4; see also Fig. 17-3). The area consists of the paleocortex (see Chapter 14) of the uncus (periamygdaloid cortex) together with adjacent parts of the entorhinal area, in the anterior part of the parahippocampal gyrus, and the limen insulae (Fig. 17-3). The uncus, entorhinal area, and limen insulae are collectively known as thepyriform cortex (or lobe) because the homologous area has a pear-shaped outline in some animals. Part of the amygdaloid body (amygdala) is also included in the lateral olfactory area; the uncus is its landmark on the medial surface of the temporal lobe. The dorsomedial part of the amygdala, consisting of the corticomedial group of nuclei, receives olfactory fibers. The larger ventrolateral portion, a component of the limbic system, is considered in Chapter 18. The lateral olfactory area, believed to be the principal region for conscious awareness of olfactory stimuli, is also called the primary olfactory area.
Axons of the olfactory tract also connect with neurons in the anterior perforated substance. In the human brain, this region blends into the ventral pallidum and the nucleus accumbens of the striatum (see Chapter 12).
Neuroanatomical tracing experiments in non-human primates and functional imaging studies
in humans indicate that the lateral part of the orbital surface of the frontal lobe is the olfactory association cortex, receiving afferents from the primary olfactory area. Positron emission tomography (PET) studies of the human brain show increased blood flow in the right orbitofrontal cortex when olfactory stimuli are presented to both sides of the nose. The orbital cortex is otherwise better known for its essential roles in foresight, decision making, and social interactions with other people (see Chapter 15). Subtle ipsilateral impairment of odor identification occurs after surgical removal of parts of the temporal lobe that are not otherwise known to be connected with the olfactory system. The olfactory association cortex may prove to extend beyond the currently recognized areas.
FIGURE 17-3 Some components of the olfactory system seen on the ventral surface of the brain. The right temporal pole has been cut away to give a clear view of the olfactory trigone, anterior perforated substance, and limen insulae.
Another group of neurons in the anterior perforated substance, the nucleus of the diagonal band, is a major source of centrifugal fibers to the olfactory bulb; the other source is the contralateral anterior olfactory nucleus.
Olfactory stimuli induce visceral responses by modulating the activities of the autonomic nervous system. Examples are salivation when pleasing aromas from the preparation of food are present and nausea or even vomiting evoked by an offensive stench. The olfactory system shares the entorhinal cortex with the limbic system, and the limbic system has extensive connections with the septal area and the hypothalamus. Most of the fibers that connect the septal area and hypothalamus with autonomic nuclei are situated in the medial forebrain bundle. This bundle, which
contains fibers projecting rostrally as well as caudally, traverses the lateral part of the hypothalamus. Descending fibers from the hypothalamus proceed to autonomic nuclei in the brain stem and spinal cord. Other descending fibers of the medial forebrain bundle end in raphe reticular nuclei and in the solitary nucleus.
FIGURE 17-4 Components of the olfactory tract.
Deterioration of the sense of smell often occurs with normal aging. It can also be an early symptom of degenerative disorders, including Parkinson's (Chapter 7) and Alzheimer's diseases (Chapter 12). The olfactory deficit is associated with neuronal loss in the corticomedial nuclei of the amygdala.
Fractures of the floor of the anterior fossa of the skull often involve the cribriform plate of the ethmoid bone, damaging the olfactory nerves and causing anosmia. The same injury may result in leakage of cerebrospinal fluid (CSF) from the subarachnoid space into the nasal cavity, so that the fluid runs from the nose (CSF rhinorrhea). This abnormal communication with the external environment is dangerous because it provides a route whereby bacteria may enter and attack the meninges and the brain.
A tumor, usually a meningioma, in the floor of the anterior cranial fossa may interfere with the sense of smell because of pressure on the olfactory bulb or olfactory tract. It is necessary to test each nostril separately because the olfactory loss is likely to be unilateral.
An irritating lesion that affects the lateral olfactory area may cause uncinate fits, characterized by an imaginary disagreeable odor, by involuntary movements of the lips and tongue, and often by other features of disturbed function of the temporal lobe (see Chapter 18). Ipsilateral olfactory impairment follows destructive lesions of the temporal lobe but is detectable only by careful testing. Such impairment can occur even when the damage is outside the recognized olfactory areas.
Terminal and Vomeronasal Nerves
Two small cranial nerves associated with the olfactory system were discovered after the 12 main cranial nerves were given their numbers. The terminal nerve (nervus terminalis) is present,
although of microscopic size, in the adult human brain. Sometimes it is called cranial nerve zero because it is located medially (and therefore perhaps rostrally) to the olfactory nerves. The terminal nerve is mentioned in Chapter 11 as the conduit through which certain neurons migrate from the olfactory placode into the preoptic area and hypothalamus.
The vomeronasal system appears only transiently in human embryonic development, but in most other terrestrial vertebrates, it has important functions in adult life.
The fibers of the tiny terminal nerve lie along the medial side of the olfactory bulb and olfactory tract. Bipolar neuronal cell bodies are present in small ganglia along the course of the nerve. Their distal processes pass through the cribriform plate and are distributed to the nasal septum. In animals, the proximal processes have been traced experimentally to the septal and preoptic areas.
The vomeronasal nerve is part of an accessory olfactory system present in most terrestrial vertebrate animals other than humans. It is used for detection of pheromones that serve for sexual attraction and territorial marking. The human vomeronasal receptor organ and nerve are present only from the 8th to the 14th weeks of intrauterine life.
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