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.
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.
Olfactory areas shown on myelin-stained coronal sections (A, C) and corresponding MRIs (B, D). The inset shows the approximate planes of section.
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.
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;315:1243-1249.)
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.