**2. The olfactory system**

The main role of the olfactory system is the detection of odors. This function is critical for food selection by detecting olfactory and gustatory signals. Moreover, our sense of smell plays a role in reproductive and neuroendocrine regulation and is relevant for memory, aggression, emotion, social organization, and recognition of prey and predators [1]. Social chemical stimuli or semiochemical signals are processed by the olfactory system in most mammals. These chemicals differ from general odorants and mediate physiological aspects of mating and aggression. These chemical signals are processed in the accessory olfactory bulb in the brain which is part of the vomeronasal system [1].

The olfactory pathway starts deep in the nasal cavity with an olfactory epithelium that sits on the superior conchae (**Figure 1**). This pseudostratified ciliated columnar epithelium houses olfactory sensory neurons, supporting cells (sustentacular cells), and basal stem cells. In addition, Bowman's glands located in the connective tissue under the epithelium (lamina propria) send ducts to the surface of the epithelium and secrete a serous fluid that immerses the cilia of olfactory receptor neurons in a mucous layer to trap odorant molecules. Odorant molecules bind to olfactory receptor proteins in the cilia of olfactory sensory neuron dendrites. The number of cilia that emerges from the dendrite of an olfactory sensory neuron is relatively small, 20 to 30, compared to the ciliated cells that are found in the respiratory epithelium (~300 cilia). Air-borne odorant molecules in the air that we breathe in activate the olfactory receptor proteins in the olfactory cilia. Odorant molecules can find their way to the olfactory sensory neurons either through the

#### **Figure 1.**

*Schematic representation of olfactory pathways. Olfactory sensory neurons in the olfactory epithelium of the nasal cavity send their axons to form synapses with secondary sensory neurons in the olfactory bulb. A small number of neurons from the olfactory bulb participate in olfactory processing as they exchange information with both limbic system components and cortical structures.*

**99**

*Neurological and Neuropsychiatric Disorders in Relation to Olfactory Dysfunction*

nose (orthonasal stimulation) or from the mouth to the nose (retronasal stimulation) [2]. Often this retronasal olfactory stimulation is confused with taste, which takes place in taste buds in the tongue and soft palate of the oral cavity. However, food odors and the consistency of the food ('crunchiness') together with tastants contribute to the flavor or aroma of food. The membrane of olfactory sensory neuron cilia houses odorant receptor proteins and thereby activates these neurons in the nasal epithelium. The olfactory receptor proteins form a large gene family (1000 genes in rodents, 350 in humans, [3, 4]). Each olfactory sensory neuron sends an axon through the cribriform plate of the ethmoid bone to the ipsilateral main olfactory bulb in the brain (**Figure 1**). The axons of olfactory sensory neurons coalesce to form the olfactory nerve (cranial nerve I) and olfactory nerve layer of

The main olfactory bulb is a cortical structure of the cerebrum. However, the main olfactory bulb is not part of the neocortex but part of the allocortex as shown by its fetal development and cytoarchitecture. Neocortical structures undergo a prenatal phase that results in six layers, whereas allocortical structures have three or four layers in the mature brain [5]. While the main olfactory bulb presents itself as a small extension of the brain in humans, in rodents, the main olfactory bulb is a large structure that fills roughly a quarter of the length of the cranial cavity [6] and

Several million sensory neurons are present in the olfactory epithelium. A given olfactory receptor protein is expressed by several thousand of them. The olfactory sensory neurons that express the same olfactory receptor protein send their axon to the same one or two glomeruli in the main olfactory bulb to form synaptic contacts (**Figure 1**). The dendrites of interneurons (juxtaglomerular cells) and output neurons (mitral and tufted neurons) in the olfactory bulb synapse with olfactory sensory neurons. Compared to the large number of olfactory sensory neurons, only relatively few output neurons innervate each glomerulus. These output neurons send their axons to higher order brain centers for brain processing of olfactory signals [8]. The precise sending of olfactory sensory neuron axons to specific glomeruli is critical for the discrimination of odorants [2]. The axons of output neurons leave the main olfactory bulb through the lateral olfactory tract and terminate in various higher order olfactory centers such as the anterior olfactory nucleus (AON), piriform cortex, the anterior parahippocampal cortex (entorhinal cortex), and the cortico-medial amygdala, all of which belong to limbic system (**Figure 1**) and are on the ipsilateral brain side. In contrast to other sensory modalities, the olfactory pathway routes sensory information directly from the olfactory bulb to cortical

The amygdala is a collection of nuclei in the limbic system [9]. The basolateral nucleus is the largest one and receives input from sensory cortices (vision, hearing) as well as direct auditory signals through a subcortical structure, the medial geniculate nucleus which is part of the thalamus. The olfactory bulb and piriform cortex send sensory information to the cortical and medial nuclei of the amygdala, the cortico-medial nucleus [10, 11]. In addition, the amygdala receives input from other cortical and subcortical brain systems, such as the prefrontal cortex with the anterior cingulate and orbitofrontal cortices. In turn, both piriform cortex and amygdala project to the orbitofrontal cortex to regulate emotion and associative learning. The amygdala is also connected with the entorhinal and hippocampal system for long-term memory [12]. Furthermore, the amygdala is a target for fibers from the hippocampus and rhinal (olfactory) cortices [10, 11]. Functionally, it has been established that odors have the ability to evoke strong emotions and trigger the recall

is dedicated to the processing of odorant information [1, 2, 7].

centers and bypasses the thalamus [1, 2].

of emotional memories and modulate cognition [11].

*DOI: http://dx.doi.org/10.5772/intechopen.93888*

the main olfactory bulb.

#### *Neurological and Neuropsychiatric Disorders in Relation to Olfactory Dysfunction DOI: http://dx.doi.org/10.5772/intechopen.93888*

nose (orthonasal stimulation) or from the mouth to the nose (retronasal stimulation) [2]. Often this retronasal olfactory stimulation is confused with taste, which takes place in taste buds in the tongue and soft palate of the oral cavity. However, food odors and the consistency of the food ('crunchiness') together with tastants contribute to the flavor or aroma of food. The membrane of olfactory sensory neuron cilia houses odorant receptor proteins and thereby activates these neurons in the nasal epithelium. The olfactory receptor proteins form a large gene family (1000 genes in rodents, 350 in humans, [3, 4]). Each olfactory sensory neuron sends an axon through the cribriform plate of the ethmoid bone to the ipsilateral main olfactory bulb in the brain (**Figure 1**). The axons of olfactory sensory neurons coalesce to form the olfactory nerve (cranial nerve I) and olfactory nerve layer of the main olfactory bulb.

The main olfactory bulb is a cortical structure of the cerebrum. However, the main olfactory bulb is not part of the neocortex but part of the allocortex as shown by its fetal development and cytoarchitecture. Neocortical structures undergo a prenatal phase that results in six layers, whereas allocortical structures have three or four layers in the mature brain [5]. While the main olfactory bulb presents itself as a small extension of the brain in humans, in rodents, the main olfactory bulb is a large structure that fills roughly a quarter of the length of the cranial cavity [6] and is dedicated to the processing of odorant information [1, 2, 7].

Several million sensory neurons are present in the olfactory epithelium. A given olfactory receptor protein is expressed by several thousand of them. The olfactory sensory neurons that express the same olfactory receptor protein send their axon to the same one or two glomeruli in the main olfactory bulb to form synaptic contacts (**Figure 1**). The dendrites of interneurons (juxtaglomerular cells) and output neurons (mitral and tufted neurons) in the olfactory bulb synapse with olfactory sensory neurons. Compared to the large number of olfactory sensory neurons, only relatively few output neurons innervate each glomerulus. These output neurons send their axons to higher order brain centers for brain processing of olfactory signals [8]. The precise sending of olfactory sensory neuron axons to specific glomeruli is critical for the discrimination of odorants [2]. The axons of output neurons leave the main olfactory bulb through the lateral olfactory tract and terminate in various higher order olfactory centers such as the anterior olfactory nucleus (AON), piriform cortex, the anterior parahippocampal cortex (entorhinal cortex), and the cortico-medial amygdala, all of which belong to limbic system (**Figure 1**) and are on the ipsilateral brain side. In contrast to other sensory modalities, the olfactory pathway routes sensory information directly from the olfactory bulb to cortical centers and bypasses the thalamus [1, 2].

The amygdala is a collection of nuclei in the limbic system [9]. The basolateral nucleus is the largest one and receives input from sensory cortices (vision, hearing) as well as direct auditory signals through a subcortical structure, the medial geniculate nucleus which is part of the thalamus. The olfactory bulb and piriform cortex send sensory information to the cortical and medial nuclei of the amygdala, the cortico-medial nucleus [10, 11]. In addition, the amygdala receives input from other cortical and subcortical brain systems, such as the prefrontal cortex with the anterior cingulate and orbitofrontal cortices. In turn, both piriform cortex and amygdala project to the orbitofrontal cortex to regulate emotion and associative learning. The amygdala is also connected with the entorhinal and hippocampal system for long-term memory [12]. Furthermore, the amygdala is a target for fibers from the hippocampus and rhinal (olfactory) cortices [10, 11]. Functionally, it has been established that odors have the ability to evoke strong emotions and trigger the recall of emotional memories and modulate cognition [11].

*Sino-Nasal and Olfactory System Disorders*

part of the vomeronasal system [1].

The main role of the olfactory system is the detection of odors. This function is critical for food selection by detecting olfactory and gustatory signals. Moreover, our sense of smell plays a role in reproductive and neuroendocrine regulation and is relevant for memory, aggression, emotion, social organization, and recognition of prey and predators [1]. Social chemical stimuli or semiochemical signals are processed by the olfactory system in most mammals. These chemicals differ from general odorants and mediate physiological aspects of mating and aggression. These chemical signals are processed in the accessory olfactory bulb in the brain which is

The olfactory pathway starts deep in the nasal cavity with an olfactory epithelium that sits on the superior conchae (**Figure 1**). This pseudostratified ciliated columnar epithelium houses olfactory sensory neurons, supporting cells (sustentacular cells), and basal stem cells. In addition, Bowman's glands located in the connective tissue under the epithelium (lamina propria) send ducts to the surface of the epithelium and secrete a serous fluid that immerses the cilia of olfactory receptor neurons in a mucous layer to trap odorant molecules. Odorant molecules bind to olfactory receptor proteins in the cilia of olfactory sensory neuron dendrites. The number of cilia that emerges from the dendrite of an olfactory sensory neuron is relatively small, 20 to 30, compared to the ciliated cells that are found in the respiratory epithelium (~300 cilia). Air-borne odorant molecules in the air that we breathe in activate the olfactory receptor proteins in the olfactory cilia. Odorant molecules can find their way to the olfactory sensory neurons either through the

*Schematic representation of olfactory pathways. Olfactory sensory neurons in the olfactory epithelium of the nasal cavity send their axons to form synapses with secondary sensory neurons in the olfactory bulb. A small number of neurons from the olfactory bulb participate in olfactory processing as they exchange information* 

*with both limbic system components and cortical structures.*

**2. The olfactory system**

**98**

**Figure 1.**

Not only does the olfactory bulb send axons to higher order olfactory centers (afferent fibers), an even larger number of centrifugal axons originating in higher olfactory centers innervate the olfactory bulb glomeruli (efferent fibers) [6, 13, 14]. These centrifugal neurons have been shown to provide modulatory feedback to neurons in the different layers of the main olfactory bulb which is important for experiencedependent modulation [13]. The origin of the centrifugal fibers is in the locus coeruleus (noradrenergic), the horizontal limb of the diagonal band of Broca (cholinergic), and the raphe nucleus (serotonergic) [15–18]. The centrifugal fibers travel mainly through the anterior olfactory nucleus and the anterior commissure, and very little through the lateral olfactory tract [13].
