Аксоны каких клеток образуют обонятельный нерв

10.1.1 Olfactory nerve

The olfactory nerve is shown in Figure 10.1.

The ON→ET→PG Circuit

ON provides monosynaptic input to all ET cells, which in turn monosynaptically excite PG cells. ON-evoked monosynaptic EPSCs in ET cells are followed by a longer latency, compound inhibitory postsynaptic current, which is due to GABAergic input from PG cells. Thus, one extension of the ON→ET→PG circuit is an ON→ET→PG→ET feedback circuit. The temporal sequence of excitation followed by feedback inhibition generated by this circuit may function to shape postsynaptic responses to sensory input possibly by creating a temporal ‘window of opportunity’ for sensory signals to achieve glomerular throughput and influence downstream olfactory circuits. Since only 20% of PG cells receive monosynaptic ON input, some of the intraglomerular inhibition of M/T cell dendrites, classically attributed to the ON→M/T→PG→M/T circuit, may actually be due to the operation of an ON→ET→PG→MT cell circuit.

The olfactory nerve is the first cranial nerve and conveys special sensory information related to smell. It is the shortest of the cranial nerves and passes from its receptors in the nasal mucosa to the forebrain. It enters the skull through the cribriform plate of the ethmoid bone. It then sends its impulses to be interpreted at various brain regions including the temporal lobe, amygdala, and entorhinal cortex. Simple bedside testing of the olfactory nerve can be done using vanilla essence or coffee extracts. The sense of smell can be altered due to a variety of conditions referred to as hyperosmia, hypoosmia, anosmia, and dysosmia. However, the most common pathology to affect the olfactory nerve is the common cold.

Olfactory (First)

Olfactory nerves transmit the sensation of smell to the brain. As the work that led to the 2004 Nobel Prize in Physiology or Medicine has shown, olfaction begins with highly complex, genetically determined specific G protein‐coupled odorant receptors. Odoriferous molecules bind onto one or more receptors, which leads to their identification. Rats, who live by their sense of smell, have about 1400 olfactory receptor genes. Humans have about 350 olfactory receptor genes, which comprise almost 1.5% of their total genome.

From the olfactory receptors located deep in the nasal cavity, branches of the pair of olfactory nerves pass upward through the multiple holes in the cribriform plate of the skull to several areas of the brain. Some terminate on the undersurface of the frontal cortex, home of the olfactory sensory areas. Others terminate deep in the hypothalamus and amygdala—cornerstones of the limbic system (see Fig. 16‐5). The olfactory nerves’ input into the limbic system, at least in part, accounts for the influence of smell on psychosexual behavior and memory.

To test the olfactory nerve, the patient is asked to identify certain substances by smelling through one nostril while the examiner compresses the other nostril. Testing must be done with readily identifiable and odoriferous but innocuous substances, such as coffee. Volatile and irritative substances, such as ammonia and alcohol, are not suitable because they may trigger intranasal trigeminal nerve receptors and bypass a possibly damaged olfactory nerve. For detailed testing, physicians might use a commercial set of “scratch and sniff” odors.

When disorders impair both olfactory nerves, patients, who are then said to have anosmia, cannot perceive smells or appreciate the aroma of food. Anosmia has potentially life‐threatening consequences, as when people cannot smell escaping gas. More commonly, food without a perceptible aroma is left virtually tasteless. Thus, people with anosmia, to whom food is completely bland, tend to have a decreased appetite.

One‐sided anosmia may result from tumors adjacent to the olfactory nerve, such an olfactory groove meningioma. In the classic Foster‐Kennedy syndrome, a meningioma compresses the olfactory nerve and the nearby optic nerve. The damage to those two nerves causes the combination of unilateral blindness and anosmia. If the tumor grows into the frontal lobe, it can also produce personality changes, dementia, or seizures.

In most cases of bilateral anosmia, the underlying disturbance is mundane. Anosmia is routine in anyone with nasal congestion and those who regularly smoke cigarettes. Head trauma, even from minor injuries, can shear off the olfactory nerves as they pass through the cribriform plate and cause anosmia (see Head Trauma, Chapter 22).

With advancing age, otherwise normal individuals begin to lose their sense of smell. Studies have shown that more than 50% of individuals older than 65 years and 75% of those older than 80 years have some degree of anosmia. Patients with Alzheimer’s disease, Parkinson’s disease, or other neurodegenerative diseases have even a higher incidence of anosmia. Some researchers have even proposed that testing smell can detect Alzheimer’s disease before cognitive function overtly deteriorates. Schizophrenic patients also have an increased incidence of anosmia but not to the degree of those with the neurodegenerative diseases.

Studies have also shown that loss of olfactory acuity—inability to identify smells—is a risk factor for Alzheimer’s disease. In both older age and neurodegenerative illnesses, particularly Alzheimer’s and Parkinson’s diseases, anosmia reflects degeneration of the olfactory tracts rather than the brain’s olfactory center. In Alzheimer’s disease, portions of the olfactory bulb have the same plaques and tangles that characterize the changes in the cerebral cortex. Similarly, in Creutzfeldt‐Jakob disease, the olfactory nerves contain the same spongiform changes found in the cerebral cortex (see Chapter 7).

Humans with genetic defects in their G protein‐coupled receptor complex have anosmia for one or more specific odors.

Anosmia may, of course, be psychogenic. A psychogenic origin can be revealed when a patient reports being unable to smell either irritative or innocuous, aromatic substances. Such a complete sensory loss would be possible only if an illness completely obliterated both pairs of trigeminal and olfactory nerves.

Olfactory hallucinations may represent the first phase or aura (Latin, breeze) of partial complex seizures that originate in the medial‐inferior surface of the temporal lobe. These auras usually consist of several second episodes of ill‐defined and unpleasant, but often sweet or otherwise pleasant, smells superimposed on impaired consciousness and behavioral disturbances (see Chapter 10). Also, although most migraine auras are visual hallucinations, some individuals experience an olfactory migraine aura (see Chapter 9).

On the other hand, olfactory hallucinations can be purely psychogenic. In contrast to smells induced by uncinate seizures, psychogenic “odors” are almost always foul smelling, are continuous, and not associated with impaired consciousness. However, most abnormal smells, which are typically putrid, originate in sinusitis and other cranial, dental, and cervical infections.

Olfactory Nerve Synapses

The mitral cell response to olfactory nerve electric stimulation usually exhibits a long-lasting excitatory postsynaptic potential that is mediated by AMPA, NMDA, and type-1 metabotropic glutamate receptors. This process is initially triggered by release of glutamate from olfactory axon terminals and then prolonged by secondary and regenerative glutamate release from excited mitral/tufted-cell dendrodendritic synapses in the glomerulus. Such recurrent excitation further involves glutamate spillover within a glomerulus (Figure 1(a), lower-left and upper-right insets). One likely function for these mechanisms is to amplify weak olfactory input. They are also involved in coordinating intraglomerular neuronal synchrony, as described further below in the section titled ‘Intraglomerular microcircuits.’

Olfactory (First)

Olfactory nerves transmit the sensation of smell to the brain. As the work that led to the 2004 Nobel Prize in Physiology or Medicine has shown, olfaction begins with highly complex, genetically determined specific G protein-coupled olfactory receptors. Odiferous molecules bind to one or more receptors that lead to their identification. Rats, which live by their sense of smell, have about 1400 olfactory receptor genes. Humans have about 350 olfactory receptor genes, but they comprise almost 1.5% of our total genome.

From the olfactory receptors located deep in the nasal cavity, branches of the pair of olfactory nerves pass upward through the multiple holes in the cribriform plate of the skull to several areas of the brain. Some branches terminate in entorhinal cortex and other regions on the undersurface of the frontal lobe. Others terminate deep in the hypothalamus and amygdala – cornerstones of the limbic system (see Fig. 16.5). The olfactory nerves’ input into the limbic system accounts, at least in part, for the influence of smell on sexual behavior and memory. Also, unlike other sensations – touch, vision, and hearing – whose pathways synapse in the thalamus or geniculate bodies en route to the cerebral cortex, some olfactory pathways project directly to cortex without an intervening synapse in the diencephalon.

To test the olfactory nerve, neurologists compress one nostril and ask the patient to identify certain substances by smelling through the other. Neurologists use readily identifiable and aromatic but innocuous substances, such as coffee. They do not use volatile or irritative substances, such as ammonia and alcohol, because they may trigger intranasal trigeminal nerve receptors and bypass a possibly damaged olfactory nerve. Patients are unreliable when estimating their sense of smell. For qualitative and quantitative testing, especially for research, neurologists utilize a commercial, standardized set of “scratch and sniff” odors, such as the University of Pennsylvania Smell Identification Test.

When disorders impair both olfactory nerves, patients cannot perceive smells or appreciate the aroma of food. Neurologists say that these patients have anosmia. Anosmia carries potentially life-threatening consequences, for example when patients cannot smell escaping gas. More commonly, their food, without perceptible aroma, is left tasteless. Thus, people with anosmia, to whom food is bland, tend to have a decreased appetite and lose weight.

Lack of smell sensation in one nostril may result from head trauma or a tumor adjacent to the olfactory nerve, such as an olfactory groove meningioma. In the classic Foster–Kennedy syndrome, a meningioma compresses the olfactory nerve and the nearby optic nerve. Damage to those two nerves causes the combination of unilateral blindness and anosmia. If the tumor grows into the frontal lobe, it can also produce personality changes, dementia, or seizures.

Anosmia commonly afflicts anyone with nasal congestion and those who regularly smoke cigarettes. With advancing age, otherwise normal individuals begin to lose their sense of smell. More than 50% of individuals older than 65 years and 75% of those older than 80 years have some degree of anosmia. Also, individuals with genetic mutations in their G protein-coupled receptor complex have anosmia for one or more specific odors.

Although mundane problems underlie most cases of bilateral anosmia, it may reflect more serious issues. Inadvertently inhaling zinc, which had been a constituent of popular “cold remedies,” has caused anosmia. Another situation where inhaled metal caused anosmia has occurred in welders who routinely inhale fumes containing vaporized iron, chromium, aluminum, and other metals. Head trauma, even from minor injuries, can shear the olfactory nerves as they pass through the cribriform plate and cause anosmia (see Traumatic Brain Injury, Chapter 22).

Loss of the sense of smell is also a manifestation of many neurodegenerative illnesses. For example, almost 90% of patients with Parkinson, dementia with Lewy bodies, Wilson, Creutzfeldt–Jakob, and Alzheimer diseases develop anosmia. In fact, among Parkinson disease patients, more have anosmia than tremor, and anosmia correlates with the most disabling manifestation of the illness – dementia. Similarly, anosmia serves as a risk factor for Alzheimer disease. Recent studies have found that the olfactory bulb manifests the same pathology as the cerebral cortex (see Chapter 7) in Alzheimer and Creutzfeldt–Jakob diseases. Schizophrenic patients also have an increased incidence of anosmia, but not to the degree brought on by neurodegenerative diseases.

In a situation opposite to anosmia, sometimes individuals have a heightened sense of smell: hyperosmia. Migraine patients before or during an attack and pregnant women frequently report hypersensitivity to smells or irritation by common, innocuous ones.

Anosmia may, of course, be psychogenic. A psychogenic origin can be revealed when a patient reports being unable to “smell” irritative substances. Such a complete sensory loss would be possible only if an illness completely obliterated both pairs of trigeminal as well as olfactory nerves.

Olfactory hallucinations may represent the first phase or aura (Latin, breeze) of seizures that originate in the medial-inferior surface of the temporal lobe, the uncus. These auras usually consist of a series of several-second episodes of ill-defined and unpleasant, but occasionally sweet or otherwise pleasant, smells preceding or superimposed on impaired consciousness and behavioral disturbances (see Chapter 10). Also, although most migraine auras consist of visual hallucinations, sometimes olfactory hallucinations represent an aura (see Chapter 9).

On the other hand, olfactory hallucinations as well as anosmia can be psychogenic. In contrast to smells induced by seizures, psychogenic “odors” are typically foul-smelling, continuous, and not associated with impaired consciousness. Olfactory hallucinations or delusions may constitute a manifestation of a psychiatric illness. As for identifying malingering, two tests are helpful. Malingerers may claim inability to “smell” a noxious, volatile substance, such as ammonia, that actually stimulates the trigeminal nerve. In the other test, given a forced-choice test of four smells, the malingering individual chooses a correct response less frequently than by chance, i.e., less than 25%.

3.1 Olfactory nerve pathways

Olfactory nerve pathways are considered as a major component of nose-to-brain delivery. It was reported that the intranasally administrated 3 kDa fluorescein dextran was transferred in the connective tissue surrounding the olfactory nerve bundles to the olfactory bulb within 15 min (Jansson and Bjork, 2002). The drug concentrations in the olfactory bulbs are generally higher than other CNS parts (Graff et al., 2005; Thorne et al., 2008), and increase of the drug concentration in the olfactory bulbs results in simultaneous increase of drug concentrations in other CNS parts (Dhuria et al., 2009).

Olfactory pathways arise in the olfactory region, which contains four major cell types: ciliated olfactory receptor neurons, supporting cells, basal cells, and microvillar cells (Moran et al., 1982). Olfactory neurons mediate the sense of smell by conveying sensory information from the nasal cavity to the CNS. The dendrites of olfactory neurons extend into the mucous layer of the olfactory epithelium. The axons of these bipolar neurons extend along the lamina propria, pass through the cribriform plate of the ethmoid bone and the subarachnoid space containing cerebrospinal fluid (CSF), and terminate on mitral cells in the olfactory bulbs. Then the neural projections extend to multiple brain regions including the olfactory tract, anterior olfactory nucleus, piriform cortex, amygdala, and hypothalamus (Buck, 2000). Besides, chemosensory neurons in the Grueneberg ganglion project axons to glomeruli in the olfactory bulbs (Fuss et al., 2005).

Olfactory neurons in the olfactory epithelium regenerate every 3–4 weeks because of their direct and frequent contact with foreign toxins. Therefore, the proteolytic enzymes, tight junction proteins, and efflux transporters in the nasal passages may not be fully functional during the maturation of olfactory neurons, resulting in a “leaky” nasal barrier to the CNS (Balin et al., 1986). In addition, olfactory ensheathing cells envelope the axons of olfactory neurons, creating continuous, fluid-filled perineurial channels that remain open despite the degeneration and regeneration of olfactory neurons (Luzzati et al., 2004).

Given the unique characteristics of the olfactory mucosa and olfactory neurons, it is possible for intranasally administered drugs to reach the CNS via extracellular or intracellular mechanisms along olfactory nerves. Extracellular transport mechanisms involve the rapid movement of drugs between cells in the nasal epithelium, and only several minutes are needed for a drug to reach the olfactory bulbs and other CNS parts (Frey, 2002). Transport may involve bulk flow mechanisms within the channels created by the olfactory ensheathing cells (Thorne et al., 2004). Drugs may also be transported within these channels by the structural changes that occur during depolarization and axonal propagation of the action potential in adjacent axons (Luzzati et al., 2004). Intracellular transport mechanisms involve the uptake of drugs into olfactory neurons by passive diffusion, receptor-mediated endocytosis, or adsorptive endocytosis, followed by slower axonal transport, taking several hours to days for a drug to appear in the olfactory bulbs and other brain areas (Broadwell and Balin, 1985). It has been reported that small, lipophilic molecules such as gold particles (Gopinath et al., 1978) and aluminum salts (Perl and Good, 1987) can be transported through intracellular mechanisms. However, intracellular mechanisms may be not the dominating way of drug transport. Most of the published studies about nose-to-brain delivery showed rapid delivery of drugs to the CNS, almost immediately after or within an hour of intranasal administration, consistent with the rapid extracellular mechanisms (Charlton et al., 2008; Hanson et al., 2004). Further, receptor-mediated transport mechanisms cannot be the main way of transport because of the need of various kinds of specific receptors. Although some large molecules, such as galanin-like peptide, exhibit saturable transport pattern into the CNS (Nonaka et al., 2008), most of large molecules such as nerve growth factor and insulin-like growth factor-I (Thorne et al., 2004) are delivered into the brain in a nonsaturable and not receptor-mediated way.

Olfactory Nerve (Cranial Nerve I)

The olfactory nerve permits the smelling of odours. Unilateral anosmia is often unnoticed but bilateral anosmia causes loss of ability to smell odours; in practice, the patient may complain of loss of taste rather than of smell. Anosmia is common in upper respiratory infections and after head injuries, as the nerves may be torn as they pass through the cribriform plate; this is experienced especially in Le Fort III fractures of the middle third of the facial skeleton. Olfactory neuroblastoma is a rare tumour linked tentatively to dental staff. An olfactory lesion is confirmed by inability to smell substances, such as orange, soap, coffee, cloves or peppermint oil. Each nostril is tested separately. Ammoniacal solutions must not be used, as they stimulate the trigeminal rather than the olfactory nerve.

Cranial nerve I

Olfactory nerve dysfunction can occur secondary to meningeal sarcoidosis involving the subfrontal region. However, anosmia or hyposmia may also result from local nasal granulomatous invasion by sarcoidosis, and, therefore, in a patient with olfactory complaints, an otolaryngological evaluation is necessary before attributing impaired olfaction to CNS disease.

Cranial nerve II

Optic nerve involvement in sarcoidosis is much less frequent than other ocular manifestations of sarcoidosis such as uveitis. Optic nerve involvement can present with an acute or subacute, painful, or chronic, painless visual loss (Graham et al., 1986; Stern and Corbett, 2007; Pawate et al., 2009). This visual loss may be due to bulbar or retrobulbar invasion of the optic nerve by granulomas, compression of the optic nerve by a granulomatous mass, or optic atrophy. Optic disc edema may be secondary to papilledema due to sarcoidosis-induced increased intracranial pressure or as a direct local invasive effect of sarcoidosis. A chiasmal syndrome has also been reported (Gelwan et al., 1988).

Cranial nerves III, IV, and VI

Disorders of ocular motility may follow involvement of the III, IV, or VI cranial nerves in the granulomatous process (Stern et al., 1985). Typically, these nerves are damaged in their extra-axial course in the subarachnoid space as they traverse the meninges. However, they may also be involved via local orbital disease, and rarely, brainstem intra-axial central nervous system pathways can be affected by sarcoidosis (Kirkham and Kline, 1976). Uncommonly, disordered ocular motility may be due to sarcoidosis involving the extraocular muscles themselves (Obenauf et al., 1978). Occasionally, pupillary dysfunction is caused by neurosarcoidosis (Henkind and Gottlieb, 1973; Kirkham and Kline, 1976; Cohen and Reinhardt, 1982; Poole, 1984). For instance, Horner’s syndrome due to disruption of the cervical sympathetic nerves has been reported (Cohen and Reinhardt, 1982).

Cranial nerve V

Trigeminal nerve disease may present as facial numbness or, rarely, trigeminal neuralgia (Stern et al., 1985). Headache may also represent trigeminal nerve dysfunction intracranially. Involvement of the muscles of mastication is unusual.

Cranial nerve VII

Of all the cranial nerve syndromes, peripheral facial cranial nerve (VII) palsy is the most common, and it is also the single most frequent neurologic manifestation of sarcoidosis. It develops in 25–50% of all patients with neurosarcoidosis. Although usually unilateral, bilateral facial palsy also can occur presenting with either simultaneous or sequential paralysis. Over half of all patients with facial palsy also have other forms of nervous system involvement. In patients with a solitary facial palsy, spinal fluid examination typically has been reported as normal, but in individuals in whom there are other associated forms of neurosarcoidosis, the spinal fluid examination is reported to be abnormal in 80% of patients. The specific reason for a facial nerve palsy in sarcoidosis may vary. Rarely is the facial palsy caused by parotid inflammation. More likely, the nerve is compromised as it traverses the meninges and subarachnoid space, and as suggested by Oksanen (Oksanen, 1986; Oksanen and Salmi, 1986), facial paresis probably is also due to intra-axial sarcoidosis-induced inflammation involving the facial nerve. In general the prognosis for the facial palsy is good with over 80% of patients having a good outcome in terms of recovery of facial function (Stern et al., 1985; Luke et al., 1987).

Cranial nerve VIII

Eighth cranial nerve involvement is the second most common form of cranial nerve dysfunction in sarcoidosis. Sarcoidosis may involve the auditory or vestibular portions of the nerve. When either loss of hearing or vestibular dysfunction occur, they may be sudden or insidious and often fluctuate over time (Hybels and Rice, 1976; Jahrsdoerfer et al., 1981; Colvin, 2006). If hearing loss occurs, it is typically a sensorineural loss. As with facial nerve palsy, bilateral VIII nerve disease may occur. In fact, either bilateral VII or VIII nerve dysfunction is suggestive of neurosarcoidosis (Wiederholt and Siekert, 1965; Stern et al., 1985; Oksanen and Salmi, 1986).

Cranial nerves IX and X

Glossopharyngeal and vagus nerve involvement by sarcoidosis causes dysphagia and dysphonia. Hoarseness is more commonly due to laryngeal nerve dysfunction from intrathoracic disease than CNS inflammation involving the vagus nerve (El-Kassimi et al., 1990).

Cranial nerves XI and XII

Eleventh and twelfth cranial nerve disease can occur but seems to be quite rare in sarcoidosis.

Myelination of the olfactory bulb and tract

Primary olfactory nerve axons remain unmyelinated throughout life, related to continuous turnover and regeneration from progenitor cells in the olfactory epithelium. Myelin forms around axons of mitral and tufted cells of the olfactory bulb, including their projection through the olfactory tract. In the full-term neonate no myelination has as yet been identified by luxol fast blue myelin stain or even by the more sensitive myelin basic protein immunoreactivity (Sarnat and Yu, 2016). Myelination proceeds postnatally during the first few months of age. Secondary postsynaptic projections of the anterior olfactory nucleus and tertiary olfactory fibers in the amygdala, hypothalamus, and neocortex myelinate even later, their cycles extending beyond infancy.