xRead - Olfactory Disorders (September 2023)

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INTERNATIONAL CONSENSUS ON OLFACTION

V ANATOMY AND PHYSIOLOGY A Olfactory Epithelium to Olfactory Bulb The peripheral olfactory organ is the OE, a true neuroep ithelium that lines the olfactory cleft (OC) of the nasal cavity, including the ventral cribriform plate, the medial vertical lamellae of the superior turbinates as well as vari able portions of the middle turbinates, and the superior portion of the nasal septum. 83–86 While the remainder of the nasal cavity and paranasal sinuses are lined by respiratory mucosa, the specialized olfactory neuroepithe lium is composed of several distinct cell types: olfactory sensory neurons (OSNs), basal cells, sustentacular cells, microvillar cells, and ducts from Bowman glands. Deep to the OE lies a lamina propria containing olfactory nerve fascicles with nonmyelinating ensheathing glia, blood vessels, and Bowman glands. Immune cell populations may be abundant within the olfactory mucosa. Inspired odors selectively activate OSNs, whose axons form cranial nerve I and project to the PBs, terminating on specific glomeruli. 87 Odor molecules reaching the OC are detected by olfactory receptors (ORs), G-protein–coupled receptors expressed on neuronal immotile cilia embedded in the mucus layer at the OE surface. 1,88 Odorant molecules use the mucus layer to bind to these receptors, and binding triggers OSN depolarization. The OR family in humans contains ≈ 350 genes, and evidence suggests that a given OSN generally expresses a single OR. 88,89 Distinct ORs are activated by specific sets of odors and may be broadly or narrowly tuned. 90 Each OB glomerulus receives input from a subset of OSNs expressing the same OR proteins. 91 In this way, the pattern of glomerular activation in the OB maps the neural response to different odorants. An important feature of the OE is its reparative capac ity. OSNs, exposed to the nasal airspace, are vulnerable to injury, and neuronal lifespan is variable and regulated by multiple factors. 92–94 Like other self-renewing epithe lia, basal stem and progenitor cells in the OE divide and produce new cells as needed to maintain epithelial home ostasis under typical conditions. 95,96 In animal models, OE basal cells can produce OSNs, sustentacular cells, and microvillar cells. 97,98 Olfactory injury and repair has been well studied in rodent models, 100,101,99 and evidence sug gests that similar repair mechanisms are active in adult humans. 89 Nonetheless, acquired olfactory disorders in humans and the potential recovery from them—or lack thereof—remain incompletely understood.

B Olfactory Bulb to olfactory cortical structures The axonal projections from the sensory neurons of the OE are conveyed by the olfactory nerve (cranial nerve I) to the OB. The bulb is a laminated structure consisting, from superficial to deep, of (1) an outermost olfactory nerve layer; (2) a glomerular layer encompassing over a thousand regions of neuropil, each termed a glomerulus, wherein olfactory axons synapse with the interneurons that surround the glomeruli and with the deeper relay neurons; (3) an external plexiform layer that contains one type of relay neuron, the tufted (T) cells, and several other interneuronal cell types; (4) the mitral (M) cell layer, the other type of projection neuron; (5) an internal plexiform layer with multiple additional interneuronal types; (6) an internal granular layer with its massive population of axonless granule cells that sharpen the patterns of M/T cell activity; and (7) a vestigial ependymal layer derived from the olfactory ventricle that serves as the migratory pathway for newly born periglomerular neurons and gran ule cells throughout life. 103 Projections from the M/T cells in the lateral olfactory tract sweep over the surface of the three-layered paleocortex of the ventral forebrain before synapsing in cortical layer I. 104 Multiple distinct areas are innervated by the OB and are collectively categorized as the primary olfactory cortex (POC), including the anterior olfactory nucleus, olfactory tubercle, piriform cortex, cortical amygdala, and lateral entorhinal area. These cortical areas are extensively interconnected ipsilaterally and contralaterally with each other. 103 Smell information encoded by the POC is carried from the lateral entorhinal area to the hippocampus via the lateral perforant path, to deep portions of the amygdala and the lateral hypothala mus by the projection of the endopiriform nucleus deep to the POC, and to the OFC both directly and via the mediodorsal nucleus of the thalamus. 103 The receptotopic organization of the projections from the OE to the OB converts odorant stimuli into a spa tial map of activity across the glomerular layer of the OB, with different patterns produced by different odorants. 105 The spatial map of activity is sharpened by the circuitry of the bulb. The neural processing by the bulb is also modulated on the basis of sensory experience; parts of the OB that respond to odorants that are behaviorally asso ciated with positive or negative reinforcement incorpo rate a larger number of newly born interneurons. 106 In contrast, the projection of the bulb onto the piriform cor tex is spatially diffuse 104 ; the axons of M/T cells receiving synaptic input from a single glomerulus disperse among