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Olfactory system

The olfactory system is the sensory apparatus responsible for the sense of smell, or olfaction, which enables the detection, discrimination, and perception of volatile chemical compounds known as odorants in the environment.^[1] It comprises peripheral components in the nasal cavity, including the olfactory epithelium where specialized receptor neurons bind odorants, and central neural pathways that transmit and process these signals directly to the brain without an intervening thalamic relay, a unique feature among sensory systems.^[1] This system plays a critical role in survival by detecting potential dangers such as spoiled food or smoke, contributes to flavor perception through integration with gustatory inputs, and influences emotions and memory via connections to the limbic system.^[2] Anatomically, the olfactory epithelium lines the superior nasal cavity, just below the cribriform plate of the ethmoid bone, and contains millions of bipolar olfactory sensory neurons, each expressing one of approximately 400 types of G-protein-coupled odorant receptors encoded by genes comprising about 2.4% of the human genome.^[2] These neurons are supported by sustentacular cells and basal stem cells, embedded in a mucus layer secreted by Bowman's glands that solubilizes odorants for binding to ciliary receptors on the neuron surface.^[1] Upon binding, odorants trigger a signaling cascade involving the G-protein subunit Gαolf, increased cyclic AMP (cAMP), and opening of cyclic nucleotide-gated ion channels, leading to depolarization and action potentials that propagate along unmyelinated axons forming the olfactory nerve (cranial nerve I).^[1] These axons bundle into fila olfactoria, penetrate the cribriform plate, and synapse in the olfactory bulb's glomeruli with second-order neurons such as mitral and tufted cells, where initial odor coding occurs through spatial and temporal patterns.^[2] From the olfactory bulb, the olfactory tract projects to primary olfactory cortical areas, including the anterior olfactory nucleus, piriform cortex, olfactory tubercle, and parts of the amygdala and entorhinal cortex, facilitating odor identification and emotional valence assignment.^[1] Higher-order processing in the orbitofrontal cortex integrates olfactory signals with taste and somatosensory inputs to form the multisensory experience of flavor, while the system's direct limbic connections underpin its role in innate behaviors, social cues, and associative learning.^[2] Humans can discriminate among at least 1 trillion distinct odors, highlighting the system's remarkable sensitivity and specificity, though olfactory acuity declines with age and can be impaired by factors like viral infections, head trauma, or neurodegenerative diseases such as Parkinson's (affecting up to 90% of early-stage patients) and Alzheimer's.^[2] Olfactory dysfunction, including anosmia and hyposmia, underscores the system's clinical significance, with interventions like olfactory training demonstrating neural plasticity.^[1]

Anatomy

Peripheral olfactory system

The peripheral olfactory system encompasses the anatomical structures in the nasal cavity responsible for detecting odorants, beginning with the olfactory epithelium located in the superior region of the nasal cavity, specifically the roof near the cribriform plate of the ethmoid bone. This pseudostratified columnar epithelium, approximately 2.5 cm² per nostril (totaling 5 cm² in humans), consists of multiple cell types that support odor detection. Sustentacular cells, also known as supporting cells, form the apical layer and provide structural support, metabolic assistance, and a barrier function to the underlying neurons. Basal cells serve as stem cells for regeneration, dividing to produce new sensory cells. Bowman's glands, situated in the underlying lamina propria, secrete a seromucous fluid that forms a protective mucus layer over the epithelium, aiding in the solubilization and transport of odorants.^[3]^[4] Olfactory receptor neurons (ORNs), the primary sensory cells, are bipolar neurons embedded within the olfactory epithelium, numbering approximately 6 to 10 million per nostril (totaling 12 to 20 million in humans). Each ORN extends a single dendrite apically, from which 10-30 non-motile cilia project into the mucus layer to interact with odorants; the axon extends basally toward the brain. Critically, each ORN expresses only one of approximately 400 functional olfactory receptor (OR) genes, enabling specific odorant binding and contributing to the diversity of smell perception.^[3]^[5] The axons of these ORNs bundle into approximately 20-40 fila olfactoria, forming the olfactory nerve (cranial nerve I), a collection of unmyelinated sensory fibers that traverse the cribriform plate foramina to reach the olfactory bulb. This nerve lacks the typical Schwann cell myelination seen in other peripheral nerves, relying instead on ensheathing cells for support. ORNs exhibit remarkable regenerative capacity, with a turnover rate of 30-60 days; aged or damaged neurons apoptose and are replaced by differentiation from basal cells, ensuring continuous sensory renewal.^[3]^[6] In some mammals, the peripheral olfactory system includes the vomeronasal organ, a specialized structure detecting pheromones, but in adult humans, it is vestigial or absent, with no functional sensory role. The olfactory nerve provides the direct afferent pathway from the peripheral structures to the central olfactory bulb.^[7]

Central olfactory system

The central olfactory system begins with the olfactory bulb, a specialized structure in the forebrain that serves as the primary site for initial processing of olfactory signals from the peripheral nervous system. Unlike other sensory pathways, olfactory information bypasses the thalamus and projects directly to cortical regions. The olfactory bulb receives input from olfactory receptor neurons (ORNs) in the nasal epithelium via the olfactory nerve. Within the bulb, ORN axons converge and synapse onto the dendrites of mitral and tufted cells in approximately 5,600 spherical neuropil structures known as glomeruli, with each glomerulus representing a functional unit for odorant-specific signaling.^[8] Periglomerular cells, a type of inhibitory interneuron, surround the glomeruli and modulate incoming signals through lateral inhibition, while granule cells in the deeper layers provide feedback inhibition to mitral and tufted cells, refining the output pattern.^[9] Olfactory ensheathing cells (OECs), unique glial cells within the bulb, ensheath bundles of ORN axons and facilitate their continuous regeneration throughout adulthood by promoting axonal growth and remyelination.^[10] From the olfactory bulb, processed signals are relayed via the olfactory tract and lateral olfactory striae, which carry axons primarily from mitral and tufted cells to the primary olfactory cortex. These projections target key regions including the piriform cortex, a paleocortical area responsible for basic odor representation, and the anterior olfactory nucleus (AON), which integrates ipsilateral and contralateral bulb inputs to support associative processing.^[11] The pathway remains largely ipsilateral, preserving spatial information from the nasal cavity without decussation at the midline, a feature that distinguishes olfaction from visual or somatosensory systems.^[12] Olfactory signals then extend to higher brain centers for integration with other sensory and cognitive functions. The piriform cortex sends dense projections to the entorhinal cortex, which interfaces with the hippocampus to link odors to memory formation. Parallel connections reach the amygdala, modulating emotional responses to scents, and the orbitofrontal cortex, which contributes to conscious odor perception and reward evaluation.^[13] Recent functional magnetic resonance imaging (fMRI) studies have revealed distinct activation patterns in the olfactory bulb and connected regions, such as odor-specific glomerular recruitment and sequential engagement of piriform and orbitofrontal areas during odor stimulation, highlighting the system's dynamic spatial organization.^[14]

Physiology

Olfactory transduction

Olfactory transduction begins when hydrophobic odorant molecules dissolve in the nasal mucus and bind to olfactory receptors (ORs), which are seven-transmembrane domain G-protein-coupled receptors (GPCRs) located on the cilia of olfactory sensory neurons (OSNs) in the olfactory epithelium. These ORs, encoded by a large multigene family, recognize a diverse array of volatile compounds, enabling the discrimination of at least 1 trillion distinct odors at sensitivity thresholds as low as parts per billion.^[15] The binding specificity arises from the structural features of ORs, which feature an extracellular N-terminal domain and intracellular loops that interact with odorants, initiating a conformational change in the receptor. Recent cryo-EM structures (as of 2023) have revealed detailed conformations of human ORs, confirming ligand-binding mechanisms.^[16]^[17] Upon odorant binding, the activated OR stimulates the heterotrimeric G-protein Golf (Gαolfβγ), leading to the exchange of GDP for GTP on the Gα subunit and its dissociation from the βγ complex.^[18] The free Gαolf then activates adenylyl cyclase type III (ACIII), catalyzing the conversion of ATP to cyclic adenosine monophosphate (cAMP), the primary second messenger in this pathway:

\text{ATP} \rightarrow \text{cAMP} + \text{PP}_\text{i}

via adenylyl cyclase.^[17] Elevated cAMP levels directly bind to and open cyclic nucleotide-gated (CNG) channels in the ciliary membrane, permitting influx of Na⁺ and Ca²⁺ ions, which causes a graded depolarization of the OSN.^[18] This depolarization is amplified by the subsequent activation of Ca²⁺-gated Cl⁻ channels (TMEM16B), which allow Cl⁻ efflux due to the high intracellular Cl⁻ concentration maintained by the Na⁺-K⁺-2Cl⁻ cotransporter, further depolarizing the neuron and generating action potentials that propagate via axonal projections to the olfactory bulb. Signal termination occurs rapidly to prevent overstimulation and enable adaptation. Phosphodiesterases (PDEs), particularly PDE1C and PDE2A, hydrolyze cAMP to 5'-AMP, reducing its concentration and closing CNG channels.^[18] Additionally, Ca²⁺ influx triggers negative feedback through calmodulin binding to CNG channels, decreasing their affinity for cAMP, while Ca²⁺ extrusion via Na⁺/Ca²⁺ exchangers (NCKX4) and plasma membrane Ca²⁺-ATPases (PMCA) restores baseline levels.^[17] The human OR gene family, comprising about 390 functional genes and 465 pseudogenes, is organized in clusters across multiple chromosomes, with major clusters on chromosomes 1, 6, and 11 containing over 100 OR genes collectively.^[19] Recent post-2020 studies using CRISPR/Cas9 in model organisms like Drosophila have confirmed the essential role of specific ORs in odor detection and behavioral responses, highlighting the genetic precision of transduction.

Olfactory coding and perception

Olfactory coding begins in the olfactory bulb, where incoming signals from olfactory receptor neurons converge to form spatial patterns known as glomerular coding. Each glomerulus receives input exclusively from neurons expressing a single type of olfactory receptor, creating discrete modules that represent specific odorant features.^[20] This organization allows for combinatorial coding, in which individual odorants activate unique combinations of glomeruli, typically involving responses from approximately 50-100 olfactory receptors per odorant, enabling the discrimination of at least 1 trillion distinct odors.^[15] Seminal studies in rodents have demonstrated that this spatial mapping preserves odor identity through overlapping yet distinct activation patterns across the glomerular array.^[21] Temporal coding complements spatial patterns by encoding odor information through the timing and dynamics of neural activity. In the olfactory bulb, mitral and tufted cells exhibit varying firing rates that correlate with odor intensity, while synchronized oscillations—such as theta rhythms (4-8 Hz) during inhalation and gamma rhythms (40-100 Hz) during odor sampling—facilitate the binding of odor features across glomeruli.^[22] These rhythms, observed in both rodents and humans, enhance signal-to-noise ratios and support rapid odor discrimination, with gamma oscillations particularly prominent in the piriform cortex during active sniffing.^[23] For instance, respiration-driven gamma activity provides temporal windows for integrating sensory inputs, optimizing perceptual acuity.^[24] Perception of odors arises from the interplay of these codes in higher brain regions, sparking debate between labeled-line and population coding models. Labeled-line coding posits dedicated pathways for specific odors, especially innate ones like pheromones, whereas population coding—supported by combinatorial activation—emphasizes distributed ensembles for complex, learned scents, allowing nuanced discrimination.^[25] This population approach dominates in the main olfactory system, where odor mixtures are decoded via overlapping glomerular responses. Olfactory perception also involves cross-modal integration, particularly with gustation to form flavor; retronasal odors during eating activate shared neural representations in the orbitofrontal cortex, enhancing taste identification and hedonic evaluation.^[26] Additionally, the amygdala assigns hedonic valence, encoding pleasant or aversive qualities along a spectrum, with neurons firing differentially to positive versus negative odors.^[27] Specific perceptual phenomena highlight coding adaptability. Olfactory adaptation, or fatigue, occurs through rapid desensitization of receptors and central habituation, reducing sensitivity after prolonged exposure to maintain responsiveness to novel stimuli; this peripheral mechanism involves calcium-mediated feedback in olfactory neurons.^[28] Sex differences influence sensitivity, with women generally exhibiting lower detection thresholds and superior discrimination for a broad range of odors, linked to hormonal variations and larger olfactory bulb volumes.^[29]^[30] Recent advancements post-2020 have leveraged technology for olfactory research and application. Olfactory virtual reality (OVR) systems deliver controlled scents during immersive simulations, aiding training for anosmia recovery and cognitive enhancement. Machine learning models now simulate odor spaces by mapping combinatorial receptor activations to perceptual qualities, using graph neural networks to predict odor similarity and generate principal odor maps that unify tasks like identification and valence assessment.^[31] These AI analogies to biological coding reveal how high-dimensional chemical spaces are compressed into perceptual dimensions, advancing artificial olfaction.^[32]

Disorders

Types of olfactory dysfunction

Olfactory dysfunction encompasses a range of impairments in the sense of smell, affecting quality of life through diminished ability to detect odors, altered perceptions, or even heightened sensitivity. The most common forms include anosmia, defined as the complete loss of smell, and hyposmia, a partial reduction in olfactory sensitivity that hinders odor detection at normal concentrations.^[33]^[34] Parosmia involves distorted smell perception, where familiar odors are misinterpreted as unpleasant or unfamiliar scents, often emerging during recovery from other dysfunctions.^[34] Phantosmia refers to the perception of phantom odors, such as burnt or metallic smells, without any external stimulus present.^[33] Hyperosmia, characterized by an abnormally heightened sense of smell, is less commonly classified as a dysfunction but can lead to sensory overload in response to everyday odors.^[35] Olfactory dysfunctions are broadly classified into conductive and sensorineural types based on the underlying mechanism of impairment. Conductive losses result from physical obstructions that block airflow to the olfactory epithelium, such as nasal polyps or mucosal swelling, preventing odorants from reaching the sensory receptors.^[36]^[6] In contrast, sensorineural losses involve damage to the olfactory neurons or neural pathways, often due to viral infections, toxins, or neurodegenerative processes, leading to impaired signal transduction or transmission to the brain.^[36]^[6] Diagnosis of olfactory dysfunction typically begins with standardized psychophysical testing to quantify impairment objectively. The University of Pennsylvania Smell Identification Test (UPSIT), a 40-item scratch-and-sniff assessment, evaluates odor identification and is widely used for its reliability in detecting anosmia and hyposmia.^[37]^[38] The Sniffin' Sticks test measures olfactory thresholds, discrimination, and identification through felt-tip pens releasing specific odors, providing a composite threshold-discrimination-identification (TDI) score to classify dysfunction severity.^[38]^[39] Imaging modalities, such as magnetic resonance imaging (MRI), assess structural changes like olfactory bulb volume reduction, which correlates with sensorineural loss and aids in differentiating causes.^[40] In the general population, olfactory dysfunction affects approximately 20% of individuals, with prevalence increasing with age and varying by measurement method—ranging from 19% to 24% in population-based studies using objective tests.^[41]^[42] Post-viral anosmia has seen a notable surge since 2020 due to COVID-19, with initial dysfunction rates of 27-60% persisting in subsets of patients at six months and beyond, contributing to long-term impacts in long COVID cases. As of 2025, persistent post-COVID olfactory dysfunction affects 5-20% of infected individuals beyond one year, with olfactory training yielding recovery in 30-50% of long-term cases, demonstrating neural plasticity.^[43]^[44]^[45] Emerging approaches to managing olfactory dysfunction include olfactory training protocols, which involve repeated exposure to strong odors like rose, lemon, clove, and eucalyptus twice daily for several months to promote neural plasticity and recovery, particularly in post-viral cases.^[35]^[46] Biomarkers such as MRI-measured olfactory bulb height or volume serve as predictors of prognosis, with reduced volumes indicating poorer recovery potential in sensorineural dysfunction.^[40]^[47]

Causes of olfactory dysfunction

Olfactory dysfunction encompasses a range of impairments, from partial hyposmia to complete anosmia, arising from diverse etiological factors that disrupt the olfactory epithelium, receptor neurons (ORNs), or central processing pathways. These causes can be broadly categorized into age-related changes, infections, toxic exposures, trauma, neurodegenerative diseases, genetic disorders, iatrogenic effects, and environmental influences, each involving specific mechanisms such as neuronal loss, inflammation, or structural damage.^[48] Age-related causes. Presbyosmia, the progressive decline in olfactory function with aging, primarily results from the loss of ORNs and a slowdown in the regenerative capacity of basal stem cells in the olfactory epithelium. By age 65-80, over 50% of individuals experience significant olfactory impairment, with prevalence rising to up to 80% beyond age 80, attributed to cumulative ORN degeneration and reduced turnover rates that fail to replenish damaged cells effectively. This age-associated regeneration deficit involves diminished activity of olfactory ensheathing cells (OECs), specialized glia that support axonal regrowth and ensheathment in the olfactory nerve layer, leading to incomplete repair of the cribriform plate perforations.^[49]^[50]^[51] Infectious causes. Viral infections, particularly upper respiratory tract pathogens, are a leading cause of olfactory dysfunction through direct epithelial invasion or inflammatory sequelae. For instance, SARS-CoV-2, the virus causing COVID-19, enters the nasal mucosa via TMPRSS2 and ACE2 receptors predominantly expressed on sustentacular support cells rather than ORNs, triggering local inflammation, apoptosis of these cells, and secondary disruption of ORN function. This mechanism explains the acute anosmia in up to 50% of cases, with post-viral persistence in 10-20% of patients due to prolonged epithelial regeneration delays and immune-mediated damage.^[52]^[53] Toxic exposures. Environmental and occupational toxins can directly damage the olfactory epithelium or interfere with signal transduction. Cadmium, a heavy metal found in industrial emissions and tobacco smoke, induces ORN apoptosis and epithelial atrophy by generating reactive oxygen species and disrupting metal homeostasis in the nasal mucosa. Organic solvents, such as toluene and xylene, commonly encountered in paints and fuels, cause hyposmia by solvent-induced demyelination of olfactory fila and inhibition of cyclic nucleotide-gated channels critical for transduction. These effects are dose-dependent, with chronic low-level exposure linked to 20-40% prevalence of dysfunction in affected workers.^[54]^[55]^[56] Traumatic causes. Head trauma, especially from acceleration-deceleration forces in traumatic brain injury (TBI), shears delicate olfactory fila as they traverse the cribriform plate, severing connections between ORNs and the olfactory bulb. This mechanical disruption occurs in 10-20% of moderate to severe TBI cases, with milder injuries showing lower rates of 7-15%, often compounded by secondary edema or hemorrhage in the bulb. Recovery is limited due to the central nervous system's poor regenerative capacity beyond the peripheral olfactory pathway.^[57]^[58] Neurodegenerative causes. Olfactory dysfunction frequently precedes motor symptoms in neurodegenerative disorders like Parkinson's disease (PD) and Alzheimer's disease (AD), serving as an early biomarker. In PD, alpha-synuclein aggregates accumulate in the olfactory bulb and anterior olfactory nucleus, impairing synaptic transmission and ORN signaling as early as Braak stage 1. Similarly, in AD, tau tangles and amyloid-beta plaques infiltrate the olfactory cortex and extend to ORNs via retrograde transport, reducing bulb volume and detection thresholds by 20-30% in prodromal phases. These proteinopathies highlight olfaction's vulnerability as a sentinel for central neurodegeneration.^[59]^[60] Genetic causes. Congenital genetic disorders disrupt olfactory development from embryonic stages. Kallmann syndrome, caused by mutations in genes like KAL1 (encoding anosmin-1) or FGFR1, leads to anosmia through failed migration of gonadotropin-releasing hormone neurons and olfactory axons, resulting in aplasia or hypoplasia of the olfactory bulbs in nearly 100% of cases. This X-linked or autosomal form affects 1 in 30,000-50,000 individuals, combining smell loss with hypogonadotropic hypogonadism.^[61] Iatrogenic causes. Medical interventions, particularly chemotherapy, induce olfactory loss via neurotoxic effects on the epithelium. Agents like cisplatin and methotrexate cause dose-dependent hyposmia in 20-40% of patients by damaging proliferating basal cells and ORNs through oxidative stress and apoptosis, with effects persisting 6-12 months post-treatment in severe cases. Radiation therapy to the head and neck can exacerbate this by fibrosing the nasal mucosa.^[62]^[63] Environmental causes. Emerging evidence links chronic exposure to air pollutants, such as fine particulate matter (PM2.5), to olfactory impairment via inflammatory cascades. PM2.5 particles deposit in the nasal cavity, activating Toll-like receptors on epithelial cells and releasing pro-inflammatory cytokines like IL-6 and TNF-alpha, which erode ORNs. Chronic exposure to PM2.5 has been associated with increased risk of anosmia, with odds ratios of approximately 1.6-1.7 for sustained exposure levels. A 2023 study on particulate matter confirmed associations with impaired olfactory performance in urban populations, positioning ambient PM2.5 as a potentially modifiable risk factor.^[64]^[65]^[66]

History

Early discoveries

The earliest conceptualizations of the olfactory system emerged in ancient Greece and Rome, where philosophers and physicians sought to explain smell through rudimentary models of perception. Aristotle, in the 4th century BCE, proposed that smell arises from the detection of vaporous exhalations or "vapors" emitted by objects, distinguishing between watery vapors (tasteless and inodorous) and fumid ones that interact with the sense organ.^[67] This vapor theory positioned olfaction as an aerial sense analogous to taste but mediated through air rather than direct contact. Building on this, the Roman poet Lucretius, in the 1st century BCE, advanced an atomic explanation in his De rerum natura, describing odors as resulting from thin films or "idols" of atoms shed from objects, which travel through the void and impinge on the nostrils to produce sensation.^[68] In the 2nd century CE, the physician Galen further integrated olfaction with brain anatomy, describing the cribriform plate of the ethmoid bone as a "porous" or sieve-like structure—likened to a Roman sieve (cribrum romanum)—that connected the nasal cavity to the brain. Galen viewed this plate not primarily as a pathway for incoming odors but as a route for expelling brain waste toward the nose, though he acknowledged its role in sensory transmission.^[69] Early comparative dissections during this period also highlighted anatomical variations, such as the relative size or prominence of olfactory structures across species; for instance, observations in animals like dogs revealed more developed olfactory bulbs compared to humans, underscoring olfaction's varying adaptive importance.^[70] During the medieval and Renaissance periods, Islamic scholars refined these ideas while European anatomists began visual documentation. In the 11th century, Avicenna (Ibn Sina) in his Canon of Medicine categorized odors as sensory qualities tied to humoral balance, describing them as indicators of bodily health—such as the sweet, non-putrid smell of healthy blood—and integrating smell into diagnostics alongside taste and touch.^[71] This emphasis on odor qualities influenced medical practice by linking scents to therapeutic properties, like aromatic vapors for brain stimulation. By the 16th century, Andreas Vesalius advanced anatomical precision in De humani corporis fabrica (1543), providing detailed illustrations of the nasal passages, cribriform plate, and olfactory nerves as distinct filaments emerging from the brain's anterior region, correcting Galenic errors through human dissections and emphasizing their sensory role.^[72] The 17th and 18th centuries marked a shift toward empirical identification of neural pathways and sensory limits. In 1675, Richard Lower, collaborating with Thomas Willis, contributed to the delineation of cranial nerves in Cerebri anatome, identifying the olfactory nerves as the first pair ("smelling nerves") arising from the brain's inferior surface and penetrating the cribriform plate to reach the nasal mucosa.^[73] This work built on dissection techniques to affirm olfaction's direct neural connection to the brain. Later in the 18th century, Albrecht von Haller explored olfactory sensitivity in Elementa physiologiae corporis humani (1763), classifying odors by hedonic valence—pleasant (ambrosial), foul (stenches), or neutral (e.g., roasted coffee)—and noting thresholds of detection influenced by concentration and individual variability, framing smell as a less dominant but physiologically distinct sense in upright humans.^[74]

Modern advancements

In the 19th century, significant advancements in visualizing the olfactory system's structure emerged through histological techniques. Camillo Golgi's application of silver chromate staining in 1873 revealed the glomerular organization within the olfactory bulb, demonstrating how olfactory nerve fibers converge into discrete spherical structures that facilitate initial sensory processing. Similarly, Santiago Ramón y Cajal's histological studies in the 1890s, building on Golgi's staining method, detailed the axonal projections from olfactory receptor neurons in the nasal epithelium to their synapses in the olfactory bulb, confirming the continuity of the peripheral and central pathways.^[75] The early 20th century brought electrophysiological insights into olfactory function. Edgar Adrian's recordings from the olfactory bulb in the 1950s captured oscillatory patterns in response to odors, highlighting the dynamic neural activity that underlies smell perception and influencing subsequent models of sensory coding. A landmark breakthrough occurred in 1991 when Linda Buck and Richard Axel identified a large family of G-protein-coupled receptors expressed in ORNs, which they proposed as the molecular basis for odor detection; this discovery earned them the 2004 Nobel Prize in Physiology or Medicine.90245-C) Building on this, Buck's subsequent work in the 1990s mapped these olfactory receptors (ORs) to topographically organized zones in the olfactory epithelium, revealing how spatial patterns contribute to odor discrimination.90391-L) Genomic sequencing in the post-2000 era further elucidated OR diversity and evolution. The human genome contains approximately 400 functional OR genes alongside over 500 pseudogenes, reflecting a partial degeneration compared to other mammals and underscoring species-specific adaptations in olfactory capability. Evolutionary comparisons highlight this contrast; for instance, dogs possess around 800 intact OR genes, enabling a far superior sense of smell suited to their predatory lifestyle. In the 2010s, optogenetics revolutionized the study of olfactory coding by allowing precise activation of specific ORNs and bulb circuits. Techniques using channelrhodopsin-2 to stimulate genetically targeted glomeruli demonstrated how individual ORs encode odor quality and intensity, providing causal evidence for glomerular maps in perception. Recent years have seen accelerated research into olfactory disorders, spurred by the global COVID-19 pandemic, which highlighted anosmia as a common symptom and prompted investigations into viral impacts on ORNs. Concurrently, advancements in regenerative medicine include clinical trials exploring stem cell therapies to regenerate ORNs in patients with congenital or acquired anosmia, with early-phase studies showing promising restoration of epithelial function. From 2022 to 2025, artificial intelligence models have advanced odor prediction and design. Machine learning approaches, such as graph neural networks trained on molecular datasets, enable the prediction of odor profiles from chemical structures, facilitating applications in perfumery and sensory neuroscience.

References

[1]
Physiology, Olfactory - StatPearls - NCBI Bookshelf
The olfactory system is at the roof of the nasal cavity at the cribriform plate - a perforated portion of the ethmoid bone separating the frontal lobe of the ...
[2]
The Olfactory System: Basic Anatomy and Physiology for General ...
The orbitofrontal cortex is responsible for combining taste and olfactory stimuli to form flavor by associative learning. In addition to being indicatory of ...
[3]
Neuroanatomy, Cranial Nerve 1 (Olfactory) - StatPearls - NCBI - NIH
Aug 14, 2023 · The olfactory nerve is the first cranial nerve and is instrumental in our sense of smell. The olfactory nerve contains only afferent sensory nerve fibers.Structure And Function · Blood Supply And Lymphatics · Review Questions<|control11|><|separator|>
[4]
Anatomy and Cellular Constituents of the Human Olfactory Mucosa
Its structure, function, and physiology are unique yet poorly understood. Diseases associated with the olfactory system lead to an array of complex secondary ...
[5]
Update on the olfactory receptor (OR) gene superfamily - PMC
The olfactory receptor gene (OR) superfamily is the largest in the human genome. The superfamily contains 390 putatively functional genes and 465 pseudogenes.
[6]
Pathophysiology of Olfactory Disorders and Potential Treatment ...
Interestingly, olfactory neurons are relatively short-lived, with an estimated lifespan of only weeks to months [17]. Because of this, mammals have retained the ...
[7]
The clinical significance of the human vomeronasal organ - PMC - NIH
Feb 9, 2023 · The human VNO is likely a vestigial organ with non-operational sensory function, and it is not necessary to avoid damaging it during septal ...
[8]
Principles of Glomerular Organization in the Human Olfactory Bulb
Jul 9, 2008 · The human OB had on average 5,568±830 (mean±S.E.M.) glomeruli in each OB with a range of 2,975–9,325 (see Supplementary Table S1 for further ...
[9]
Neuronal organization of olfactory bulb circuits - PMC - NIH
Both mitral and tufted cells project a single primary dendrite into a single glomerulus, where they receive synaptic inputs from the axons of olfactory sensory ...Missing: paper | Show results with:paper
[10]
Defining the role of olfactory ensheathing cells in facilitating axon ...
OECs promote axon regeneration and functional recovery indirectly by augmenting the endogenous capacity of host Schwann cells to invade the damaged spinal cord.
[11]
Synaptic Organization of Anterior Olfactory Nucleus Inputs to ...
Dec 2, 2020 · The anterior olfactory nucleus (AON) receives direct input from the olfactory bulb and sends an associative projection to piriform cortex that ...
[12]
Olfactory Functions Are Mediated by Parallel and Hierarchical ...
From the olfactory cortex and amygdala, the third neuron reaches targets in the orbitofrontal cortex, subiculum, thalamus, hypothalamus, brainstem, and ...
[13]
Connectivity of Pathology: The Olfactory System as a Model for ...
Beyond the primary olfactory cortex, neocortical areas, such as the lateral entorhinal cortex and the orbitofrontal cortex, receive substantial olfactory input ...
[14]
Functional MRI of murine olfactory bulbs at 15.2T reveals ... - Nature
Aug 16, 2023 · This is here explored with single-shot fMRI studies on the olfactory bulbs of male and female mice performed at 15.2T.
[15]
Signal Transduction in Vertebrate Olfactory Cilia - NCBI - NIH
This chapter will review the molecular mechanisms underlying the functional role of vertebrate olfactory cilia.Missing: paper | Show results with:paper<|control11|><|separator|>
[16]
https://www.nature.com/articles/s41586-023-06496-4
[17]
Evolution of olfactory receptor genes in the human genome - PNAS
Sep 24, 2003 · We have identified the complete set of OR genes and their chromosomal locations from the latest human genome sequences.Abstract · Sign Up For Pnas Alerts · Results<|separator|>
[18]
Principles of Glomerular Organization in the Human Olfactory Bulb
The data suggest that the initial coding of odor information in the human OB may differ from the models developed for rodents.
[19]
Coding and Transformations in the Olfactory System - Annual Reviews
Jul 8, 2014 · A long-standing debate in neural coding is whether and how timing of spikes conveys information to downstream neurons. Although we know that ...Missing: paper | Show results with:paper
[20]
Temporal Coding in Olfaction - NCBI - NIH
The fact that gamma-band (or beta-band) oscillations occur simultaneously with odor perception may suggest that they are in some way implicated in odor ...
[21]
Smell-induced gamma oscillations in human olfactory cortex are ...
3 key oscillatory rhythms are an integral part of the human olfactory cortical response to smell: Odor induces theta, beta, and gamma rhythms in human piriform ...
[22]
Mechanisms and functions of respiration-driven gamma oscillations ...
Feb 20, 2023 · In all, these findings demonstrate that respiration-driven gamma oscillations provide an optimal temporal window for olfaction. Figure 7 ...
[23]
Encoding innately recognized odors via a generalized population ...
May 10, 2021 · The labeled-line model is incompatible with the population code observed in the main olfactory system. Not only are individual M/T cells tuned ...
[24]
Multisensory Integration Underlies the Distinct Representation of ...
May 15, 2024 · This multisensory process generates robust associations between odors and tastes, significantly influencing the perceptual judgment of flavors.
[25]
Human Amygdala Represents the Complete Spectrum of Subjective ...
Although the amygdala is a major locus for hedonic processing, how it encodes valence information is poorly understood. Given the hedonic potency of odor ...Odor Stimuli · Multivariate Fmri Analyses · Multivariate Fmri Results...
[26]
Repeated exposure to odors induces affective habituation of ...
Apr 10, 2014 · Peripheral olfactory adaptation (or olfactory fatigue) is a phenomenon characterized by a decrease of the olfactory receptors' sensitivity due ...
[27]
Comparable responses to a wide range of olfactory stimulation in ...
Jun 3, 2023 · The evidence for differences between women and men in terms of olfactory abilities is contradictory. We analyzed women and men's performance ...Stimuli, Instruments, And... · Extended Olfactory Exposure · Olfactory Acuity And Sensory...
[28]
Can immersive olfactory training serve as an alternative treatment ...
Jun 11, 2024 · An immersive olfactory training featuring full‐body exposure to dozens of distinct odors could also improve overall olfactory function.
[29]
A principal odor map unifies diverse tasks in olfactory perception
Aug 31, 2023 · We used graph neural networks to generate a principal odor map (POM) that preserves perceptual relationships and enables odor quality prediction ...
[30]
The possibilities and limits of machine learning in olfaction - PMC
Sep 1, 2022 · Machine learning models in olfaction hold the promise of obtaining such generalizable structure-odor rules that could reduce the vast chemical ...
[31]
Smell (Olfactory) Disorders—Anosmia, Phantosmia & Others | NIDCD
Jul 31, 2023 · Hyposmia [high-POSE-mee-ah] is a reduced ability to detect odors. Anosmia [ah-NOSE-mee-ah] is the complete inability to detect odors.
[32]
Types of smell and taste impairment - SmellTaste
Anosmia – the inability to smell · Hyposmia – reduced ability to smell · Parosmia – smells are distorted · Phantosmia – smelling things that aren't present in the ...
[33]
Get Smell Disorders Treatment | Cleveland Clinic
Anosmia (total loss of smell). Dysosmia (distorted sense of smell). Hyperosmia (increased sense of smell). Hyposmia (reduced sense of smell). Phantosmia ...Diagnosing Smell Disorders... · Locations · Olfactory Training
[34]
Disorders of Taste and Smell - Medscape Reference
Mar 27, 2024 · The disorders of smell are classified as "-osmias" and those of taste as "-geusias." Anosmia - Inability to detect odors. Hyposmia - Decreased ...
[35]
Smell and Taste Disorders: Diagnosis - Medical Clinical Policy ...
The University of Pennsylvania Smell Identification Test (UPSIT) is an objective, quantitative test of olfactory function. The test consists of 40 odors, each ...
[36]
Diagnosis of Anosmia and Hyposmia: A Systematic Review - PMC
Jul 5, 2021 · The most utilized diagnostic tools were orthonasal smell tests (such as the Sniffin' Sticks and the UPSIT, along with validated abridged smell tests).
[37]
Olfactory Dysfunction: Etiology, Diagnosis, and Treatment - PMC
Exclusive categorization of olfactory disorders as conductive or sensorineural should no longer be practiced, because, for example, olfactory dysfunction in ...
[38]
MR Imaging–Based Evaluations of Olfactory Bulb Atrophy in ...
Mar 1, 2018 · MR imaging evaluations of olfactory bulb atrophy can be used to objectively diagnose olfactory dysfunction in patients with subjective olfactory loss.
[39]
The Prevalence of Olfactory Dysfunction in the General Population
Aug 3, 2020 · Results: A total of 175,073 subjects were identified (mean age 63.5 years, range 18 to 101) with an overall OD prevalence of 22.2% (95% CI 14.8- ...
[40]
Association of Olfactory Impairment With All-Cause Mortality
Apr 7, 2022 · Population-based studies of olfactory impairment (OI) indicate an overall prevalence ranging from 19% to 24%, with a prevalence exceeding ...
[41]
Post-viral olfactory loss and parosmia - BMJ Medicine
Jul 20, 2023 · After covid-19, the reported prevalence of olfactory dysfunction was 27-60% at six months,44 82 83 26.5-46% at one year,83 84 and 8.3% at two ...
[42]
Functional but Not Structural Brain Changes After Olfactory Training ...
Mar 28, 2025 · Olfactory training (OT) significantly improves olfactory function in patients with post-viral olfactory dysfunction compared to healthy ...Missing: biomarkers | Show results with:biomarkers
[43]
Clinical significance of MRI-measured olfactory bulb height as an ...
Oct 28, 2024 · MRI-measured OBH is decreased in iPD regardless of age and sex and may be correlated with the progression of motor symptoms in the iPD.
[44]
Olfactory dysfunction in COVID-19: new insights into the underlying ...
Nov 16, 2022 · Since the regeneration of olfactory receptor neurons takes 2–3 weeks, the mostly short-lived loss of smell cannot be caused by death and ...
[45]
The influences of age on olfaction: a review - PMC - PubMed Central
Feb 7, 2014 · Decreased olfactory function is very common in the older population, being present in over half of those between the ages of 65 and 80 years.
[46]
Sensorineural Organs Dysfunction and Cognitive Decline: A Review ...
Olfactory loss. With a prevalence of more than 50% in individuals aged between 65 and 80 years, and up to 80% in those age above 80 years, olfaction ...Hearing Loss · Visual Impairment · Olfactory Loss
[47]
Embryonic-Derived Olfactory Ensheathing Cells Remyelinate Focal ...
Jul 1, 2013 · OECs displayed highly similar morphological and antigenic properties at each age. ... The age-related decrease in CNS remyelination efficiency is ...<|control11|><|separator|>
[48]
Expression of the SARS-CoV-2 Entry Proteins, ACE2 and TMPRSS2 ...
These data suggest that sustentacular cells are involved in SARS-CoV-2 virus entry and impairment of the sense of smell in COVID-19 patients. We also show that ...
[49]
Mechanisms of COVID-19-associated olfactory dysfunction - PMC
While the loss of sustentacular cells may explain the transient olfactory dysfunction experienced by the majority of the patients, the mechanism of persistent ...
[50]
In vivo visualization of olfactory pathophysiology induced by ...
Intranasal exposure to cadmium has been related to olfactory dysfunction in humans and to nasal epithelial damage and altered odorant-guided behavior in ...Missing: solvents | Show results with:solvents
[51]
Olfactory dysfunction revisited: a reappraisal of work-related ...
Sep 4, 2018 · The human sense of smell may be impaired by exposure to metal compounds involving cadmium, chromium and nickel, and to formaldehyde.
[52]
Toxin-induced chemosensory dysfunction: A case series and review
Toxic chemical exposures are estimated to account for 1–5% of all olfactory disorders. Both olfactory neurons and taste buds are in direct contact with ...
[53]
Post-traumatic anosmia in patients with mild traumatic brain injury ...
May 6, 2016 · We explained to the patient that her anosmia was most likely due to a shearing of the fine nerves of the fila olfactoria and tearing at the ...
[54]
Olfactory dysfunction following moderate to severe traumatic brain ...
Sep 7, 2022 · The reported incidence of olfactory dysfunction following mild TBI ranges from 0 to 13% and these rates can increase to 15 to 30% following ...Missing: fila | Show results with:fila
[55]
The human olfactory system in two proteinopathies: Alzheimer's and ...
Jun 3, 2020 · Potential pathways of abnormal tau and alpha-Synuclein dissemination in sporadic Alzheimer's and Parkinson's diseases. Cold Spring Harb ...Missing: ORNs | Show results with:ORNs
[56]
Lamina-specific immunohistochemical signatures in the olfactory ...
Jan 24, 2022 · Interestingly, one AD and one PD case used in this study showed both tau and alpha-synuclein pathology in the AON and clustered together in this ...Missing: ORNs | Show results with:ORNs
[57]
Kallmann syndrome - Genetics - MedlinePlus
Dec 1, 2016 · In Kallmann syndrome, the sense of smell is either diminished (hyposmia) or completely absent (anosmia). This feature distinguishes Kallmann ...
[58]
Olfactory changes among patients receiving chemotherapy - PubMed
Taste and smell changes (TSCs) are known side effects of chemotherapy, but smell changes (SCs) in the absence of taste changes are understudied.Missing: iatrogenic | Show results with:iatrogenic
[59]
Drug-induced olfactory and gustatory dysfunction: Analysis of FDA ...
A recent analysis of drug induced taste and smell dysfunction identified up to 50% of the top 100 drugs of 2017 with the potential to induce chemosensory ...
[60]
Exposure to Particulate Matter Air Pollution and Anosmia
May 27, 2021 · In this study, long-term airborne exposure to PM 2.5 was associated with anosmia. Ambient PM 2.5 represents a potentially ubiquitous and modifiable risk factor.
[61]
Is air pollution causing us to lose our sense of smell? - BBC
Feb 20, 2023 · The simple question he wanted to answer was this: were a disproportionate number of anosmia patients living in areas of higher PM2.5 pollution?<|separator|>
[62]
On Sense and the Sensible by Aristotle - The Internet Classics Archive
For vaporous exhalation consists of mere water [which, being tasteless, is inodorous]; and fumid exhalation cannot occur in water at all, though, as has been ...
[63]
Lucretius | Internet Encyclopedia of Philosophy
The poet explains atomic motion and shapes and argues that the atoms do not have secondary qualities (color, smell, heat, moisture, etc.). Book 3. After a ...
[64]
(PDF) Cribriform Plate and Galen's Cribrum Romanum
Apr 16, 2016 · ... structure of the cribriform plate. The foramina allow the olfactory nerves to course through toward the olfactory bulb [3] [4][5]. The ...
[65]
Poor Human Olfaction is a Nineteenth Century Myth - PMC
May 12, 2017 · A myth – that humans are “microsmatic” animals with tiny olfactory bulbs and a very poor sense of smell compared to other animals.
[66]
https://link.springer.com/article/10.1007/s00420-023-01956-x
[67]
An otolaryngological tour of Vesalius' De Humani Corporis Fabrica
Mar 10, 2023 · This article explores the importance of this text to contemporary ENT, by demonstrating Vesalius' fresh, precise and hands-on approach to anatomy.
[68]
Then there were 12: The illustrated cranial nerves from Vesalius to ...
Mar 3, 2022 · This article describes the works of some of the great artists in the period from Vesalius to Soemmerring and how they used illustration to supplement and ...
[69]
Odors as cognitive constructs: history of odor classification and ...
Later, in the mid-1700's, Albrecht von Haller followed the ancients in employing hedonics, classifying odors into pleasant (e.g. ambrosial), foul (stenches), ...