Sense of smell

The sense of smell, also known as olfaction, is the chemosensory detection of volatile odorant molecules in the environment, enabling organisms to perceive and discriminate among thousands of distinct scents through specialized neural pathways.^[1] In humans, olfaction is primarily mediated by the olfactory nerve (cranial nerve I), which transmits signals from the nasal cavity to the brain, playing essential roles in survival by identifying food safety, environmental hazards, and social cues.^[2] Anatomically, the olfactory system begins in the olfactory epithelium, a specialized tissue located at the roof of the nasal cavity near the cribriform plate of the ethmoid bone, covering an area of approximately 10 cm² in adults and containing millions of olfactory sensory neurons.^[1] These bipolar neurons feature cilia extending into a mucus layer that traps odorants, with their axons bundling to form about 20 olfactory fila passing through the cribriform plate to synapse in the olfactory bulb, which contains approximately 5,500 glomeruli per bulb for initial odor processing.^[1][3] Nasal turbinates and airflow dynamics further enhance odorant delivery to this region, while the trigeminal nerve (cranial nerve V) contributes to sensations like irritation from pungent smells.^[2] Physiologically, odorants dissolve in the nasal mucus and bind to G-protein-coupled receptors on the cilia of olfactory neurons, activating a signaling cascade involving adenylyl cyclase, cyclic AMP (cAMP), and calcium influx that depolarizes the neuron and generates action potentials.^[1] These signals converge in the olfactory bulb's glomeruli, where they are relayed via mitral and tufted cells through the olfactory tract to primary cortical targets like the piriform cortex, as well as limbic structures such as the amygdala and entorhinal cortex, bypassing the thalamus for direct emotional and memory integration.^[2] Humans possess approximately 400 functional olfactory receptor genes, encoding proteins that allow detection of a vast array of odorants at low concentrations, though sensitivity varies and declines with age.^[2][4] Beyond basic detection, olfaction profoundly influences human behavior and health, enhancing flavor perception in combination with taste, evoking memories and emotions through limbic connections, and serving as an early indicator of neurodegenerative diseases like Alzheimer's and Parkinson's, where up to 90% of patients experience impairment.^[2][5] Notably, the COVID-19 pandemic has emerged as a major cause of olfactory dysfunction. Olfactory dysfunction, or anosmia, affects about 24.5% of adults over 53 and 62.5% over 80 as of a 2002 study, often due to viral infections, trauma, or sinonasal issues, underscoring its vulnerability and clinical significance.^[1][6]

Historical Perspectives

Early Discoveries and Ancient Views

In ancient Greek medicine, the Hippocratic Corpus emphasized the sense of smell as a diagnostic tool, noting that the odor of a patient's breath or bodily excretions could indicate underlying diseases, such as foul smells associated with internal imbalances or infections.^[7] Hippocratic texts also advocated aromatic substances like herbs and fumigations to restore health by counteracting harmful vapors, reflecting a belief in olfaction's role in maintaining humoral equilibrium.^[8] Aristotle, in his work De Anima, described smell as a sense analogous to taste, perceiving odors through air as a medium, and classified them into categories like sweet and bitter, mirroring flavor distinctions, while viewing pleasant and unpleasant odors as subjective responses rather than nourishing qualities.^[9] He positioned olfaction as an intermediate sense between distant perception (like sight) and contact senses (like touch), influencing early philosophical understandings of sensory hierarchy.^[10] The Roman physician Galen advanced anatomical insights into olfaction, observing that the nasal passages connected directly to the brain via perforations in the ethmoid bone, allowing odors carried by inhaled air to reach sensitive neural structures for perception.^[11] Galen proposed that odoriferous particles traveled from the nasal cavity to the brain's olfactory regions, distinguishing this pathway from mucus drainage, and integrated these ideas with humoral theory to explain smell's effects on temperament and vitality.^[12] Cultural practices in ancient civilizations highlighted olfaction's ritual significance, as Egyptians burned incense like myrrh and frankincense in temple ceremonies to purify spaces, invoke deities, and facilitate spiritual connections, believing these scents bridged the human and divine realms.^[13] In Roman rituals, similar use of aromatic resins in sacrifices and public ceremonies evoked sensory experiences tied to piety and social order, with odors symbolizing offerings' acceptability to the gods.^[14] During medieval Islamic scholarship, Avicenna (Ibn Sina) synthesized Greek precedents in his Canon of Medicine, detailing the olfactory system's anatomy as originating in specialized protrusions within the brain's divided regions, accessible via nasal channels that processed scent vapors.^[15] He expanded on Galenic views by theorizing that smells influenced the soul through these pathways, contributing to a comprehensive doctrine of the senses that emphasized olfaction's role in cognition and health.^[16] These ideas persisted into the Renaissance, where anatomists like Berengario da Carpi refined descriptions of olfactory structures through dissections, providing detailed accounts of the meninges and cranial nerves including the olfactory nerve.^[17]

Modern Scientific Milestones

In the late 19th century, the foundations of olfactory psychophysics were established through systematic quantitative studies of odor perception thresholds and intensity scaling, pioneered by Hendrik Zwaardemaker, who developed methods to measure odor detection limits and categorize scents into descriptive classes, building on earlier sensory research traditions.^[18] These efforts marked a shift from qualitative observations to experimental precision, enabling the identification of just-noticeable differences in odor concentrations and influencing subsequent sensory measurement standards.^[19] A pivotal breakthrough occurred in 1991 when Linda Buck and Richard Axel identified a large family of genes encoding odorant receptors in mammals, revealing that approximately 1,000 such receptors enable the detection of diverse volatile molecules through G-protein-coupled mechanisms.^[20] Their work demonstrated that each olfactory sensory neuron expresses a single receptor type, with axons converging to form glomeruli in the olfactory bulb, thus elucidating the molecular basis of odor discrimination. For these discoveries, Buck and Axel shared the 2004 Nobel Prize in Physiology or Medicine, highlighting the genetic architecture underlying olfactory coding.^[21] Advancements in electrophysiological techniques further propelled olfactory research in the late 20th century, with the patch-clamp method—developed by Erwin Neher and Bert Sakmann—applied to isolated olfactory receptor neurons by the mid-1980s to record ion channel responses to odorants. This approach revealed cyclic nucleotide-gated channels activated by odor-induced second messengers, providing direct evidence of transduction currents in mammalian neurons.^[22] By the 2010s, optogenetics emerged as a transformative tool for olfaction, allowing precise light-mediated activation of channelrhodopsin-expressing olfactory neurons to dissect circuit dynamics and behavioral responses without chemical confounds.^[23] Studies using this technique, such as those mapping cholinergic modulation in the olfactory bulb, demonstrated how specific neuronal ensembles drive odor-guided behaviors like attraction or aversion.^[24] In the 2020s, single-cell RNA sequencing has unveiled extensive transcriptional diversity among olfactory sensory neurons, identifying distinct subtypes beyond traditional odorant receptor classifications, including non-canonical populations like Cd36-expressing cells with roles in lipid-derived odor detection.^[25] This technology, applied to mouse and human tissues, has mapped regulatory networks governing neuronal specification and plasticity, revealing how epigenetic factors orchestrate subtype differentiation during development.^[26] Concurrently, artificial intelligence has advanced odor mapping by constructing principal odor maps via graph neural networks trained on perceptual datasets, enabling prediction of molecular scents for over 500,000 untested compounds and unifying tasks like odor similarity and quality description.^[27] These AI models, validated against human psychophysical data, bridge chemical structure to sensory experience, with applications emerging by 2023 in fragrance design and olfactory diagnostics.^[28] More recent work as of 2024 has shown that human olfaction can detect rapid changes in odors within milliseconds, rivaling the speed of vision, while 2025 studies introduced 3D models of nasal tissue to better understand olfactory epithelium function.^[29][30]

Fundamental Mechanisms

Olfactory Detection Process

The olfactory epithelium, a pseudostratified neuroepithelium located in the superior nasal cavity of vertebrates, serves as the primary site for odor detection. It consists of several cell types, including olfactory sensory neurons (OSNs) with apical cilia extending into the mucus layer, sustentacular (supporting) cells that provide structural support and metabolic assistance to OSNs, and basal cells that act as progenitors for neuronal replacement. Bowman's glands, embedded in the underlying lamina propria, secrete a seromucous fluid that forms a protective mucus layer over the epithelium, facilitating odorant solubility and transport to receptor sites.^[31][32] Odorants, volatile molecules dissolved in the nasal mucus, diffuse to the ciliary surface of OSNs where they bind to specific G-protein-coupled receptors (GPCRs), known as odorant receptors (ORs), embedded in the plasma membrane. This binding induces a conformational change in the OR, activating the associated heterotrimeric G-protein, specifically G_olf in vertebrates, which dissociates into Gα_olf and Gβγ subunits. The activated Gα_olf then stimulates adenylyl cyclase type III (ACIII), catalyzing the conversion of ATP to cyclic AMP (cAMP), thereby increasing intracellular cAMP levels.^[33][34] Elevated cAMP binds to and opens cyclic nucleotide-gated (CNG) ion channels, predominantly composed of CNGA2 subunits, on the ciliary membrane, permitting influx of Na⁺ and Ca²⁺ ions. This cation influx causes membrane depolarization, which further amplifies the signal through Ca²⁺-activated chloride channels (e.g., ANO2), leading to Cl⁻ efflux and additional depolarization. The signal transduction pathway can be summarized as: odorant binding to receptor → G_olf activation → adenylyl cyclase stimulation → cAMP production → CNG channel opening → Ca²⁺ influx and depolarization. These electrical changes generate action potentials in the OSN axon that project to the olfactory bulb.^[33][35] To prevent overstimulation and enable dynamic odor detection, adaptation mechanisms rapidly modulate the transduction process. Receptor desensitization occurs primarily through phosphorylation of the OR by G-protein receptor kinases (GRKs), such as GRK3, which recruits β-arrestin to uncouple the receptor from G_olf, thereby attenuating downstream signaling. Additionally, elevated Ca²⁺ levels activate calmodulin, which binds to and closes CNG channels, contributing to short-term adaptation.^[36][37]

Neural Pathways and Processing

Olfactory sensory neurons (OSNs) transmit signals from the olfactory epithelium to the olfactory bulb, the primary central relay station for olfaction, where axons converge in a structured glomerular layer. Each OSN expresses a single type of odorant receptor, and axons from OSNs sharing the same receptor type project to one or a few specific glomeruli, ensuring that odorant information is organized by receptor identity from the outset of central processing.^[38][39][40] This convergence creates discrete functional units, with the human olfactory bulb containing an average of approximately 5,500 glomeruli, far exceeding initial estimates and reflecting a high degree of spatial precision in odor mapping.^[41] Within these glomeruli, excitatory inputs from OSNs synapse onto the primary dendrites of second-order neurons, primarily mitral and tufted cells, which integrate and relay the signals forward.^[42] Mitral and tufted cells serve as the principal output neurons of the olfactory bulb, projecting their axons via the lateral olfactory tract to multiple cortical and subcortical targets that form the core of the olfactory cortex. The primary recipient is the piriform cortex, a paleocortical structure dedicated to initial odor representation and discrimination, followed by connections to the entorhinal cortex, which links olfaction to memory and spatial navigation via hippocampal pathways.^[43][44] Further projections reach the orbitofrontal cortex, a higher-order association area that integrates olfactory inputs with other sensory modalities and is critical for conscious odor perception and hedonic evaluation.^[45][46] These pathways lack a thalamic relay, allowing direct cortico-cortical transmission unique among sensory systems, which facilitates rapid and flexible processing of olfactory information.^[47] Olfactory signals are encoded through a combination of spatial and temporal mechanisms that preserve odor identity across brain regions. Spatial coding arises from the topographic glomerular maps, where distinct odors activate unique combinations of glomeruli, creating a distributed representation that mitral and tufted cells convey to downstream areas.^[48] Temporal coding complements this by modulating firing patterns, such as oscillatory rhythms and latency differences, which refine odor discrimination and concentration encoding.^[49] A key principle underlying this efficiency is sparse coding, in which only a small subset of neurons in the olfactory bulb or cortex activates per odor stimulus, enabling robust pattern separation with minimal metabolic cost and high information capacity.^[50][48] In addition to the main olfactory system, many vertebrates, particularly non-human species, possess an accessory olfactory system specialized for detecting pheromones and social cues, primarily via the vomeronasal organ (VNO). VNO sensory neurons express vomeronasal receptors and project axons to the accessory olfactory bulb, where they converge into glomeruli analogous to the main system but with broader receptive fields.^[51] Output from this bulb travels via mitral and tufted-like cells to the medial amygdala and then directly to the hypothalamus, bypassing the primary olfactory cortex to drive instinctive behaviors like mating and aggression without conscious awareness.^[51][52] This segregated pathway underscores the dual architecture of olfaction, with the accessory route emphasizing rapid, subcortical modulation of endocrine and autonomic responses.^[53]

Functions and Roles

Sensory Integration and Perception

The sense of smell profoundly influences flavor perception through retronasal olfaction, where odorants released during chewing travel from the mouth to the olfactory epithelium via the nasopharynx, integrating with gustatory signals to form a multisensory experience. This process accounts for approximately 80% of what is perceived as flavor, as demonstrated in psychophysical studies where blocking retronasal airflow significantly diminishes taste intensity ratings for sweet and bitter stimuli.^[54] Retronasal olfaction thus enhances the salience of food-related odors, creating a unified percept that distinguishes flavor from mere taste.^[55] Olfaction also interacts with vision to guide attentional processes, such as when congruent odors direct gaze toward matching visual objects, improving detection speed and accuracy in cluttered scenes. For instance, the scent of strawberries can bias visual search toward images of strawberries, reflecting cross-modal facilitation at early perceptual stages.^[56] Interactions with audition are evident in rare cases of auditory-olfactory synesthesia, where sounds involuntarily evoke specific odors, or in broader cross-modal effects where olfactory stimuli modulate auditory processing in the olfactory bulb.^[57] These integrations highlight olfaction's role in multisensory binding, potentially rooted in shared neural coding mechanisms in higher cortical areas.^[58] Perceptual phenomena in olfaction include illusions like "olfactory white," where mixtures of 30 or more equi-intense odorants spanning physicochemical space converge to a neutral, indistinct quality analogous to white noise in audition.^[59] Hedonic valence—judgments of pleasantness or unpleasantness—is a primary dimension of odor perception, with activation in the orbitofrontal cortex (OFC) differentiating positive and negative odors; for example, pleasant scents engage medial OFC regions, while unpleasant ones activate lateral areas, influencing emotional responses.^[60] Human olfactory thresholds vary widely but can reach extreme sensitivity, as seen with mercaptans like ethyl mercaptan, detectable at concentrations as low as 0.4 parts per billion (ppb), enabling early warning for hazards like gas leaks.^[61] Discrimination abilities are similarly acute, with just-noticeable differences (JNDs) in odor intensity influenced by trigeminal components; odors with stronger irritant properties yield lower JNDs, allowing finer perceptual resolution.^[62] A 2014 study estimated that humans can discriminate among more than one trillion distinct olfactory mixtures, though this figure has been challenged by subsequent analyses suggesting a substantially lower capacity, underscoring the system's capacity for nuanced perception.^[63][64]

Behavioral and Survival Applications

The sense of smell plays a crucial role in food detection and foraging, enabling animals to identify nutritious sources and avoid harmful substances. Many frugivorous species, such as elephants, rely on olfactory cues to assess fruit ripeness by detecting volatile organic compounds emitted during maturation, which signal higher sugar content and palatability.^[65] For instance, African elephants can distinguish between ripe and unripe fruits based solely on scent, optimizing their energy intake in resource-scarce environments.^[65] Similarly, spider monkeys use chemical signatures from fruit volatiles to select ripe specimens, associating specific odors with nutritional quality during foraging.^[66] In addition to attraction to beneficial foods, olfaction aids in toxin avoidance; bitter almonds, containing the cyanogenic glycoside amygdalin, produce a characteristic almond-like odor primarily from benzaldehyde released during hydrolysis, serving as a warning against ingestion since amygdalin can yield toxic hydrogen cyanide, which is lethal in high doses.^[67][68] This sensory mechanism integrates with taste to enhance overall flavor perception and safety in feeding behaviors.^[69] Olfaction contributes to inbreeding avoidance by allowing individuals to detect genetic compatibility through major histocompatibility complex (MHC) odor cues, which influence mate selection in various species. In rodents, such as mice, MHC-disparate individuals produce distinct body odors that females prefer, promoting genetic diversity and reducing the risk of deleterious recessive traits from close kin mating.^[70] This preference is mediated by volatile peptides from MHC proteins, enabling olfactory discrimination of kin versus non-kin.^[71] Evidence in humans similarly shows that women rate the body odors of MHC-dissimilar men as more pleasant, suggesting an evolutionary adaptation for outbreeding, though this effect may be modulated by factors like oral contraceptives.^[72] Such MHC-dependent olfactory signaling underscores smell's role in reproductive fitness by facilitating choices that enhance offspring viability.^[73] Pheromonal communication via olfaction is essential for mating, territory marking, and kin recognition, coordinating social and reproductive behaviors in insects and mammals. In social insects like ants, trail pheromones—volatile hydrocarbons deposited during foraging—guide colony members to food sources and reinforce territorial boundaries, with alarm pheromones triggering defensive aggregation.^[74] Mammals, including rodents, employ pheromones from glands to mark territories, signaling ownership and deterring intruders while attracting potential mates during estrus.^[75] For kin recognition, social insects and mammals use colony-specific odor signatures, derived from cuticular hydrocarbons or urinary volatiles, to distinguish relatives and allocate cooperative behaviors like alloparenting.^[76] These chemical signals ensure reproductive success by synchronizing mating and maintaining social cohesion.^[77] Olfactory navigation supports survival through scent-based orientation and homing, as seen in insects and fish. Ants follow pheromone trails laid by foragers, using volatile cues to navigate complex terrains and return to nests efficiently, with trail strength modulating path choices based on food profitability.^[74] In salmon, olfactory imprinting during early life stages allows juveniles to memorize natal stream odors, enabling precise homing for spawning years later via detection of specific waterborne chemicals.^[78] This mechanism integrates with geomagnetic cues in some species but relies primarily on smell for fine-scale river navigation, ensuring reproductive site fidelity despite long migrations.^[79]

Genetic Foundations

Olfactory Receptor Genes

The olfactory receptor (OR) genes constitute the largest multigene family in the human genome, encoding G protein-coupled receptors that detect odorant molecules. In humans, approximately 400 of these genes are functional, out of a total of around 800 OR genes including pseudogenes. These genes are organized in clusters distributed across nearly all chromosomes, with major clusters located on chromosomes 1, 6, and 11. The pseudogene ratio is notably higher in humans compared to other mammals, such as dogs, where only about 18% of OR genes are pseudogenes, reflecting differences in olfactory reliance.^[4][80][81] Vertebrate OR genes are phylogenetically divided into two main classes: class I, which are fish-like and primarily expressed in zone 1 of the olfactory epithelium, and class II, which are terrestrial-specific and expressed in zones 2 through 4. This zonal expression pattern ensures spatial organization in the olfactory sensory neurons, contributing to the specificity of odor detection. Gene regulation involves dedicated promoters proximal to each OR gene and multiple enhancers, such as the Greek islands and Pegasus elements, that drive transcription in specific epithelial zones. A key feature is monoallelic expression, where each olfactory neuron selects and expresses only one allele of a single OR gene, ensuring singular receptor choice per cell.^{[82][83][84][85]} Evolutionary pseudogenization has significantly reduced the functional OR repertoire in humans, with about 60% of OR genes classified as pseudogenes, compared to only 18% in mice. This high rate of pseudogenization is associated with a diminished reliance on olfaction in human evolution, possibly due to enhanced visual capabilities and bipedalism. These genetic changes underlie the foundational role of OR genes in the olfactory detection process, where expressed receptors bind odorants to initiate sensory signaling.^[86][87][88]

Genetic Diversity and Evolution

Genetic diversity in olfactory receptor (OR) genes contributes significantly to individual differences in odor perception among humans. Single nucleotide polymorphisms (SNPs) and deletions in OR genes can lead to specific anosmias, where individuals are unable to detect particular odors. A well-documented example is the OR7D4 gene, which encodes a receptor sensitive to androstenone, a steroidal compound found in sweat and pork; variants such as the RT/WM haplotype in OR7D4 reduce or eliminate perception of this odor in approximately 30% of the population, leading to specific anosmia.^[89] These polymorphisms highlight how subtle genetic variations can alter olfactory sensitivity without affecting overall smell function, influencing experiences like food preferences or social cues derived from body odors.^[90] Evolutionary pressures have shaped the size and composition of OR gene repertoires across vertebrate lineages, reflecting adaptations to environmental demands. In aquatic vertebrates, such as teleost fish, the OR gene family has undergone significant expansion, with over 100 functional genes in some species dedicated to detecting water-soluble odorants like amino acids, which are crucial for foraging and navigation in aquatic habitats. Conversely, in primates, including humans, there has been a notable contraction of the OR repertoire—down to about 400 functional genes from an ancestral mammalian estimate of around 1,000—correlated with the evolutionary shift toward enhanced visual reliance and reduced dependence on olfaction for survival.31060-0) This trade-off illustrates how sensory priorities drive genetic changes, with pseudogenization of OR genes in hominids potentially linked to adaptations in social and dietary behaviors. Twin studies provide evidence for a substantial genetic basis underlying variations in olfactory sensitivity. Analyses of monozygotic and dizygotic twins indicate that heritability accounts for 40-60% of the variance in odor identification, intensity perception, and threshold detection, with the remainder attributed to environmental factors.^[91] These estimates underscore the interplay between genetics and experience in shaping olfactory abilities, as shared environments explain only a minor portion of differences. Recent advancements in gene therapy have explored the potential to address defects causing olfactory dysfunction in animal models of ciliopathies, offering insights into therapeutic restoration of olfaction. A 2021 study in a mouse model of the ciliopathy Bardet-Biedl syndrome demonstrated that adenoviral-mediated delivery of wild-type BBS1 can restore olfactory cilia structure and partially recover olfactory signaling and behavioral responses to odors.^[92] Such findings highlight the feasibility of precision interventions for genetic olfactory disorders, though challenges remain in translating these to humans.

Comparative Olfaction

Across Vertebrates

The sense of smell in vertebrates exhibits remarkable diversity, shaped by evolutionary adaptations to diverse environments, from aquatic to terrestrial habitats. Olfactory systems across vertebrate classes vary in receptor types, neural organization, and sensitivity, reflecting ecological demands such as foraging, predation, and navigation. While all vertebrates share a basic chemosensory architecture involving olfactory epithelia and central processing in the brain, differences in receptor gene repertoires and accessory structures underscore specialized functions. In fish, olfaction primarily detects water-soluble odorants through G-protein-coupled receptor (GPCR) mechanisms, such as vomeronasal-like receptors and trace amine-associated receptors, which are optimized for amino acids and other hydrophilic molecules essential for locating prey or mates in aquatic environments. These systems achieve extraordinary sensitivity; for instance, sharks can detect blood (specifically amino acids like glycine) at dilutions as low as 1 part in 10 million, enabling them to sense injured prey from kilometers away. This high acuity is facilitated by a large olfactory epithelium and direct neural projections to the pallium, bypassing more complex processing seen in tetrapods. Amphibians and reptiles possess bimodal olfactory systems capable of processing both water- and air-borne odorants, an adaptation to their semi-aquatic or transitional lifestyles. In amphibians like frogs, the main olfactory epithelium handles aqueous cues during larval stages, while adults rely more on volatile detection; reptiles extend this versatility with the vomeronasal organ (VNO), or Jacobson's organ, which in lizards and snakes allows tongue-based sampling of pheromones and environmental scents by delivering them to the organ's sensory lining. This accessory structure enhances chemoreception for social signaling and hunting, with reptiles showing a higher density of vomeronasal receptors compared to the main olfactory system. Birds generally have a reduced olfactory capability relative to other vertebrates, with approximately 500 functional olfactory receptor (OR) genes, a contraction from the ancestral vertebrate repertoire, reflecting their emphasis on vision and audition. However, certain species feature macroglomeruli in the olfactory bulb—enlarged synaptic structures—for processing food-related odors, aiding in foraging; procellariiform seabirds, for example, use smell to locate prey patches at sea. In migratory birds like pigeons, olfaction contributes to navigation, with experiments showing they can home using odor cues alone when visual landmarks are obscured. This olfactory role, though secondary, integrates with geomagnetic and visual senses for orientation. Mammals display a broad spectrum of olfactory prowess, with macrosmatic species—those relying heavily on smell—showing expansions in OR genes; dogs, for instance, possess around 1,100 functional OR genes, enabling discrimination of scents at sensitivities up to 300 times greater than humans, crucial for tracking and detection tasks. This genetic expansion correlates with an enlarged olfactory bulb and vomeronasal system, supporting roles in predation, social bonding, and territory marking. In contrast, microsmatic mammals like primates have fewer OR genes (around 400 in humans), prioritizing other senses, yet retain functional olfaction for flavor perception and hazard detection.02745-7)

In Invertebrates and Other Animals

Invertebrate olfactory systems exhibit remarkable diversity, adapted to aquatic, terrestrial, and aerial environments, with chemosensory structures often integrated into appendages like antennae or antennules. In insects, olfaction primarily occurs through specialized sensilla on the antennae, which house olfactory receptor neurons that detect volatile odorants. These sensilla contain odorant-binding proteins (OBPs) that solubilize and transport hydrophobic odor molecules across the sensillar lymph to the receptors on the neuronal membrane.^[93] Insects utilize two main receptor types: conventional odorant receptors (ORs), which are heteromers of a tuning OR and the co-receptor Orco forming ligand-gated ion channels, and ionotropic receptors (IRs), which are variant ionotropic glutamate receptors functioning as ligand-gated cation channels for detecting a broader range of cues including pheromones and general odorants.01002-6) Pheromone detection in moths, for instance, involves specialized ORNs projecting to the macroglomerular complex (MGC) in the antennal lobe, a male-specific structure where individual glomeruli process specific pheromone components to elicit oriented flight behaviors toward mates.^[94][95] Crustaceans, as aquatic arthropods, rely on antennular aesthetascs—tufts of hair-like sensilla on the antennules—for detecting water-borne odors, enabling behaviors such as foraging, mating, and predator avoidance. These aesthetascs contain olfactory sensory neurons (OSNs) that express a variety of chemoreceptors, including gustatory receptors (GRs) and ionotropic receptors (IRs), alongside G protein-coupled receptors (GPCRs) resembling vertebrate ORs in decapods like lobsters.^[96][97] In species such as the spiny lobster Panulirus argus, these OR-like GPCRs are tuned to amino acids and peptides in seawater, facilitating prey localization through plume tracking.^[98] The olfactory signals are processed in the antennular lobe, analogous to the insect antennal lobe, where OSN axons converge into glomeruli for initial odor coding.^[99] Cnidarians, basal metazoans lacking a centralized brain, possess simple chemosensory cells distributed across their epidermis that detect dissolved chemical cues for prey capture and environmental navigation. These cells, often nematocyte-associated or free-standing, express G protein-coupled receptors (GPCRs) and other chemoreceptors to sense amino acids and peptides, triggering feeding responses in polyps and medusae.^[100] Such rudimentary chemosensation represents an evolutionary precursor to the more complex bilaterian olfactory systems, providing insights into the origins of metazoan chemical signaling.^[101] Recent advances in connectomics have illuminated the fine-scale organization of invertebrate olfactory circuits, particularly in the fruit fly Drosophila melanogaster. Electron microscopy reconstructions from the 2020s have mapped the antennal lobe's approximately 50 glomeruli, revealing distinct synaptic motifs where broadly tuned glomeruli integrate diverse odor inputs via extensive local neuron connections, while narrowly tuned ones, such as those for pheromones, exhibit specialized circuitry for precise behavioral outputs.^[102] These glomerular modules parallel the functional segregation seen in vertebrate olfactory bulbs, underscoring conserved principles in odor coding across phyla.^[103]

Olfaction Beyond Animals

Volatile Detection in Plants

Plants perceive airborne volatile organic compounds (VOCs) through specialized receptor proteins that initiate signaling cascades, enabling responses to environmental cues without a centralized nervous system. Unlike animal olfaction, which relies on G-protein-coupled receptors in olfactory neurons, plant detection involves membrane-bound receptors such as those for the gaseous hormone ethylene, including ETR1 and ERS1, which bind ethylene directly to modulate downstream gene expression via histidine kinase signaling. For jasmonic acid derivatives like the volatile methyl jasmonate (MeJA), perception occurs through the COI1-JAZ co-receptor complex, which ubiquitinates repressor proteins to activate defense-related transcription factors. Emerging research also implicates KARRIKIN INSENSITIVE2 (KAI2) as a key receptor in a broader pathway for detecting stress-induced VOCs, facilitating inter-plant communication by integrating signals from diverse airborne molecules.^[104] Upon detecting these volatiles, plants trigger rapid physiological responses, often involving induced defenses against herbivores or pathogens. For instance, when tomato plants (Solanum lycopersicum) are infested by herbivores like the beet armyworm (Spodoptera exigua), they release herbivore-induced plant volatiles (HIPVs) such as (E)-β-ocimene and (3E)-4,8-dimethyl-1,3,7-nonatriene, which attract predatory wasps (Cotesia marginiventris) to parasitize the herbivores, thereby reducing damage to the plant.^[105] These responses are mediated by jasmonic acid signaling, leading to transcriptional reprogramming that enhances volatile emission within hours of perception.^[106] Volatile detection also underpins plant communication, including kin recognition and pollinator attraction. In kin recognition, receiver plants exposed to VOCs from damaged relatives exhibit enhanced defense responses compared to those from non-kin; for example, in sagebrush (Artemisia tridentata), volatiles from clipped kin neighbors reduce subsequent herbivory on receivers by up to 42% more effectively than those from strangers, indicating kin-specific communication for mutual protection.^[107] Floral scents, composed of VOC blends like monoterpenes and benzenoids, serve to attract specific pollinators; for example, petunia flowers (Petunia hybrida) emit volatile methyl benzoate to draw nocturnal moths, with emission rhythms synchronized to pollinator activity for optimal reproductive success.^[108] Evolutionarily, plants have adapted volatile detection as a sessile strategy for environmental monitoring, relying on decentralized signaling rather than neural processing. Perception of GLVs, for instance, induces cytosolic calcium waves that propagate systemically, activating calcium-dependent protein kinases and altering gene expression for defense priming without requiring a nervous system.^[109] This calcium-mediated transduction, coupled with changes in reactive oxygen species and hormone levels, allows rapid acclimation to threats, highlighting the sophistication of plant chemical sensing despite the absence of specialized sensory organs.

Engineered and Artificial Systems

Engineered and artificial systems aim to replicate the olfactory capabilities of biological noses through sensor arrays and computational processing, enabling machines to detect and identify volatile compounds. Electronic noses (e-noses) typically consist of an array of gas sensors, such as metal-oxide semiconductor (MOS) sensors, that respond to volatile organic compounds (VOCs) by generating electrical signals based on changes in resistance or conductance. These signals form a pattern that is analyzed using pattern recognition algorithms, like principal component analysis (PCA) or artificial neural networks (ANNs), to classify odors without identifying individual molecules.^[110] For instance, in food quality control, e-noses have been employed to monitor freshness and detect spoilage in products like meat and dairy by recognizing patterns indicative of bacterial contamination or oxidation.^[111] Bio-inspired designs draw from biological olfaction to enhance sensor performance, incorporating synthetic G-protein-coupled receptors (GPCRs) or nanomaterials that mimic olfactory receptors (ORs) for improved selectivity. These systems often integrate nanomaterials, such as carbon nanotubes functionalized with peptides derived from OR binding sites, to simulate the molecular recognition in biological noses. In the 2020s, advancements in AI have further refined these designs; deep learning models, including convolutional neural networks (CNNs), have achieved classification accuracies exceeding 90% for complex odor mixtures by processing sensor data as images or time-series inputs.^[112] For example, hybrid CNN-linear discriminant analysis (LDA) models have demonstrated 93% accuracy in distinguishing environmental pollutants.^[113] Such bio-mimetic approaches provide a brief nod to biological transduction mechanisms, where odorants bind to receptors to trigger signaling cascades.^[114] Applications of these systems span security, healthcare, and environmental monitoring. In explosive detection, e-noses equipped with polymer or MOS sensors identify trace vapors from nitroaromatic compounds, offering portable alternatives to canine detection with response times under 10 seconds.^[115] For medical diagnostics, breath analysis via e-noses detects disease biomarkers, such as VOCs associated with lung cancer, enabling non-invasive screening with sensitivities comparable to traditional methods.^[116] In robotics, drone-mounted e-noses facilitate real-time environmental monitoring, mapping odor plumes from wastewater treatment plants or industrial emissions to localize pollution sources over large areas.^[117] Despite progress, engineered olfactory systems face significant challenges compared to their biological counterparts, particularly in sensor specificity and long-term stability. MOS sensors often suffer from cross-sensitivity to humidity and interfering gases, leading to reduced selectivity for target odors, whereas biological noses achieve high specificity through diverse receptor tuning.^[118] Additionally, sensor drift—gradual shifts in baseline response over time due to environmental factors or material degradation—necessitates frequent recalibration, limiting reliability in field applications and contrasting with the adaptive homeostasis of living olfactory epithelia.^[119] Ongoing research focuses on drift compensation algorithms and hybrid bio-electronic interfaces to bridge these gaps.^[120]

Societal and Pathological Dimensions

Cultural Representations of Smell

Across human languages, odor vocabulary remains notably limited compared to other sensory domains, with most cultures possessing only a handful of basic terms for smells. Cross-cultural research indicates that while Indo-European languages like English typically feature around four primary odor categories (e.g., "stinky," "fruity," "spicy," "burnt"), some non-industrialized languages exhibit richer lexicons, such as the Maniq foragers of Thailand, who use over a dozen dedicated terms to describe specific olfactory qualities. This variation underscores smell's abstract nature in linguistic expression, often relying on metaphors that link odors to moral or social concepts, as in the English idiom "stinking rich," which equates foul smells with excess or corruption.^{[121][122][123]} Historically, smell has been integral to cultural and religious practices, particularly through the use of perfumes and incenses. In ancient Egypt, kyphi—a sacred compound of up to 16 ingredients including resins, honey, wine, and spices—was burned in temples for rituals, believed to appease gods and promote healing, reflecting the society's view of aromas as bridges between the earthly and divine realms. During the Renaissance in Europe, perfumes gained prominence among the elite to counteract body odors resulting from infrequent bathing, with alcohol-based formulations like rosemary-infused "Queen of Hungary Water" marking innovations in scent application for social status and hygiene.^[13][124] Literature has long captured smell's evocative power, as seen in Marcel Proust's In Search of Lost Time (1913–1927), where the aroma of a madeleine cake steeped in lime-blossom tea triggers an involuntary flood of childhood memories for the narrator, illustrating olfaction's unique capacity to bypass conscious recall and access the subconscious. This "Proustian moment" has influenced cultural understandings of smell as a profound mnemonic device.^[125] Cultural attitudes toward body odor reveal stark contrasts, with Western societies often imposing taboos that equate natural scents with uncleanliness or social deviance, driving the deodorant industry's growth since the early 20th century. In contrast, some Indigenous groups, such as certain Amazonian communities, view unmasked body odors as neutral or even integral to identity and social bonding, without the stigma prevalent in industrialized contexts.^[126][127] In contemporary arts and technology, smell is increasingly harnessed for immersive experiences. Olfactory installations, like Norwegian artist Sissel Tolaas's scent-based works exploring urban and human odors, have appeared in major venues such as the Institute of Contemporary Art in Philadelphia (2022), challenging viewers to engage with aroma as an artistic medium. By 2025, virtual reality scent technologies have advanced, incorporating olfactory displays that release targeted aromas during simulations—such as in therapeutic VR games for cognitive training—enhancing multisensory immersion and emotional depth.^{[128][129][130]}

Disorders and Clinical Impacts

Olfactory disorders include several conditions that disrupt normal smell perception. Anosmia represents the total inability to detect odors, whereas hyposmia denotes a diminished capacity to sense smells.^[131] Parosmia involves the distortion of odors, leading to incorrect perceptions of scents, and phantosmia manifests as the hallucination of smells without any external stimulus.^[132][133] These qualitative and quantitative impairments can significantly affect quality of life, nutrition, and safety by reducing detection of hazards like smoke or spoiled food. Causes of olfactory dysfunction are broadly classified as congenital or acquired. Congenital forms often stem from genetic anomalies, such as Kallmann syndrome, a rare disorder with a prevalence of approximately 1 in 30,000 to 50,000 individuals, occurring more frequently in males (1 in 30,000) than females (1 in 125,000), characterized by anosmia or hyposmia alongside delayed puberty due to hypogonadotropic hypogonadism.^[134][135] Acquired causes predominate in clinical practice and include viral upper respiratory infections, with COVID-19 leading to temporary olfactory loss in 50-80% of cases through mechanisms like epithelial inflammation and viral persistence in the olfactory mucosa. Long-term studies as of 2025 show that up to 66% of individuals with prior COVID-19 infection but no self-reported change exhibit hyposmia on testing, highlighting persistent subclinical effects.^{[136][137][138]} Other common etiologies encompass head trauma, which damages olfactory nerves or bulbs in up to 15% of severe cases, and neurodegenerative conditions like Parkinson's disease, where hyposmia affects over 90% of patients and often emerges years before motor symptoms.^[136][138] Diagnosis relies on objective assessments to differentiate and quantify impairment. Standardized psychophysical tests, such as the University of Pennsylvania Smell Identification Test (UPSIT), evaluate odor identification through a 40-item scratch-and-sniff format, yielding scores that classify anosmia (below 20), hyposmia (20-34), or normosmia (above 34) while accounting for age and gender norms.^[139] Structural evaluation via magnetic resonance imaging (MRI) detects olfactory bulb atrophy or volume reduction, which correlates with chronic dysfunction and helps rule out tumors or congenital malformations.^[140] Management strategies target underlying causes and promote recovery where possible. Olfactory training, involving daily exposure to essential oils like rose, lemon, clove, and eucalyptus for 20-30 seconds each over 3-6 months, achieves recovery rates of 30-50% in postviral and posttraumatic hyposmia by stimulating neural plasticity.^[141] Corticosteroids, such as oral prednisone or intranasal sprays, address inflammatory causes like postviral sinusitis, with short courses (1-2 weeks) improving function in 25-40% of select cases, though evidence is mixed for COVID-19-related loss.^[142] For congenital genetic disorders like Kallmann syndrome, hormone replacement remains standard, but research into gene therapies targeting mutations in genes such as ANOS1 is ongoing, with recent identification of novel variants as of 2025.^[143]