Source: Module 4, Chapter 12 | Course: A Brain-Mind Odyssey (UC Berkeley)
Tags: olfaction, smell, olfactory receptor cells, olfactory receptor proteins, GPCRs, G-protein-coupled receptors, pseudogene, essential oil, aroma, thiols, anosmia, hyperosmia, olfactory bulb, pheromone, vomeronasal organ
Smell works through olfactory receptor cells in the nasal epithelium whose cilia carry G-protein-coupled receptor proteins (GPCRs). Humans have roughly 350 functional olfactory GPCRs (plus about 600 pseudogenes, remnants of a once-larger repertoire). Each odorant activates a unique subset of these receptors, producing a combinatorial "fingerprint" that allows discrimination of a vast number of smells. Neural signals travel from the olfactory bulb to pyriform cortex, amygdala, thalamus, and ultimately orbitofrontal cortex for conscious perception.
Olfaction
The action or capacity of smelling; the sense of smell.
Olfactory receptor cells
Neurons embedded in the nasal epithelium. Their cilia extend into the mucus lining the nasal passage and contain the receptor proteins that bind odorant molecules.
Olfactory stem cells
Cells within the nasal epithelium flexible enough to differentiate into various types of olfactory receptor cells. They replace receptor cells roughly every one to two months, compensating for damage caused by direct exposure to potentially toxic environmental substances.
Cilia (olfactory)
Filamentous structures extending from olfactory receptor cells into nasal mucus. They provide a large surface area packed with olfactory receptor proteins.
Olfactory receptor proteins (olfactory GPCRs)
G-protein-coupled receptors, each responsive to molecules with specific molecular shapes. Humans have about 350 functional olfactory GPCRs; mice have roughly 1,300; fish may have around 100.
Combinatorial odorant coding
The principle that a given odorant molecule activates a specific subset of olfactory GPCRs, each to a different degree. Different odorants activate different subsets, making it possible to discriminate a very large number of distinct smells from a limited receptor repertoire.
Pseudogene
A nonfunctional gene that resembles a gene coding for an olfactory GPCR but is altered so it does not produce a functional receptor protein. Humans carry about 600 olfactory pseudogenes, thought to be remnants of a more sophisticated ancestral sense of smell.
Essential oil
An oily concentrate of aromatic molecules from a plant. The oil is hydrophobic (aroma-carrying molecules tend to be hydrophobic) and is typically prepared by distillation, heating an extract and concentrating the more volatile components. "Essential" refers to the plant's essence or hallmark scent (from Latin esse, to be).
Aroma
From the Greek word for spice. Plant aromas are composed of dozens of different molecules that activate various combinations of olfactory receptor proteins when inhaled.
Thiols
Organic molecules containing an -SH (sulfhydryl) group. Examples include 2-butene-1-thiol, 3-methyl-1-butanethiol, and 2-quinolinemethanethiol. Often smell unpleasant. "Thio" refers to sulfur.
Specific anosmia
Reduced or absent sensitivity to a specific kind or category of smell. Example: inability to detect the distinctive odour of urine after eating asparagus.
General anosmia
Loss of sensitivity to a broad range of aromas, sometimes complete loss of smell. Causes include nasal congestion, head trauma, developmental factors, and degenerative brain disease.
Hyperosmia
Increased sensitivity to odours. Often appears transiently with migraine headaches. Women sometimes report hyperosmia during pregnancy.
Olfactory bulb
Structure located immediately above and adjacent to the nasal cavity. Olfactory receptor cell axons synapse here with dendrites of mitral cells. The axons of the receptor cells come together to form cranial nerve 1 (the olfactory nerve).
Pyriform cortex
A cortical region buried deep in the brain's interior. Receives input from mitral cells of the olfactory bulb. Sends axons onward to the thalamus.
Orbitofrontal cortex
Region of the frontal lobe that receives olfactory input (via thalamus) and is associated with conscious perception of aroma.
Pheromone
A chemical that carries signal information for social communication between members of the same species (from Greek pherein, to carry). Roles include identity recognition, social status, mate attraction, territorial marking, trail marking, and danger signalling. Best studied in insects. Thought to elicit innately programmed behaviours or biochemical changes.
Vomeronasal organ
A distinct olfactory sensory structure and neural pathway that responds somewhat selectively to pheromones. Present in many vertebrates. Its existence and functionality in humans and other primates remains debated.
Receptor cells sit in the nasal epithelium with cilia extending into the mucus lining
Cilia increase the surface area available for odorant binding
Olfactory stem cells replace receptor cells every one to two months, because direct environmental exposure causes cumulative cellular damage
Each GPCR responds to molecules of a particular shape
Species differ widely in receptor count:
Fish: ~100 olfactory GPCRs
Humans: ~350 functional olfactory GPCRs
Mice: ~1,300 olfactory GPCRs
A single odorant binds to multiple GPCRs at varying activation levels
Different odorants produce different activation patterns across the receptor set
This combinatorial scheme allows discrimination of far more odorants than the number of receptor types
Humans carry about 600 olfactory pseudogenes alongside their 350 functional receptors
These are thought to be remnants of a larger ancestral set
Evolutionary hypothesis: as primate ancestors moved from ground-dwelling to arboreal to upright posture, vision became more important and olfactory receptors were lost through mutation, though gene remnants persist
Plant aromas are complex mixtures of dozens of molecules, not single compounds
Essential oils are hydrophobic concentrates prepared by distillation
Thiols (containing -SH groups) are a class of molecules that tend to smell unpleasant
Specific anosmia: reduced or absent sensitivity to one category of smell
General anosmia: broad loss of olfactory sensitivity, with causes ranging from congestion to neurodegeneration
Hyperosmia: heightened olfactory sensitivity, sometimes seen with migraines or pregnancy
The signal path from nose to conscious perception:
Odorant binds to GPCRs on cilia of olfactory receptor cells
Receptor cell axons form cranial nerve 1 (olfactory nerve)
Axons synapse in the olfactory bulb with mitral cell dendrites
Mitral cells project to pyriform cortex and amygdala (limbic system)
Pyriform cortex projects to thalamus
Thalamus connects to orbitofrontal cortex of the frontal lobe, where conscious aroma perception arises
Pheromones are chemical signals between members of the same species
They play roles in identity, social status, mate attraction, territory, and danger
Many vertebrates have a vomeronasal organ that preferentially detects pheromones
Whether humans have a functional vomeronasal system remains an open question
⚠️ Understand combinatorial coding: know that a single odorant activates multiple GPCRs and that different odorants produce different activation patterns. This is a core principle for how ~350 receptors can discriminate thousands of smells.
⚠️ The olfactory pathway bypasses the thalamus initially (going straight to olfactory bulb and then pyriform cortex/amygdala), unlike most other senses. The thalamus is reached indirectly, via pyriform cortex.
⚠️ Be able to distinguish specific anosmia (one category) from general anosmia (broad loss). Know that hyperosmia is the opposite (increased sensitivity).
⚠️ Pseudogene count (~600) vs. functional receptor count (~350) in humans is a commonly tested fact.
⚠️ Olfactory receptor cells are regularly replaced (every 1–2 months) by stem cells. This is unusual for neurons.
Q: How does combinatorial coding allow humans to discriminate thousands of odours with only ~350 olfactory receptor types?
A: Each odorant molecule activates a unique subset of the 350 GPCRs, each to a varying degree of activation. The resulting pattern of activation across the receptor set forms a "fingerprint" for that odorant. Different odorants produce different patterns, so the number of discriminable smells vastly exceeds the number of receptor types.
Q: What is the olfactory neural pathway from receptor cell to conscious perception?
A: Odorant binds to GPCRs on olfactory receptor cell cilia. Axons of receptor cells form cranial nerve 1 and synapse in the olfactory bulb with mitral cells. Mitral cells project to the pyriform cortex and amygdala. Pyriform cortex then sends signals to the thalamus, which connects to the orbitofrontal cortex for conscious perception of aroma.
Q: Why do humans have about 600 olfactory pseudogenes?
A: They are thought to be remnants of a larger set of functional olfactory receptor genes possessed by evolutionary ancestors. As primates shifted from ground-dwelling to arboreal to upright living, vision became more important than smell, and many olfactory receptor genes accumulated mutations that rendered them nonfunctional.
Q: What is the difference between specific anosmia and general anosmia?
A: Specific anosmia is reduced or absent sensitivity to a particular category of smell (e.g. inability to detect asparagus-related urine odour). General anosmia is a broad loss of olfactory sensitivity across many or all categories, with causes ranging from nasal congestion to degenerative brain disease.
Q: Why are olfactory receptor cells replaced regularly, and what makes this possible?
A: Direct exposure to potentially toxic environmental substances causes cumulative cellular damage. Olfactory stem cells in the nasal epithelium differentiate into new receptor cells, replacing the old ones roughly every one to two months.
olfaction, smell, olfactory receptor cells, nasal epithelium, cilia, olfactory receptor proteins, GPCRs, G-protein-coupled receptors, combinatorial coding, pseudogene, essential oil, aroma, thiols, sulfhydryl group, specific anosmia, general anosmia, hyperosmia, olfactory bulb, mitral cells, pyriform cortex, amygdala, thalamus, orbitofrontal cortex, cranial nerve 1, olfactory nerve, pheromone, vomeronasal organ, olfactory stem cells