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Bi / CNS 150
Lecture 16
Wednesday, November 5, 2014
Olfaction
Bruce Cohen
Reading: Kandel Chapter 32, pp 712-726 (not taste)
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Olfactory memory
•The nose can detect and (in principle)
classify thousands of different
compounds.
•The ‘mapping’ of these compounds
probably occurs by matching to
memory templates stored in the brain
• A smell is categorized based on one’s
previous experiences of it and on the
other sensory stimuli correlated with its
appearance.
2
Olfactory system can distinguish stereoisomers of a compound
Carvone
Stereo center
•The nose can distinguish
similar compounds, such as
chemical isomers, as different
smells.
•An example: the two
stereoisomers of carvone smell
like spearmint (R) and caraway
(S).
•This implies that there are
stereoisomer-specific carvone
receptors.
•Also implies that odorant
receptors are proteins
3
Anatomy of the mammalian olfactory system
In many mammals (rodent shown here), the
olfactory organs within the nose are split
into the main olfactory epithelium (MOE)
and the vomeronasal organ (VNO).
MOE neurons project to the main olfactory
bulb (MOB).
VNO neurons project to the accessory
olfactory bulb (AOB).
MOB output neurons project to regions of
cortex, while AOB output neurons project
only to the (ventral) amygdala.
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Cells of the mammalian main olfactory epithelium
To olfactory bulb
Basal
cells
Axon
Olfactory neurons have
apical dendrites with long
ciliary extensions, where
the transduction
components are located.
Olfactory
sensory
neuron
Dendrite
Supporting
cells
Mucus
Cilia are embedded in the
mucus layer.
Olfactory neurons turn over
and are replaced every 60
days.
Cilia
Figure 32-2
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Olfactory receptor proteins in vertebrates and most other phyla
(except insects which use ligand-gated channels)
•Odorants bind to 7-helix (G-protein coupled) receptors.
•In mice, >1000 genes (2-3% of genes!) encode these receptors.
•Humans have about 350 odorant receptors
•Receptor sequences also are quite variable, especially in putative
odorant-binding helices.
•Thus, the repertoire of receptors is extremely diverse.
•In mammals, each neuron probably expresses only a single receptor.
•Surprisingly, odorant receptors were recently found in human skin cells,
and are also expressed in liver, heart, kidney, and even sperm cells
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•Odorant binding and signal transduction occurs in the cilia (top left)
•Amino-acid sequences of odorant receptors are highly variable (black dots indicate
most variable residues) (bottom left)
•Odorant binding to GPCR triggers a cascade that opens a cAMP-gated cation
channel (right)
7
Olfactory neurons have
cAMP-activated Na+/Ca2+ Channels
receptor
G protein
i q s t
effector
channel enzyme
Excised
“inside-out” patch
allows access
to the inside surface
of the membrane
+cAMP
intracellular
messenger
cAMP
Ca2+ cGMP
channel
no cAMP
no channel openings
open
+cAMP
closed
8
More about olfactory channels and their role in olfactory transduction
Olfactory cAMP-gated channels are permeable to Na+ and Ca2+
Thus, odorant binding causes depolarization of the olfactory neuron through
Na+ entry.
Ca2+ also enters and activates a Cl - channel, increasing depolarization (ECl
is near zero in these cells).
This process stimulates the olfactory neuron to fire action potentials.
9
Olfactory
bulb
Olfactory
epithelium
Expression zones of 4 individual olfactory receptors
(rat nose, coronal section)
Olfactory
receptor
K20
The olfactory turbinates display four ‘expression zones’.
Each receptor is expressed in a small, randomly
K21
distributed subset of neurons within one of the 4 zones
.
There are ~1000 receptors within a zone.
L45
Neurons within each expression zone send axons to a
A16
different quadrant of the olfactory bulb.
Another gene class, expressed in all olfactory neurons
Figure 32-5
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Projections
to the olfactory bulb
To lateral olfactory tract
Olfactory neurons send axons to the glomeruli (synaptic
balls shielded by glia) of the olfactory bulb.
Olfactory neurons excite mitral cells, which are the bulb
glomus, ball of yarn (Latin)
output cells.
like a bishop’s miter (hat)
Inhibitory
Mitral cell
Tufted
cell
Periglomerular cell
perforated (Latin)
Olfactory sensory neuron
Figures 32-1, 32-6
11
Each glomeruli receives inputs from sensory neurons
expressing the same odorant receptor
Neurons expressing a specific
olfactory receptor project their
axons to a single glomerulus in
each half-bulb.
Axons converge from many
directions onto the target.
This projection specificity is at
least partly determined by the
receptor itself, but the
mechanisms are unknown.
12
Mapping glomerular odorant responses: Ca2+ imaging in a fish
Individual glomeruli are
selectively activated by
specific odorants.
In fish, “odorants” are
soluble amino acids.
Imaging studies now show
that specific glomeruli in
mammals are also
activated in response to
odorants.
13
Maps of mitral cell projections to higher olfactory areas
Piriform cortex neurons receive projections from mitral cells corresponding to
many glomeruli that receive input from ORNs expressing different receptors.
Mitral cells also project to olfactory tubercle and other areas.
Integration of odorant responses and odorant identification may take place in
cortex, although some integration is also likely to occur in the bulb.
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The vomeronasal organ
The VNO is thought to respond to pheromones.
It is a cup-shaped organ near the front of the rodent nose; its neurons are
divided into basal and apical (near the lumen) layers.
The microvilli of the VNO neurons face the lumen.
Neurons in the apical layer express the G protein α subunit Gαi2, while those in
the basal layer express Gαo.
The transduction channel and the receptors are located on the microvilli at the
edge of the lumen.
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VNO receptor molecules
The 2 distinct families of VNO G protein-coupled receptors are all unrelated to MOE receptors.
Each VNO neuron probably expresses only one odorant receptor, as in the MOE.
V1Rs (~180 genes) are expressed by
V2Rs (~100 genes in the rodent) are
different subsets of neurons within the
expressed in a random pattern by basal layer
apical layer (Gi-expressing neurons).
neurons (Go-expressing neurons). V2Rs have
large N-terminal extracellular domains.
Figure 32-9
16
The GPCR pathway in a VNO cell
resembles the Gq pathway
receptor
G protein
i q s t
effector
channel enzyme
intracellular
messenger
Ca2+
cAMP
cGMP
IP3
DAG
channel
17
(like the GPCR lecture)
VNO signal transduction
TRPC2 channel
phosphatidyl inositol
4,5 bisphosphate = PI(4,5)P2
Like Alberts 15-36
© Garland
18
Response characteristics of VNO neurons
VNO neurons respond to urine.
Some neurons selectively respond to urine from mice of the same sex,
others to urine of the opposite sex.
Unlike ORNs, their responses are narrowly tuned; no neurons were ever
observed to respond to more than one compound.
A behavioral assay: mice produce ultrasonic calls (‘whistling’) in response
to contact with urine from the opposite sex; production of these calls
requires both the VNO and the MOE.
In TRPC2 knockout mice, VNO neurons do not respond to urine; and mice
do not vocalize in response to urine
19
Acessory olfactory bulb (AOB) projections to the brain
Mitral cells in the AOB have apical dendrites that arborize in multiple glomeruli.
The AOB projects to the amygdala (directly), and the hypothalamus (via the
amygdala).
The projections from the rostral and caudal AOB halves are superimposed in the
amygdala.
This implies that integration of pheromone signals may take place primarily in the
AOB.
20
Odorant perception by the vomeronasal system is
largely unconscious
•The main olfactory system mediates cortical responses to volatile odorants, and
these cortical responses are used to drive conscious behavior (food-seeking,
predator avoidance, etc).
•The VN system is thought to mediate unconscious responses to water-soluble
pheromone compounds found in urine and secretions of other individuals.
•Despite the apparent absence of the vomeronasal organ in humans, we still
apparently detect and respond to some pheromones, including ones that control
the menstrual cycle
21
Chemical composition of pheromones
The various pheromones include
prostaglandins in fish,
androstenone in pigs, and
protein ligands such as hamster aphrodisin.
In most cases, however, individual pure compounds don’t elicit strong responses.
Natural pheromones are mixtures of many substances,
perhaps combinations of (protein carriers) plus (bound small organic compounds).
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End of Lecture 16
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