Download Chemosensory Systems

University of Connecticut Graduate School
MEDS 371, Systems Neuroscience
2010
Chemosensory Systems
Marion E. Frank, Ph.D.
Learning Objectives
The student will:
1. Become familiar with the characteristics of the chemicals that taste or smell.
2. Learn how taste and smell receptor cells differ structurally and functionally.
3. Understand the differences in gustatory and olfactory pathways.
4. Learn how gustatory and olfactory systems are thought to code stimulus quality.
I. Introduction.
A. Taste [Gustation] evaluates beneficial or dangerous chemicals taken into the mouth,
assists nutrition, prevents poisoning, and contributes to eating pleasures.
B. Smell [Olfaction] detects and analyzes environmental chemicals; contributes to
social, reproductive, and nutritional choices, as well as choice of habitat. Olfactory
stimuli have subconscious effects and olfactory memories have hedonic elements.
II. Gustatory System.
A. Taste Receptors & Taste-Stimulus Transduction.
1. Taste receptor cells (TRC) occur in spherical clusters, taste buds [Fig. 32-13], in
lingual epithelium and elsewhere in oropharyngeal mucosa. TRCs turn over, with
~10-day life span, and depend on neuro-trophism. Type I, II and III taste bud
cells have distinct shapes, biochemical features and likely distinct functions.
2. Taste buds occur on the tongue: in fungiform papillae on the dorsal anterior
2/3rds, in foliate papillae on lateral edges and in circumvallate papillae on dorsal
posterior tongue; and in palatal and oral pharyngeal mucosa (epiglottis) [Fig. 3212].
3. Taste stimuli are sweet [sugars, some amino acids, and artificial sweeteners
(saccharin, aspartame, etc.)], bitter [alkaloids, thioureas, bile acids, glycosides,
some amino acids, KCl, MgSO4 & salts with large organic cations e.g.,
denatonium benzoate and quinineHCl], salty [NaCl and NaBr are pure salty] and
sour [acids, which are also irritants, activating the common chemical sense].
Species differences can be tremendous, especially for the many compounds with
bitter tastes.
4. Stimulus-receptor interaction occurs in taste-bud pores, into which taste-bud cells
project microvilli. Membrane ion channels directly transduce ionic taste stimuli.
E.g., rodent Na+-salt taste is transduced (not human salty taste) by influx of Na+
through an amiloride-sensitive, ion channel (ENaC) that depolarizes TRCs. Sour
taste may be mediated via TRP channel: PKD2L1. Non-ionic taste stimuli bind
receptor proteins in TRC apical membranes that are coupled to 2 nd-messenger
systems [Fig. 32-14]. Gustducin, a G-protein with  subunit like rod transducin, is
involved. A family of G-protein-coupled receptors (GPCRs):T2Rs with bitter
ligands and a single heterodimeric GPCR (T1R2/T1R3) with sweet ligands are
located in separate TRC.
5. Increases in intracellular Ca++ and transmitter release at synapses at TRC basolateral membranes activate nerves. ATP may be involved in neurotransmission.
B. Regions of Taste Sensitivity and Taste Nerves (Peripheral Taste).
1. Primary afferent taste neurons, occurring in 3 cranial nerves (CN), are pseudounipolar neurons with small myelinated and unmyelinated axons with somata in 3
peripheral ganglia [Fig. 32-17]. The chorda tympani (CT), innervating taste buds
in fungiform papillae, and greater superficial petrosal (GSP), innervating taste
buds on the palate, are sensory branches of CN VII (facial); neural somata are in
geniculate ganglia and central axonal processes in the intermediate root,
between CN VII and VIII. The lingual branch of CN IX (glossopharyngeal: GL)
innervates taste buds in the foliate and circumvallate papillae; petrosal ganglia
contain GL somata. Superior laryngeal branches of CN X (vagus), with somata in
nodose ganglia, innervate pharyngeal taste buds.
2. The location and chemical sensitivities of the 3 taste bud fields suggest distinct
functions: CN VII, food selection; CN IX, reflexes of ingestion; & CN X, airway
protection.
3. Single nerve fibers in the CT and GL nerves respond selectively to taste
compounds [Fig. 32-18]. Sucrose-sensitive CT fibers respond to other
sweeteners like fructose and D-phenylalanine; they are specialists and hardly
respond to non-sweet stimuli. NaCl-sensitive specialists respond specifically to
sodium and lithium salts and are inhibited by the ENaC channel blocker,
amiloride, in rodents. Sweet and salt receptors, their TRCs and specialist
neurons form peripheral labeled lines to the brain. CT fibers that are sensitive to
HCl and other acids that are sour, also respond to salty and bitter salts; these
electrolyte-sensitive CT generalists are not quality-specific in rodents.
4. See abstract and reference to recent review on the peripheral gustatory nervous
system and taste quality coding.
C. Central Taste Pathways & Taste Behaviors.
1. Primary taste afferents enter the brain stem, join the solitary tract and make
synaptic contact with surrounding cells of the nucleus of the solitary tract (NST)
in the medulla oblongata. CN VII enters most rostrally, then CN IX; CN X enters
most caudally [Fig. 32-17]. Taste-responsive neurons are concentrated in the
most rostral pole of the NST.
2. NST neurons respond differently across taste qualities and have more complex
receptive fields than CT afferents. For example, some NST neurons respond to
sweet and salty stimuli, others are excited by sweet and inhibited by salty stimuli,
making average NST neurons less tuned to quality than CT neurons. The
decrease in average quality tuning suggests taste quality may be represented by
patterns of activity in the CNS. In the NST, glutamate is an excitatory and amino butyric acid (GABA) is an inhibitory neurotransmitter. Receptive fields of
NST neurons include taste fields served by different nerves. In fact, a single NST
neuron may respond to sucrose on the palate and NaCl on the tongue, a
convergence combining quality- and place-specific information.
3. There are major species differences in taste projections. In primates, NST taste
neurons project to the thalamus [VPMpc, medial parvicellular (small-celled) part
of the ventral posterior-medial nucleus, medial to the somatosensory
representation of the tongue] via the central tegmental tract [Fig. 32-17]. In rats,
NST taste neurons project not to the thalamus but nearby to a parabrachial
nucleus (PBN) in the pons, which, in turn, projects to thalamus. Thalamic taste
neurons have more complex response properties than brain-stem taste neurons.
Brainstem taste neurons also project into medullary reflex circuits to impact
secretion of saliva, swallowing and other reflexive responses.
4. Thalamic taste neurons project to primary taste cortex [anterior insula and
adjacent frontal operculum [Fig. 32-17]], the pathway possibly involved in taste
discrimination and perception, and learning of taste/flavor aversions. Primary
taste cortex is close to the somatosensory cortical representation of the tongue.
Bilateral taste and lingual somatosensory pathways differ. Somatosensory are
primarily crossed but taste show right hemispheric dominance. Cortical taste
neurons vary in quality-specificity; some responding to a “natural” sweet juice
containing glucose more than pure glucose, others to preferred stimuli of several
taste qualities.
5. A secondary cortical taste area in the orbito-frontal cortex integrates taste,
olfactory and visual aspects of foods. Some of its neurons respond less and less
as a taste stimulus is repeatedly sampled, showing “stimulus-specific satiety.”
Pathways to amygdala and hypothalamus [limbic areas] add motivational and
hedonic aspects to taste.
6. Taste consciousness composed of 4 distinct qualities, signaling nutritious and
harmful substances, is challenged by discovery of a 5th taste: savory (umami).
Evoked by monosodium L-glutamate (MSG), it may signal sources of protein via
a variant of a metabotropic glutamate receptor (mGluR4) or the heterodimeric
GPCR: T1R1/T1R3. In the 19th century, Henning proposed that all taste
perceptions could be represented by the surface of a taste tetrahedron: primaries
at the 4 corners, mixed tastes elsewhere on the surface. Today debate continues
about the existence and/or number of primary tastes.
7. Genetic variation in tasting affects choice of food and drink. Tasting of the bitter
n-propylthiouracil (PROP) is polymorphic in humans due to variation in a gene:
T2R38 on chromosome 7. PROP super-tasters (homozygous for 3 amino acids
PAV) drink less alcohol than PROP non-tasters (AVI homozygous).
8. Taste aversions, learned with 1 experience when a taste is followed by gastrointestinal upset, require forebrain circuits, which are not involved in facial
expressions and motor reflexes of acceptance and rejection.
D. Summary: Gustation. Taste is a chemical sense that deals with evaluation of food.
We perceive sweet, salty, sour and bitter taste qualities. Taste-bud receptor cells
(TRCs) transduce chemicals in aqueous solution, utilizing GPCR for sweet (T1Rs)
and bitter (T2Rs) and ion channels such as ENaC for salty and sour. TRCs turn over
and there is a neuron-taste bud neuro-trophism. Primary afferent neurons are
specialists or generalists with respect to taste quality. Specialists are labeled lines
sending specific quality information from the receptors to the brain. CNS processing
of taste information begins in the nucleus of the solitary tract (NST), where neurons
receive convergent inputs, show inhibition, and project to VPMpc in the thalamus.
Thalamic taste neurons project to primary taste cortex in anterior insula and frontal
operculum. Taste-quality discrimination and learning require thalamo-cortical
pathways, which are supplemented by pathways to amygdala and hypothalamus to
add motivational and hedonic features to tastes.
III. The Olfactory System.
A. The Olfactory Mucosa & Olfactory-Stimulus Transduction.
1. Olfactory sensory neurons [OSNs], 5x106 in 2-5 cm2 bilateral patches of
olfactory mucosa, line parts of superior and middle nasal turbinates, and nasal
septum [Fig. 32-1]. During normal breathing, nasal conchae divert air-flow
upward, deflecting odor molecules toward OSN. “Breathing in” [ortho-nasal]
samples external sources, “breathing out” [retro-nasal] samples oral-pharyngeal
sources when eating. The olfactory mucosa contains OSN, supporting cells,
basal stem-cells and glands that secrete mucus. Supporting cells store secretory
granules and project microvilli into the mucus layer. An OSN is a bipolar neuron
with one dendritic and one axonal process. The dendritic process is topped by an
olfactory knob, which projects 10-20 olfactory “cilia” about 0.1 mm into the
mucus. Ciliary membranes contain molecular odor receptors (ORs).
2. OSNs turn over in adults, having a ~60-day life span. The olfactory epithelium
degenerates if OSN axons are severed; but, in time, may reappear.
Reconstitution of the olfactory epithelium begins with increased mitotic activity of
basal cells, is followed by appearance of differentiated OSNs, and eventually
odor perception.
3. In contrast to taste, there is no general agreement on a valid set of human
perceptual odor qualities. Many distinct odor qualities are perceived, such as
sweaty isovaleric acid, fecal methyl indole, camphorous cineole and sweet
vanillin.
4. ORs are GPCR proteins (like opsins), with 7 hydrophobic transmembrane
segments, coupled to G-proteins [Fig. 32-4]. There are hundreds, perhaps 1000,
ORs specific to the olfactory mucosa that bind odorous compounds [Fig. 32-4]. A
tissue-specific G-protein  subunit (Golf) and adenylyl cyclase provide the basis
for a 2nd-messenger pathway for olfactory signaling that results in stimulusevoked cAMP increase. With the opening of a specific cyclic-nucleotide-gated
Na+ channel, OSNs depolarize and action potentials are generated in the axon of
the OSN [Fig. 32-5]. The olfactory cation channel is homologous to the channel
involved in visual transduction.
B. The Olfactory Nerve & Olfactory Bulb.
1. Fine axons, 0.1-0.3 m, of OSN comprise the fila olfactoria, in which single
Schwann cells surround small bundles of the axons. The fila (CN I) project to the
olfactory bulb through the cribriform plate of the ethmoid bone [Fig. 32-1].
Projections of all OSN expressing a particular molecular OR converge to only a
few sites in the olfactory bulb.
2. Slow potentials (surface negative voltages) are recorded with an electrode placed
on the olfactory mucosal surface and action potentials are recorded with a
microelectrode inserted to the base of the olfactory epithelium. The slow potential
3.
4.
5.
6.
7.
electro-olfactogram (EOG) reflects OSN generator potentials. The action
potentials are recorded from OSN axons. Different regions of the mucosal
surface show different chemical sensitivities. E.g., n-butanol, an unpleasant odor,
is more effective with the EOG electrode on the anterior, but, d-limonene, a
pleasant odor, is more effective when the electrode is placed on the posterior
mucosal surface. Furthermore, 1 of 4 subfamilies of ORs is exclusively
expressed in OSNs in 1 of 4 distinct zones of the olfactory mucosa [Fig. 32-6].
Within one zone, OSNs (each expressing a specific OR) respond to multiple
molecules.
Effective stimuli elicit short-latency excitatory OSN responses. Some OSN axons
respond to multiple odor chemicals but others respond specifically to chemicals
with a single functional group and restricted carbon chain lengths [Fig. 32-3]. In 1
well-studied case, OR I7, heptyl (C7), octyl (C8), nonyl (C9), and decyl (C10)
aldehydes were effective ligands.
Axons of OSN enter the complex, layered olfactory bulb [Fig. 32-7A] in the
superficial olfactory nerve layer. Axonal endings of OSN form excitatory
synapses with primary dendrites of mitral and tufted cells, output neurons, in
spherical neuropil (glomeruli) in the deeper glomerular layer. One medial and one
lateral glomerulus receive exclusive input from hundreds of OSNs expressing a
single OR making the glomerulus a functional unit, the central representation of a
single OR. Intrinsic peri-glomerular cells form inhibitory synapses with primary
dendrites of output cells in multiple glomeruli, allowing for lateral inhibition.
In the external plexiform layer, secondary dendrites of the output neurons receive
inhibitory synapses from granule cells, also intrinsic to the bulb, allowing for
feedback inhibition. Peri-glomerular and granule cells use the inhibitory
transmitter GABA and are generated in the subventricular zone throughout
adulthood, rarity for neurons. Reciprocal excitatory-inhibitory synapses occur
between dendrites of output and intrinsic cells of the olfactory bulb. The
excitatory neurotransmitter is glutamate. Reciprocal synapses between mitral
cells and granule cells are common. The mitral cell and granule cell layers form
the deepest layers of the olfactory bulb [Fig. 32-7B].
Mitral cells respond selectively to odor quality and intensity. The bulb is divided
into functional regions, specialized for processing distinct odor chemicals. E.g.,
aldehydes activate mitral cells in the dorsal-medial bulb but aromatic
hydrocarbons activate mitral cells in the vental-medial bulb. Within a region,
individual mitral cells may be tuned to compounds of specific C-chain length.
Inhibitory inputs from neighboring glomeruli may sharpen tuning to the best
stimulus or suppress responses to compounds in stimulus mixtures. Humans
cannot identify individual odors in mixtures of more than 3 compounds.
During stimulation, mitral cells show excitatory-inhibitory responses. A low level
of a stimulus elicits a simple excitatory response in the mitral cell; a higher
stimulus level elicits a short excitatory response followed by inhibition. This
inhibition lengthens with increasing amount of stimulus, may be self-inhibition of
the excited mitral cell by a granule cell via a reciprocal synapse, and may help
explain the rapid adaptation of smells. Thus, the intensity and quality of an odor
is represented in a spatial-temporal pattern of neural activity across the olfactory
bulb.
C. Higher Olfactory Pathways & Olfactory Behaviors.
1. Axons of mitral and tufted cells exit the olfactory bulb in lateral olfactory tracts
and project to all regions of the olfactory cortex [Fig. 32-9]. The olfactory cortex is
a 3-layered, paleo-cortex with 5 parts: the anterior olfactory nucleus, olfactory
tubercle, piriform cortex (including peri-amygdaloid cortex), anterior cortical
amygdaloid nucleus, and lateral entorhinal cortex. Extensive intrinsic connections
among regions arise mostly from the anterior olfactory nucleus, piriform and
entorhinal cortex.
2. The anterior olfactory nucleus connects the two bulbs via the anterior
commissure, suggesting odor processing is inter-hemispheric. The piriform
cortex and olfactory tubercle project directly or via a relay in the medial dorsal
thalamus to orbito-frontal and ventral agranular insular cerebral cortex, and likely
have roles in odor discrimination and perception. The amygdala and entorhinal
cortex are ventral forebrain structures with olfactory projections to the
hypothalamus or hippocampus that are involved in emotion, motivation and
learning. Thus, the output neurons of the olfactory bulb project directly, or via few
synapses, to the diencephalon and limbic system. Most olfactory projection sites
send centrifugal input back to the bulb and there are ascending projections to the
bulb from the brain stem. Feedback and brain-stem projections control olfactory
inputs to the olfactory bulb.
3. Early in the 20th century, Henning proposed a “smell prism”, the corners
representing six “primary” odor qualities: flowery, foul, fruity, burnt, spicy and
resinous, odors of such compounds as phenethyl alcohol, ethanethiol, geranial,
acrolein, cinnamaldehyde and pinene, respectively; but many other distinct odor
qualities are perceived. Names of odors are often associated with environmental
processes, objects and events, not abstract sensory qualities as are names for
tastes or colors.
4. The diverse olfactory projections help explain why odors elicit complex specific
situational and emotional memories in addition to odor qualities. Based upon
such non-perceptual effects of odors, aromatherapies have been devised to
alleviate psychological stress with presentation of pleasant, familiar and
meaningful odors.
5. The ability of the OSN to recover from injury helps explain return of olfactory
function months after smell loss due to head trauma. The OSN population is not
strictly maintained with aging, however, and the sense of smell deteriorates.
D. Summary: Olfaction. Smell is a chemical sense that evaluates vaporous
environmental chemicals. We perceive many odor qualities, notes perhaps each
associated with one of the hundreds of olfactory receptors (OR). Olfactory sensory
neurons (OSN) have dendrites with olfactory cilia containing the G-protein-coupled
OR and axons that communicate to the olfactory bulb. OSN can regenerate, giving
them an unusual ability to recover from injury. OSN located in separate regions use
4 subfamilies of OR, individual OSN express single OR variants, and all OSN
expressing one of the hundreds of variants project to a few sites (glomeruli) in the
olfactory bulb. OSN may respond to many compounds, generating distinct spatial-
temporal patterns of neural activity across OSN for each stimulus. Periglomerular
and granule inhibitory neurons modify olfactory signals within the olfactory bulb and
mitral and tufted cell output neurons relay olfactory signals to higher levels. Olfactory
signals are relayed from the olfactory bulb to the olfactory paleo-cortex, then
thalamus and cerebral cortex, where odor qualities are discriminated. Projections to
the hypothalamus and hippocampus are sites where experience and emotion
interact with odor.
Reference:
Buck, L.B. (2000). Smell and Taste: The Chemical Senses. In Principles of Neural
Science, 4th Ed. (Kandel, E.R., Schwartz, J.H., Jessel, T.M.; Eds.), McGraw Hill; pp.
625-647. [Figures referred to in the syllabus are from this reference.]
Reference Abstract:
Frank, M.E., Lundy, R.F. Jr, Contreras, R.J. (2008) Cracking taste codes by tapping into
sensory neuron impulse traffic. Progress in Neurobiology, 86:245-263.
Insights into the biological basis for mammalian taste quality coding began with
electrophysiological recordings from ‘‘taste’’ nerves and this technique continues to
produce essential information today. Chorda tympani (geniculate ganglion) neurons,
which are particularly involved in taste quality discrimination, are specialists or
generalists. Specialists respond to stimuli characterized by a single taste quality as
defined by behavioral cross-generalization in conditioned taste tests. Generalists
respond to electrolytes that elicit multiple aversive qualities. Na+-salt (N) specialists in
rodents and sweet-stimulus (S) specialists in multiple orders of mammals are well
characterized. Specialists are associated with species’ nutritional needs and their
activation is known to be malleable by internal physiological conditions and
contaminated external caloric sources. S specialists, associated with the heterodimeric
G-protein coupled receptor T1R, and N specialists, associated with the epithelial sodium
channel ENaC, are consistent with labeled line coding from taste bud to afferent neuron.
Yet, S-specialist neurons and behavior are less specific than T1R2-3 in encompassing
glutamate and E generalist neurons are much less specific than a candidate, PDK TRP
channel, sour receptor in encompassing salts and bitter stimuli. Specialist labeled lines
for nutrients and generalist patterns for aversive electrolytes may be transmitting taste
information to the brain side by side. However, specific roles of generalists in taste
quality coding may be resolved by selecting stimuli and stimulus levels found in natural
situations. T2Rs, participating in reflexes via the glossopharynygeal nerve, became
highly diversified in mammalian phylogenesis as they evolved to deal with dangerous
substances within specific environmental niches. Establishing the information afferent
neurons traffic to the brain about natural taste stimuli imbedded in dynamic complex
mixtures will ultimately ‘‘crack taste codes.’’