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University of Groningen
Gustatory neural processing in the brainstem of the rat
Streefland, Cerien
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CHAPTER 1
General Introduction
14
Chapter 1
GENERAL INTRODUCTION
to a study on gustatory neural processing in the brainstem of the rat
1. Preface
The work presented in this thesis is the result of neuroanatomical and physiological investigations on the gustatory system of the rat. It focuses on the
identification of gustatory neurons, their projection patterns and their possible
influence on autonomic output. This first chapter summarizes briefly the relevant
knowledge about gustation, the characteristics of gustation, the physiology and
neuroanatomical organization of the gustatory system, both peripherally and
centrally, and finally the physiological and neuroanatomical background of
viscerogustatory interactions in response to ingestion. The final paragraph
formulates the aim and outline of the thesis, followed by a summary of results.
1.1 Gustation; A Special Visceral Afferent System
The chemical sense of taste is (together with olfaction) the most primitive of
specialized sensory systems, with an evolutionary history of some 500 million
years. Accordingly, it deals with one of the most fundamental requirements of life
necessary to sustain the individual: feeding.
The sense of taste evaluates the acceptability of a chemical in the mouth and
guides the decision to ingest or reject. A decision to swallow is final, so the
organism must select wisely from its chemical environment. While the organism
must not accept toxins, it cannot afford to bypass nutrients. Diverse nutrients are
called for, and the optimal mix may change with age, disease and nutritional or
reproductive status. Rats and other animals do select a proper diet over time.
Therefore taste responses are influenced not only by chemicals that are taken into
the mouth, but also by past experiences and the momentary physiological status
of the organism. So, the sense of taste manages dietary selection not only by its
analysis of the quality and intensity of potential food substances, but also through
communication with the visceral senses.
Gustation should be seen as intermediary between the physical sensory
systems and visceral sensation. It possesses certain features of nonchemical
senses, such as identification of stimulus quality and intensity through spatiotemporal codes. Yet, taste may be classified as a visceral afferent system
according to its embryological, anatomical and functional characteristics shared
General Introduction
15
with the other afferent neurons of the cranial parasympathetic nerves that
innervate the body cavity 122. The location of gustatory receptors at the transition
between the external and internal environment also supports the classification of
taste as a special visceral afferent system.
1.2 Characteristics of the Sense of Taste
1.2.1 Primary Taste Qualities
Perception of food is a complex experience based on multiple senses: taste per
se, olfaction, somesthesis, thermoreception and nociception. Taste qualities are
commonly divided into four categories or primary taste qualities: sweet
(represented by sucrose), sour (represented by HCl), salty (represented by NaCl)
and bitter (represented by quinine-HCl). However, the concept of four basic
qualities is questionable, since psychophysical data have shown that various
sapid substances did not fall within the range spanned by the four qualities 158.
Among these is umami (Japanese for the specific taste sensation elicited by
monosodium glutamate), which is qualitatively different from any of the four basic
tastes 216. Furthermore, data from conditioned taste aversion paradigms clearly
show inter- and intra-species differences concerning the perception of taste
quality 80,127,143. As early as 1916, Henning 70 proposed the terms "taste quality
continuum" or "taste space", because four tastes obviously do not account for the
whole range of taste sensitivities.
1.2.2 Taste Dimensions
For physical sensory systems like vision or audition, one quality dimension is
determined by stimulus wavelength. The presence of a rational stimulus dimension
urges the experimental approach to deciphering the particular sensory system. On
the contrary, taste dimensions are very hard to define. In spite of the absence of
obvious stimulus dimensions, particular taste qualities are known to be determined
by a number of stimulus characteristics. These include pH, hydrophobicity,
molecular weight and configuration 106. However, they fail to relate to the entire
range of taste sensation 106. Moreover, molecules that elicit similar verbal reports
of taste from humans or neural activity in gustatory afferent nerves often bear little
chemical relation to one another. For example, many mono- and disaccharides
taste sweet to humans. Not all sugars however, taste particularly sweet 161, but
many other unrelated molecules such as glycine and alanine, do so. Thus, the
choice of stimulating chemicals and their concentrations remain a theoretical
16
Chapter 1
issue, rather than a simple starting point for analysis. For sensory data, various
multi variate statistical analyzes have been used to describe stimulus relationships
20
. Among these are, hierarchical cluster analysis (which may show the presence
of different clusters of stimuli and attributes each stimulus to a cluster) and
multidimensional scaling (which may show interrelationships between different
stimuli) are often used to map the distinguishability of data.
1.2.3 Gustatory Neural Coding
The neural coding of taste qualities in vertebrates is addressed by the labeled line
127,134
and the across-fiber pattern 41,133,159 theories. The basic differences between
these theories are as follows. The labeled line (LL) model proposes that each
taste quality is transmitted via a separate 'neural line' through the medulla,
thalamus and cortex. This model assumes that individual gustatory fibers are more
or less narrowly tuned to one of the primary taste qualities and that the function
of any one neuron would be to signal its particular encoded taste quality. The
across-fiber pattern (AFP) model proposes that individual afferent fibers lack
absolute specificity. The afferent neuronal message for quality is expressed in
terms of the relative amount of neuronal activity across neurons or across classes
of neurons. These two theories reflect two completely different ways of looking at
the central nervous system. The LL model emphasizes a single neuron's activity,
as is common in many attempts to elucidate CNS functioning by the single-unit
recording technique. The AFP model, on the other hand, emphasizes the
importance of patterns of neuronal activity, occurring and changing continuously
in the CNS. Gustatory neural coding may utilize both types of mechanisms.
1.3 Anatomy and Physiology of the Peripheral Gustatory System
1.3.1 Taste Buds and Taste Receptor Cells
In vertebrates, taste is perceived through specialized epithelial cells, taste
receptor cells, which are organized within discrete ovoid clusters: taste buds.
Taste buds are found within the oral cavity, embedded in the epithelium of the
tongue. Focal collections of taste buds are termed taste papillae. The fungiform,
circumvallate and foliate papillae are found on the anterior two-thirds of the
tongue, the posterior tongue and the lateral edge of the tongue, respectively.
Mammals also have scattered non-papillar taste buds that populate the soft
palate, larynx, pharynx, epiglottis and the upper part of the esophagus 91. A typical
vertebrate taste bud contains 50 - 100 elongated receptor cells with microvillar
General Introduction
17
processes extending into an apical taste pore 89. Mature taste receptor cells have
a life span of 10 - 14 days and are continually replenished from precursor cells,
found at the base of the taste bud.
Taste stimuli are dissolved during mastication and reach the apical microvilli
of taste cells by mixing and diffusion through saliva. Solutes in the oral cavity
make contact with the apical membranes of the taste receptor cells via the taste
pore, but are shielded from direct contact with the lateral and basal aspects of the
taste cells, which are connected via tight junctions 79,172. Saliva is an aqueous
mixture of electrolytes, proteins (enzymes), etc., whose composition is variable
and largely a function of parasympathetic stimulation 8. From the view of taste
transduction, saliva plays a role in depolarization of taste receptor cells in
response to taste stimulation.
There is a significant amount of lateral connectivity between taste receptor
cells within a bud; both electrical and chemical 91. It appears that the taste bud
functions as a signal processor to sum and shape taste responses from the
interconnected taste receptor cells.
1.3.2 Taste Transduction
Taste receptor cells are secondary receptor cells, i.e. electrically excitable cells
not capable of generating action potentials. Direct interaction of taste stimuli with
apically located ion channels mediates the transduction of monovalent salts, sour
and some bitter components. Voltage-dependent channels for Na+, K+ and Ca2+
have been shown to be present in taste receptor cells 90,152. Specific membrane
receptors appear to be required for the transduction of amino acids, sweet stimuli
and some bitter-tasting compounds. There are at least two ligand-gated cation
channels for the amino acids arginine and alanine 52,84,85,185 and a glutamate gated
channel which responds to monosodium glutamate 184 in taste receptor cells.
Sweet and bitter taste are transduced by second messenger mediated pathways.
Both sweet and bitter compounds are thought to bind to specific G-protein coupled
receptors , and activate the second messengers cAMP and IP3, respectively 27,103.
Recently McLaughlin and Margolskee 108 cloned a G-protein, gustducin, that is
specifically expressed in gustatory tissue 108 and may play a role in sweet and
bitter taste transduction.
1.3.3 Cranial Nerves
The sensory fibers that innervate the taste receptors travel in cranial nerves VII,
IX and X to form synapses in the nucleus of the solitary tract (NTS) in the medulla.
18
Chapter 1
The greater superficial petrosal nerve and the chorda tympani nerve (CT) carry
fibers from the facial nerve (VII) to innervate taste buds on the palate and the
anterior portion of the tongue (fungiform), respectively. Buds within the
circumvallate papillae and the posterior portion of the foliate papillae are
innervated by the lingual branch of the glossopharyngeal nerve (IX) and the taste
buds of the larynx, pharynx, epiglottis and esophagus are innervated by the
superior laryngeal branch of the vagal nerve (X). Several papillae are innervated
by branches from the same fiber and one papilla is innervated by branches
originating from several fibers 110.
Apart from conveying gustatory information, taste fibers are known to interact
among one another. In gerbil, lateral inhibition between chorda tympani nerves
was observed, which may function to reduce spurious sensory signals in taste
axons 146. Furthermore, chorda tympani nerve fibers are known to modulate ion
transport and thereby possibly taste transduction, across lingual epithelium in dog
171
.
In rodents, the cranial nerves that carry gustatory axons from the oropharyngeal region penetrate the lateral medulla in fascicles, traverse the spinal
trigeminal tract and nucleus, collect in the solitary tract and terminate in an
overlapping rostrocaudal order within the NTS 5,86,191.
1.3.4 Peripheral Chemosensitivity
Sensitivity to the four classical taste qualities is distributed variably among
receptor cells. A number of researchers have recorded intracellular responses of
taste receptor cells to chemical stimulation 131,157. They all showed that single cells
responded to more than one taste quality. In the rat only 10 to 17% of the taste
receptor cells respond exclusively to one of the four taste compounds used. The
remaining cells respond to two, three or all four chemicals 131.
The same lack of specificity is found among taste buds and papillae, although
taste buds in different oral regions display different best responses to the four
taste qualities 47,48,116.
As early as 1941, Pfaffmann showed that one gustatory fiber could be
activated by several of the four stimuli and that the qualitative sensitivity
determined for each fiber depends on the set of stimuli applied 133. However, the
relatively effective chemical stimuli differentiate among the gustatory nerves and
nerve branches. For example, in the rat CT there is one type of fiber that responds
well to both acid and sodium 22,47. The response to sugars and to quinine is more
species specific.
General Introduction
19
1.4 The Primary Gustatory Nucleus
The nucleus of the solitary tract (NTS), as found in mammals, birds, reptiles,
amphibians and fish, comprises the primary sensory nucleus for both the gustatory
and general visceral modalities. The NTS is a heterogeneous nuclear complex in
the form of a long column, extending rostro-caudally from the pontomedullary
junction to the caudal medulla.
1.4.1 Topographic and Chemotopic Organization
The NTS has three major subdivisions 97, the rostral gustatory (rNTS), intermediate (iNTS) and caudal autonomic part (cNTS), which, in turn, are composed
of several subnuclei. The iNTS, located at the level of the fourth ventricle and area
postrema, separates the gustatory and visceral regions. The cNTS receives
afferent innervation from all major organs in the body and, as such, is the major
visceral sensory relay group in the brain. The cardiovascular, pulmonary, respiratory tract and gastrointestinal receptor afferents all project to specific areas in
the caudal NTS 97 and innervate the medial, interstitial, and the parvocellular
subnuclei, respectively 7,42,71,97. The gustatory NTS receives, from rostral to caudal,
the central axonal processes of primary afferents from taste receptors located in
the anterior two-thirds and posterior one-third of the tongue, the larynx, pharynx,
epiglottis and esophagus 122. Some somatosensory afferents from the oral cavity,
head and face also terminate in the gustatory part of the NTS 67,96,102 and the rNTS
also receives intranuclear input from caudal NTS subnuclei 10. In addition, the NTS
receives considerable centrifugal input from forebrain structures (see 5.1,
reciprocal connections).
Within the gustatory NTS a rough chemotopy of taste afferent terminations is
present; this topographic organization is related to the chemosensitivitiy and
peripheral spatial distribution of the gustatory afferents 68. For example, although
neurons responsive to anterior and posterior tongue stimulation are widespread
within the gustatory part of the NTS 183, anterior tongue responding neurons are
generally located rostrally to posterior tongue responding neurons 203,204. Despite
their differential distribution, sucrose-activated neurons are distributed evenly
along the medio-lateral axis of the NTS, while quinine-activated neurons are
concentrated medially 68.
1.4.2 Chemosensitivity
Units recorded in the NTS are not easily identified; they may be presynaptic
20
Chapter 1
afferents, postsynaptic afferents or even interneurons involved in intranuclear data
processing. Most units recorded are subject to this ambiguity. In two recent studies
Nakamura and Norgren extracellularly recorded single-unit responses of NTS
neurons in awake rats, after gustatory stimulation with the standard four taste
stimuli 114 and a number of additional stimuli that were chemically or behaviorally
related to the standard stimuli 115. Taste neurons in the NTS most often responded
best to sucrose (41%), less frequently to citric acid (30%) and NaCl (25%) and
infrequently to quinine (4%). At the concentration used, 44.6% of the taste cells
responded significantly to only one of the gustatory stimuli. Among these specific
neurons, 51.1% was citric acid specific, 40% was sucrose specific, 6.7% was NaCl
specific and 2.2% was quinine specific. By use of comparable data from
unanesthetized preparations, they stated that the breadth of responsiveness (i.e.,
the frequency of occurrence of specific taste cells) remained virtually unchanged
between the CT and the NTS neurons . Norgren and Nakamura also showed 114
that taste neurons in behaving animals responded differently from those in
anesthetized preparations. In awake animals NTS neurons responded more
selectively to the four standard taste qualities, they displayed a higher mean
spontaneous firing rate and the percentage of neurons that responded to only one
stimulus, the so-called specific neurons, was much higher (34 vs. 5.5 %). Earlier
experiments in anesthetized animals 199,200 showed that second-order NTS cells
are more broadly responsive compared to chorda tympani fibers as far as their
sensitivity to the four standard stimuli is concerned. These contradictory results
are probably due to anesthesia. Two other important factors that may account for
differences that are found concerning the chemosensitivities of NTS gustatory
neurons in different experiments, were discussed by MA and Erickson 100. First,
the differences in application of gustatory stimuli (whole mouth stimulation, vs.
stimulation of the anterior tip of the tongue by a tongue chamber) causes
stimulation of different sets of taste buds. Second, they showed that the best
stimulus labels of responding NTS neurons, which are usually determined by
response magnitude, are considerably different for different analysis intervals. For
instance, in their study, 23 of the 45 responding NTS neurons were labeled as
bitter-best and 7 as acid-best in the first second, whereas in the 2-5 second
interval one bitter-best and 18 acid-best labels occurred. These differences are
caused by quality-specific differences in temporal response patterns.
Monroe and DiLorenzo 111 showed that the chemosensitivity of NTS neurons
may not only depend on their input, but may also be related to their projection
target. Using gustatory stimulation of the tongue and extracellular single-unit
General Introduction
21
recording of NTS neurons in anesthetized rats, they found that gustatory NTS
neurons that project to the pontine parabrachial nucleus (PBN) are most frequently
acid-best, while neurons that do not project to the PBN are most frequently NaClbest.
1.4.3 Sensory Processing
The fact that first-order gustatory fibers and second-order gustatory neurons
closely resemble each other in their chemosensitivity, suggests that there is little
sensory processing of responses past the first synapses in the gustatory pathway.
However, there are various indications for the occurrence of neural processing of
sensory information within the NTS. When compared to primary taste afferents,
rNTS neurons show a higher spontaneous activity and, after gustatory stimulation
of the tongue, display a different pattern of neuronal discharge and a higher spike
frequency 38. Furthermore, there is extensive convergence of first-order taste
fibers onto second-order neurons 109,183,199,203. For example, nerves innervating the
anterior tongue and the palate converge on rNTS neurons 204. The same holds
true for fibers innervating the anterior tongue and the nasoincisor ducts 176 and for
the quinine-evoked input of the glossopharyngeal and chorda tympani nerve 179.
Activity of individual taste fibers might sum up, inhibit each other's actions or work
synergistically, leading to neural processing in rNTS neurons. Finally, the different
morphological, biophysical and pharmacological properties of gustatory NTS
neurons also indicate evidence for considerable processing by the rNTS. rNTS
neurons are not a homogenous set of cells. They can be separated into
morphological groups based on visual inspection (multipolar or stellate, elongate
or fusiform and ovoid cells) and on quantitative differences (number, length and
the extent of branching of their dendrites) 95,212. Neurons have also been separated
into groups based on there intrinsic membrane properties 24,25, such as repetitive
discharge patterns and ionic conductances. In addition, rNTS neurons receive
multiple inputs and respond to both excitatory (glutamate, substance P) and
inhibitory (GABA) neurotransmitters 23,88,95,101,209.
In sum, these results indicate that the rNTS is capable of considerable
synaptic processing of afferent sensory information.
1.5 Central Gustatory Pathways
A common pattern of connectivity for the primary gustatory nucleus exists across
all vertebrates. This involves an ascending (lemniscal and limbic) system, a local
22
Chapter 1
reflex system and a descending visceral system that influences autonomic output.
It is hypothesized, that only about 20% of NTS gustatory neurons contribute to
ascending projections 128 and that the remainder form medullary connections or
contribute to autonomic output 121.
1.5.1 Ascending Gustatory Pathways
Gustatory neurons from the NTS project largely ipsilaterally to the pontine
parabrachial nuclei (PBN). Parabrachial gustatory cells send axons both to the
ventral forebrain and to the thalamic taste relay. Thalamic taste neurons ascend
and synapse in the insular gustatory cortex. Some PBN axons project directly to
the insular cortex 94; whether this monosynaptic projection is specifically gustatory
remains unproven. The PBN taste neurons projecting into the ventral forebrain
reach many more and larger neural structures, but the function of these nuclei is
apparently not gustatory or even purely sensory. These parabrachial ventral
forebrain projections include the hypothalamus, amygdala, preoptic area and the
bed nucleus of the stria terminalis. These gustatory limbic connections are thought
to be responsible for the affective and hedonic aspects of gustation, which guide
and regulate feeding behavior 135,136. The thalamocortical pathway is responsible
for the associative aspects of gustation and the discriminative capacity of the taste
system 135,136. Details on the relevant structures are given in the following
paragraphs.
PBN. The ascending gustatory projections originate from the rostral, central
division of the rNTS 65,193 and project largely to the PBN. The PBN is known as the
pontine taste area 125, although this nucleus is involved in processing visceral
sensory information as well. The functional-topographic specificity seen in the
NTS is maintained in the PBN 64,71, the lateral PBN subnuclei being the visceralsensory parts and the medial subnuclei the gustatory parts. Projections from the
gustatory NTS are found in the caudomedial parts of the PBN complex 10,145,188,193,
in the "waist area" and in the medial, external medial, ventral lateral and
centrolateral PBN subnuclei 71. In rat, the most intense taste responses were
recorded rostrally in the medial PBN, just ventral to the brachium conjunctivum.
Weaker responses were recorded within the "waist area" and within the ventral
lateral and centrolateral PBN 125. These responses resulted from sapid stimuli
applied to the anterior tongue alone. The terminations within the external medial
PBN have not been associated with taste function yet 71, however, they project to
and terminate in close vicinity of the thalamic taste relay 201.
General Introduction
23
The parabrachial gustatory neurons display the same degree of chemospecificity as second-order NTS neurons and first-order gustatory fibers. PBN
neurons can be grouped based on a higher response to a preferential stimulus
among four, but breadth of responsiveness does not change compared to NTS
neurons or primary taste fibers 114.
Thalamus. Gustatory PBN projections to the thalamus are bilateral and
terminate densely in the parvocellular part of the ventral posteromedial nucleus
(VPMpc) and to a lesser extent in the parafascicular, central medial and other
midline nuclei 63,120,122. This area was defined as a gustatory thalamic relay,
although it represents a relay for all lingual sensory modalities, rather than just
taste 124.
The response characteristics of thalamic taste neurons have been shown to
differ in a number of ways from primary and secondary gustatory neurons
122,163,165,166
. Chemical stimulation of the tongue may inhibit thalamic spontaneous
activity, all four standard taste stimuli evoked responses of similar magnitude and
only 20 % of the thalamic gustatory neurons responded with increasing neuronal
activity to increasing concentration of stimuli 167. These more complex response
properties may assist in fine discriminations between related stimuli, but they
might also participate in relating gustatory neuronal activity to other sensory
events 122.
Gustatory Neocortex. The primary gustatory neocortex is situated immediately
ventral to the somatosensory cortex and receives gustatory input from the PBN 94
and VPMpc 11,63,92,120. So, the anatomical relationship between taste and
somesthesis is fulfilled through the cortical level. After gustatory stimulation of the
oral cavity, gustatory neurons were observed in the granular and dysgranular
cortex; most of these cortical neurons responded to mechanical stimulation as well
129
.
Limbic projections. The limbic gustatory pathway terminates mainly in the
central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis
(BNST). Weaker projections reach the lateral hypothalamus (LHA)19,63,120,122,145,156.
These ventral forebrain projections originate predominantly from the PBN, but
there are also some direct projections from the rNTS to the LHA and the
paraventricular hypothalamic nucleus 145,188,190. Gustatory responses have been
recorded from neurons in the LHA and CeA 6,218; however, these responses are
24
Chapter 1
nor pure, nor plentiful. For instance, gustatory neurons in the CeA are responsive
to tactile, thermal and chemical stimuli 6.
Reciprocal Connections. Both thalamocortical and ventral forebrain gustatory
systems form reciprocal connections with the PBN and the NTS 13,120,156,206. In
addition, the gustatory cortex projects heavily back to the thalamic taste relay
120,214
.
The majority of these data are strictly anatomical and only a few studies
document that the descending forebrain projections actually engage gustatory
neurons 51,217. It seems nevertheless reasonable to assume that by reciprocal
connections, a network is established by which factors such as motivation or
conditioning can influence gustatorily mediated acceptance-rejection reflexes.
1.5.2 Local Medullary Gustatory Pathways
Neuroanatomical and neurophysiological studies have demonstrated that local
medullary pathways link oral afferent nerves to oral motor nuclei 10,187,210, and that
gustatory information may influence oral motor behavior. Electromyographic
analyzes have shown that taste nerve sectioning can disrupt the patterns of motor
activity associated with licking, swallowing and gaping 196. Furthermore,
electrophysiological experiments showed that the medullary reticular formation,
which receives rNTS input, contains neurons that are active during licking and
swallowing 4,174,195,197. The hypoglossal motor neurons, innervating the tongue
musculature 192,194,198, receive direct rNTS input. The facial and trigeminal motor
nuclei which are responsible for muscle control of face, lips and jaw 192,194 receive
indirect gustatory input through the parvocellular and medullary reticular formation
187,202
. Anterograde tracing studies have shown that neurons in the rostral central
subdivision of the rNTS primarily contribute to ascending projections, but also
project to the ventral part of the rNTS 9,10,65. Neurons in the ventral part of the rNTS
give rise to intramedullary projections and represent the gustatory premotor
outflow. So, a multi synaptic pathway links the gustatory afferent rostral central
subdivision with the premotor cells in the ventral subdivision of the rNTS.
1.5.3 Descending Gustatory Pathways
The NTS subserves a major efferent function via regulation of autonomic mechanisms 31,98,180, including vagal parasympathetic and orthosympathetic control. The
rostral parvocellular reticular formation receives direct input from the rNTS and
projects to the preganglionic parasympathetic neurons of the superior salivatory
General Introduction
25
nucleus 82,117,211. Furthermore, the medullary reticular formation that receives rNTS
input, directly projects to the preganglionic ortho- and parasympathetic neurons
of the dorsal motor nucleus of the vagus (DMnX), the nucleus ambiguus (Amb)
and the intermediolateral cell column 35,99,148,186,189. Whether these descending
autonomic pathways are of gustatory origin remains to be established.
1.6 Viscerogustatory Interactions in Response to Ingestion
Ingestion may have physiological consequences (adverse or beneficiary) that
become associated with the prior taste experience. In turn, this association may
influence later ingestive behavior. This association implies the occurrence of gustatory and visceral interactions. Gustation is closely and reciprocically related
to metabolic factors associated with ingestion. Neuroanatomically seen, the NTS
is well situated to integrate gustatory and visceral related consequences. The
rNTS receives afferent gustatory information, while the majority of the caudal half
receives input from the gastrointestinal tract 83. In addition, hepatic vagal afferents
terminate in the medial subdivision of the left NTS 72. Although direct connections
between gustatory and viscerosensory regions of the NTS have not been established yet 121, taste cell dendrites extend into the viscerosensory NTS and a
viscerogustatory link through the medullary reticular formation has been
demonstrated 72.
There are at least two possible ways in which gustatory information may
interact with visceral afferent and efferent responses. First, general visceral inputs
may alter gustatory responses and feeding behavior. Physiological experiences
caused by ingestion, (such as illness), continuously accommodate the gustatory
code. The physiological condition of the animal induces short-term fluctuations in
gustatory sensitivity, which promote or inhibit feeding and encourage consumption
of a nutritionally replete diet. Second, gustatory information may change neuronal
responses to general visceral receptor input or induce changes in autonomic
output. This would mainly be established by the occurrence of cephalic reflexes
that anticipate the digestion and often even the ingestion of food.
1.6.1 Visceral Influence on Gustatory Responses
Experiences. The gustatory experiences of suckling rats establish preferences that
persist into adulthood 30. Preferences also develop through association of taste
with positive reinforcement 144,162, particularly with a visceral reinforcement such
as occurs with the administration of a nutrient of which the animal has been
26
Chapter 1
deprived 104. Gustatory preferences may even be established in humans and other
animals by mere familiarity or through constant exposure 39. However, the most
potent effect of experience on subsequent preferences occurs at the development
of a conditioned taste aversion (CTA). This is a form of associative learning, in
which animals or humans react aversively to the taste of a food that has previously
been paired with illness. Robust aversions can be acquired after a single pairing
of a taste (conditioned stimulus; CS) with a drug-induced (often LiCl) illness
(unconditioned stimulus). Chang and Scott have recorded modified neural
responses to gustatory stimulation with the CS in the NTS of the rat after establishment of a CTA 32. Other studies showed changes of NTS neuronal activity by
changes in c-fos expression in the NTS to a CS before and after conditioning 75,182.
Several investigators have demonstrated that both permanent and temporary
lesions of the gustatory PBN severely impair, if not abolish, the rat's ability to
acquire a CTA 36,46,58,77,175. However, it remains to be established whether the
proposed deficit in taste-visceral integration is the result of damage to the PBN
neurons themselves or to their projections to the forebrain. Several experiments
have demonstrated that lesions in certain forebrain structures cause deficits in the
acquisition of a CTA. For example, lesions of the gustatory neocortex 87, central
amygdala 170, lateral hypothalamus 160 or the ventroposterior medial (gustatory)
thalamus 93 impair the ability of rats to acquire a postoperative CTA. Recent
studies have shown that in rats with a lesioned NTS acquisition and retention of
a CTA was still possible 58,59. These results demonstrate that the rNTS is not
essential for the chemical identification necessary for CTA learning.
Physiological Condition. The physiological condition of an animal is closely
related to its choice of foods. Compensatory feeding behavior that may occur as
a response to deprivation of specific nutrients results from a taste-directed change
in food selection. It is presumed that the recovery from nutrient deficiencies is
paired with the taste that preceded this recovery. In this way a conditioned taste
preference is established, by which the hedonic value of the taste is enhanced.
This implies that the hedonic value of a taste experience must be subject to changes 164.
Specific food preferences appear to result from deficiencies, such as cravings
for thiamine 149,153,168, threonine or histidine 66,155. In many species, depleting
sodium stores of the body triggers an innate appetite for sodium. During such an
episode concentrations of sodium salts that are normally rejected are avidly
ingested 113. This compensatory response to the physiological need for salt results
General Introduction
27
from a change in the hedonic value of tasted sodium 34,40. Jacobs et al. 78 recorded
gustatory NTS neurons in sodium-deprived and normal rats and demonstrated a
profound depression in responsiveness of salt-oriented neurons and a sharp
increase in activity in sweet-oriented cells. They suggested that the perceived
quality of sodium in sodium-deficient rats was shifted from salty to sweet. If rats
restore depleted sodium levels following deprivation, the responsiveness of
gustatory NTS neurons returns to a predeprived state 107.
The expression of sodium appetite following acute NaCl depletion is eliminated
by PBN lesioning 46. Supracollicular decerebration experiments (rostral to the
PBN) have demonstrated to impair concentration-dependent NaCl intake, in
contrast to sucrose intake 45. This implies that the brainstem mechanisms are not
adequate for the control of sodium intake. This is not due to an inability to taste
the stimulus. Rather, decerebration appears to disrupt the stimulatory effects of
postabsorptive feedback, provided by the NaCl solution related to hydrational
needs 45. The neuronal mechanisms controlling hydrational balance have been
localized to the forebrain 21,74,173. Hydrational factors and not taste factors, seem
to stimulate the ascending portion of sodium intake functioning 45.
Satiety, mimicked by gastric distension was demonstrated to selectively depress gustatorily induced taste responses in the NTS of the rat 57. The greatest
effect on activity was evoked by sucrose, followed by NaCl and HCl; the
responses to quinine-HCl were unmodified. Relief from distension reversed this
effect within a 45 min period.
Signals from gastric mechanoreceptors are carried by the vagus nerve and
might act on rNTS neurons through the PCRt 50,72,219. The involvement of both the
NTS and DMnX in gastric distension has recently been demonstrated by c-fos
expression 213. However, other results suggest that gastric distension affects
gustatory activity through the release of factors that inhibit gastric emptying. This
phenomenon is not dependent on gastric vagal afferents 53.
While changes in amino acid or sodium levels are appreciated over several
days, the availability of certain macronutrients, specifically sugars, is of more
immediate concern. Giza and Scott and Giza et al. 54,56 demonstrated that
exogenous administration of glucose, insulin or glucagon suppress multi-unit
activity evoked from gustatorily responsive NTS neurons to lingual application of
glucose, NaCl and HCl in the rat. They hypothesized that chemicals increasing
glucose availability may promote satiety for palatable taste substances by
reducing afferent activity in gustatory neurons. Psychophysical studies 28,29 and
common experience showed that a decrease in gustatory responsiveness has a
28
Chapter 1
perceptual counterpart. Perceived glucose intensity declines and the decrease of
hedonic appeal promotes meal termination.
There are several possible mechanisms through which circulating glucose,
insulin or glucagon might exert their actions on gustatory responsiveness.
Firstly, this may be brought about by stimulation of gastrointestinal and hepatic
chemoreceptors and subsequent activation of the vagus nerve 126,207. Visceral
information is projected to the NTS through vagal activation. It has not been
demonstrated yet, that first-order gustatory and visceral vagal afferents converge
upon NTS neurons 72. Neuroanatomical and electrophysiological experiments
have demonstrated overlapping projections from hepatic (vagal) and gustatory
regions of the NTS within the immediate subjacent parvocellular reticular formation
(PCRt) as well as in the PBN 72,73. Herewith, the PBN and PCRt emerge as the first
brainstem nuclei in which significant integrative processing of gustatory and
visceral afferent information occurs.
Secondly, gustatory neurons in the NTS might be influenced by feedback from
forebrain structures associated with feeding. The hypothalamus and central
amygdala are both associated with hedonic mechanisms accompanying ingestion
3,150
. Aside from possible centrifugal contributions to changes in taste activity,
several of these forebrain structures have been shown to possess glucose, insulin
and glucagon sensitive sites 76,130,145, through which they might exert their actions
on gustatory NTS neurons. However, several lines of evidence suggest that the
brainstem independently mediates ingestive responses to glucoregulatory
challenges 37,44,147, thereby excluding the involvement of forebrain structures.
The third mechanism that may alter gustatory responsiveness is a direct action
on NTS neurons through glucoreceptors and insulin receptors sensitive to
endogenous glucose and insulin levels, respectively 2,205. Caudal NTS activity has
been demonstrated to be modifiable by iontophoretic application of glucose and
insulin 118,208. These activity changes might directly affect the rNTS or reach the
rNTS through the PCRt 72,123. Insulin and glucose may also act on the area
postrema 2,208, which passes on the signal to the gustatory NTS 112.
Finally, gustatory responsiveness might be altered through the release of
catecholamines, somatostatin or growth hormone. Up to now these effects have
not been evaluated.
1.6.2 Gustatory Influence on Visceral Responses
Cephalic Phase Responses. Cephalic phase responses (CPRs) are autonomic
and endocrine reflexes that are triggered by sensory contact with food, rather than
General Introduction
29
by postingestional consequences of food 26,105,138. The digestive effects that result
from cephalic reflexes are initiated most reliably by the taste and smell of food.
The sight of food and other circumstances associated with eating may also act as
stimuli, although these seem to be less potent. The cephalically stimulated responses are rapid (generally occurring within minutes after sensory stimulation), small
(relative to the magnitude achieved when food is actually being metabolized) and
transient (returning to near-baseline levels within minutes) 105. Cephalic reflexes
include the secretion of saliva 132, release of gastric juices 81, pancreatic enzymes
and insulin 26. Other, less studied CPRs are changes in gastric motility, hepatic
control of blood glucose and bile flow 138. CPRs have been examined in man, monkey, dog, cat, sheep, rabbit and rat 1,138. In functional terms, the CPRs make the
gastrointestinal tract ready to move, digest and absorb food. They prepare the
viscera to metabolize and store nutrients. In sum, CPRs act as feedforward
mechanisms to inform the organism about the ultimate postingestional consequences of food. CPRs can be evoked by normally ineffective stimuli, once they
have been paired several times with an inherently effective stimulus, as in a
classical conditioning paradigm 14,215. The gustatory afferent contribution to CPRs,
therefore, cannot always be asserted.
The most frequently studied CPR is the cephalic phase insulin release (cPIR)
or preabsorptive insulin release, by the endocrine pancreas 16,139,177,181. After oral
intake of glucose, insulin is released by the endocrine pancreas within one minute,
before the blood glucose level starts to rise 33,61,177. The cPIR is vagally mediated
through efferent parasympathetic fibers that innervate the pancreatic ß-cell 119,
since it can be blocked by atropine 137 and vagotomy 18,26,141. Much research has
been done on the localization of the vagal preganglionics and the identification of
the vagal branches that mediate the cPIR . Powley and Berthoud 17,18,140,141 have
shown that the perikarya of the vagal preganglionics controlling the response are
located in the medial columns of the DMnX. These neurons send their axons
through the two hepatic and gastric branches of the abdominal vagus. Each of
these branches can independently mediate a cPIR .
Although lesions of the ventromedial hypothalamus (VMH) 15,49,178, CeA 151 and
the lateral hypothalamus (LH) 60,178 alter the cPIR, the local circuitry of the brainstem seems to be sufficient to elicit the cPIR, since cephalic insulin release
persists in decerebrated animals 43. The CNS integrating pathways of the cPIR are
not fully defined. Higher diencephalic brain centers (including the hypothalamus)
seem to exert a modulatory role on the main brainstem relay systems 12,142, rather
than being the exclusive site for the integration of gustatory afferent information
30
Chapter 1
and efferent control over pancreatic $-cells. Indeed, Hayama et al. 69 showed that
the neural structures above pre- or midcollicular levels have tonic inhibitory or
facilitatory influences on response properties of extracellularly recorded NTS taste
units after oral stimulation with the four classical taste stimuli. This modulatory role
may determine several aspects of the cPIR. Glucose elicits a potent cPIR, but it
does no longer do after it has been paired with LiCl injection in intact rats 14. CTA
does not seem to be a capacity of the chronic decerebrate rat 62, so the
modification of the cPIR in CTA may also require the forebrain.
2 Aim and Outline of the Study and Summary of Results
The aim of the present thesis is to determine the neuroanatomy and physiology
of gustatory information processing in the brainstem of the rat. It focuses on the
neuroanatomical background of viscerogustatory interactions in response to
ingestion, with special attention to the cPIR. In the experiments we describe the
main focus is on the brainstem. CTA and sodium appetite following NaCl
deprivation are examples of viscerogustatory interactions which require
information processing with forebrain structures associated with feeding. However,
the brainstem is capable to influence ingestive behavior on the basis of taste
information, independently from forebrain nuclei. For example, the neural circuitry
of the brainstem mediates ingestive responses to glucoregulatory challenges and
is sufficient to induce the cPIR, thereby excluding the involvement of forebrain
structures .
Gustatory input activates parasympathetic reflexes (such as the cPIR) to
anticipate and to support the digestive process. The pathway that conveys
gustatory information to the endocrine pancreas should involve the rostral NTS,
where primary, gustatory afferents terminate. Since these gustation-induced
reflexes are vagally mediated, the DMnX should also be part of this descending
parasympathetic pathway (Fig.1). The aim of the present thesis is to demonstrate
which brainstem connections are essential to elicit the cPIR and how specific their
involvement is in this response. Accordingly, the study combines neurobiology
with metabolic physiology.
In chapter 2 experiments are described in which a retrograde transneuronal
viral tracer (pseudorabies virus ,PrV) was injected into the endocrine pancreas,
to demonstrate descending projections conveying gustatory information. The major
advantage of viral tracing is the visualization of functional chains of neurons. The
results of this study did not substantiate a direct connection between the rNTS and
General Introduction
31
the DMnX. Therefore, we suggested the involvement of one or more intermediate
Figure 1. Schematic drawing summarizing possible pathways in the brainstem to connect
oral/pharyngeal/esophagal taste receptors to DMnX areas innervating the pancreas.
stations. Based on the viral tracing results, we proposed the intermediate or
caudal NTS, the medullary reticular formation and the PBN as candidates to
complete this pathway (Fig.1).
For the studies described in chapter 3 we used c-fos immunocytochemistry
to detect sweet taste-activated neurons in the brainstem. Several studies have
demonstrated a tight correlation between neuronal activity and the expression of
c-fos 154,169. In this experiment rats drank a sucrose solution which acted as a
stimulus to induce c-fos expression and the subsequent production of Fos protein
in transsynaptically activated neurons 154. Sucrose taste-activated neurons
involved in the processing of gustatory information were detected in the
32
Chapter 1
intermediate NTS, caudal DMnX and in the medial and lateral PBN, which are
known to process information related to ingestive behavior.
In chapter 4 we again applied the c-fos technique in rat brainstem, after intraoral infusion of sucrose and saccharin and intra-gastric infusion of sucrose. During
the infusion, we took several blood samples to analyze plasma glucose and insulin
levels. This experimental design enabled us to discriminate between Fos
synthesis caused by sweet taste and by the postingestive effects following
ingestion of a sweet tasting solution. The results demonstrated that the NTS is
also activated by visceral afferents conveying information about glycemia and
through direct activation of NTS glucoreceptors by circulating glucose. Sweet taste
information inducing a cephalic phase response is probably responsible for the
remaining c-fos expression in the NTS. Neuronal activation by sweet taste
information inducing the cPIR is reflected in the vagal preganglionics of the medial
columns in the DMnX of saccharin-infused animals.
Chapter 5 describes the intramedullary projections of the rNTS, which were
anterogradely traced with Phaseolus vulgaris Leucoagglutinin (Pha-L). rNTS
projections on hypoglossal motoneurons and 'premotor' cells in the medullary
reticular formation provide neuroanatomical evidence for taste influence on oral
motor behavior. Gustatory influence on parasympathetic reflexes, such as the
cPIR, was found to reach the DMnX through the medullary reticular formation or
through intra-NTS projections to the intermediate NTS.
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