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Gustatory and reward brain circuits in the control of food intake
Albino J. Oliveira-Maia1,6, Craig D. Roberts1, Sidney A. Simon1,3,4, and Miguel A.L.
Nicolelis1,2,3,4,5
1Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710,
USA
2Department of Psychology and Neurosciences, Duke University Medical Center, Durham, North
Carolina 27710, USA
3Department of Biomedical Engineering, Duke University Medical Center, Durham, North Carolina
27710, USA
4Center for Neuroengineering, Duke University Medical Center, Durham, North Carolina 27710,
USA
5Edmond and Lily Safra International Institute for Neuroscience of Natal, Natal, Rio Grande do
Norte 59066-060, Brazil
Abstract
Gustation is a multisensory process allowing for the selection of nutrients and the rejection of
irritating and/or toxic compounds. Since obesity is a highly prevalent condition that is critically
dependent on food intake and energy expenditure, a deeper understanding of gustatory processing
is an important objective in biomedical research. Recent findings have provided evidence that
central gustatory processes are distributed across several cortical and sub-cortical brain areas.
Furthermore, these gustatory sensory circuits are closely related to the circuits that process reward.
Here, we present an overview of the activation and connectivity between central gustatory and
reward areas. Moreover, and given the limitations in number and effectiveness of treatments
currently available for overweight patients, we discuss the possibility of modulating neuronal
activity in these circuits as an alternative in the treatment of obesity.
Keywords
Taste; postingestive; feeding; deep brain stimulation
Introduction
In most societies the prevalence of obesity has risen dramatically to reach epidemic
proportions. In the United States alone, a staggering 30% of all adults are obese (Stein and
Colditz 2004). Increase in adiposity leads to significant metabolic dysregulation, with
important health and economic consequences (Stein and Colditz 2004). Increased
availability of palatable and high-calorie food and reduced requirement for energy
expenditure through physical activity are usually identified as the main culprits of this
obesity epidemic (Keith, Redden et al. 2006). Nonetheless, the participation of genetic
factors in the definition of individual susceptibility for the occurrence of obesity is also
6To whom correspondence should be addressed: Albino Jorge Oliveira-Maia, P.O. Box 3209, Department of Neurobiology, Duke
University Medical Center, Durham, NC 27710, USA, Telephone number: (919) 684-4967, Fax number: (919) 668-0734,
maia@neuro.duke.edu.
NIH Public Access
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widely accepted and has been extensively described (O'Rahilly and Farooqi 2006). While
such factors are commonly assumed to influence metabolic rate or the partitioning of excess
calories into fat, current data suggests that a significant part of the genetic influence on
human obesity has a direct impact on neural regulation of hunger, satiety and food intake
(Friedman 2009). An important objective in neuroscience research is thus to further
understand the central mechanisms of food reward and appetite regulation, which will
predictably allow a deeper comprehension of eating disorders such as obesity.
Gustation and the gustatory system: definitions
Gustation has historically been defined as a synonym of taste. Recently, however, this term
has been used to define a broader concept, which extends beyond taste (Simon, de Araujo et
al. 2006). In this broader sense, gustation is considered as the multisensory process that
allows for the selection of nutrients and rejection of irritating and/or toxic compounds
(Simon, de Araujo et al. 2006).
Gustatory processing begins when a motivated animal searches for and detects a desired
food, usually using visual and/or olfactory cues. Once a desired substance is found, the
decision to pursue and maintain consumption usually involves active oral exploration. The
unitary sensory perception resulting from taste, odour, texture and temperature of that
stimulus, i.e., its’ flavour, will be a central contributor in the decision of ingestion vs.
rejection (Small and Prescott 2005). Gustatory decision making is also impacted by the
organisms’ internal state. The central nervous system (CNS) detects a multitude of neural
and humoral signals from the periphery, reflecting several aspects of homeostatic balance
such as gastrointestinal status, current energy needs and availability, and energy stores
(Broberger 2005). The maintenance of energy homeostasis and stable body weight depends
on the integration of these endogenous signals with sensory feedback, and the ability to
respond adequately through modulation of both energy expenditure and food intake
(Schwartz and Porte 2005). Finally, the memories of orosensory, olfactory and postingestive
effects of previous encounters with a similar substance also influence food seeking and
ingestion (Sclafani 2004), as do emotional, cognitive and social factors (Wilson 2002).
The multisensory properties of intra-oral and ingested stimuli are conveyed to the brain
through specialized taste, somatosensory, olfactory and visceral sensory neurons that
converge on several CNS centres. Thus, once beyond the periphery, single neurons
responding to gustatory stimuli are often found to be broadly tuned to diverse combinations
of chemosensory, somatosensory, olfactory and even visual information (Rolls and Baylis
1994). Furthermore, the CNS detects humoral signals that cross the blood-brain barrier and
transmit information not only about the properties of ingested stimuli, but also about
physiological states, such as satiety (Zheng and Berthoud 2008), providing additional
modulatory influences for central gustatory neurons (Nakano, Oomura et al. 1986). Neurons
with these multimodal response properties, distributed through several CNS areas, integrate
sensory and homeostatic information, participating with neural circuits of affective,
cognitive and motor processing to organize ingestive behaviour (Kelley, Baldo et al. 2005).
Orosensory gustatory input
The peripheral gustatory system extracts multisensory information from substances placed
in the mouth, and conveys this information through multiple neural pathways to brainstem
structures (Kawamura, Okamoto et al. 1968). Taste receptor cells (TRCs) are responsive to
the type and quantity of chemicals dissolved in saliva and allow for the detection of at least
five distinctive taste qualities: salt, sweet, bitter, sour (acidic) and umami (savoury taste of
amino acids) (Spector and Travers 2005). Information about less water-soluble compounds,
as well as food characteristics such as texture, viscosity and temperature, is primarily
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transduced by specialized somatosensory neurons with endings distributed throughout the
oral epithelium (Halata and Munger 1983).
In vertebrates, TRCs are found in specialized microscopic taste receptor organs – the taste
buds. Mammalian taste buds are onion-shaped cell groups embedded at the surface of
several intra-oral structures, mainly the palate and tongue, where they cluster into
macroscopic structures named gustatory papillae. Each taste bud contains several distinct
morphological cell types that can be distinguished by ultrastructural and
immunohistochemical features (Murray 1971). Type I or dark cells have processes that
envelop nerve fibres and other taste cells and, given their expression profile of
neurotransmitter-related enzymes and transporters, are thought to have a support function
(Bartel, Sullivan et al. 2006). However, a recent report demonstrated that type I cells have
responses that depend on epithelial sodium channels (ENaCs – see below), suggesting a
possible role in salt taste transduction (Vandenbeuch, Clapp et al. 2008). Type II (light or
receptor cells) and type III (intermediate or presynaptic cells) are considered the main
chemosensing TRCs. Type II receptor cells express G-protein-coupled receptors (GPCRs),
phospholipase C β2 (PLCβ2) and transient receptor potential ion channel 5 (TRPM5).
Different type II cell subtypes appear to respond exclusively to sweet, bitter or umami
tastants (Tomchik, Berg et al. 2007). Given their ultrastructural and molecular
characteristics, these cells do not seem to have conventional synapses and, rather, appear to
release transmitters via pannexin or connexin hemichannels (Huang, Maruyama et al. 2007).
Type III presynaptic cells have synaptic contacts with intragemmal nerve fibres and,
accordingly, express synapse-related proteins such as SNAP-25 (synaptosomal-associated
protein of 25kD) (Yang, Crowley et al. 2000). Since they have broadly tuned responses to
tastants of multiple qualities, some authors propose that presynaptic cells may receive
converging information from receptor cells, presumably via purinergic signaling (Tomchik,
Berg et al. 2007). Finally, type IV or basal cells, in contrast to the remaining cell types, do
not have an elongated shape. They are thought to have a proliferative role to support
constant cell turnover in the taste bud (Murray 1971).
Microvillar processes from taste receptor cells extend towards the bud pore, on the mucosal
surface, where contact with sapid chemical stimuli occurs. Taste receptors are
transmembrane proteins found on these microvilli and are the basis for many of the
chemosensory properties of TRCs. Upon detection of a specific stimulus, they will activate
intracellular transduction cascades to initiate the process of gustatory neural signalling
(Margolskee 2002). Proteins belonging to the GPCR superfamily have been established as
receptors for sweet (T1R2/T1R3 receptors), umami (T1R1/T1R3 receptors), and bitter (T2R
receptors) tastants (Zhao, Zhang et al. 2003; Mueller, Hoon et al. 2005). The predominant
downstream signaling pathways for these receptors require PLCβ2 and TRPM5 (Zhang,
Hoon et al. 2003). There is also evidence implicating gustducin, a G-protein almost
exclusively expressed in TRCs, in bitter and sweet taste transduction (Wong, Gannon et al.
1996). Sour and salt taste qualities rely on a different set of receptors and signaling
pathways (Zhang, Hoon et al. 2003). Recently, two TRP ion channels from the polycystic
kidney disease-like family, co-expressed in a subset of TRCs that are necessary for sour
taste transduction (Huang, Chen et al. 2006), were proposed to form a candidate sour
receptor (Ishimaru, Inada et al. 2006). Alternate mechanisms for detection of sour tastants
have been described, but it is unclear to what degree these putative pathways for sour taste
are specific for different species and/or regions of the tongue (Huque, Cowart et al. 2009).
For salt taste, at least two distinct mechanisms exist in rodents: an amiloride-sensitive
epithelial sodium channel (ENaC), accounts for part of the responses to sodium and lithium
ions (Heck, Mierson et al. 1984) while other, amiloride-insensitive mechanisms, serve as
receptors for multiple ions including sodium, potassium, ammonium and calcium
(DeSimone, Lyall et al. 2001). A variant of TRPV1, a transient receptor potential vanilloid
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receptor, has been proposed as an amiloride-insensitive salt taste receptor (Lyall, Heck et al.
2004) but the perceptual relevance of this receptor mechanism is still controversial
(Treesukosol, Lyall et al. 2007).
Perception of a given taste quality seems to reflect the activation of a specific population of
TRCs rather than the properties of a specific interaction between a tastant and a taste
receptor (such as the kinetics of taste receptor activation). In fact, taste receptors for sweet,
bitter, umami and sour are present in largely segregated populations of taste cells that
function as narrowly tuned sensors for each of these taste qualities (Zhang, Hoon et al. 2003;
Huang, Chen et al. 2006). Additionally, the selective activation of a TRC population
expressing a particular taste receptor is, in itself and irrespective of the actual receptor being
activated, sufficient to generate approach or rejection behaviours that are specific for that
taste quality (Zhao, Zhang et al. 2003; Mueller, Hoon et al. 2005). It is therefore clear that
sweet, bitter, umami and sour taste pathways are segregated at the TRC level. However, this
labelled-line model does not seem to be conserved in the CNS, where most authors suggest
the occurrence of multisensory and distributed gustatory processing (Simon, de Araujo et al.
2006).
Adenosine triphosphate (ATP) signaling is necessary for transmission of taste information to
the CNS. Tastant evoked ATP release activates P2X2/P2X3 ionotropic purinoreceptors on
primary gustatory afferent nerve terminals (Finger, Danilova et al. 2005). Serotonin and
norepinephrine are also released from taste buds upon chemosensory stimulation, but their
functional role is not as clear as that of ATP (Heath, Melichar et al. 2006; Huang, Maruyama
et al. 2008). Other transmitters, peptides and respective receptors, namely acetylcholine,
glutamate, cholecystokinin (CCK), vasoactive intestinal peptide, substance P and leptin,
have also been identified in taste cells. Many of these compounds are thought to modulate,
in an autocrine or paracrine manner, the responses to tastants (Heath, Melichar et al. 2006;
Huang, Maruyama et al. 2008).
The chorda tympani and greater superior petrosal branches of the facial (VIIth) nerve carry
sensory axons of cells in the geniculate ganglion and innervate taste buds respectively in the
anterior tongue and palate. Sensory axons of the glossopharyngeal (IXth) nerve, with cell
bodies in the petrosal ganglion, terminate in taste buds in the posterior tongue (lingual
branch) and pharynx (pharyngeal branch). The nodose ganglion of the vagus (Xth) nerve
contains primary taste neurons with axons that integrate the pharyngeal, superior laryngeal
and internal laryngeal branches to innervate taste buds in the epiglottis, larynx and
oesophagus (Miller 1995). Primary sensory neurons in these nerves transmit activity
generated in TRCs centrally to the solitary tract nucleus (NTS) (Simon, de Araujo et al.
2006).
Peripheral neural taste pathways are functionally and anatomically very close to the
somatosensory system, allowing chemical, thermal and tactile detection to act in concert to
evaluate substances in the mouth. In fact, the glossopharyngeal and vagal nerves also carry
somatosensory nerve fibres from the oral and upper digestive mucosa, as does the lingual
branch of the trigeminal (V) cranial nerve (Matsumoto, Emori et al. 2001), allowing for the
transduction of information relating to the temperature and texture of ingested stimuli
(Halata and Munger 1983). Some intra-oral somatosensory nerve endings are activated by
high concentrations of the same chemical stimuli that define some primary tastants, such as
NaCl (Wang, Erickson et al. 1993), usually producing irritating sensations. Oral mucosa
nerve endings may also have other chemosensing properties, as exemplified by the
responses to capsaicin, found in chilli peppers and producing a burning sensation (Liu and
Simon 1996), and to menthol, producing a cooling sensation (Chuang, Neuhausser et al.
2004), mediated by the thermo-sensitive TRPV1 and TRPM8 channels respectively.
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Furthermore, dietary fats and oils, thought to be sensed mainly by their texture (Kadohisa,
Verhagen et al. 2005) have recently been shown to activate chemosensory mechanisms, such
as a fatty acid receptor/transporter, CD36, which is expressed in TRCs and modulates
preference for long-chain fatty acid-enriched solutions (Laugerette, Passilly-Degrace et al.
2005). On the other hand, physical variables, such as temperature, can affect TRC taste
transduction function, as exemplified by thermal modulation of sweet taste intensity
(Talavera, Yasumatsu et al. 2005). Thus, it becomes clear that, already in the mouth, input to
the gustatory system is inherently multisensory.
Postingestive sensory processes
Once a stimulus has been ingested it is not beyond detection by the CNS. In fact, there are
multiple and complex humoral and neural postingestive mechanisms that signal not only the
presence but also the character of intestinal content. Neural signals depend on the intrinsic
and extrinsic enervation of the gastrointestinal tract (GIT). The latter is performed by the
autonomic nervous system through both its divisions: parasympathetic (vagal and pelvic
nerves) and sympathetic (splanchnic nerves) (Zheng and Berthoud 2008). These nerves, the
vagus in particular, contain afferent neurons that transmit mechanical (i.e., touch, distension,
contraction) and chemical sensory information from the GIT to the brain. The neural
transmission of chemical information is thought to result from the detection of signaling
peptides, such as CCK, produced by enteroendocrine epithelial cells with chemosensing
properties (Cummings and Overduin 2007). These peptides also reach the circulation, acting
on the brain as humoral signals, and are thus called ‘gut hormones.’ Absorbed nutrients
(e.g., glucose) and feeding-related peptides produced in sites other than the gut (e.g.,
insulin), can also be humoral signals that modulate the activity of central gustatory circuits
(Zheng and Berthoud 2008).
With a single exception, discussed below, all known sensory mechanisms originating in the
gut are negative feedback signals that lead to decreases in food intake. They are called
satiety or satiation signals (Cummings and Overduin 2007). Gastric content is detected by
vagal afferent fibres in the mucosa, sensitive to touch, while other mechanosensory vagal
afferents, in or between muscle layers, report intragastric volume (Wang and Powley 2000).
While gastric satiation processes are predominantly mechanosensory, those originating from
the intestine are essentially chemosensory or nutritive (Powley and Phillips 2004).
Enteroendocrine cells in the gut lining detect chemical properties of intraluminal content and
respond by releasing peptides through their basolateral membrane (Cummings and Overduin
2007). Chemosensing activity in enteroendocrine cells is thought to occur through
mechanisms and transduction molecules similar to those used in taste, such as T1R3
receptors and gustducin, involved in both orosensory and intestinal responses to sugars
(Margolskee, Dyer et al. 2007).
CCK, glucagon-like peptide 1 (GLP-1), oxyntomudulin, peptide YY (PYY) and ghrelin are
all examples of gut hormones that have been well established as regulators of food intake
(Cummings and Overduin 2007). CCK is produced in the duodenal and jejunal mucosa,
mainly in response to lipids and proteins, and acts hormonally or via the vagal nerve to
reduce food intake (Smith, Jerome et al. 1981; Blevins, Stanley et al. 2000). GLP-1,
oxyntomudulin and PYY are produced in the more distal segments of the small intestine and
the colon, in response to lipids and carbohydrates and, to a lesser extent, proteins (Brubaker
and Anini 2003). When administered systemically or directly into the CNS, these peptides
act as satiation factors (Turton, O'Shea et al. 1996; Dakin, Gunn et al. 2001; Batterham,
Cowley et al. 2002) and, again, their effects upon peripheral administration involve afferent
activity in the vagus nerve (Abbott, Monteiro et al. 2005). Many other gut peptides have
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been described but, at this time, the regulation of their secretion and their status as
physiologic modulators of feeding is unclear (Berthoud 2008).
Ghrelin is the only gut hormone that has been described to act as a positive feed forward
stimulus of ingestion (Tschop, Smiley et al. 2000). It is secreted from neuroendocrine cells
in the gastric mucosa with a temporal pattern of release that is out of phase from all other
known gut and pancreatic peptides. Peak circulating levels occur prior to meals and a rapid
decrease is observed when nutrients are emptied into the duodenum (Cummings, Purnell et
al. 2001). Other than ghrelin and palatable oral gustatory stimulation, other ingestion-
stimulating mechanisms have been proposed to exist, but remain undefined (Sclafani 2004).
Gut peptides are not the only humoral factors that modulate food intake. Free fatty acids,
amino acids and glucose, can also convey information about nutritional status to the CNS. In
fact, in the first theories for control of energy balance, circulating levels of glucose (Mayer
1953) or of lipids (Kennedy 1953) were proposed as the signals of nutritional status. We
now know that nutrients in the bloodstream can cross the blood-brain barrier (Lam,
Schwartz et al. 2005) and act directly on the CNS. Oleic acid (a long-chain fatty acid)
(Obici, Feng et al. 2002), the amino acid leucine (Cota, Proulx et al. 2006) and glucose
(Booth 1968) are examples of nutrients shown to inhibit food intake when administered
centrally. Direct CNS nutrient sensing is thought to occur through key intracellular energy
sensors in CNS neurons, found predominantly in the hypothalamus, such as ATP-sensitive
potassium channels (Obici, Feng et al. 2002), malonyl-coenzyme A (malonyl-CoA) (Loftus,
Jaworsky et al. 2000), AMP-activated protein kinase (Minokoshi, Alquier et al. 2004), long-
chain fatty acyl-CoAs (Lam, Pocai et al. 2005) and mTOR (a highly conserved serine-
threonine kinase) (Cota, Proulx et al. 2006).
Circulating nutrients also activate chemosensors in the pancreas and liver, resulting in the
release of hormonal satiation peptides and/or vagal afferent activation (Cummings and
Overduin 2007). In response to caloric load or vagal efferent activity, the pancreas releases
insulin, pancreatic polypeptide (PP) and amylin (Lutz, Geary et al. 1995; Schwartz, Woods
et al. 2000; Katsuura, Asakawa et al. 2002). With the exception of PP, that acts peripherally
(Banks, Kastin et al. 1995), these peptides have effects directly in the CNS to exert an
anorectic effect (Lutz, Del Prete et al. 1995; Obici, Feng et al. 2002). Portal-hepatic vagal
afferents are also sensitive to circulating metabolites such as glucose (Niijima 1969), amino
acids (Tanaka, Inoue et al. 1990) and fatty acids (Orbach and Andrews 1973), and also to
gut peptides such as GLP-1 (Mithieux, Misery et al. 2005). While the chemosensing
mechanisms in the porto-hepatic system are still unclear (Langhans 1996), it is well
established that the activity of this system is relevant for the regulation of food intake
(Tordoff and Friedman 1986). Finally, glucose-sensing cells have also been described in the
carotid body (Pardal and Lopez-Barneo 2002).
Central gustatory sensory pathways
Taste pathways in the CNS are intimately associated with general viscerosensory afferents
from the cardiovascular, respiratory and, importantly, gastrointestinal systems (Lundy and
Norgren 2004). This is the case for all central taste relays, namely the NTS, parabrachial
nuclei (PbN) of the pons, parvicellular division of the ventral posterior nucleus of the
thalamus (VPpc) and insular or gustatory cortex, through which gustatory taste and visceral
projections ascend mostly ipsilaterally (Lundy and Norgren 2004). However, in contrast to
what happens in rodents, the primate PbN are essentially visceral relays and the NTS
projects taste afferents directly to the thalamus (Norgren 1984). Circulating metabolic
signals can also modulate neural responses in relays of the gustatory system, such as the
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NTS, and in areas that receive direct or indirect gustatory afferents such as the hypothalamic
homeostatic centres and reward-related areas in the midbrain (Zheng and Berthoud 2008).
Taste-related information derived from all chemoresponsive cranial nerves, and visceral
input, mainly from the vagus nerve, converge in the NTS. The rostral division of the nucleus
(rNTS) receives mostly taste afferents while the caudal NTS (cNTS) is the main target for
vagal visceral information (Altschuler, Bao et al. 1989). Trigeminal somatosensory inputs
from oral branches of the fifth nerve also project to the rNTS (Torvik 1956). Thus,
trigeminal stimulants with irritating effects can modulate taste responses in the rNTS
(Simons, Boucher et al. 2003), as does afferent vagal activity, such as that produced by
gastric distension (Glenn and Erickson 1976). The NTS has ascending projections to the
PbN and local or descending projections to somatic and visceral premotor/motor areas
(Norgren 1978). Local medullary connections with somatic motor or autonomic
preganglionic nuclei, either directly or through interneurons in the parvicellular reticular
formation, are substrates for reflexes involved in chewing (motor nuclei of the trigeminal
and facial nerves), tongue movement (hypoglossal nucleus), salivation (superior and inferior
salivatory nuclei), swallowing (nucleus ambiguus) and GI motility and secretion (dorsal
motor nucleus of the vagal nerve) (Contreras, Gomez et al. 1980; Travers and Norgren 1983;
Beckman and Whitehead 1991). Thus, circuits in the hindbrain are sufficient for decerebrate
rats to display both acceptance and rejection behaviours to oral stimulation with tastants
(Grill and Norgren 1978).
The parabrachial complex is a collection of nuclei located in the dorsolateral aspect of the
pons. The PbN nuclei are physically divided into medial and lateral subdivisions by fibres of
the superior cerebellar peduncle. In rodents, ascending neural pathways from the NTS
synapse in the ipsilateral PbN (Norgren and Leonard 1971). The segregation of taste and
visceral projections to the rat PbN is not as clear as in the NTS (Hermann, Kohlerman et al.
1983). Nevertheless, visceral afferent projections arising from the cNTS terminate primarily
in nuclei of the lateral subdivision while taste responsive neurons are found mainly in the
medial PbN (Karimnamazi, Travers et al. 2002). From the PbN, third order neurons ascend
to form two gustatory projection systems: one projecting dorsally to the thalamus and
another projecting ventrally to the forebrain (Norgren and Leonard 1973).
PbN projections to forebrain centres are mostly reciprocal. In fact, taste-responsive PbN
neurons are modulated by electrical stimulation of forebrain sites (Di Lorenzo 1990; Li, Cho
et al. 2005). The rNTS is also a target of descending forebrain projections from the insular
and prefrontal cortices, central nucleus of the amygdala (CeA), lateral hypothalamus (LH),
bed nucleus of the stria terminalis and substantia innominata (van der Kooy, Koda et al.
1984). These descending neural pathways are presumably involved in the modulation of
taste activity by physiological and experiential factors (Li, Cho et al. 2005).
In primates, including humans, rNTS projection fibres have not been shown to terminate in
the PbN and synapse directly in the VPpc (Beckstead, Morse et al. 1980). Thus, input to the
primate PbN is essentially viscerosensory, the bulk of the projections from PbN are directed
towards the ventral forebrain (Pritchard, Hamilton et al. 2000) and the VPpc receives most
of its gustatory input directly from the NTS (Norgren 1984). In rodents, the dorsal
thalamocortical pathway, originating mainly in the medial PbN, synapses in the VPpc of the
thalamus and terminates in the insula. The VPpc is the dorsal thalamic relay for orosensory
and visceral information. PbN efferents to this thalamic nucleus are bilateral with an
ipsilateral predominance (Fulwiler and Saper 1984). In fact, while the receptive field for
parabrachial gustatory neurons is ipsilateral (Hayama, Ito et al. 1987), they can be
antidromically driven from the thalamus on either side (Ogawa, Hayama et al. 1984).
However, viscerosensory projections to the thalamus from the external medial parabrachial
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subnucleus are mainly contralateral (Cechetto and Saper 1987). VPpc neurons respond to
combinations of chemosensory and/or somatosensory oral stimulation (Nomura and Ogawa
1985) with a medial to lateral arrangement described for taste, thermal and tactile responses
(Kosar, Grill et al. 1986), and also for taste, GI and cardiovascular/respiratory responses
(Cechetto and Saper 1987). Neurons in the VPpc projects to the insular cortex and also to
the amygdala (Ottersen and Ben-Ari 1979).
The primary taste cortex in macaques is defined as the area receiving afferents from the
VPpc, extending posteriorly ~4mm from its anterior limit at the junction of the orbitofrontal
and opercular cortices (Scott and Plata-Salaman 1999). Functional neuroimaging studies
have shown that, in the human brain, homologous gustatory cortical areas, in the insula and
frontal operculum, respond to unimodal taste stimuli (Small, Zald et al. 1999). The rodent
insula is a cortical region ventral to the oral region of the somatosensory cortex and dorsal to
the rhinal sulcus. According to the presence or absence of a granule cell layer, the insular
cortex is divided into two histologically distinct subdivisions: the granular and agranular
insular cortices. In the dorsal segment of the agranular cortex, adjacent to the granular area,
there are scattered granule cells that define a thin strip of dysgranular cortex (Lundy and
Norgren 2004). It has been noted that insular somatosensory and visceral responses occur in
the more dorsal granular insula, whereas taste responses occur ventrally, in the dysgranular
area, that is thus proposed to be the primary gustatory cortex (GC) (Cechetto and Saper
1987; Lundy and Norgren 2004). This stringent definition of the GC as a distinct functional
unit, anatomically separated from the more dorsal granular viscerosensory and
somatosensory cortex, is challenged by the fact that single neurons in the insula can respond
to multiple sensory modalities, namely taste, somatosensory, visceral and nociceptive
stimuli (Hanamori, Kunitake et al. 1998). Also, upon stimulation of the entire oral cavity,
taste responsive neurons are found not only in the dysgranular but also the granular and, to a
lesser extent, the agranular insular cortex (Ogawa, Ito et al. 1990). Recent work with optical
imaging of the rat insular cortex upon stimulation of the tongue with multiple tastants has
equally described responses that include but are not restricted to the dysgranular insula
(Accolla, Bathellier et al. 2007).
The different insular regions projects back to their respective thalamic sensory relays and to
other cortical areas (Shi and Cassell 1998). The orbitofrontal cortex (OFC), sometimes
defined as a secondary taste cortical area (Rolls, Yaxley et al. 1990), receives converging
projections from the GC and primary olfactory cortex, proposed as relevant for the
perception of flavor (Small and Prescott 2005).
Amygdala and brain reward pathways
The ventral forebrain gustatory projection system includes projections to several structures
in the limbic forebrain, such as the hypothalamus (Zaborszky, Beinfeld et al. 1984),
amygdala, substantia innominata and bed nucleus of the stria terminalis (Fulwiler and Saper
1984). The amygdala and the hypothalamus receive other ascending and descending
projections from gustatory sensory relays and have important roles in the integration of
gustatory input. In the amygdala, the central (CeA) and basolateral (BLA) nuclei are the
main sites receiving gustatory projections from the NTS (Ricardo and Koh 1978), PbN
(Fulwiler and Saper 1984; Karimnamazi and Travers 1998), VPpc (Ottersen and Ben-Ari
1979) and insula (Ottersen 1982). The CeA projects back to the NTS and PbN (Krettek and
Price 1978) while the BLA has projections to the insula (Krettek and Price 1977). The two
amygdalar areas are also interconnected (Ottersen 1982).
The amygdala is reciprocally connected with areas of the midbrain dopaminergic reward
system. The latter arises from ventral tegmental area (VTA) dopamine producing neurons
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that project to the nucleus accumbens (NAcc) and participate in the processing of food
reward (Wise 2006). The amygdala is connected both with the VTA (Phillipson 1979) and
the NAcc (Kirouac and Ganguly 1995) through the CeA and the BLA. The NAcc also
receives afferents directly from other gustatory-related centres, namely the NTS (Ricardo
and Koh 1978), insula (Brog, Salyapongse et al. 1993) and LH (Baldo, Daniel et al. 2003).
Additionally, circulating pancreatic and gut hormones such as insulin (Figlewicz 2003),
PYY (Batterham, ffytche et al. 2007) and ghrelin (Abizaid, Liu et al. 2006) have been shown
to directly modulate the activity of midbrain dopamine neurons. The NAcc seems to be a
central interface in the integration of sensory, emotional and cognitive controls of food
intake (Kelley, Baldo et al. 2005). Single accumbens neurons receive convergent inputs
from the hippocampus, BLA and prefrontal cortex (French and Totterdell 2002; French and
Totterdell 2003), and dopamine regulates the effect of these afferents on NAcc neurons
(Goto and Grace 2005). NAcc projections to the LH, either direct or through the ventral
pallidum, are thought to be its’ major effector pathway in the control of feeding behaviours
(Stratford and Kelley 1999).
Food reward, however, is not a unitary concept, and its different conceptual components
have been ascribed to different neural substrates. The dissociation between motivational
(“wanting” or incentive salience) and hedonic (“liking” or affective salience) components of
food reward is one that has been extensively explored (Berridge 2009). While incentive and
affective salience often occur simultaneously and are modulated by neurons found in the
same brain areas, such as the NAcc and ventral pallidum, they are behaviourally and
neurally distinguishable. “Wanting” reflects the value of a rewarding stimulus in terms of its
capacity to elicit an action to obtain that stimulus, and is thought to depend highly on
mesolimbic dopamine neurotransmission. “Liking,” on the other hand, is the actual
pleasurable sensation obtained upon contact with that stimulus, which is often quantified
according to stereotypical orofacial responses that can be observed during consumption
(Berridge 1996). While activation of opioid receptors in the NAcc is a potent stimulant of
food intake, this effect is specific for palatable foods (Woolley, Lee et al. 2006).
Furthermore, opioidergic stimulation of a small subsection of the NAcc (“hedonic hotspot”)
can specifically modulate orofacial “liking” responses in rats, suggesting a central role for
endogenous opioid neurotransmission as a substrate for affective salience (Berridge 2009).
Hypothalamus, brainstem and energy homeostasis
Other than the amygdala, the hypothalamus is the main target of the ventral forebrain
gustatory projections system. The NTS projects directly to the median preoptic,
paraventricular (PVH), dorsomedial (DMH) and lateral (LH) hypothalamic nuclei (Ricardo
and Koh 1978), while the PbN nuclei project to the median preoptic, PVH, LH, and
ventromedial hypothalamus (VMH) (Fulwiler and Saper 1984; Zaborszky, Beinfeld et al.
1984). Furthermore, descending projections from the agranular insular cortex target the LH
(Yasui, Breder et al. 1991). Lesion studies have established the importance of the
hypothalamus for the control of feeding, weight and energy homeostasis. Destruction of the
VMH, DMH or PVH induces hyperphagia and obesity (Hetherington and Ranson 1940;
Brobeck, Tepperman et al. 1943) while LH lesions induces hypophagia (Anand and Brobeck
1951). These findings led to the dual centre model for appetite regulation, with the ‘satiety
centre’ based in the VMH and the ‘hunger centre’ in the LH (Stellar 1954).
More recently, the VMH has been determined to be the main brain region mediating the
effects of leptin (Dhillon, Zigman et al. 2006) - a protein produced and secreted in white
adipose tissue that is one of the most important homeostatic mediators of hypophagia
(Zhang, Proenca et al. 1994). Subsets of LH neurons, on the other hand, contain either
orexin (also known as hypocretin) or melanin concentrating hormone (MCH) (Elias, Saper
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et al. 1998) and both of these peptides are potent stimulators of food intake (Qu, Ludwig et
al. 1996; Sakurai, Amemiya et al. 1998). The two hypothalamic centres are connected
reciprocally to the arcuate nucleus of the hypothalamus (ARC), that is thought to be the
master central regulator of energy balance and food intake (Zaborszky and Makara 1979;
Horvath, Diano et al. 1999). Separate subsets of GABAergic ARC neurons have opposed
effects on feeding behaviour. Pro-opiomelanocortin (POMC) is a precursor to α- and β-
melanocyte stimulating hormones (MSH), two melanocortins that, when released from
anorexigenic neurons, act to reduce food intake and body weight while increasing energy
expenditure (Biebermann, Castaneda et al. 2006). Orexigenic ARC neurons express
neuropeptide Y (NPY) which stimulates feeding and reduces energy expenditure (Baskin,
Breininger et al. 1999). The same neurons also express agouti gene-related transcript, an
antagonist of melanocortin receptors that inhibits the anorectic effects of α-MSH (Ollmann,
Wilson et al. 1997). The ARC is located just above the median eminence, where the blood-
brain barrier comprises fenestrated capillaries allowing access to humoral signals that do not
reach most other brain areas (Gao and Horvath 2007). Neurons in the ARC are sensitive to
glucose (Wang, Liu et al. 2004) and possibly also to intermediates of fatty acid metabolism
(Loftus, Jaworsky et al. 2000). Additionally, they express receptors and respond to a variety
of other metabolic factors including insulin, leptin and ghrelin (Willesen, Kristensen et al.
1999; Spanswick, Smith et al. 2000; Cowley, Smart et al. 2001).
The area postrema (AP), lying immediately dorsal to the NTS, is also a circumventricular
organ, that lies outside the blood-brain barrier (Broadwell and Brightman 1976). Some NTS
neurons have dendrites in this zone (Herbert, Moga et al. 1990) and AP neurons project to
the reticular formation and the PbN in a manner very similar to that of NTS neurons
(Shapiro and Miselis 1985; Herbert, Moga et al. 1990). AP neurons express receptors for,
and in some cases have been shown to respond to, amylin (Rowland, Crews et al. 1997),
CCK (Moran, Robinson et al. 1986), GLP-1 (Rowland, Crews et al. 1997) and insulin
(Werther, Hogg et al. 1987). The AP participates, with the NTS and the dorsal motor
nucleus of the vagus, in the control of food intake by the caudal brainstem. In fact, the
caudal hindbrain contains glucose-sensitive neurons that are involved in ingestive and
sympathoadrenal responses to glucopenia (Ritter, Slusser et al. 1981) and also neurons that
express receptors for, and coordinate ingestive responses to, both leptin (Grill, Schwartz et
al. 2002) and ghrelin (Faulconbridge, Cummings et al. 2003). Thus, even when the
brainstem is isolated from all forebrain connections, rats exhibit not only acceptance and
rejection behaviours to oral stimulation with tastants (Grill and Norgren 1978), but also
basic satiety-related behaviours (Grill and Norgren 1978). However, these animals are
unable to increase meal size in response to food deprivation, suggesting that the forebrain is
needed to respond adequately to a long-term homeostatic challenge (Grill and Kaplan 2001).
Novel opportunities in the management of obesity?
In the introduction to our description of the gustatory system, the dramatic increase in the
prevalence of obesity was referred to as the underlying motivation for the study of the
central mechanisms of food reward and appetite regulation. In fact, obesity is not without
consequence. Excess weight has been linked to the development of cardiovascular and
cerebrovascular disease, hypertension, type 2 diabetes, dyslipidemia, a variety of cancers,
gallstones, osteoarthritis, sleep apnea, asthma, cataracts, benign prostatic hypertrophy and
depression, among other disorders (Stein and Colditz 2004). In fact, obesity is second only
to smoking as a leading cause of both preventable mortality and health-related economic
burdens. While the health consequences of obesity are important and potentially life-
threatening, they are also reversible: even modest reductions in weight lead to improvement
in health outcomes such as blood pressure, glucose tolerance and lipid profile (Stein and
Colditz 2004).
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Treating and preventing obesity are thus important objectives in healthcare. However, the
treatment options available currently have important limitations. Counselling for dietary
modifications, exercise and pharmacologic therapy are the more conservative approaches.
Weight loss can be achieved initially but only a small proportion of excess weight is lost
and, even so, the maintenance of these losses depends, in most cases, on sustained
pharmacologic therapy (Bray and Wilson 2008). In fact, there is extensive evidence that any
deviation from a theorized weight “set-point,” thought to be based in the hypothalamus, will
activate feedback signals, such as leptin and ghrelin, leading to behavioural and metabolic
responses that resist and minimize the original weight change (Keesey and Powley 2008).
Bariatric surgery is the only effective long-term alternative for the treatment of morbid
obesity. In 2005, 140,000 such interventions are estimated to have been performed in the
U.S., and reported success rates are high, with up to 80% average excess body weight loss
(Nguyen and Wilson 2007). Furthermore, laparoscopic alternatives, with very low
perioperative mortality rates (below 1%), have become available for many bariatric
procedures. Nevertheless, bariatric surgery is not devoid of adverse consequences and is not
an option for many patients. Superobese individuals, for example, have higher surgical risks
(Buchwald, Estok et al. 2007), potentially leading to limitations in access to abdominal
surgery for those patients that need it most (Gottig, Daskalakis et al. 2009). Moreover, there
are important late complications after bariatric surgery, such as metabolic imbalances and
nutritional deficiencies (Bult, van Dalen et al. 2008), and late postoperative mortality rates
are thought to be grossly underestimated (Buchwald, Estok et al. 2007). In summary, while
the effectiveness of bariatric surgery remains unchallenged, it is clear that new alternatives
are needed for weight management, especially for extremely obese patients.
The CNS seems to be an important therapeutic target in obesity management. Most of the
pharmacological alternatives for obesity treatment act, at least partially, through effects in
the brain (Bray and Greenway 2007), and modulation of gut hormones constituting the ‘gut-
brain axis’ is thought to be responsible for some of the long-lasting effects of bariatric
surgery (Ashrafian and le Roux 2009). The possibility of manipulating food intake and
weight by lesions of the hypothalamus was demonstrated in early studies, done in rats,
leading to the dual centre model with the VMH as the ‘satiety centre’ (Hetherington and
Ranson 1940; Brobeck, Tepperman et al. 1943) and the LH as the ‘hunger centre’ (Anand
and Brobeck 1951). LH lesions have also been performed in a small group of obese patients
with significant, albeit temporary, effects in reducing food intake and promoting weight loss
(Quaade, Vaernet et al. 1974).The use of electrical stimulation to modify neuronal activity in
discrete brain areas has revolutionized functional neurosurgery, with widespread use in the
treatment of movement disorders, namely Parkinson’s disease (Benabid, Chabardes et al.
2009). The use of deep brain stimulation (DBS) has also been attempted for several
psychiatric disorders, namely Tourette’s syndrome, obsessive-compulsive disorder and
major depression, with promising results (Larson 2008). The consideration of
neuropsychiatric factors underlying the pathophysiology of obesity (Volkow and O'Brien
2007) has thus led some to propose the use of DBS in hypothalamic or ventral striatal
regions for the treatment of obesity (Halpern, Wolf et al. 2008). The feasibility of such an
approach is suggested by research in animals, demonstrating inhibition of food consumption
(Hoebel and Teitelbaum 1962), or prevention of weight gain (Sani, Jobe et al. 2007) by
hypothalamic stimulation in rodents. Furthermore, a case of bilateral ventral hypothalamic
DBS for treatment of morbid obesity has been reported in the literature, with moderate
weight loss and few side effects (Hamani, McAndrews et al. 2008). While there is still very
little information for or against the use of this technique in the treatment of obesity, the
possibility of conducting DBS surgery under local anaesthesia (Benabid, Chabardes et al.
2009) may prove to be an advantage for those patients where abdominal surgery poses a
significant risk.
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Neural stimulation outside of the brain might also prove to be a valid alternative for obese
patients. Several experimental treatments, such as gastric electrical stimulation (Hasler
2009) and intra-abdominal vagal blocking therapy (Camilleri, Toouli et al. 2008) are
currently being pursued with this purpose. It is critical to validate these approaches to weight
control and accurately understand the mechanisms by which they act.
Conclusions
Gustatory, homeostatic and reward circuits in the mammalian brain are part of a complex
and distributed neural system that coordinates feeding and other aspects of energy
homeostasis. Therapeutic or experimental manipulation of neuronal activity in this system
can reduce food consumption and promote weight control, in some cases with dramatic and/
or long-lasting effects. Furthermore, with an ever-growing arsenal of neurobiological
approaches to understanding brain function, knowledge on the physiology and
pathophysiology of feeding behaviour, especially as it relates to hyperphagia and obesity, is
already substantial. There are, however, still many unanswered questions. Treatments for
obesity that reduce food intake are thought to modulate CNS activity mostly indirectly,
through mechanisms that are still poorly understood but presumed to involve changes in
neural and/or humoral input to the brain. On the other hand, experimental interventions that
directly modify anatomical and/or functional properties of the brain and result in weight loss
are yet to be applied clinically. In years to come, new approaches for the management of
obesity are critically necessary. Research on the central neural mechanisms of gustation
could contribute significantly towards uncovering novel avenues for the treatment of obesity
and even related metabolic disorders such as diabetes.
Acknowledgments
We thank Susan Halkiotis for assistance in reviewing our original manuscript. This work was supported by Grant
Number R01DC001065 to Sidney Simon from the National Institute on Deafness and Other Communication
Disorders (NIDCD). The content is solely the responsibility of the authors and does not necessarily represent the
official views of the NIDCD or the National Institutes of Health.
Abbreviations
AMP Adenosine monophophate
AP Area postrema
ARC Arcuate nucleus of the hypothalamus
ATP Adenosine triphosphate
BLA Basolateral amygdale
CCK Cholecystokinin
CeA Central nucleus of the amygdala
CNS Central nervous system
cNTS Caudal division of the solitary tract nucleus
CoA Coenzyme A
DBS Deep brain stimulation
DMH Dorsomedial nucleus of the hypothalamus
ENaC Epithelial sodium channel
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GABA Gamma-aminobutyric acid
GC Gustatory cortex
GIT Gastrointestinal tract
GLP-1 Glucagon-like peptide 1
GPCR G-protein coupled receptors
IC Insular cortex
LH Lateral hypothalamus
MCH Melanin concentrating hormone
MSH Melanocyte stimulating hormone
NAcc Nucleus accumbens
NPY Neuropeptide Y
NTS Solitary tract nucleus
OFC Orbitofrontal cortex
PbN Parabrachial nuclei
PLCβ2Phospholipase C β-2
POMC Pro-opiomelanocortin
PP Pancreatic polypeptide
PVH Paraventricular nucleus of the hypothalamus
PYY Peptide YY
rNTS Rostral division of the solitary tract nucleus
SNAP-25 Synaptosomal-associated protein of 25kD
TRC Taste receptor cell
TRP Transient receptor potential ion channel
VMH Ventromedial nucleus of the hypothalamus
VPpc Parvicellular division of the ventral posterior nucleus of the thalamus
VTA Ventral tegmental area
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Fig. 1. Peripheral Taste Mechanisms
Tastants activate two classes of taste bud cells: Type II or receptor cells and Type III or
presynaptic cells. Different subclasses of receptor cells (green, red, and blue cells), express
T1R2/T1R3, T2R or T1R1/T1R3 G-protein-coupled taste receptors and are activated
respectively by sweet, bitter or umami compounds. Downstream signaling pathways in these
cells require phospholipase C β2 and transient receptor potential ion channel M5 (TRPM5).
When activated, receptor cells release adenosine triphosphate (ATP), which is then thought
to act upon intragemmal taste nerve fibers (black fibres) and/or presynaptic cells.
Presypnaptic cells (purple cell) express synapse-related proteins such as synaptosomal-
associated protein of 25kD and form conventional synapses with intragemmal processes of
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peripheral taste neurons. In contrast with receptor cells, presynaptic cells are broadly tuned
to tastants of multiple qualities – currently, they are thought to be activated directly by sour
stimuli, through a different set of receptors and signaling pathways than those used by
receptor cells, and indirectly by sweet, bitter and umami compounds, through ATP released
from receptor cells. Serotonin (5-HT) is also released from taste buds upon chemosensory
stimulation, presumably in synapses between receptor cells and taste neurons. Several taste
bud cell types, including receptor cells and type I cells, have been proposed to transduce salt
stimuli, but there is still no consensus (see text; adapted from Tomchik, Berg et al. 2007,
used with permission).
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Fig. 2. Gut Nutrient Signaling Pathways
Ingested nutrients elicit mechanosensory and chemosensory responses in the gut, as
represented in green on the right. Postingestive responses depend mainly on the production
of gut hormones, such as CCK and GLP-1, that signal nutrient presence and quality by
activating vagal afferents (blue, dashed lines) and/or entering blood circulation via the portal
vein (red, solid lines). Absorbed nutrients (glucose and other ‘fuels’) and feeding-related
peptides produced in sites other than the gut (liver, muscle, adipose tissue and pancreas, on
the bottom left), are two other categories of gustatory humoral signals. The postingestive
sensory information thus generated, modulates the activity of central neural circuits at
several levels of the brain, represented on the top left (from Zheng and Berthoud 2008, used
with permission).
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Fig. 3. Anatomy of the main central gustatory pathways
Taste-specific information is conveyed by cranial nerves VII, IX and X (blue lines) to the
rostral division of the solitary tract nucleus (rNTS) in the medulla. In primates, fibres (red
lines) from second-order taste neurons in the rNTS project ipsilaterally to the parvicellular
division of the ventral posterior nucleus of the thalamus (VPpc). Thalamic efferents (green
lines) then project to the insula, defining the primary gustatory cortex which, in turn,
projects (black lines) to the orbitofrontal cortex, sometimes defined as a secondary cortical
taste area. The parabrachial nuclei (PbN) of the pons are shown in orange. In rodents these
are a relay for taste afferents from the rNTS. In both primates and rodents, the PbN also
receive second order visceral sensory fibres from the caudal division of the solitary tract
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nucleus (cNTS), transmitted mainly through the vagus nerve (not shown). The PbN has a
dorsal thalamocortical projection to the VPMpc and also a ventral projection that terminates
in amygdalar and hypothalamic nuclei, among others (adapted from Simon, de Araujo et al.
2006, used with permission).
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Fig. 4. Hedonic and homeostatic regulation of feeding
Current literature considers the hypothalamus as the main centre for feeding regulation.
Lateral hypothalamus neurons that produce orexin (also known as hypocretin - Hcrt) and
melanin concentrating hormone (MCH) are potent stimulators of food intake. Neurons in the
arcuate nucleus of the hypothalamus synthesize melanocyte stimulating hormone (MSH) or
neuropeptide Y (NPY) that have opposed effects in the control of food intake and energy
expenditure. The hypothalamic nuclei are traditionally considered homeostatic centre for
feeding regulation since they respond to peripheral metabolic hormones and fuels (such as
leptin and ghrelin) that are critical for energy homeostasis (Gao and Horvath 2007). The
mesencephalic dopamine system, on the other hand, responds robustly to a diverse array of
rewarding stimuli, including food, and plays a critical role in the behavioural responses to
these stimuli (Wise 2006). Orosensory responses to palatable food are sufficient for the
occurrence of dopamine (DA) responses in the mesolimbic system (Hajnal, Smith et al.
2004), which have generally been considered as a system for ‘hedonic’ regulation of food
intake. However, some of the peripheral hormones that modulate the behavioural
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components of energy homeostasis also impact the activity in this system (see text).
Furthermore, in a recent publication, de Araujo and Oliveira-Maia et al (de Araujo, Oliveira-
Maia et al. 2008) have shown, using ‘taste-blind’ mice (Zhang, Hoon et al. 2003), that the
caloric value of sucrose, in the absence of taste transduction, is also sufficient to activate the
midbrain reward circuitry. While the physiological details of the signaling mechanisms
involved remain to be described, it seems reasonable to suggest that the distinction between
hedonic and homeostatic regulation of feeding is redundant. GABA, gamma-aminobutyric
acid; Glut, glutamate; Hyp, hypothalamus, NAcc, nucleus accumbens; PFC, prefrontal
cortex, VTA, ventral tegmental area (from Andrews and Horvath 2008, used with
permission from Elsevier).
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