MINI REVIEW ARTICLE
published: 29 November 2011
doi: 10.3389/fnsys.2011.00099
Sweet taste signaling and the formation of memories
of energy sources
Ivan E. de Araujo*
The John B. Pierce Laboratory, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
Edited by:
Edmund Rolls, University of
Oxford, UK
Reviewed by:
Milagros Gallo, University of
Granada, Spain
Edmund Rolls, University of
Oxford, UK
*Correspondence:
Ivan E. de Araujo, The John B.
Pierce Laboratory, Department of
Psychiatry, Yale University School of
Medicine, 290 Congress Avenue,
New Haven, CT 06519, USA.
e-mail: iaraujo@jbpierce.org
The last decade witnessed remarkable advances in our knowledge of the gustatory
system. Application of molecular biology techniques not only determined the identity of
the membrane receptors and downstream effectors that mediate sweetness, but also
uncovered the overall logic of gustatory coding in the periphery. However, while the ability
to taste sweet may offer the obvious advantage of eliciting rapid and robust intake of
sugars, a number of recent studies demonstrate that sweetness is neither necessary
nor sufﬁcient for the formation of long-lasting preferences for stimuli associated with
sugar intake. Furthermore, uncoupling sweet taste from ensuing energy utilization may
disrupt body weight control. This minireview examines recent experiments performed
in both rodents and Drosophila revealing the taste-independent rewarding properties of
metabolizable sugars. Taken together, these experiments demonstrate the reinforcing
actions of sugars in the absence of sweet taste signaling and point to a critical role
played by dopamine systems in translating metabolic sensing into behavioral action. From
a mechanistic viewpoint, current evidence favors the concept that gastrointestinal and
post-absorptive signals contribute in parallel to sweet-independent sugar acceptance and
dopamine release.
Keywords: carbohydrates, dopamine, glucose oxidation, nutrient selection, reward, striatum, sweet taste, TRPM5
INTRODUCTION
Glucose-containing carbohydrates, the ingestion of which are
critical for most forms of animal life, reliably elicit the highly
pleasurable sensation of sweetness. Such mechanism allows the
brain to rapidly trigger acceptance responses upon recognizing
the presence of nutritive carbohydrates in the oral cavity.
Given the consistency of this behavioral response, one would
hypothesize that sweet taste is both necessary and sufﬁcient
for the appropriate control of sugar intake. However, mounting
evidence from both mammals and insects now favors the
possibility that long-term food choices depend primarily on the
detection of the energy content of the food sources, without
requiring the stimulation of sweet taste effectors. This minireview
concentrates on describing recent studies in both rodents and
Drosophila revealing that the formation of long-term sugar acceptance
and preference requires the activation of energy-sensing
pathways.
THE GUSTATORY SYSTEM
Recent reviews have covered in depth the anatomy of both
the peripheral and central gustatory pathways (Carleton et al.,
2010; Kinnamon, 2011), which we will mention only brieﬂy.
The peripheral gustatory system consists of the neural-epithelial
machinery linking the sensory epithelial cells in the oral cavity
to the ﬁrst gustatory relay center in the brain. G-proteincoupled
receptors (GPCRs) expressed on the apical end of taste
receptor cells (TRCs) function as the receptors for sweet, some
L-amino acids, and bitter tastants while ion channels of the
transient receptor potential are thought to mediate sour and salty
tastes (Chandrashekar et al., 2006; Roper, 2007). It is noticeable
that taste receptor expression has been detected at other organs
including the gastrointestinal tract (Margolskee et al., 2007;
Hass et al., 2010), pancreas (Nakagawa et al., 2009), and brain
(Ren et al., 2009), although extra-oral physiological functions
remain to be determined. On the tongue, sweet taste is speciﬁcally
mediated by the taste genes Tas1r2 and Tas1r3, whose T1R2
and T1R3 products assemble to form the heterodimeric sweet
receptor T1R2/T1R3 (Chandrashekar et al., 2006). T1R2/T1R3
activation is effected via the downstream signals phospholipase
PLCβ2 and TRPM5, a non-selective ionic taste channel,
the deletion of either inducing severe impairment in—if
not taste-blindness for—sweet, umami, and bitter transduction
(Zhang et al., 2003). Sweet tastant-induced TRC depolarization—
mediated by TRPM5—produces the release of chemical messages
onto cranial nerve afferents innervating the basolateral aspect of
TRCs. The cell bodies of taste-responsive cranial nerve ganglia
synapse into the rostral division of the nucleus tractus solitarius
(rNTS) in the medulla (Hamilton and Norgren, 1984), which in
turn projects, in rodents, ipsilaterally to the parabrachial nucleus
(PBN, Norgren and Leonard, 1971). From PBN two pathways
ascend in parallel to the forebrain: a “dorsal” pathway projecting
to parvicellular areas of the ventroposterior medial nucleus of the
thalamus (whose afferents deﬁne anatomically the primary gustatory
cortex in the insula), and one ventral pathway projecting
to the amygdala, lateral hypothalamus, and the bed nucleus of the
stria terminalis (Norgren, 1976). Noticeably NTS taste projections
seem to ascend directly to thalamus, therefore bypassing the PBN
(Small and Scott, 2009).
Frontiers in Systems Neuroscience www.frontiersin.org November 2011 | Volume 5 | Article 99 | 1
SYSTEMS NEUROSCIENCE
de Araujo Sweet taste and memories of calories
SWEET TASTE AND BRAIN DOPAMINE RELEASE
Robust attraction toward sweet tastants is pervasive across most
species. Animals will avidly consume sweet solutions even when
required to learn complex operant behaviors (Kare, 1971). Innate
attraction to sweetness is presumed in humans given the stereotyped
oral/facial reactions observed in children upon their ﬁrst
exposure to sugary solutions (Ganchrow et al., 1983). However,
recent evidence reveals that early childhood ﬂavor exposures
rather than innateness per se mold long-term food preferences
(Beauchamp and Mennella, 2009; Ventura and Mennella, 2011).
It does, therefore, seem logical to presume that neural pathways
must exist that link peripheral sweet receptors to brain rewardrelated
circuits (McCaughey, 2008). Among such circuits we must
stress the brain cells producing the reward-related monoaminergic
transmitter dopamine. Dopamine is a major regulator of sweet
sugar intake. In fact, dopamine receptor antagonism decreases
the attraction toward sweet-tasting nutrients given that animals
pretreated with either D1- or D2-type dopamine receptor antagonists
approach high concentrations of sucrose solutions as if
they had been diluted (Xenakis and Sclafani, 1981; Wise, 2006).
Conversely, palatable foods elevate extracellular dopamine concentrations
in the nucleus accumbens (NAcc) of the ventral striatum
(Hernandez and Hoebel, 1988), a brain region critical for the
expression of normal feeding behaviors (Kelley et al., 2005). In
humans, striatal dopamine release reﬂects the perceived pleasantness
of a meal (Small et al., 2003). Sweet-elicited stimulation of
the central dopamine systems occurs upon intra-oral stimulation
but does not require intestinal sugar absorption (as demonstrated
in “sham-feeding” preparations combined with microdialysis
measurements, Hajnal et al., 2004), as effect found to depend on
the integrity of the “ventral” taste pathway (Norgren and Hajnal,
2005). It does, therefore, appear that sensing sweetness per
se would account for the high acceptance associated with
sugar intake.
SWEETNESS-INDEPENDENT ATTRACTION TO SUGARS
While sweet sensation is a powerful drive of feeding behavior,
it remains to be proven that animals rely entirely on the
orosensory properties of sugars to evaluate energy sources. In
fact, it has been long established that approach or satiation
responses to a given ﬂavor can be conditioned by postingestive
consequences (Sclafani and Xenakis, 1984; Booth, 1985; Rolls,
2005). For instance, in ﬂavor-nutrient conditioning experiments,
gut infusions of a given nutrient or control solution
are conditionally linked to the oral intake of a distinct ﬂavor,
usually represented by odorant solutions that had been
artiﬁcially sweetened (Sclafani and Xenakis, 1984; Booth, 1985).
These experiments show very clearly that rodents (Booth, 1985;
Sclafani, 2001) and humans (Hellstrom et al., 2004) will develop
strong preferences for ﬂavors that had been paired to infusions
of nutrients compared to control infusions, with a bias
toward glucose-containing sugars over other isocaloric nutrients
(Ackroff and Sclafani, 2006).
Would animals develop preferences for sugars even when not
paired to distinct sweet ﬂavors? To assess this possibility the
author designed a conditioning protocol where mice are allowed
to form memories of sipper locations that had been previously
associated with the oral delivery of sugars, water, or non-caloric
sweeteners (de Araujo et al., 2008). The study involved employing
wild-type as well as knockout mice lacking functional TRPM5
channels (Zhang et al., 2003). As was mentioned above, the
TRPM5 ion channel is expressed in TRCs (Perez et al., 2002)
and is required for sweet taste signaling (Zhang et al., 2003).
Accordingly, it was hypothesized that sweet-blind Trpm5 knockout
mice would be able to form robust preferences for those
spouts previously associated with the oral presentation of sucrose
solutions as long as these animals were allowed sufﬁcient time to
detect the solutions’ postingestive effects. This was accomplished
by ﬁrst determining the initial side-preferences using a series
of pre-conditioning two-bottle water tests, followed by exposing
animals to 30 min-long conditioning sessions where either water
(assigned to the same side of initial bias) or sucrose (assigned to
the opposite side) were consumed freely while access to the other
sipper was blocked.
Results from this experiment demonstrated that, unlike
during short-term exposure, during the 30 min conditioning
sessions both wild-type and knockout animals consumed signiﬁcantly
larger amounts of sucrose compared to water. In
addition, during post-conditioning two-bottle tests, both wildtype
and knockout animals reversed their initial side-preference
biases by consuming signiﬁcantly more water from those sippers
that during conditioning sessions had been associated with
sucrose. Therefore, oral stimulation with sweetness or otherwise
distinct ﬂavors was not required to induce strong biases
toward consuming nutritive sucrose. These effects were in fact
dependent on the energy content, rather than sweetness per
se, associated with sucrose since when the same experiments
were performed using the non-caloric sucrose-derived sweetener
sucralose instead of sucrose, only wild-type animals consumed
more sucralose than water during the conditioning
sessions.
However, and critical to our argument in this review, during
the two-bottle post-conditioning water sessions, neither knockout
nor wild-type mice showed preferences for sippers associated
with the delivery of sucralose. Overall, these results provide evidence
in favor of the hypothesis that sweetness is neither necessary
nor sufﬁcient to induce long-term sugar preferences if unaccompanied
by detectable physiological effects.
POSTINGESTIVE SIGNALS AND BRAIN DOPAMINE
RELEASE
Given the above, it would be natural to conclude that sweetness
may not be required for dopamine to be released during sucrose
intake. In fact, microdialysis measurements revealed on one hand
that the non-caloric sweetener sucralose produced signiﬁcantly
higher increases in NAcc dopamine levels in wild-type compared
to TRPM5 knockout animals (de Araujo et al., 2008). These
results are consistent with the ability of sweetness per se to stimulate
dopamine release in NAcc (Hajnal et al., 2004). Now, when
the same comparison was performed using sucrose, no differences
were found between NAcc dopamine levels in wild-type and
TRPM5 knockout mice. In conclusion, while sweet taste stimulation
without caloric content only produced signiﬁcant increases
in accumbal dopamine levels in wild-type, caloric sucrose evoked
Frontiers in Systems Neuroscience www.frontiersin.org November 2011 | Volume 5 | Article 99 | 2
de Araujo Sweet taste and memories of calories
the same levels of dopamine increase in both wild-type and
sweet-blind mice.
The above is also consistent with the fact that rats treated
with local infusions in NAcc with a D1-receptor antagonist
display dose-dependent reductions in intake of a ﬂavor
paired with intra-gastric infusions of glucose (Touzani et al.,
2008). Interestingly, the effect of dopamine signaling antagonism
on post-conditioning preferences tests was less compelling
(Touzani et al., 2008). In any event, these results demonstrate
that D1-like receptors in the NAcc are required for the acquisition
of glucose-conditioned ﬂavor preferences. Finally it must be
noted that in addition to striatum other brain regions including
the amygdala, lateral hypothalamus, and medial prefrontal cortex
mediate postingestive inﬂuences on behavior (Sclafani et al.,
2011), although it is intriguing to note that all those are densely
targeted by dopaminergic afferents.
SWEETNESS-INDEPENDENT ATTRACTION FOR
SUGARS IN DROSOPHILA
The attraction to sugars in the absence of sweetness or distinct
ﬂavors does not seem to be limited to vertebrates. Two very
interesting recent studies independently report that ﬂies not only
survive by feeding on a tasteless metabolizable sugar, but will form
odor-sugar memories only when sugar cues provide metabolic
beneﬁt. Their strategy was based on the elegant idea of comparing
the results obtained from attempting to condition behavioral
approach to a sweet, non-metabolizable sugar against those
obtained from conditioning approach to a non-sweet, nutritional
sugar (reviewed in Wright 2011). Burke and Waddell (2011) have
shown that ﬂies will not form lasting memories for odors that
had been previously associated with non-metabolizable sugars
such as arabinose. In fact, when these authors added the nonsweet
(to ﬂies) alcohol sugar D-sorbitol to arabinose, memory
retrieval was as efﬁcient as when odors were paired to
sucrose.
The ability of ﬂies to recognize the nutritional value of sugars
independently of taste was also shown by Fujita and Tanimura
(2011). These authors have also shown that ﬂies can form
associations between odors and arabinose only if D-sorbitol is
added. In addition, ﬂies were able to maintain normal physiological
functions when given D-sorbitol as the only nutrient
available (Fujita and Tanimura, 2011). These authors have
also shown that neural mechanisms must be involved in the
learning processes described above, since null mutants of the
synapsin gene syn97, which encodes a protein necessary for
synaptic function, showed signiﬁcant reductions in the ability
to associate arbitrary odors with tasteless nutritive sugars
(Fujita and Tanimura, 2011).
It is intriguing to note that in Drosophila, as in mammals,
dopaminergic pathways play a role in regulating behavioral
responses to rewarding stimuli such as cocaine, nicotine, and
ethanol (Bainton et al., 2000). In addition, blocking transmission
in dopaminergic neurons abolishes the expression of conditioned
preferences for ethanol-associated cues (Kaun et al., 2011). It is
therefore plausible to hypothesize that dopamine may mediate the
ability to sense the nutritional value of sugars, including tasteless
sorbitol, in ﬂies as it does in mammals.
UNCOUPLING SWEET TASTE FROM ENERGY UTILIZATION
Another interesting aspect associated with the relationship
between sweet taste and sugar metabolism relates to the fact
that the usage of non-caloric sweeteners may disrupt the predictive
relationship between sweetness and energy intake. Swithers,
Davidson, and colleagues developed an experimental rodent
model to study the role of sweet taste as a predictor of energy
intake (see e.g., Swithers and Davidson, 2008; Swithers et al.,
2009). Overall, the results reveal that intake of foods (or ﬂuids)
containing non-nutritive sweeteners, when compared to the
intake of glucose, leads to signiﬁcant weight gain, increased fat
deposition, and impaired ability to caloric compensation. Overall,
these results suggest that consumption of saccharin or other
non-caloric sweeteners may decrease the ability of the organism
to upregulate energy utilization, a physiological response that
usually follows sugar ingestion (Swithers et al., 2009).
ON THE IDENTITY OF THE POSTINGESTIVE
REINFORCING SIGNAL
A critical question that remains to be resolved regards the identity
of the taste-independent reinforcement signal. Generally speaking,
candidate signals could be classiﬁed into two major groups,
according to whether they are generated during either pre- or
post-absorptive phases of food intake. The former group includes,
broadly speaking, those signals occurring previous to nutrient
delivery into the bloodstream but simultaneous to the arrival of
nutrients to the gut. The latter group on the other hand refers
to those events occurring after nutrients reach the bloodstream,
and non-exclusively includes a variety of signals such as fuel
utilization metabolites and changes in plasma hormonal levels.
Experiments based on ﬂavor-nutrient conditioning paradigms
indicate that pre-absorptive signals may mediate the ability to
form associations between orally delivered ﬂavors and intragastrically
delivered sugars. In fact, no ﬂavor preference learning
was obtained when ﬂavor intake was paired with portal
infusions of glucose (Ackroff et al., 2010). It is interesting to
note that ﬂavor-nutrient conditioning is robustly achieved even
when infusions bypass the stomach and are delivered directly to
the small intestine (Ackroff et al., 2010). These results are supported
by the fact that abdominal vagotomy does not interfere
with ﬂavor preferences conditioned by glucose-containing sugars
(Sclafani and Lucas, 1996). Altogether, the above allowed Sclafani
and colleagues to infer that a currently unknown glucose sensor
expressed in the intestine mediates ﬂavor-nutrient conditioning
to glucose-containing sugars (Ackroff et al., 2010).
Physiological signals generated post-absorption also seem to
regulate sweet-independent attraction to sugars. We have recently
assessed in our laboratory the potential role of metabolic signals
in taste-independent nutrient selection by comparing the behavioral
responses to glucose and weakly gluconeogenic L-amino
acids in wild-type and Trpm5 knockout mice. Brieﬂy, Trpm5
knockout mice, despite displaying insensitivity to the tastes of
both glucose and L-serine during short-term (10 min) tests,
did form strong preferences for glucose-associated sippers during
conditioning sessions, as well as ingested signiﬁcant larger
amounts of glucose during longer-term sessions (Ren et al.,
2010). These results were conﬁrmed by indirect calorimetry
Frontiers in Systems Neuroscience www.frontiersin.org November 2011 | Volume 5 | Article 99 | 3
de Araujo Sweet taste and memories of calories
measurements, which demonstrated that higher intake levels of
glucose were closely associated with glucose oxidation levels, in
such a way that respiratory quotient measures functioned as
highly efﬁcient predictors of intake, even more so than blood
glucose levels. This ﬁnding points to a role for post-absorptive
nutrient utilization in postingestive reinforcement.
Consistent with the above, glucose utilization rates were also
found to act as one powerful regulator of dopamine release. In
fact, we have shown in the same study that an intravenous infusion
of the anti-metabolic glucose analog, 2-deoxy-D-glucose
(henceforth “2-DG”) resulted in signiﬁcant decreases in extracellular
dopamine levels. In addition, such inhibitory effects of
FIGURE 1 | Post-oral pathways modulating dopamine release. Infusions
of nutrients into post-oral peripheral sites exert controlling actions over
dopamine release, as measured from microdialysates collected from either
the ventral or dorsal striatum. The ﬁgure illustrates the concept that
different peripheral sites may produce stimulatory effects on dopamine
release. Upper panel gastric injections of either non-gluconeogenic amino
acids or sugars produce marked changes (reductions or increases,
respectively) in extracellular dopamine levels in ventral striatum while
isocaloric injections of glucose do increase dopamine levels in dorsal striatum
(Ren et al., 2010). This ﬁnding establishes that stimulating the oral cavity is
not required for stimulating dopamine release during nutrient intake.
However, the relative contributions of gastric vs. intestinal sensing remain to
be dissected because the effects if infusing nutrients directly into the
intestine on dopamine release remain to be assessed (interrogation mark).
Furthermore, jugular infusions of a glucose antimetabolite, 2-DG, suppress
dopamine release in dorsal striatum, an effect that can be attenuated by
subsequent infusions of glucose (Ren et al., 2010). This ﬁnding establishes
that stimulating the gastrointestinal system is not required for stimulating
dopamine release during nutrient intake. Therefore, a network of pre- and
post-absorptive physiological signals converges onto dopamine circuits to
regulate ingestive behavior. Chromatogram represents the use of liquid
chromatography coupled to electrochemical detection (HPLC-ECD) methods
to separate and quantify dopamine (DA) and serotonin (5HT) content in brain
dialysates. Lower panel invertebrates, such as Drosophila melanogaster,
ﬁgure as a promising model for investigating the molecular bases of how
post-oral nutrient sensing exerts inﬂuence over the central nervous system.
However, a number of important questions remain to be addressed, in
particular whether postingestive reinforcement in these insects require gut
stimulation or, likewise rodents, also involves post-absorptive pathways (see
also Wright, 2011).
Frontiers in Systems Neuroscience www.frontiersin.org November 2011 | Volume 5 | Article 99 | 4
de Araujo Sweet taste and memories of calories
2-DG on dopamine release were attenuated, or almost reversed,
by a subsequent intravenous glucose infusion that counteracted
2-DG effects and contributed to restore normal glucose oxidation
rates (Ren et al., 2010). Finally, but always consistent with a
role for glucose utilization in mediating sweet-independent sugar
reinforcement, we have also found that after 2-DG injections
Trpm5 knockout mice produced signiﬁcantly higher numbers of
licks to glucose compared to after saline injections. Thus, within
30 min of 2-DG administration, glucose becomes more attractive
if contributing to reinstate glucose oxidation levels.
Altogether, the results above indicate that both intestinal
and metabolic factors simultaneously convey physiological signals
that affect the central nervous system. It is important
to note that these two pathways are not necessarily mutually
exclusive. In fact, they are more likely to cooperate to control
both acceptance and preference for environmental stimuli associated
with sugars. For example, it is possible that metabolic
signals are important for regulating overall sugar intake levels
(as demonstrated by the 2-DG experiments performed by
Ren et al., 2010) whereas preferences for ﬂavors associated with
intra-gastric glucose depend on vagus-independent intestinal signals
(Ackroff et al., 2010). Alternatively, the intestine may trigger
the release of incretin factors that ultimately may enhance
insulin release, and, therefore, glucose uptake and utilization.
Future research must determine the signaling pathways that
allow brain dopamine systems to sense the energy of sugars
without requiring inputs form the oral cavity. One interesting
hypothesis consists in the possibility that dopamine neurons
have the ability to sense the internal energy levels of the cell,
modulating transmitter release accordingly, possibly via cellular
sensors such as AMPK. This feature would place dopamine neurons
among the brain’s glucosensors, as hypothesized previously
(Levin, 2000).
CONCLUSION
We have reviewed evidence that favors the conclusion that sweet
taste signaling is neither necessary nor sufﬁcient to allow for the
formation of lasting memories or preferences for sugar-associated
stimuli. Furthermore, brain circuits, particularly dopaminergic
systems, show marked sensitivity to the energy content of sugars
independently of oral stimulation. Current evidence points to the
possibility that the brain monitors both gastrointestinal signals
and energy utilization rates to control sugar intake independently
of the sense of sweet. Future research must determine the
physiological pathways allowing the gastrointestinal system and
intracellular energy sensors to control dopamine release during
sugar intake (See Figure 1).
ACKNOWLEDGMENT
This work was supported by NIH grant DC009997 to IEA.
REFERENCES
Ackroff, K., and Sclafani, A. (2006).
Energy density and macronutrient
composition determine ﬂavor preference
conditioned by intragastric
infusions of mixed diets. Physiol.
Behav. 89, 250–260.
Ackroff, K., Yiin, Y. M., and Sclafani, A.
(2010). Post-oral infusion sites that
support glucose-conditioned ﬂavor
preferences in rats. Physiol. Behav.
99, 402–411.
Bainton, R. J., Tsai, L. T., Singh, C.
M., Moore, M. S., Neckameyer, W.
S., and Heberlein, U. (2000). Dopamine
modulates acute responses to
cocaine, nicotine and ethanol in
Drosophila. Curr. Biol. 10, 187–194.
Beauchamp, G. K., and Mennella, J.
A. (2009). Early ﬂavor learning and
its impact on later feeding behavior.
J. Pediatr. Gastroenterol. Nutr.
48(Suppl. 1), S25–S30.
Booth, D. A. (1985). Food-conditioned
eating preferences and aversions
with interoceptive elements: conditioned
appetites and satieties. Ann.
N. Y. Acad. Sci. 443, 22–41.
Burke, C. J., and Waddell, S. (2011).
Remembering nutrient quality of
sugar in Drosophila. Curr. Biol. 21,
746–750.
Carleton, A., Accolla, R., and Simon,
S. A. (2010). Coding in the mammalian
gustatory system. Trends
Neurosci. 33, 326–334.
Chandrashekar, J., Hoon, M. A., Ryba,
N. J., and Zuker, C. S. (2006). The
receptors and cells for mammalian
taste. Nature 444, 288–294.
de Araujo, I. E., Oliveira-Maia, A.
J., Sotnikova, T. D., Gainetdinov,
R. R., Caron, M. G., Nicolelis,
M. A., and Simon, S. A. (2008).
Food reward in the absence of
taste receptor signaling. Neuron 57,
930–941.
Fujita, M., and Tanimura, T. (2011).
Drosophila evaluates and learns the
nutritional value of sugars. Curr.
Biol. 21, 751–755.
Ganchrow, J. R., Steiner, J. E., and
Daher, M. (1983). Neonatal facial
expressions in response to different
qualities and intensities of gustatory
stimuli. Infant Behav. Dev. 6,
473–484.
Hajnal, A., Smith, G. P., and Norgren,
R. (2004). Oral sucrose stimulation
increases accumbens dopamine in
the rat. Am. J. Physiol. Regul. Integr.
Comp. Physiol. 286, R31–R37.
Hamilton, R. B., and Norgren, R.
(1984). Central projections of gustatory
nerves in the rat. J. Comp.
Neurol. 222, 560–577.
Hass, N., Schwarzenbacher, K.,
and Breer, H. (2010). T1R3 is
expressed in brush cells and
ghrelin-producing cells of murine
stomach. Cell Tissue Res. 339,
493–504.
Hellstrom, P. M., Geliebter, A.,
Naslund, E., Schmidt, P. T., Yahav,
E. K., Hashim, S. A., and Yeomans,
M. R. (2004). Peripheral and
central signals in the control of
eating in normal, obese and bingeeating
human subjects. Br. J. Nutr.
92(Suppl. 1), S47–S57.
Hernandez, L., and Hoebel, B. G.
(1988). Food reward and cocaine
increase extracellular dopamine in
the nucleus accumbens as measured
by microdialysis. Life Sci. 42,
1705–1712.
Kare, M. R. (1971). “Comparative study
of taste,” in Handbook of Sensory
Physiology, ed L. M. Beidler (Berlin:
Springer-Verlag), 278–292.
Kaun, K. R., Azanchi, R., Maung,
Z., Hirsh, J., and Heberlein, U.
(2011). A Drosophila model for
alcohol reward. Nat. Neurosci. 14,
612–619.
Kelley, A. E., Schiltz, C. A., and
Landry, C. F. (2005). Neural systems
recruited by drug- and food-related
cues: studies of gene activation
in corticolimbic regions. Physiol.
Behav. 86, 11–14.
Kinnamon, S. C. (2011). Taste receptor
signalling - from tongues to lungs.
Acta Physiol. (Oxf) 203, 1–11.
Levin, B. E. (2000). Glucose-regulated
dopamine release from substantia
nigra neurons. Brain Res. 874,
158–164.
Margolskee, R. F., Dyer, J., Kokrashvili,
Z., Salmon, K. S., Ilegems, E., Daly,
K., Maillet, E. L., Ninomiya, Y.,
Mosinger, B., and Shirazi-Beechey,
S. P. (2007). T1R3 and gustducin in
gut sense sugars to regulate expression
of Na+-glucose cotransporter
1. Proc. Natl. Acad. Sci. U.S.A. 104,
15075–15080.
McCaughey, S. A. (2008). The taste of
sugars. Neurosci. Biobehav. Rev. 32,
1024–1043.
Nakagawa, Y., Nagasawa, M., Yamada,
S., Hara, A., Mogami, H., Nikolaev,
V. O., Lohse, M. J., Shigemura, N.,
Ninomiya, Y., and Kojima, I. (2009).
Sweet taste receptor expressed in
pancreatic beta-cells activates the
calcium and cyclic AMP signaling
systems and stimulates insulin
secretion. PLoS One, 4, e5106. doi:
10.1371/journal.pone.0005106
Norgren, R. (1976). Taste pathways
to hypothalamus and amygdala. J.
Comp. Neurol. 166, 17–30.
Norgren, R., and Hajnal, A. (2005).
Taste pathways that mediate accumbens
dopamine release by sapid
sucrose. Physiol. Behav. 84, 363–369.
Norgren, R., and Leonard, C. M.
(1971). Taste pathways in rat brainstem.
Science 173, 1136–1139.
Perez, C. A., Huang, L., Rong, M.,
Kozak, J. A., Preuss, A. K., Zhang,
H., Max, M., and Margolskee, R.
F. (2002). A transient receptor
Frontiers in Systems Neuroscience www.frontiersin.org November 2011 | Volume 5 | Article 99 | 5
de Araujo Sweet taste and memories of calories
potential channel expressed in taste
receptor cells. Nat. Neurosci. 5,
1169–1176.
Ren, X., Ferreira, J. G., Zhou, L.,
Shammah-Lagnado, S. J., Yeckel, C.
W., and de Araujo, I. E. (2010).
Nutrient selection in the absence of
taste receptor signaling. J. Neurosci.
30, 8012–8023.
Ren, X., Zhou, L., Terwilliger, R.,
Newton, S. S., and de Araujo, I. E.
(2009). Sweet taste signaling functions
as a hypothalamic glucose sensor.
Front. Integr. Neurosci. 3, 12.
doi:10.3389/neuro.07.012.2009
Rolls, E. T. (2005). Emotion Explained.
Oxford: Oxford University Press.
Roper, S. (2007). Signal transduction
and information processing
in mammalian taste buds. Pﬂugers
Arch. 454, 759–776.
Sclafani, A. (2001). Post-ingestive positive
controls of ingestive behavior.
Appetite 36, 79–83.
Sclafani, A., and Lucas, F. (1996).
Abdominal vagotomy does not
block carbohydrate-conditioned
ﬂavor preferences in rats. Physiol.
Behav. 60, 447–453.
Sclafani, A., Touzani, K., and Bodnar,
R. J. (2011). Dopamine and learned
food preferences. Physiol. Behav.
104, 64–68.
Sclafani, A., and Xenakis, S. (1984).
Sucrose and polysaccharide induced-obesity
in the rat. Physiol.
Behav. 32, 169–174.
Small, D. M., Jones-Gotman, M., and
Dagher, A. (2003). Feeding-induced
dopamine release in dorsal striatum
correlates with meal pleasantness
ratings in healthy human volunteers.
Neuroimage 19, 1709–1715.
Small, D. M., and Scott, T. R. (2009).
Symposium overview: what happens
to the pontine processing?
Repercussions of interspecies differences
in pontine taste representation
for tasting and feeding. Ann. N.
Y. Acad. Sci. 1170, 343–346.
Swithers, S. E., Baker, C. R., and
Davidson, T. L. (2009). General and
persistent effects of high-intensity
sweeteners on body weight gain and
caloric compensation in rats. Behav.
Neurosci. 123, 772–780.
Swithers, S. E., and Davidson, T. L.
(2008). A role for sweet taste: calorie
predictive relations in energy regulation
by rats. Behav. Neurosci. 122,
161–173.
Touzani, K., Bodnar, R., and Sclafani,
A. (2008). Activation of dopamine
D1-like receptors in nucleus accumbens
is critical for the acquisition,
but not the expression, of nutrientconditioned
ﬂavor preferences in
rats. Eur. J. Neurosci. 27, 1525–1533.
Ventura, A. K., and Mennella, J. A.
(2011). Innate and learned preferences
for sweet taste during childhood.
Curr. Opin. Clin. Nutr. Metab.
Care 14, 379–384.
Wise, R. A. (2006). Role of brain
dopamine in food reward and reinforcement.
Philos. Trans. R Soc.
Lond. B Biol. Sci. 361, 1149–1158.
Wright, G. A. (2011). Appetitive learning:
memories need calories. Curr.
Biol. 21, R301–R302.
Xenakis, S., and Sclafani, A. (1981). The
effects of pimozide on the consumption
of a palatable saccharin-glucose
solution in the rat. Pharmacol.
Biochem. Behav. 15, 435–442.
Zhang, Y., Hoon, M. A., Chandrashekar,
J., Mueller, K. L., Cook,
B. W. D., Zucker, C. S., and Ryba,
N. J. (2003). Coding of sweet, bitter,
and umami tastes: different receptor
cells sharing similar signaling
pathways. Cell 112, 293–301.
Conﬂict of Interest Statement: The
authors declare that the research was
conducted in the absence of any commercial
or ﬁnancial relationships that
could be construed as a potential conﬂict
of interest.
Received: 10 September 2011; accepted:
18 November 2011; published online: 29
November 2011.
Citation: de Araujo IE (2011) Sweet taste
signaling and the formation of memories
of energy sources. Front. Syst. Neurosci.
5:99. doi: 10.3389/fnsys.2011.00099
Copyright © 2011 de Araujo. This is
an open-access article distributed under
the terms of the Creative Commons
Attribution Non Commercial License,
which permits non-commercial use, distribution,
and reproduction in other
forums, provided the original authors
and source are credited.
Frontiers in Systems Neuroscience www.frontiersin.org November 2011 | Volume 5 | Article 99 | 6