TRPM4 and PLCß3 contribute to normal behavioral responses to an array of sweeteners and carbohydrates but PLCß3 is not needed for taste-driven licking for glucose.

The peripheral taste system is more complex than previously thought. The novel taste-signaling proteins TRPM4 and PLCß3 appear to function in normal taste responding as part of Type II taste cell signaling or as part of a broadly responsive (BR) taste cell that can respond to some or all classes of tastants. This work begins to disentangle the roles of intracellular components found in Type II taste cells (TRPM5, TRPM4, and IP3R3) or the BR taste cells (PLCß3 and TRPM4) in driving behavioral responses to various saccharides and other sweeteners in brief-access taste tests. We found that TRPM4, TRPM5, TRPM4/5, and IP3R3 knockout (KO) mice show blunted or abolished responding to all stimuli compared with wild-type. IP3R3 KO mice did, however, lick more for glucose than fructose following extensive experience with the 2 sugars. PLCß3 KO mice were largely unresponsive to all stimuli except they showed normal concentration-dependent responding to glucose. The results show that key intracellular signaling proteins associated with Type II and BR taste cells are mutually required for taste-driven responses to a wide range of sweet and carbohydrate stimuli, except glucose. This confirms and extends a previous finding demonstrating that Type II and BR cells are both necessary for taste-driven licking to sucrose. Glucose appears to engage unique intracellular taste-signaling mechanisms, which remain to be fully elucidated.

Hypothalamic melanin-concentrating hormone neurons integrate food-motivated appetitive and consummatory processes in rats.

The lateral hypothalamic area (LHA) integrates homeostatic processes and reward-motivated behaviors. Here we show that LHA neurons that produce melanin-concentrating hormone (MCH) are dynamically responsive to both food-directed appetitive and consummatory processes in male rats. Specifically, results reveal that MCH neuron Ca2+ activity increases in response to both discrete and contextual food-predictive cues and is correlated with food-motivated responses. MCH neuron activity also increases during eating, and this response is highly predictive of caloric consumption and declines throughout a meal, thus supporting a role for MCH neurons in the positive feedback consummatory process known as appetition. These physiological MCH neural responses are functionally relevant as chemogenetic MCH neuron activation promotes appetitive behavioral responses to food-predictive cues and increases meal size. Finally, MCH neuron activation enhances preference for a noncaloric flavor paired with intragastric glucose. Collectively, these data identify a hypothalamic neural population that orchestrates both food-motivated appetitive and intake-promoting consummatory processes.

Early-life influences of low-calorie sweetener consumption on sugar taste.

Children and adolescents are the highest consumers of added sugars, particularly from sugar-sweetened beverages (SSB). Regular consumption of SSB early in life induces a variety of negative consequences on health that can last into adulthood. Low-calorie sweeteners (LCS) are increasingly used as an alternative to added sugars because they provide a sweet sensation without adding calories to the diet. However, the long-term effects of early-life consumption of LCS are not well understood. Considering LCS engage at least one of the same taste receptors as sugars and potentially modulate cellular mechanisms of glucose transport and metabolism, it is especially important to understand how early-life LCS consumption impacts intake of and regulatory responses to caloric sugars. In our recent study, we found that habitual intake of LCS during the juvenile-adolescence period significantly changed how rats responded to sugar later in life. Here, we review evidence that LCS and sugars are sensed via common and distinct gustatory pathways, and then discuss the implications this has for shaping sugar-associated appetitive, consummatory, and physiological responses. Ultimately, the review highlights the diverse gaps in knowledge that will be necessary to fill to understand the consequences of regular LCS consumption during important phases of development.

Dietary experience with glucose and fructose fosters heightened avidity for glucose-containing sugars independent of TRPM5 taste transduction in mice.

OBJECTIVE: Experience with metabolically distinct sugars, glucose and fructose, enhances attraction to the orosensory properties of glucose over fructose. To gain insight into which sensory signals are affected, we investigated how this nutritive learning reshapes behavioral responding to various sugars in brief access taste tests in C57BL6/J (B6) mice and assessed whether sugar-exposed mice lacking the TRPM5 channel involved in G-protein coupled taste transduction could acquire these types of preferences for glucose-containing sugars. METHODS: B6, TRPM5 knockout (KO), and TRPM5 heterozygous (Het) mice were given extensive access to water (sugar naïve) or 0.316, 0.56, and 1.1 M glucose and fructose (sugar-exposed) and then tested, whilst food deprived, for their relative avidities for glucose, fructose, sucrose, maltose, and/or a non-metabolizable glucose analog in a series of taste tests. RESULTS: Sugar-exposed B6 mice licked relatively more for glucose than fructose, driven by an increased avidity for glucose, not an avoidance of fructose, and licked more for maltose, compared to their sugar-naïve counterparts. Sugar-exposed B6 mice did not lick with such avidity for a non-metabolizable glucose analog. TRPM5 KO mice took longer to acquire the sugar discrimination than the Het controls, but both groups ultimately licked significantly more for glucose than fructose. Het mice displayed clear preferential licking for sucrose over fructose, while licking comparably high for glucose, sucrose, and maltose. KO mice licked significantly more for maltose than sucrose. CONCLUSIONS: Collectively, the findings suggest that ingestive experience with glucose and fructose primarily reprograms behavioral responding to a TRPM5-independent orosensory signal generated by glucose-containing sugars.

Early Life Low-Calorie Sweetener Consumption Impacts Energy Balance during Adulthood.

Children frequently consume beverages that are either sweetened with sugars (sugar-sweetened beverages; SSB) or low-calorie sweeteners (LCS). Here, we evaluated the effects of habitual early life consumption of either SSB or LCS on energy balance later during adulthood. Male and female rats were provided with chow, water, and a solution containing either SSB (sucrose), LCS (acesulfame potassium (ACE-K) or stevia), or control (no solution) during the juvenile and adolescent periods (postnatal days 26-70). SSB or LCS consumption was voluntary and restricted within the recommended federal daily limits. When subsequently maintained on a cafeteria-style junk food diet (CAF; various high-fat, high-sugar foods) during adulthood, ACE-K-exposed rats demonstrated reduced caloric consumption vs. the controls, which contributed to lower body weights in female, but not male, ACE-K rats. These discrepant intakes and body weight effects in male ACE-K rats are likely to be based on reduced gene expression of thermogenic indicators (UCP1, BMP8B) in brown adipose tissue. Female stevia-exposed rats did not differ from the controls in terms of caloric intake or body weight, yet they consumed more SSB during CAF exposure in adulthood. None of the SSB-exposed rats, neither male nor female, differed from the controls in terms of total adult caloric consumption or body weight measures. The collective results reveal that early life LCS consumption alters sugar preference, body weight, and gene expression for markers of thermogenesis during adulthood, with both sex- and sweetener-dependent effects.

Early-life low-calorie sweetener consumption disrupts glucose regulation, sugar-motivated behavior, and memory function in rats.

Low-calorie sweetener (LCS) consumption in children has increased dramatically due to its widespread presence in the food environment and efforts to mitigate obesity through sugar replacement. However, mechanistic studies on the long-term impact of early-life LCS consumption on cognitive function and physiological processes are lacking. Here, we developed a rodent model to evaluate the effects of daily LCS consumption (acesulfame potassium, saccharin, or stevia) during adolescence on adult metabolic, behavioral, gut microbiome, and brain transcriptomic outcomes. Results reveal that habitual early-life LCS consumption impacts normal postoral glucose handling and impairs hippocampal-dependent memory in the absence of weight gain. Furthermore, adolescent LCS consumption yielded long-term reductions in lingual sweet taste receptor expression and brought about alterations in sugar-motivated appetitive and consummatory responses. While early-life LCS consumption did not produce robust changes in the gut microbiome, brain region-specific RNA-Seq analyses reveal LCS-induced changes in collagen- and synaptic signaling-related gene pathways in the hippocampus and nucleus accumbens, respectively, in a sex-dependent manner. Collectively, these results reveal that habitual early-life LCS consumption has long-lasting implications for glucoregulation, sugar-motivated behavior, and hippocampal-dependent memory in rats, which may be based in part on changes in nutrient transporter, sweet taste receptor, and central gene pathway expression.

A glucokinase-linked sensor in the taste system contributes to glucose appetite.

OBJECTIVES: Dietary glucose is a robust elicitor of central reward responses and ingestion, but the key peripheral sensors triggering these orexigenic mechanisms are not entirely known. The objective of this study was to determine whether glucokinase, a phosphorylating enzyme with known glucosensory roles, is also expressed in taste bud cells and contributes to the immediate hedonic appeal of glucose-containing substances. METHODS AND RESULTS: Glucokinase (GCK) gene transcripts were localized in murine taste bud cells with RNAScope®, and GCK mRNA was found to be upregulated in the circumvallate taste papillae in response to fasting and after a period of dietary access to added simple sugars in mice, as determined with real time-qPCR. Pharmacological activation of glucokinase with Compound A increased primary taste nerve and licking responses for glucose but did not impact responsivity to fructose in naïve mice. Virogenetic silencing of glucokinase in the major taste fields attenuated glucose-stimulated licking, especially in mice that also lacked sweet receptors, but did not disrupt consummatory behaviors for fructose or the low-calorie sweetener, sucralose in sugar naïve mice. Knockdown of lingual glucokinase weakened the acquired preference for glucose over fructose in sugar-experienced mice in brief access taste tests. CONCLUSIONS: Collectively, our data establish that glucokinase contributes to glucose appetition at the very first site of nutrient detection, in the oral cavity. The findings expand our understanding of orosensory inputs underlying nutrition, metabolism, and food reward.

A Subregion of Insular Cortex Is Required for Rapid Taste-Visceral Integration and Consequent Conditioned Taste Aversion and Avoidance Expression in Rats.

Postingestive signals are important for shaping appetitive and consummatory responses, but the brain mechanisms required to assimilate interoceptive events with those at the frontlines of ingestion (taste-guided) are poorly understood. Here, we investigated whether an insular cortex (IC) region, which receives viscerosensory input, including gustatory, is required to modify taste-elicited consummatory reactions in response to a real-time interoceptive change using a serial taste reactivity (TR) test where the rats' oromotor and somatic reactions to intraoral (IO) infusions of sucrose were periodically assessed over 45 min following lithium chloride (LiCl) administration. Results showed that neurally-intact rats shifted from an ingestive repertoire to an aversive one as LiCl took effect. Overall, this hedonic shift was delayed in rats with bilateral neurotoxic IC lesions. Rats with greater neuronal loss in posterior gustatory IC displayed fewer aversive reactions to sucrose following this initial LiCl injection. We further assessed whether the failure to integrate interoceptive feedback with ongoing taste-guided behavior impaired acquisition and/or expression of conditioned aversion and/or avoidance in these same rats. Although, as a group, LiCl-injected rats with IC lesions subsequently avoided the sugar in a 48-h two-bottle test, their preference for sucrose was significantly greater than that of the LiCl-injected neurally-intact rats. Overall lesion size, as well as proportion of the posterior gustatory and/or anterior visceral IC were each associated with impaired avoidance. These findings reveal new roles for the posterior gustatory and anterior visceral ICs in multisensory integrative function.

Neural Isolation of the Olfactory Bulbs Severely Impairs Taste-Guided Behavior to Normally Preferred, But Not Avoided, Stimuli.

Here we systematically tested the hypothesis that motivated behavioral responsiveness to preferred and avoided taste compounds is relatively independent of the olfactory system in mice whose olfactory bulbs (main and accessory) were surgically disconnected from the rest of the brain [bulbotomy (BULBx)]. BULBx was confirmed histologically as well as functionally with the buried food test. In brief access taste tests, animals received 10-s trials of various concentrations of a taste compound delivered quasirandomly. BULBx C57BL/6 (B6) mice displayed severely blunted concentration-dependent licking for the disaccharide sucrose, the maltodextrin Maltrin, and the fat emulsion Intralipid relative to their sham-operated controls (SHAM B6). Licking for the noncaloric sweetener saccharin was also blunted by bulbotomy, but less so. As expected, mice lacking a functional "sweet" receptor [T1R2+T1R3 knockout (KO)] displayed concentration-dependent responsiveness to Maltrin and severely attenuated licking to sucrose. Like in B6 mice, responsiveness to both stimuli was exceptionally curtailed by bulbotomy. In contrast to these deficits in taste-guided behavior for unconditionally preferred stimuli, BULBx in B6 and KO mice did not alter concentration-dependent decreases for the representative avoided stimuli quinine and citric acid. Nor did it temper the intake of and preference for high concentrations of affectively positive stimuli when presented in long-term (23-h) two-bottle tests, demonstrating that the surgery does not lead to a generalized motivational deficit. Collectively, these behavioral results demonstrate that specific aspects of taste-guided ingestive motivation are profoundly disturbed by eliminating the anatomic connections between the main/accessory olfactory bulbs and the rest of the brain.

The Role of Post-Ingestive Feedback in the Development of an Enhanced Appetite for the Orosensory Properties of Glucose over Fructose in Rats.

The simple sugars glucose and fructose share a common "sweet" taste quality mediated by the T1R2+T1R3 taste receptor. However, when given the opportunity to consume each sugar, rats learn to affectively discriminate between glucose and fructose on the basis of cephalic chemosensory cues. It has been proposed that glucose has a unique sensory property that becomes more hedonically positive through learning about the relatively more rewarding post-ingestive effects that are associated with glucose as compared to fructose. We tested this theory using intragastric (IG) infusions to manipulate the post-ingestive consequences of glucose and fructose consumption. Food-deprived rats with IG catheters repeatedly consumed multiple concentrations of glucose and fructose in separate sessions. For rats in the "Matched" group, each sugar was accompanied by IG infusion of the same sugar. For the "Mismatched" group, glucose consumption was accompanied by IG fructose, and vice versa. This condition gave rats orosensory experience with each sugar but precluded the differential post-ingestive consequences. Following training, avidity for each sugar was assessed in brief access and licking microstructure tests. The Matched group displayed more positive evaluation of glucose relative to fructose than the Mismatched group. A second experiment used a different concentration range and compared responses of the Matched and Mismatched groups to a control group kept naïve to the orosensory properties of sugar. Consistent with results from the first experiment, the Matched group, but not the Mismatched or Control group, displayed elevated licking responses to glucose. These experiments yield additional evidence that glucose and fructose have discriminable sensory properties and directly demonstrate that their different post-ingestive effects are responsible for the experience-dependent changes in the motivation for glucose versus fructose.

Hypothalamus-hippocampus circuitry regulates impulsivity via melanin-concentrating hormone.

Behavioral impulsivity is common in various psychiatric and metabolic disorders. Here we identify a hypothalamus to telencephalon neural pathway for regulating impulsivity involving communication from melanin-concentrating hormone (MCH)-expressing lateral hypothalamic neurons to the ventral hippocampus subregion (vHP). Results show that both site-specific upregulation (pharmacological or chemogenetic) and chronic downregulation (RNA interference) of MCH communication to the vHP increases impulsive responding in rats, indicating that perturbing this system in either direction elevates impulsivity. Furthermore, these effects are not secondary to either impaired timing accuracy, altered activity, or increased food motivation, consistent with a specific role for vHP MCH signaling in the regulation of impulse control. Results from additional functional connectivity and neural pathway tracing analyses implicate the nucleus accumbens as a putative downstream target of vHP MCH1 receptor-expressing neurons. Collectively, these data reveal a specific neural circuit that regulates impulsivity and provide evidence of a novel function for MCH on behavior.

Parabrachial Complex: A Hub for Pain and Aversion.

The parabrachial nucleus (PBN) has long been recognized as a sensory relay receiving an array of interoceptive and exteroceptive inputs relevant to taste and ingestive behavior, pain, and multiple aspects of autonomic control, including respiration, blood pressure, water balance, and thermoregulation. Outputs are known to be similarly widespread and complex. How sensory information is handled in PBN and used to inform different outputs to maintain homeostasis and promote survival is only now being elucidated. With a focus on taste and ingestive behaviors, pain, and thermoregulation, this review is intended to provide a context for analysis of PBN circuits involved in aversion and avoidance, and consider how information of various modalities, interoceptive and exteroceptive, is processed within PBN and transmitted to distinct targets to signal challenge, and to engage appropriate behavioral and physiological responses to maintain homeostasis.

Conditioned taste aversion versus avoidance: A re-examination of the separate processes hypothesis.

Rats not only avoid ingesting a substance associated with LiCl toxicosis, but they display rejection reflexes (e.g., gapes) to its taste; this latter response is thought to reflect disgust or taste aversion. Prior work has shown that rats also avoid consuming foods/fluids associated with other adverse gastrointestinal (GI) effects like lactose indigestion but without the concomitant change in oromotor responses (taste reactivity; TR) indicative of aversion. Because of interpretive limitations of the methods used in those studies, we revisited the taste aversion-avoidance distinction with a design that minimized non-treatment differences among groups. Effects on intake and preference (Experiments 1a, 1b, and 2), as well as consummatory (TR, Experiment 1a and 1b) and appetitive (Progressive Ratio, Experiment 2) behaviors to the taste stimulus were assessed after training. In both experiments, rats were trained to associate 0.2% saccharin (CS) with intraduodenal infusions of LiCl, Lactose, or NaCl control. Rats trained with 18% lactose, 0.3 and 1.5 mEq/kg dose of LiCl subsequently avoided the taste CS in post-training single-bottle intake tests and two-bottle choice tests. However, only those trained with 1.5 mEq/kg LiCl displayed post-conditioning increases in taste CS-elicited aversive TR (Experiment 1a and 1b). This dose of LiCl also led to reductions in breakpoint for saccharin. The fact that conditioned avoidance is not always accompanied by changes in other common appetitive and/or consummatory indices of ingestive motivation further supports a functional dissociation between these processes, and highlights the intricacies of visceral influences on taste-guided ingestive motivation.

T1R2+T1R3-independent chemosensory inputs contributing to behavioral discrimination of sugars in mice.

Simple sugars are thought to elicit a unitary sensation, principally via the "sweet" taste receptor type 1 taste receptor (T1R)2+T1R3, yet we previously found that rats with experience consuming two metabolically distinct sugars, glucose and fructose, subsequently licked more for glucose than fructose, even when postingestive influences were abated. The results pointed to the existence of an orosensory receptor that binds one sugar but not the other and whose signal is channeled into neural circuits that motivate ingestion. Here we sought to determine the chemosensory nature of this signal. First, we assessed whether T1R2 and/or T1R3 are necessary to acquire this behavioral discrimination, replicating our rat study in T1R2+T1R3 double-knockout (KO) mice and their wild-type counterparts as well as in two common mouse strains that vary in their sensitivity to sweeteners [C57BL/6 (B6) and 129X1/SvJ (129)]. These studies showed that extensive exposure to multiple concentrations of glucose and fructose in daily one-bottle 30-min sessions enhanced lick responses for glucose over fructose in brief-access tests. This was true even for KO mice that lacked the canonical "sweet" taste receptor. Surgical disconnection of olfactory inputs to the forebrain (bulbotomy) in B6 mice severely disrupted the ability to express this experience-dependent sugar discrimination. Importantly, these bulbotomized B6 mice exhibited severely blunted responsiveness to both sugars relative to water in brief-access lick tests, despite the fact that they have intact T1R2+T1R3 receptors. The results highlight the importance of other sources of chemosensory and postingestive inputs in shaping and maintaining "hardwired" responses to sugar.

The Functional and Neurobiological Properties of Bad Taste.

The gustatory system serves as a critical line of defense against ingesting harmful substances. Technological advances have fostered the characterization of peripheral receptors and have created opportunities for more selective manipulations of the nervous system, yet the neurobiological mechanisms underlying taste-based avoidance and aversion remain poorly understood. One conceptual obstacle stems from a lack of recognition that taste signals subserve several behavioral and physiological functions which likely engage partially segregated neural circuits. Moreover, although the gustatory system evolved to respond expediently to broad classes of biologically relevant chemicals, innate repertoires are often not in register with the actual consequences of a food. The mammalian brain exhibits tremendous flexibility; responses to taste can be modified in a specific manner according to bodily needs and the learned consequences of ingestion. Therefore, experimental strategies that distinguish between the functional properties of various taste-guided behaviors and link them to specific neural circuits need to be applied. Given the close relationship between the gustatory and visceroceptive systems, a full reckoning of the neural architecture of bad taste requires an understanding of how these respective sensory signals are integrated in the brain.

Behavioral evidence that select carbohydrate stimuli activate T1R-independent receptor mechanisms.

Three decades ago Tony Sclafani proposed the existence of a polysaccharide taste quality that was distinguishable from the taste generated by common sweeteners and that it was mediated by a separate receptor mechanism. Since that time, evidence has accumulated, including psychophysical studies conducted in our laboratory, buttressing this hypothesis. The use of knockout (KO) mice that lack functional T1R2 + T1R3 heterodimers, the principal taste receptor for sugars and other sweeteners, have been especially informative in this regard. Such KO mice display severely diminished electrophysiological and behavioral responsiveness to sugars, artificial sweeteners, and some amino acids, yet display only slightly impaired concentration-dependent responsiveness to a representative polysaccharide, Polycose. Moreover, although results from gene deletion experiments in the literature provide strong support for the primacy of the T1R2 + T1R3 heterodimer in the taste transduction of sugars and other sweeteners, there is also growing evidence suggesting that there may be T1R-independent receptor mechanism(s) activated by select sugars, especially glucose. The output of these latter receptor mechanisms appears to be channeled into brain circuits subserving various taste functions such as cephalic phase responses and ingestive motivation. This paper highlights some of the findings from our laboratory and others that lend support for this view, while emphasizing the importance of considering the multidimensional nature of taste function in the interpretation of outcomes from experiments involving manipulations of the gustatory system.

Post-oral sugar detection rapidly and chemospecifically modulates taste-guided behavior.

Several recent studies have shown that post-oral sugar sensing rapidly stimulates ingestion. Here, we explored the specificity with which early-phase post-oral sugar sensing influenced ingestive motivation. In experiment 1, rats were trained to associate the consumption of 0.3 M sucrose with injections of LiCl (3.0 meq/kg ip, conditioned taste aversion) or given equivalent exposures to the stimuli, but in an unpaired fashion. Then, all rats were subjected to two brief-access tests to assess appetitive and consummatory responses to the taste properties of sucrose (0.01-1.0 M), 0.12 M NaCl, and dH2O (in 10-s trials in randomized blocks). Intraduodenal infusions of either 0.3 M sucrose or equiosmolar 0.15 M NaCl (3.0 ml) were administered, beginning just before each test. For unpaired rats, intraduodenal sucrose specifically enhanced licking for 0.03-1.0 M sucrose, with no effect on trial initiation, relative to intraduodenal NaCl. Rats with an aversion to sucrose suppressed licking responses to sucrose in a concentration-dependent manner, as expected, but the intraduodenal sucrose preload did not appear to further influence licking responses; instead, intraduodenal sucrose attenuated trial initiation. Using a serial taste reactivity (TR) paradigm, however, experiment 2 demonstrated that intraduodenal sucrose preloads suppressed ingestive oromotor responses to intraorally delivered sucrose in rats with a sucrose aversion. Finally, experiment 3 showed that intraduodenal sucrose preloads enhanced preferential licking to some representative tastants tested (sucrose, Polycose, and Intralipid), but not others (NaCl, quinine). Together, the results suggest that the early phase-reinforcing efficacy of post-oral sugar is dependent on the sensory and motivational properties of the ingesta.

Behavioral Evidence for More than One Taste Signaling Pathway for Sugars in Rats.

By conventional behavioral measures, rodents respond to natural sugars, such as glucose and fructose, as though they elicit an identical perceptual taste quality. Beyond that, the metabolic and sensory effects of these two sugars are quite different. Considering the capacity to immediately respond to the more metabolically expedient sugar, glucose, would seem advantageous for energy intake, the present experiment assessed whether experience consuming these two sugars would modify taste-guided ingestive responses to their yet unknown distinguishing orosensory properties. One group (GvF) had randomized access to three concentrations of glucose and fructose (0.316, 0.56, 1.1 m) in separate 30-min single access training sessions, whereas control groups received equivalent exposure to the three glucose or fructose concentrations only, or remained sugar naive. Comparison of the microstructural licking patterns for the two sugars revealed that GvF responded more positively to glucose (increased total intake, increased burst size, decreased number of pauses), relative to fructose, across training. As training progressed, GvF rats began to respond more positively to glucose in the first minute of the session when intake is principally taste-driven. During post-training brief-access taste tests, GvF rats licked more for glucose than for fructose, whereas the other training groups did not respond differentially to the two sugars. Additional brief access testing showed that this did not generalize to Na-saccharin or galactose. Thus, in addition to eliciting a common taste signal, glucose and fructose produce distinct signals that are apparently rendered behaviorally relevant and hedonically distinct through experience. The taste pathway(s) underlying this remain to be identified. SIGNIFICANCE STATEMENT: The T1R2+T1R3 heterodimer is thought by many to be the only taste receptor for sugars. Although most sugars have been conventionally shown to correspondingly produce a unitary taste percept (sweet), there is reason to question this model. Here, we demonstrate that rats that repeatedly consumed two metabolically distinct sugars (glucose and fructose), and thus have had the opportunity to associate the tastes of these sugars with their differential postoral consequences, initially respond identically to the orosensory properties of the two sugars but eventually respond more positively to glucose. Thus, in addition to the previously identified common taste pathway, glucose and fructose must engage distinct orosensory pathways, the underlying molecular and neural mechanisms of which now await discovery.

Bilateral lesions in a specific subregion of posterior insular cortex impair conditioned taste aversion expression in rats.

The gustatory cortex (GC) is widely regarded for its integral role in the acquisition and retention of conditioned taste aversions (CTAs) in rodents, but large lesions in this area do not always result in CTA impairment. Recently, using a new lesion mapping system, we found that severe CTA expression deficits were associated with damage to a critical zone that included the posterior half of GC in addition to the insular cortex (IC) that is just dorsal and caudal to this region (visceral cortex). Lesions in anterior GC were without effect. Here, neurotoxic bilateral lesions were placed in the anterior half of this critical damage zone, at the confluence of the posterior GC and the anterior visceral cortex (termed IC2 ), the posterior half of this critical damage zone that contains just VC (termed IC3), or both of these subregions (IC2 + IC3). Then, pre- and postsurgically acquired CTAs (to 0.1 M NaCl and 0.1 M sucrose, respectively) were assessed postsurgically in 15-minute one-bottle and 96-hour two-bottle tests. Li-injected rats with histologically confirmed bilateral lesions in IC2 exhibited the most severe CTA deficits, whereas those with bilateral lesions in IC3 were relatively normal, exhibiting transient disruptions in the one-bottle sessions. Groupwise lesion maps showed that CTA-impaired rats had more extensive damage to IC2 than did unimpaired rats. Some individual differences in CTA expression among rats with similar lesion profiles were observed, suggesting idiosyncrasies in the topographic representation of information in the IC. Nevertheless, this study implicates IC2 as the critical zone of the IC for normal CTA expression.