The elusive cephalic phase insulin response: triggers, mechanisms, and functions.

The cephalic phase insulin response (CPIR) is classically defined as a head receptor-induced early release of insulin during eating that precedes a postabsorptive rise in blood glucose. Here we discuss, first, the various stimuli that elicit the CPIR and the sensory signaling pathways (sensory limb) involved; second, the efferent pathways that control the various endocrine events associated with eating (motor limb); and third, what is known about the central integrative processes linking the sensory and motor limbs. Fourth, in doing so, we identify open questions and problems with respect to the CPIR in general. Specifically, we consider test conditions that allow, or may not allow, the stimulus to reach the potentially relevant taste receptors and to trigger a CPIR. The possible significance of sweetness and palatability as crucial stimulus features and whether conditioning plays a role in the CPIR are also discussed. Moreover, we ponder the utility of the strict classical CPIR definition based on what is known about the effects of vagal motor neuron activation and thereby acetylcholine on the ß-cells, together with the difficulties of the accurate assessment of insulin release. Finally, we weigh the evidence of the physiological and clinical relevance of the cephalic contribution to the release of insulin that occurs during and after a meal. These points are critical for the interpretation of the existing data, and they support a sharper focus on the role of head receptors in the overall insulin response to eating rather than relying solely on the classical CPIR definition.

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.

A Novel Mechanism for T1R-Independent Taste Responses to Concentrated Sugars.

Recent findings from our laboratory demonstrated that the rostral nucleus of the solitary tract (rNST) retains some responsiveness to sugars in double-knock-out mice lacking either the T1R1+T1R3 (KO1+3) or T1R2+T1R3 (KO2+3) taste receptor heterodimers. Here, we extended these findings in the parabrachial nucleus (PBN) of male and female KO1+3 mice using warm stimuli to optimize sugar responses and employing additional concentrations and pharmacological agents to probe mechanisms. PBN T1R-independent sugar responses, including those to concentrated glucose, were more evident than in rNST. Similar to the NST, there were no "sugar-best" neurons in KO1+3 mice. Nevertheless, 1000 mm glucose activated nearly 55% of PBN neurons, with responses usually occurring in neurons that also displayed acid and amiloride-insensitive NaCl responses. In wild-type (WT) mice, concentrated sugars activated the same electrolyte-sensitive neurons but also "sugar-best" cells. Regardless of genotype, phlorizin, an inhibitor of the sodium-glucose co-transporter (SGLT), a component of a hypothesized alternate glucose-sensing mechanism, did not diminish responses to 1000 mm glucose. The efficacy of concentrated sugars for driving neurons broadly responsive to electrolytes implied an origin from Type III taste bud cells. To test this, we used the carbonic anhydrase (CA) inhibitor dorzolamide (DRZ), previously shown to inhibit amiloride-insensitive sodium responses arising from Type III taste bud cells. Dorzolamide had no effect on sugar-elicited responses in WT sugar-best PBN neurons but strongly suppressed them in WT and KO1+3 electrolyte-generalist neurons. These findings suggest a novel T1R-independent mechanism for hyperosmotic sugars, involving a CA-dependent mechanism in Type III taste bud cells.SIGNIFICANCE STATEMENT Since the discovery of Tas1r receptors for sugars and artificial sweeteners, evidence has accrued that mice lacking these receptors maintain some behavioral, physiological, and neural responsiveness to sugars. But the substrate(s) has remained elusive. Here, we recorded from parabrachial nucleus (PBN) taste neurons and identified T1R-independent responses to hyperosmotic sugars dependent on carbonic anhydrase (CA) and occurring primarily in neurons broadly responsive to NaCl and acid, implying an origin from Type III taste bud cells. The effectiveness of different sugars in driving these T1R-independent responses did not correlate with their efficacy in driving licking, suggesting they evoke a nonsweet sensation. Nevertheless, these salient responses are likely to comprise an adequate cue for learned preferences that occur in the absence of T1R receptors.

Oromotor and somatic taste reactivity during sucrose meals reveals internal state and stimulus palatability after gastric bypass in rats.

After Roux-en-Y gastric bypass (RYGB), rats consume less high-energy foods and fluids, though whether this reflects a concomitant change in palatability remains unclear. By measuring behavior during intraorally delivered liquid meals across days (1 water, 8 sucrose sessions), we showed that RYGB rats (RYGB, n = 8/sex) consumed less 1.0 M sucrose than their sham surgery counterparts (SHAM, n = 8 males, n = 11 females) but displayed similarly high levels of ingestive taste reactivity responses at the start of infusions. Relative to water, both groups increased intake of sucrose, and ingestive responses were dominated by tongue protrusions rather than mouth movements. Thus, RYGB animals still found sucrose palatable despite consuming less than the SHAM group. As the intraoral infusion progressed but before meal termination, aversive behavior remained low and both RYGB and SHAM animals showed fewer ingestive responses, predominantly mouth movements as opposed to tongue protrusions. This shift in responsiveness unrelated to surgical manipulation suggests negative alliesthesia, or a decreased palatability, as rats approach satiation. Notably, only in RYGB rats, across sessions, there was a striking emergence of aversive behavior immediately after the sucrose meal. Thus, although lower intake in RYGB rats seems independent of the hedonic taste properties of sucrose, taste reactivity behavior in these animals immediately after termination of a liquid meal appears to be influenced by postoral events and reflects a state of nimiety or excessive consumption. Measurement of taste reactivity behaviors during an intraorally delivered meal represents a promising way to make inferences about internal state in nonverbal preclinical models.

Food Intake Following Gastric Bypass Surgery: Patients Eat Less but Do Not Eat Differently.

BACKGROUND: Lack of robust research methodology for assessing ingestive behavior has impeded clarification of the mediators of food intake following gastric bypass (GBP) surgery. OBJECTIVES: To evaluate changes in directly measured 24-h energy intake (EI), energy density (ED) (primary outcomes), eating patterns, and food preferences (secondary outcomes) in patients and time-matched weight-stable comparator participants. METHODS: Patients [n = 31, 77% female, BMI (in kg/m2) 45.5 ± 1.3] and comparators (n = 32, 47% female, BMI 27.2 ± 0.8) were assessed for 36 h under fully residential conditions at baseline (1 mo presurgery) and at 3 and 12 mo postsurgery. Participants had ad libitum access to a personalized menu (n = 54 foods) based on a 6-macronutrient mix paradigm. Food preferences were assessed by the Leeds Food Preference Questionnaire. Body composition was measured by whole-body DXA. RESULTS: In the comparator group, there was an increase in relative fat intake at 3 mo postsurgery; otherwise, no changes were observed in food intake or body composition. At 12 mo postsurgery, patients lost 27.7 ± 1.6% of initial body weight (P < 0.001). The decline in EI at 3 mo postsurgery (-44% from baseline, P < 0.001) was followed by a partial rebound at 12 mo (-18% from baseline), but at both times, dietary ED and relative macronutrient intake remained constant. The decline in EI was due to eating the same foods as consumed presurgery and by decreasing the size (g, MJ), but not the number, of eating occasions. In patients, reduction in explicit liking at 3 mo (-11.56 ± 4.67, P = 0.007) and implicit wanting at 3 (-15.75 ± 7.76, P = 0.01) and 12 mo (-15.18 ± 6.52, P = 0.022) for sweet foods were not matched by reduced intake of these foods. Patients with the greatest reduction in ED postsurgery reduced both EI and preference for sweet foods. CONCLUSIONS: After GBP, patients continue to eat the same foods but in smaller amounts. These findings challenge prevailing views about the dynamics of food intake following GBP surgery. This trial was registered as clinicaltrials.gov as NCT03113305.

Electrophysiological responses to sugars and amino acids in the nucleus of the solitary tract of type 1 taste receptor double-knockout mice.

Strong evidence supports a major role for heterodimers of the type 1 taste receptor (T1R) family in the taste transduction of sugars (T1R2+T1R3) and amino acids (T1R1+T1R3), but there are also neural and behavioral data supporting T1R-independent mechanisms. Most neural evidence for alternate mechanisms comes from whole nerve recordings in mice with deletion of a single T1R family member, limiting conclusions about the functional significance and T1R independence of the remaining responses. To clarify these issues, we recorded single-unit taste responses from the nucleus of the solitary tract in T1R double-knockout (double-KO) mice lacking functional T1R1+T1R3 [KO1+3] or T1R2+T1R3 [KO2+3] receptors and their wild-type background strains [WT; C57BL/6J (B6), 129X1/SvJ (S129)]. In both double-KO strains, responses to sugars and a moderate concentration of an monosodium glutamate + amiloride + inosine 5'-monophosphate cocktail (0.1 M, i.e., umami) were profoundly depressed, whereas a panel of 0.6 M amino acids were mostly unaffected. Strikingly, in contrast to WT mice, no double-KO neurons responded selectively to sugars and umami, precluding segregation of this group of stimuli from those representing other taste qualities in a multidimensional scaling analysis. Nevertheless, residual sugar responses, mainly elicited by monosaccharides, persisted as small "sideband" responses in double-KOs. Thus other receptors may convey limited information about sugars to the central nervous system, but T1Rs appear critical for coding the distinct perceptual features of sugar and umami stimuli. The persistence of amino acid responses supports previous proposals of alternate receptors, but because these stimuli affected multiple neuron types, further investigations are necessary.NEW & NOTEWORTHY The type 1 taste receptor (T1R) family is crucial for transducing sugars and amino acids, but there is evidence for T1R-independent mechanisms. In this study, single-unit recordings from the nucleus of the solitary tract in T1R double-knockout mice lacking T1R1+T1R3 or T1R2+T1R3 receptors revealed greatly reduced umami synergism and sugar responses. Nevertheless, residual sugar responses persisted, mainly elicited by monosaccharides and evident as "sidebands" in neurons activated more vigorously by other qualities.

Gastric bypass in female rats lowers concentrated sugar solution intake and preference without affecting brief-access licking after long-term sugar exposure.

In rodents, Roux-en-Y gastric bypass (RYGB) decreases intake of, and preference for, foods or fluids that are high in sugar. Whether these surgically induced changes are due to decreases in the palatability of sugar stimuli is controversial. We used RYGB and sham-operated (SHAM) female rats to test the influence of prolonged ingestive experience with sugar solutions on the motivational potency of these stimuli to drive licking in brief-access (BA) tests. In experiment 1, RYGB attenuated intake of, and caloric preference for, 0.3 M sucrose during five consecutive, 46-h two-bottle tests (TBTs; sucrose). A second series of TBTs (5 consecutive, 46-h tests) with 1.0 M sucrose revealed similar results, except fluid preference for 1.0 M sucrose also significantly decreased. Before, between, and after the two series of TBTs, two sessions of BA tests (30 min; 10-s trials) with an array of sucrose concentrations (0 and 0.01-1.0 M) were conducted. Concentration-dependent licking and overall trial initiation did not differ between surgical groups in any test. In a similar experimental design in a second cohort of female rats, 0.6 and 2.0 M glucose (isocaloric with sucrose concentrations in experiment 1) were used in the TBTs; 0 and 0.06-2.0 M glucose were used in the BA tests. Outcomes were similar to those for experiment 1, except RYGB rats initiated fewer trials during the BA tests. Although RYGB profoundly affected intake of, and caloric preference for, sugar solutions and, with high concentrations, fluid preference, RYGB never influenced the motivational potency of sucrose or glucose to drive concentration-dependent licking in BA tests.

Masking the Detection of Taste Stimuli in Rats: NaCl and Sucrose.

While psychophysical and neurophysiological assessments of taste sensitivity to single chemical compounds have revealed some fundamental properties of gustatory processing, taste stimuli are rarely ingested in isolation. Arguably, the gustatory system was adapted to identify and report the presence of numerous chemicals ingested concurrently. To begin systematically exploring the detectability of a target stimulus in a background in rodents, we used a gustometer to train rats in a 2-response operant task to detect either NaCl (n = 8) or sucrose (n = 8) dissolved in water, and then tested the sensitivity of rats to the trained NaCl stimulus dissolved in a sucrose masker (0.3, 0.6, or 1.0 M, tested consecutively) versus sucrose, or the trained sucrose stimulus dissolved in a NaCl masker (0.04, 0.2, or 0.4 M) versus NaCl. Detection thresholds (EC50 values) were determined for the target stimulus dissolved in each concentration of the masker. Except for 0.04 M NaCl, all masker concentrations tested increased the target stimulus EC50. Target stimulus detectability decreased systematically as masker concentrations increased. The shift in liminal sensitivity for either target was similar when the threshold for the masker was considered. At least for these prototypical stimuli, it appears that the attenuating impact of a masker on the detection of a target stimulus depends on sensitivity to the masking stimulus. Further study will be required to generalize these results and extend them to more complex maskers, and to discern neural circuits involved in the detection of specific taste signals in the context of noisy backgrounds.

ENaC-Dependent Sodium Chloride Taste Responses in the Regenerated Rat Chorda Tympani Nerve After Lingual Gustatory Deafferentation Depend on the Taste Bud Field Reinnervated.

The chorda tympani (CT) nerve is exceptionally responsive to NaCl. Amiloride, an epithelial Na+ channel (ENaC) blocker, consistently and significantly decreases the NaCl responsiveness of the CT but not the glossopharyngeal (GL) nerve in the rat. Here, we examined whether amiloride would suppress the NaCl responsiveness of the CT when it cross-reinnervated the posterior tongue (PT). Whole-nerve electrophysiological recording was performed to investigate the response properties of the intact (CTsham), regenerated (CTr), and cross-regenerated (CT-PT) CT in male rats to NaCl mixed with and without amiloride and common taste stimuli. The intact (GLsham) and regenerated (GLr) GL were also examined. The CT responses of the CT-PT group did not differ from those of the GLr and GLsham groups, but did differ from those of the CTr and CTsham groups for some stimuli. Importantly, the responsiveness of the cross-regenerated CT to a series of NaCl concentrations was not suppressed by amiloride treatment, which significantly decreased the response to NaCl in the CTr and CTsham groups and had no effect in the GLr and GLsham groups. This suggests that the cross-regenerated CT adopts the taste response properties of the GL as opposed to those of the regenerated CT or intact CT. This work replicates the 5 decade-old findings of Oakley and importantly extends them by providing compelling evidence that the presence of functional ENaCs, essential for sodium taste recognition in regenerated taste receptor cells, depends on the reinnervated lingual region and not on the reinnervating gustatory nerve, at least in the rat.

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.

Proceedings from the 2018 Association for Chemoreception Annual Meeting Symposium: Bariatric Surgery and Its Effects on Taste and Food Selection.

This article provides a summary of the topics discussed at the symposium titled "Bariatric Surgery and Its Effects on Taste and Food Selection," which was held at the Fortieth Annual Meeting of the Association for Chemoreception Sciences. Bariatric surgery such as Roux-en-Y gastric bypass (RYGB) is currently one of the most effective treatments available for weight loss and Type 2 diabetes. For this reason, it is of great interest to clinicians as well as to basic scientists studying the controls of feeding and energy balance. Despite the commonly held view by clinicians that RYGB patients change their food preferences away from fats and sugars in favor of less energy dense alternatives such as vegetables, the empirical support for this claim is equivocal. It is currently thought that the taste and palatability of fats and sugars are affected by the surgery. Some key preclinical and clinical findings addressing these issues were evaluated in this symposium.

Drinking microstructure in humans: A proof of concept study of a novel drinkometer in healthy adults.

Microstructural analysis of ingestion provides valuable insight into the roles of chemosensory signals, nutritional content, postingestive events, and physiological state. Our aim was to develop a novel drinkometer for humans to measure detailed aspects of ingestion of an entire liquid meal or drinking session. The drinkometer records, in high definition (1 kHz), the weight of a fluid reservoir from which participants drink via a tube. An ultrasonic sensor measures the height of the fluid to derive density. Drinking speed over time can be displayed as a waveform. The smallest units of ingestion are sucks, which are organized in bursts. By applying probability density functions (PDF) on loge-transformed inter-suck intervals (ISI), an optimal burst-pause criterion (PC) can be identified. Information on ingestive volumes, rates, and durations can be then computed for the entire session, as well as for sucks and bursts. We performed a validation study on 12 healthy adults in overnight-fasted and in non-fasted states in 16 drinking sessions with 8 concentrations of sucrose (0-280 mM) presented in a blinded and random fashion. PDF determined PC = 2.9 s as optimal. Two-way RM-ANOVA revealed that total caloric intake during a drinking session depended on sucrose concentration (P < .001) and fasted state (P = .006); total drinking time (P < .001), total consumed volume (P = .003), number of sucks in total (P < .001), number of sucks per burst (P = .03), and burst duration (P = .02) were significantly influenced by fasting. In contrast, volume per suck (P = .002), suck speed (P < .001), and maximal speed per suck (P < .001) depended on sucrose concentration. We conclude that the novel drinkometer is able to detect differences in microstructural parameters of drinking behavior dependent on different motivational states, thus, adds to the technological toolbox used to explore human ingestive behavior.

Taste sensitivity to a mixture of monosodium glutamate and inosine 5'-monophosphate by mice lacking both subunits of the T1R1+T1R3 amino acid receptor.

The taste of l-glutamate and its synergism with 5'-ribonucleotides is thought to be primarily mediated through the T1R1+T1R3 heterodimer in some mammals, including rodents and humans. While knockout (KO) mice lacking either receptor subunit show impaired sensitivity to a range of monosodium glutamate (MSG) concentrations mixed with 2.5 mM inosine 5'-monophosphate (IMP) in amiloride, wild-type (WT) controls can detect this IMP concentration, hindering direct comparison between genotypes. Moreover, some residual sensitivity persists in the KO group, suggesting that the remaining subunit could maintain a limited degree of function. Here, C57BL/6J, 129X1/SvJ, and T1R1+T1R3 double KO mice ( n = 16 each to start the experiment) were trained in a two-response operant task in gustometers and then tested for their ability to discriminate 100 µM amiloride from MSG (starting with 0.6 M) and IMP (starting with 2.5 mM) in amiloride (MSG+I+A). Testing continued with successive dilutions of both MSG and IMP (in amiloride). The two WT strains were similarly sensitive to MSG+I+A ( P > 0.8). KO mice, however, were significantly impaired relative to either WT strain ( P < 0.01), although they were able to detect the highest concentrations. Thus, normal detectability of MSG+I+A requires an intact T1R1+T1R3 receptor, without regard for allelic variation in the T1R3 gene between the WT strains. Nevertheless, residual sensitivity by the T1R1+T1R3 KO mice demonstrates that a T1R-independent mechanism can contribute to the detectability of high concentrations of this prototypical umami compound stimulus.

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.

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.

Detection of maltodextrin and its discrimination from sucrose are independent of the T1R2 + T1R3 heterodimer.

Maltodextrins, such as Maltrin and Polycose, are glucose polymer mixtures of varying chain lengths that are palatable to rodents. Although glucose and other sugars activate the T1R2 + T1R3 "sweet" taste receptor, recent evidence from T1R2- or T1R3-knockout (KO) mice suggests that maltodextrins, despite their glucose polymer composition, activate a separate receptor mechanism to generate a taste percept qualitatively distinguishable from that of sweeteners. However, explicit discrimination of maltodextrins from prototypical sweeteners has not yet been psychophysically tested in any murine model. Therefore, mice lacking T1R2 + T1R3 and wild-type controls were tested in a two-response taste discrimination task to determine whether maltodextrins are 1) detectable when both receptor subunits are absent and 2) perceptually distinct from that of sucrose irrespective of viscosity, intensity, and hedonics. Most KO mice displayed similar Polycose sensitivity as controls. However, some KO mice were only sensitive to the higher Polycose concentrations, implicating potential allelic variation in the putative polysaccharide receptor or downstream pathways unmasked by the absence of T1R2 + T1R3. Varied Maltrin and sucrose concentrations of approximately matched viscosities were then presented to render the oral somatosensory features, intensity, and hedonic value of the solutions irrelevant. Although both genotypes competently discriminated Maltrin from sucrose, performance was apparently driven by the different orosensory percepts of the two stimuli in control mice and the presence of a Maltrin but not sucrose orosensory cue in KO mice. These data support the proposed presence of an orosensory receptor mechanism that gives rise to a qualitatively distinguishable sensation from that of sucrose.

An Examination of the Role of L-Glutamate and Inosine 5'-Monophosphate in Hedonic Taste-Guided Behavior by Mice Lacking the T1R1 + T1R3 Receptor.

The heterodimeric T1R1 + T1R3 receptor is considered critical for normal signaling of L-glutamate and 5'-ribonucleotides in the oral cavity. However, some taste-guided responsiveness remains in mice lacking one subunit of the receptor, suggesting that other receptors are sufficient to support some behaviors. Here, mice lacking both receptor subunits (KO) and wild-type (WT, both n = 13) mice were tested in a battery of behavioral tests. Mice were trained and tested in gustometers with a concentration series of Maltrin-580, a maltodextrin, in a brief-access test (10-s trials) as a positive control. Similar tests followed with monosodium glutamate (MSG) with and without the ribonucleotide inosine 5'-monophosphate (IMP), but always in the presence of the epithelial sodium channel blocker amiloride (A). Brief-access tests were repeated following short-term (30-min) and long-term (48-h) exposures to MSG + A + IMP and were also conducted with sodium gluconate replacing MSG. Finally, progressive ratio tests were conducted with Maltrin-580 or MSG + A + IMP, to assess appetitive behavior while minimizing satiation. Overall, MSG generated little concentration-dependent responding in either food-restricted WT or KO mice, even in combination with IMP. However, KO mice licked less to the amino acid stimuli, a measure of consummatory behavior in the brief-access tests. In contrast, both groups initiated a similar number of trials and had a similar breakpoint in the progressive ratio task, both measures of appetitive (approach) behavior. Collectively, these results suggest that while the T1R1 + T1R3 receptor is necessary for consummatory responding to MSG (+IMP), other receptors are sufficient to maintain appetitive responding to this "umami" stimulus complex in food-restricted mice.

High-resolution lesion-mapping strategy links a hot spot in rat insular cortex with impaired expression of taste aversion learning.

Gustatory cortex (GC), an assemblage of taste-responsive neurons in insular cortex, is widely regarded as integral to conditioned taste aversion (CTA) retention, a link that has been primarily established using lesion approaches in rats. In contrast to this prevailing view, we found that even the most complete bilateral damage to GC produced by ibotenic acid was insufficient to disrupt postsurgical expression of a presurgical CTA; nor were such lesions sufficient to disrupt postsurgical acquisition and initial expression of a second CTA. However, some rats with lesions were significantly impaired on these tests. Further examination of all conditioned rats with lesions, regardless of the lesion topography, revealed a significant positive association between damage in the posterior portion of GC and especially within adjacent posterior regions of insular cortex. Accordingly, we developed a high-resolution lesion-mapping program that permitted the overlay of the individual lesion maps from rats with CTA impairments to produce a groupwise aggregate lesion map. Comparison of this map with one derived from the unimpaired counterparts indicated a specific lesion "hot spot" associated with CTA deficits that included the most posterior end of GC and overlying granular layer and encompassed an area provisionally referred to in the literature as visceral cortex. Thus, the detailed mapping of the lesion in behaviorally defined subgroups of rats allowed us to exploit the variability in performance to uncloak an important potential component of the functional topography of insular cortex; such an approach could have general applicability to other brain structure-function endeavors as well.

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.

Roux-en-Y gastric bypass in rats progressively decreases the proportion of fat calories selected from a palatable cafeteria diet.

Roux-en-Y gastric bypass surgery (RYGB) decreases caloric intake in both human patients and rodent models. In long-term intake tests, rats decrease their preference for fat and/or sugar after RYGB, and patients may have similar changes in food selection. Here we evaluated the impact of RYGB on intake during a "cafeteria"-style presentation of foods to assess if rats would lower the percentage of calories taken from fat and/or sugar after RYGB in a more complex dietary context. Male Sprague-Dawley rats that underwent either RYGB or sham surgery (Sham) were presurgically and postsurgically given 8-days free access to four semisolid foods representative of different fat and sugar levels along with standard chow and water. Compared with Sham rats, RYGB rats took proportionally fewer calories from fat and more calories from carbohydrates; the latter was not attributable to an increase in sugar intake. The proportion of calories taken from protein after RYGB also increased slightly. Importantly, these postsurgical macronutrient caloric intake changes in the RYGB rats were progressive, making it unlikely that the surgery had an immediate impact on the hedonic evaluation of the foods and strongly suggesting that learning is influencing the food choices. Indeed, despite these dietary shifts, RYGB, as well as Sham, rats continued to select the majority of their calories from the high-fat/high-sugar option. Apparently after RYGB, rats can progressively regulate their intake and selection of complex foods to achieve a seemingly healthier macronutrient dietary composition.