John I. Glendinning

T1R3 taste receptor is critical for sucrose but not Polycose taste

In addition to their well-known preference for sugars, mice and rats avidly consume starch-derived glucose polymers (e.g., Polycose). T1R3 is a component of the mammalian sweet taste receptor that mediates the preference for sugars and artificial sweeteners in mammals. We examined the role of the T1R3 receptor in the ingestive response of mice to Polycose and sucrose. In 60-s two-bottle tests, knockout (KO) mice preferred Polycose solutions (4-32%) to water, although their overall preference was lower than WT mice (82% vs. 94%). KO mice also preferred Polycose (0.5-32%) in 24-h two-bottle tests, although less so than WT mice at dilute concentrations (0.5-4%). In contrast, KO mice failed to prefer sucrose to water in 60-s tests. In 24-h tests, KO mice were indifferent to 0.5-8% sucrose, but preferred 16-32% sucrose; this latter result may reflect the post-oral effects of sucrose. Overall sucrose preference and intake were substantially less in KO mice than WT mice. However, when retested with 0.5-32% sucrose solutions, the KO mice preferred all sucrose concentrations, although they drank less sugar than WT mice. The experience-induced sucrose preference is attributed to a post-oral conditioned preference for the T1R3-independent orosensory features of the sugar solutions (odor, texture, T1R2-mediated taste). Chorda tympani nerve recordings revealed virtually no response to sucrose in KO mice, but a near-normal response to Polycose. These results indicate that the T1R3 receptor plays a critical role in the taste-mediated response to sucrose but not Polycose.

How do herbivorous insects cope with noxious secondary plant compounds in their diet

Herbivorous insects use a variety of physiological mechanisms to cope with noxious (i.e., unpalatable and/or toxic) compounds in their food plants. Here, I review what is known about this coping process, focusing on one species of caterpillar, the tobacco hornworm (Manduca sexta). Herbivorous insects possess both preingestive (i.e., chemosensory) and postingestive response mechanisms for detecting plant secondary compounds. Stimulation of either class of detection mechanism inhibits feeding rapidly by reducing biting rate and/or bite size. This aversive response is highly adaptive during encounters with secondary plant compounds that are toxic. The insects dilemma is that many harmless or mildly toxic compounds also activate the aversive response. To overcome this dilemma, herbivorous insects employ at least three mechanisms for selectively deactivating their aversive response to relatively harmless secondary plant compounds: (1) the presence of carbohydrates can mask the unpalatable taste of some secondary plant compounds; (2) prolonged dietary exposure to some unpalatable secondary plant compounds can initiate long‐term adaptation mechanisms in the peripheral and central gustatory system; and (3) dietary exposure to toxic compounds can induce production of P450 detoxication enzymes. Thus, herbivorous insects utilize an integrated suite of physiological mechanisms to detect potentially toxic compounds in foods, and then selectively adapt to those that do not pose a serious threat to their growth and survivorship.

Gut T1R3 sweet taste receptors do not mediate sucrose-conditioned flavor preferences in mice

Most mammals prefer the sweet taste of sugars, which is mediated by the heterodimeric T1R2+T1R3 taste receptor. Sugar appetite is also enhanced by the post-oral reinforcing actions of the nutrient in the gut. Here, we examined the contribution of gut T1R3 (either alone or as part of the T1R3+T1R3 receptor) to post-oral sugar reinforcement using a flavor-conditioning paradigm. We trained mice to associate consumption of a flavored solution (CS+) with intragastric (IG) infusions of a sweetener, and a different flavored solution (CS-) with IG infusions of water (23 h/day); then, we measured preference in a CS+ vs. CS- choice test. In experiment 1, we predicted that if activation of gut T1R3 mediates sugar reinforcement, then IG infusions of a nutritive (sucrose) or nonnutritive (sucralose) ligand for this receptor should condition a preference for the CS+ in B6 wild-type (WT) mice. While the mice that received IG sucrose infusions developed a strong preference for the CS+, those that received IG sucralose infusions developed a weak avoidance of the CS+. In experiment 2, we used T1R3 knockout (KO) mice to examine the necessity of gut T1R2+T1R3 receptors for conditioned flavor preferences. If intact gut T1R3 (or T1R2+T1R3) receptors are necessary for flavor-sugar conditioning, then T1R3 KO mice should not develop a sugar-conditioned flavor preference. We found that T1R3 KO mice, like WT mice, acquired a strong preference for the CS+ paired with IG sucrose infusions. The KO mice were also like WT mice in avoiding a CS+ flavor paired with IG sucralose infusions These findings provide clear evidence that gut T1R3 receptors are not necessary for sugar-conditioned flavor preferences or sucralose-induced flavor avoidance in mice.

LINKING PERIPHERAL TASTE PROCESSES TO BEHAVIOR

The act of eating and drinking brings food-related chemicals into contact with taste cells. Activation of these taste cells, in turn, engages neural circuits in the central nervous system that help animals identify foods and fluids, determine what and how much to eat, and prepare the body for digestion and assimilation. Analytically speaking, these neural processes can be divided into at least three categories: stimulus identification, ingestive motivation, and digestive preparation. This review will discuss recent advances in peripheral gustatory mechanisms, primarily from rodent models, in the context of these three major categories of taste function.

Fetal ethanol exposure increases ethanol intake by making it smell and taste better.

Human epidemiologic studies reveal that fetal ethanol exposure is highly predictive of adolescent ethanol avidity and abuse. Little is known about how fetal exposure produces these effects. It is hypothesized that fetal ethanol exposure results in stimulus-induced chemosensory plasticity. Here, we asked whether gestational ethanol exposure increases postnatal ethanol avidity in rats by altering its taste and odor. Experimental rats were exposed to ethanol in utero via the dams diet, whereas control rats were either pair-fed an iso-caloric diet or given food ad libitum. We found that fetal ethanol exposure increased the taste-mediated acceptability of both ethanol and quinine hydrochloride (bitter), but not sucrose (sweet). Importantly, a significant proportion of the increased ethanol acceptability could be attributed directly to the attenuated aversion to ethanols quinine-like taste quality. Fetal ethanol exposure also enhanced ethanol intake and the behavioral response to ethanol odor. Notably, the elevated intake of ethanol was also causally linked to the enhanced odor response. Our results demonstrate that fetal exposure specifically increases ethanol avidity by, in part, making it taste and smell better. More generally, they establish an epigenetic chemosensory mechanism by which maternal patterns of drug use can be transferred to offspring. Given that many licit (e.g., tobacco products) and illicit (e.g., marijuana) drugs have noteworthy chemosensory components, our findings have broad implications for the relationship between maternal patterns of drug use, child development, and postnatal vulnerability.

Flavor preferences conditioned in C57BL/6 mice by intragastric carbohydrate self-infusion.

This study determined the feasibility of conditioning flavor preferences in mice by self-administered intragastric (IG) nutrient infusions. Male C57BL/6J mice were surgically fitted with an IG catheter that was attached by a tether system to an infusion pump. The mice were given ad-libitum access to chow and a flavored solution 23 h/day. Drinking was monitored with a computerized lickometer system that controlled the infusion pumps. In Experiment 1, drinking one flavored solution (CS+, e.g., grape-saccharin) was paired with matched infusions of 8% maltodextrin, whereas drinking another solution (CS-, e.g., cherry-saccharin) was matched with water infusions across 6 one-bottle training days. During training, the mice drank more CS+ than CS-; this was due to an increase in bout size but not bout frequency. In subsequent two-bottle choice tests, the mice strongly preferred (91%) the CS+ to the CS-. Experiment 2 obtained a significant but less robust (71%) CS+ preference in mice trained with unsweetened CS solutions. These data indicate that mice, like rats, acquire an increased acceptance and preference for flavors paired with the postingestive actions of nutrients. Our understanding of flavor-nutrient learning can be advanced by studying this process in selected mouse strains and genetically modified animals.

A peripheral mechanism for behavioral adaptation to specific "bitter" taste stimuli in an insect.

Animals have evolved several chemosensory systems for detecting potentially dangerous foods in the environment. Activation of specific sensory cells within these chemosensory systems usually elicits an aversive behavioral response, leading to avoidance of the noxious foods. Although this aversive behavioral response can be adaptive, there are many instances in which it generates “false alarms,” causing animals to reject harmless foods. To minimize the number of false alarms, animals have evolved a variety of physiological mechanisms for selectively adapting their aversive behavioral response to harmless noxious compounds. We examined the mechanisms underlying exposure-induced adaptation to specific “bitter” compounds inManduca sexta caterpillars. M. sextaexhibits an aversive behavioral response to many plant-derived compounds that taste bitter to humans, including caffeine and aristolochic acid. This aversive behavioral response is mediated by three pairs of bitter-sensitive taste cells: one responds vigorously to aristolochic acid alone, and the other two respond vigorously to both caffeine and aristolochic acid. We found that 24 hr of exposure to a caffeinated diet desensitized all of the caffeine-responsive taste cells to caffeine but not to aristolochic acid. In addition, we found that dietary exposure to caffeine adapted the aversive behavioral response of the caterpillar to caffeine, but not to aristolochic acid. We propose that the adapted aversive response to caffeine was mediated directly by the desensitized taste cells and that the adapted aversive response did not generalize to aristolochic acid because the signaling pathway for this compound was insulated from that for caffeine.

Contribution of different bitter-sensitive taste cells to feeding inhibition in a caterpillar (Manduca sexta)

Many compounds that taste bitter to humans also inhibit feeding in insects. Caterpillars (e.g., Manduca sexta) detect these compounds with a few bitter-sensitive taste cells. This study examined the role of these taste cells in feeding inhibition. Behavioral studies demonstrated that 3 bitter compounds (caffeine, salicin, and aristolochic acid) all inhibited feeding rapidly in Manduca sexta. Electrophysiological studies revealed that each pair of bitter-sensitive taste cell differs in responsiveness to the bitter compounds. Ablation studies indicated that (a) those pairs of bitter-sensitive taste cells that responded vigorously to a particular bitter compound were sufficient to inhibit feeding on diets containing the same compound, but that (b) no pair of bitter-sensitive taste cells was necessary for inhibiting feeding. Thus, the different pairs of bitter-sensitive taste cells appear to make partially redundant contributions to feeding inhibition.

Differential effects of sucrose and fructose on dietary obesity in four mouse strains

We examined sugar-induced obesity in mouse strains polymorphic for Tas1r3, a gene that codes for the T1R3 sugar taste receptor. The T1R3 receptor in the FVB and B6 strains has a higher affinity for sugars than that in the AKR and 129P3 strains. In Experiment 1, mice had 40days of access to lab chow plus water, sucrose (10 or 34%), or fructose (10 or 34%) solutions. The strains consumed more of the sucrose than isocaloric fructose solutions. The pattern of strain differences in caloric intake from the 10% sugar solutions was FVB>129P3=B6>AKR; and that from the 34% sugar solutions was FVB>129P3>B6>/=AKR. Despite consuming more sugar calories, the FVB mice resisted obesity altogether. The AKR and 129P3 mice became obese exclusively on the 34% sucrose diet, while the B6 mice did so on the 34% sucrose and 34% fructose diets. In Experiment 2, we compared total caloric intake from diets containing chow versus chow plus 34% sucrose. All strains consumed between 11 and 25% more calories from the sucrose-supplemented diet. In Experiment 3, we compared the oral acceptability of the sucrose and fructose solutions, using lick tests. All strains licked more avidly for the 10% sucrose solutions. The results indicate that in mice (a) Tas1r3 genotype does not predict sugar-induced hyperphagia or obesity; (b) sucrose solutions stimulate higher daily intakes than isocaloric fructose solutions; and (c) susceptibility to sugar-induced obesity varies with strain, sugar concentration and sugar type.

Temporal Coding Mediates Discrimination of “Bitter” Taste Stimuli by an Insect

The mechanisms that mediate discriminative taste processing in insects are poorly understood. We asked whether temporal patterns of discharge from the peripheral taste system of an insect (Manduca sexta caterpillars; Sphingidae) contribute to the discrimination of three “bitter” taste stimuli: salicin, caffeine, and aristolochic acid. The gustatory response to these stimuli is mediated exclusively by three pairs of bitter-sensitive taste cell, which are located in the medial, lateral, and epipharyngeal sensilla. We tested for discrimination by habituating the caterpillars to salicin and then determining whether the habituation generalized to caffeine or aristolochic acid. We ran habituation-generalization tests in caterpillars with their full complement of taste sensilla (i.e., intact) and in caterpillars with ablated lateral sensilla (i.e., lat-ablated). The latter perturbation enabled us to examine discrimination in caterpillars with a modified peripheral taste profile. We found that the intact and lat-ablated caterpillars both generalized the salicin-habituation to caffeine but not aristolochic acid. Next, we determined whether this pattern of stimulus-generalization could be explained by salicin and aristolochic acid generating distinct ensemble, rate, temporal, or spatiotemporal codes. To this end, we recorded excitatory responses from the bitter-sensitive taste cells and then used these responses to formulate predictions about whether the salicin-habituation should generalize to caffeine or aristolochic acid, separately for each coding framework. We found that the pattern of stimulus generalization in both intact and lat-ablated caterpillars could only be predicted by temporal coding. We conclude that temporal codes from the periphery can mediate discriminative taste processing.