Taste Pathways Research Articles

The role of nociceptin in responding for palatable rewards

Animal models suggest that sucrose activates taste afferents differently than non-caloric sweeteners. Little information exists how artificial sweeteners engage central taste pathways in the human brain. We assessed sucrose and sucralose taste pleasantness across a concentration gradient in 12 healthy control women and applied 10% sucrose and matched sucralose during functional magnet resonance imaging. The results indicate that (1) both sucrose and sucralose activate functionally connected primary taste pathways; (2) taste pleasantness predicts left insula response; (3) sucrose elicits a stronger brain response in the anterior insula, frontal operculum, striatum and anterior cingulate, compared to sucralose; (4) only sucrose, but not sucralose, stimulation engages dopaminergic midbrain areas in relation to the behavioral pleasantness response. Thus, brain response distinguishes the caloric from the non-caloric sweetener, although the conscious mind could not. This could have important implications on how effective artificial sweeteners are in their ability to substitute sugar intake.

Salt appetite is reduced by a single experience of drinking hypertonic saline in the adult rat.

Salt appetite, the primordial instinct to favorably ingest salty substances, represents a vital evolutionary important drive to successfully maintain body fluid and electrolyte homeostasis. This innate instinct was shown here in Sprague-Dawley rats by increased ingestion of isotonic saline (IS) over water in fluid intake tests. However, this appetitive stimulus was fundamentally transformed into a powerfully aversive one by increasing the salt content of drinking fluid from IS to hypertonic saline (2% w/v NaCl, HS) in intake tests. Rats ingested HS similar to IS when given no choice in one-bottle tests and previous studies have indicated that this may modify salt appetite. We thus investigated if a single 24 h experience of ingesting IS or HS, dehydration (DH) or 4% high salt food (HSD) altered salt preference. Here we show that 24 h of ingesting IS and HS solutions, but not DH or HSD, robustly transformed salt appetite in rats when tested 7 days and 35 days later. Using two-bottle tests rats previously exposed to IS preferred neither IS or water, whereas rats exposed to HS showed aversion to IS. Responses to sweet solutions (1% sucrose) were not different in two-bottle tests with water, suggesting that salt was the primary aversive taste pathway recruited in this model. Inducing thirst by subcutaneous administration of angiotensin II did not overcome this salt aversion. We hypothesised that this behavior results from altered gene expression in brain structures important in thirst and salt appetite. Thus we also report here lasting changes in mRNAs for markers of neuronal activity, peptide hormones and neuronal plasticity in supraoptic and paraventricular nuclei of the hypothalamus following rehydration after both DH and HS. These results indicate that a single experience of drinking HS is a memorable one, with long-term changes in gene expression accompanying this aversion to salty solutions.

No Taste for Health: How Tastes are Being Manipulated to Favour Foods that are not Conducive to Health and Wellbeing

No Taste for Health: How Tastes are Being Manipulated to Favour Foods that are not Conducive to Health and Wellbeing

Selective Activation of hTRPV1 by N-Geranyl Cyclopropylcarboxamide, an Amiloride-Insensitive Salt Taste Enhancer

TRPV1t, a variant of the transient receptor potential vanilloid-1 (TRPV1) has been proposed as a constitutively active, non-selective cation channel as a putative amiloride-insensitive salt taste receptor and shares many properties with TRPV1. Based on our previous chorda tympani taste nerve recordings in rodents and human sensory evaluations, we proposed that N-geranylcyclopropylcarboxamide (NGCC), a novel synthetic compound, acts as a salt taste enhancer by modulating the amiloride/benzamil-insensitive Na+ entry pathways. As an extension of this work, we investigated NGCC-induced human TRPV1 (hTRPV1) activation using a Ca2+-flux signaling assay in cultured cells. NGCC enhanced Ca2+ influx in hTRPV1-expressing cells in a dose-dependent manner (EC50 = 115 µM). NGCC-induced Ca2+ influx was significantly attenuated by ruthenium red (RR; 30 µM), a non-specific blocker of TRP channels and capsazepine (CZP; 5 µM), a specific antagonist of TRPV1, implying that NGCC directly activates hTRPV1. TRPA1 is often co-expressed with TRPV1 in sensory neurons. Therefore, we also investigated the effects of NGCC on hTRPA1-expressing cells. Similar to hTRPV1, NGCC enhanced Ca2+ influx in hTRPA1-expressing cells (EC50 = 83.65 µM). The NGCC-induced Ca2+ influx in hTRPA1-expressing cells was blocked by RR (30 µM) and HC-030031 (100 µM), a specific antagonist of TRPA1. These results suggested that NGCC selectively activates TRPV1 and TRPA1 in cultured cells. These data may provide additional support for our previous hypothesis that NGCC interacts with TRPV1 variant cation channel, a putative amiloride/benzamil-insensitive salt taste pathway in the anterior taste receptive field.

C-Fos-like Immunoreactivity in the nucleus of the solitary tract following taste stimulation of the contralateral side of the tongue

Taste receptors of the anterior tongue are innervated by the chorda tympani (CT) branch of the facial (VIIth) nerve. The CT nerve transmits information on taste to the ipsilateral nucleus of the solitary tract (NST), which is the first taste central nucleus in the medulla. Taste information is known to be transferred ipsilaterally along the taste pathway in the central nervous system. Some patients with unilateral CT damage often retain their ability to sense taste. This phenomenon is not explained by the unilateral taste pathway. We examined whether neurons in the NST receive information on taste from the contralateral side of the tongue by measuring c-Fos-like Immunoreactivity (cFLI) following taste stimulation of the contralateral side of the tongue in the anesthetized rats. We used four basic taste stimuli, 1.0 M sucrose, 0.3 M NaCl, 0.01 M citric acid, 0.03 M QHCl, and distilled water. Stimulation of one side of the tongue with taste stimuli induced cFLI in the NST bilaterally. The mean number of cFLI ranged from 23.28 ± 2.46 by contralateral QHCl to 30.28 ± 2.26 by ipsilateral NaCl stimulation. The difference between the number of cFLI in the ipsilaterl and contralateral NST was not significant. The result of the current study suggests that neurons in the NST receive information on taste not only from the ipsilateral but also the contralateral side of the tongue.

High salt recruits aversive taste pathways

In the tongue, distinct classes of taste receptor cells detect the five basic tastes, sweet, sour, bitter, sodium salt, and umami1,2. Among these qualities, bitter and sour stimuli are innately aversive, whereas sweet and umami are appetitive, and generally attractive to animals. In contrast, salty taste is unique in that increasing salt concentration fundamentally transforms an innately appetitive stimulus into a powerfully aversive one3–7. This appetitive-aversive balance helps maintain appropriate salt consumption3,4,6,8, and represents an important part of fluid and electrolyte homeostasis. We have previously shown that the appetitive responses to NaCl are mediated by taste receptor cells expressing the epithelial sodium channel, ENaC8, while the cellular substrate for salt aversion was unknown. Here we explore the cellular and molecular basis for the rejection of high concentrations of salts (>300 mM NaCl or KCl). We now show that high-salt recruits the two primary aversive taste pathways by activating the sour and bitter taste-sensing cells. We also demonstrate that genetic silencing of these pathways abolishes behavioral aversion to concentrated salt, without impairing salt attraction. Notably, mice devoid of salt-aversion pathways now exhibit unimpeded, continuous attraction even to exceedingly high concentrations of NaCl. We propose that the “co-opting” of sour and bitter neural pathways evolved as a means to ensure that high levels of salt reliably trigger robust behavioral rejection, thus preventing its potentially detrimental effects in health and well-being.

Altered Taste and Stroke: A Case Report and Literature Review

Patients with altered taste perception following stroke are at risk for malnutrition and associated complications that may impede recovery and adversely affect quality of life. Such deficits often induce and exacerbate depressive symptomatology, which can further hamper recovery. It is important for clinicians and rehabilitation specialists to monitor stroke patients for altered taste perception so that this issue can be addressed. The authors present the case of a patient who experienced an isolated ischemic infarct affecting a primary cortical taste area. This case is unusual in that the isolated injury allowed the patient to remain relatively intact cognitively and functionally, and thus able to accurately describe her taste-related deficits. The case is further used to describe the relevant neurological taste pathways and review potential taste-related therapies.

Altered Taste and Stroke: A Case Report and Literature Review

Patients with altered taste perception following stroke are at risk for malnutrition and associated complications that may impede recovery and adversely affect quality of life. Such deficits often induce and exacerbate depressive symptomatology, which can further hamper recovery. It is important for clinicians and rehabilitation specialists to monitor stroke patients for altered taste perception so that this issue can be addressed. The authors present the case of a patient who experienced an isolated ischemic infarct affecting a primary cortical taste area. This case is unusual in that the isolated injury allowed the patient to remain relatively intact cognitively and functionally, and thus able to accurately describe her taste-related deficits. The case is further used to describe the relevant neurological taste pathways and review potential taste-related therapies.

Genetic variation in TAS1R2 taste receptor and sweet taste perception and sugar intake

Taste is one of the primary determinants of food intake and variation in genes affecting taste pathways may influence taste perception and food intake. The TAS1R2 protein is part of the putative TAS1R2/TAS1R3 sweet taste receptor and likely plays a primary role in detecting sugars. Our objective was to determine whether single nucleotide polymorphisms (SNPs) in the TAS1R2 gene affect sweet (sucrose) taste (n = 95) and intake of sugars (n=535). Sucrose taste thresholds were determined using a 3 alternative forced choice staircase model with solutions ranging from 9 ×10−6 to 0.5 mol/L. Genotypes for 23 SNPs in the TAS1R2 gene were extracted from an Affymetrix 6.0 chip. Sucrose and total sugar intake was calculated using a 196 item semi‐quantitative food frequency questionnaire. A general linear model was used to compute differences between genotypes. The rs12075191 (A>G) SNP was associated with sucrose taste and intake. Carriers of the A allele had lower taste thresholds (7.00 ± 1.65 vs 9.27 ± 0.63 mmol/L, p=0.058), lower total sugar intake (111.2 ± 7.3 vs 125.9 ± 2.4 grams, p = 0.05) and lower sucrose intake(41.1 ± 3.4 vs 48.7 ± 1.1 grams, p=0.03) than TT homozygotes. These results show that the rs12075191 SNP in the TAS1R2 gene modifies both sweet taste perception and sugar intake.Grant Funding Source : The Advanced Food and Materials Network

Orosensory and Homeostatic Functions of the Insular Taste Cortex.

The gustatory aspect of the insular cortex is part of the brain circuit that controls ingestive behaviors based on chemosensory inputs. However, the sensory properties of foods are not restricted to taste and should also include salient features such as odor, texture, temperature, and appearance. Therefore, it is reasonable to hypothesize that specialized circuits within the central taste pathways must be involved in representing several other oral sensory modalities in addition to taste. In this review, we evaluate current evidence indicating that the insular gustatory cortex functions as an integrative circuit, with taste-responsive regions also showing heightened sensitivity to olfactory, somatosensory, and even visual stimulation. We also review evidence for modulation of taste-responsive insular areas by changes in physiological state, with taste-elicited neuronal responses varying according to the nutritional state of the organism. We then examine experimental support for a functional map within the insular cortex that might reflect the various sensory and homeostatic roles associated with this region. Finally, we evaluate the potential role of the taste insular cortex in weight-gain susceptibility. Taken together, the current experimental evidence favors the view that the insular gustatory cortex functions as an orosensory integrative system that not only enables the formation of complex flavor representations but also mediates their modulation by the internal state of the body, playing therefore a central role in food intake regulation.

Peripheral, central and behavioral responses to the cuticular pheromone bouquet in Drosophila melanogaster males.

Pheromonal communication is crucial with regard to mate choice in many animals including insects. Drosophila melanogaster flies produce a pheromonal bouquet with many cuticular hydrocarbons some of which diverge between the sexes and differently affect male courtship behavior. Cuticular pheromones have a relatively high weight and are thought to be — mostly but not only — detected by gustatory contact. However, the response of the peripheral and central gustatory systems to these substances remains poorly explored. We measured the effect induced by pheromonal cuticular mixtures on (i) the electrophysiological response of peripheral gustatory receptor neurons, (ii) the calcium variation in brain centers receiving these gustatory inputs and (iii) the behavioral reaction induced in control males and in mutant desat1 males, which show abnormal pheromone production and perception. While male and female pheromones induced inhibitory-like effects on taste receptor neurons, the contact of male pheromones on male fore-tarsi elicits a long-lasting response of higher intensity in the dedicated gustatory brain center. We found that the behavior of control males was more strongly inhibited by male pheromones than by female pheromones, but this difference disappeared in anosmic males. Mutant desat1 males showed an increased sensitivity of their peripheral gustatory neurons to contact pheromones and a behavioral incapacity to discriminate sex pheromones. Together our data indicate that cuticular hydrocarbons induce long-lasting inhibitory effects on the relevant taste pathway which may interact with the olfactory pathway to modulate pheromonal perception.

Temporal coding of taste in the parabrachial nucleus of the pons of the rat

Recent studies have provided evidence that temporal coding contributes significantly to encoding taste stimuli at the first central relay for taste, the nucleus of the solitary tract (NTS). However, it is not known whether this coding mechanism is also used at the next synapse in the central taste pathway, the parabrachial nucleus of the pons (PbN). In the present study, electrophysiological responses to taste stimuli (sucrose, NaCl, HCl, and quinine) were recorded from 44 cells in the PbN of anesthetized rats. In 29 cells, the contribution of the temporal characteristics of the response to the discrimination of various taste qualities was assessed. A family of metrics that quantifies the similarity of two spike trains in terms of spike count and spike timing was used. Results showed that spike timing in 14 PbN cells (48%) conveyed a significant amount of information about taste quality, beyond what could be conveyed by spike count alone. In another 14 cells (48%), the rate envelope (time course) of the response contributed significantly more information than spike count alone. Across cells there was a significant correlation (r = 0.51; P < 0.01) between breadth of tuning and the proportion of information conveyed by temporal dynamics. Comparison with previous data from the NTS (Di Lorenzo PM and Victor JD. J Neurophysiol 90: 1418-31, 2003 and J Neurophysiol 97: 1857-1861, 2007) showed that temporal coding in the NTS occurred in a similar proportion of cells and contributed a similar fraction of the total information at the same average level of temporal precision, even though trial-to-trial variability was higher in the PbN than in the NTS. These data suggest that information about taste quality conveyed by the temporal characteristics of evoked responses is transmitted with high fidelity from the NTS to the PbN.

Triphenylphosphine Oxide Is a Potent and Selective Inhibitor of the Transient Receptor Potential Melastatin-5 Ion Channel

Transient receptor potential melastatin-5 (TRPM5) is a calcium-gated monovalent cation channel expressed in highly specialized cells of the taste bud and gastrointestinal tract, as well as in pancreatic β-cells. Well established as a critical signaling protein for G protein-coupled receptor-mediated taste pathways, TRPM5 also has recently been implicated as a regulator of incretin and insulin secretion. To date, no inhibitors of practical use have been described that could facilitate investigation of TRPM5 functions in taste or secretion of metabolic hormones. Using recombinant TRPM5-expressing cells in a fluorescence imaging plate reader-based membrane potential assay, we identified triphenylphosphine oxide (TPPO) as a selective and potent inhibitor of TRPM5. TPPO inhibited both human (IC₅₀ = 12 μM) and murine TRPM5 (IC₅₀ = 30 μM) heterologously expressed in HEK293 cells, but had no effect (up to 100 μM) on the membrane potential responses of TRPA1, TRPV1, or TRPM4b. TPPO also inhibited a calcium-gated TRPM5-dependent conductance in taste cells isolated from the tongues of transgenic TRPM5(+/)⁻ mice. In contrast, TPP had no effect on TRPM5 responses, indicating a strict requirement of the oxygen atom for activity. Sixteen additional TPPO derivatives also inhibited TRPM5 but none more potently than TPPO. Structure-activity relationship of tested compounds was used for molecular modeling-based analysis to clarify the positive and negative structural contributions to the potency of TPPO and its derivatives. TPPO is the most potent TRPM5 inhibitor described to date and is the first demonstrated to exhibit selectivity over other channels.

Taste Genes Associated with Dental Caries

Dental caries is influenced by a complex interplay of genetic and environmental factors, including dietary habits. Previous reports have characterized the influence of genetic variation on taste preferences and dietary habits. We therefore hypothesized that genetic variation in taste pathway genes (TAS2R38, TAS1R2, GNAT3) may be associated with dental caries risk and/or protection. Families were recruited by the Center for Oral Health Research in Appalachia (COHRA) for collection of biological samples, demographic data, and clinical assessment of oral health, including caries scores. Multiple single-nucleotide polymorphism (SNP) assays for each gene were performed and analyzed by transmission disequilibrium test (TDT) analysis (FBAT software) for three dentition groups: primary, mixed, and permanent. Statistically significant associations were seen in TAS2R38 and TAS1R2 for caries risk and/or protection.

Effects of Aging on the Human Taste System

Losses in taste perception as well as distortions of gustatory function occur with greater frequency in older individuals, and these changes are exacerbated by certain medical conditions, pharmacologic interventions, radiation, and exposure to toxic chemicals. Medications, especially drug-drug interactions, are the most significant yet underappreciated contributors to taste disorders in the elderly. Taste disorders frequently occur when the fraction of an orally administered drug dose that reaches the systemic circulation is markedly increased due to inhibition (by a coadministered drug) of the efflux transporter P-glycoprotein and/or inhibition of the cytochrome P450 metabolism system, which normally limit systemic availability of drugs. The supratherapeutic plasma drug concentrations that result from drug-drug interactions can induce a taste from the blood side of taste cells (intravascular taste), alter taste cell biochemistry, and/or modify other aspects of the taste pathways.

Nicotine activates TRPM5-dependent and independent taste pathways

The orosensory responses elicited by nicotine are relevant for the development and maintenance of addiction to tobacco products. However, although nicotine is described as bitter tasting, the molecular and neural substrates encoding the taste of nicotine are unclear. Here, rats and mice were used to determine whether nicotine activates peripheral and central taste pathways via TRPM5-dependent mechanisms, which are essential for responses to other bitter tastants such as quinine, and/or via nicotinic acetylcholine receptors (nAChRs). When compared with wild-type mice, Trpm5(-/-) mice had reduced, but not abolished, chorda tympani (CT) responses to nicotine. In both genotypes, lingual application of mecamylamine, a nAChR-antagonist, inhibited CT nerve responses to nicotine and reduced behavioral responses of aversion to this stimulus. In accordance with these findings, rats were shown to discriminate between nicotine and quinine presented at intensity-paired concentrations. Moreover, rat gustatory cortex (GC) neural ensemble activity could also discriminate between these two bitter tastants. Mecamylamine reduced both behavioral and GC neural discrimination between nicotine and quinine. In summary, nicotine elicits taste responses through peripheral TRPM5-dependent pathways, common to other bitter tastants, and nAChR-dependent and TRPM5-independent pathways, thus creating a unique sensory representation that contributes to the sensory experience of tobacco products.

Types of taste circuits synaptically linked to a few geniculate ganglion neurons.

The present study evaluates the central circuits that are synaptically engaged by very small subsets of the total population of geniculate ganglion cells to test the hypothesis that taste ganglion cells are heterogeneous in terms of their central connections. We used transsynaptic anterograde pseudorabies virus labeling of fungiform taste papillae to infect single or small numbers of geniculate ganglion cells, together with the central neurons with which they connect, to define differential patterns of synaptically linked neurons in the taste pathway. Labeled brain cells were localized within known gustatory regions, including the rostral central subdivision (RC) of the nucleus of the solitary tract (NST), the principal site where geniculate axons synapse, and the site containing most of the cells that project to the parabrachial nucleus (PBN) of the pons. Cells were also located in the rostral lateral NST subdivision (RL), a site of trigeminal and sparse geniculate input, and the ventral NST (V) and medullary reticular formation (RF), a caudal brainstem pathway leading to reflexive oromotor functions. Comparisons among cases, each with a random, very small subset of labeled geniculate neurons, revealed "types" of central neural circuits consistent with a differential engagement of either the ascending or the local, intramedullary pathway by different classes of ganglion cells. We conclude that taste ganglion cells are heterogeneous in terms of their central connectivity, some engaging, predominantly, the ascending "lemniscal," taste pathway, a circuit associated with higher order discriminative and homeostatic functions, others engaging the "local," intramedullary "reflex" circuit that mediates ingestion and rejection oromotor behaviors.

Gustatory Neural Circuitry in the Hamster Brain Stem

The nucleus of the solitary tract (NST) and the parabrachial nuclei (PbN) are the first and second central relays for the taste pathway, respectively. Taste neurons in the NST project to the PbN, which further transmits taste information to the rostral taste centers. Nevertheless, details of the neural connections among the brain stem gustatory nuclei are obscure. Here, we investigated these relationships in the hamster brain stem. Three electrode assemblies were used to record the activity of taste neurons extracellularly and then to electrically stimulate these same areas in the order: left PbN, right PbN, and right NST. A fourth electrode, a glass micropipette, was used to record from gustatory cells in the left NST. Results showed extensive bilateral communication between brain stem nuclei at the same level: 1) 10% of 96 NST neurons projected to the contralateral NST and 58% received synaptic input from the contralateral NST; and 2) 12% of 43 PbN neurons projected to the contralateral PbN and 21% received synaptic input from the contralateral PbN. Results also showed extensive communication between levels: 1) as expected, the majority of 119 NST neurons, 82%, projected to the ipsilateral PbN, but 85% of the 20 NST neurons tested received synaptic input from the ipsilateral PbN, as did 59% of 22 NST neurons that did not project to the PbN; and 2) although few, 3%, of 119 NST cells projected to the contralateral PbN and 38% received synaptic input from the contralateral PbN. These results demonstrated that taste neurons in the NST not only project to, but also receive descending input from the bilateral PbN and that gustatory neurons in the NST and PbN also communicate with the corresponding nucleus on the contralateral side.

Sugar Substitutes Linked to Weight Gain

ALTHOUGH LOW-CALORIE SWEETeners are a dietary staple for many individuals trying to maintain or lose weight, an emerging body of evidence suggests these substances offer little help to dieters and may even help promote weight gain. A 2007 review found that laboratory, epidemiological, and clinical studies examining effects of low-calorie sweeteners presented an unclear picture of their usefulness (Bellisle F and Drewnowski A. Eur J Clin Nutr. 2007; 61[6]:691-700). Because the scientific findings are mixed, there is currently no official recommendation about using artificial sweeteners as a tool for weight control. However, some studies have suggested that low-calorie sweeteners may actually increase appetite for sweet foods, promote overeating, and lead to weight gain. Recent findings lend further support to this theory, demonstrating that artificial sweeteners blunt the body’s energy expenditure mechanisms and activate taste pathways differently than sucrose—findings that might prompt dieters to rethink their weight-loss strategies.

Sucrose activates human taste pathways differently from artificial sweetener

Animal models suggest that sucrose activates taste afferents differently than non-caloric sweeteners. Little information exists how artificial sweeteners engage central taste pathways in the human brain. We assessed sucrose and sucralose taste pleasantness across a concentration gradient in 12 healthy control women and applied 10% sucrose and matched sucralose during functional magnet resonance imaging. The results indicate that (1) both sucrose and sucralose activate functionally connected primary taste pathways; (2) taste pleasantness predicts left insula response; (3) sucrose elicits a stronger brain response in the anterior insula, frontal operculum, striatum and anterior cingulate, compared to sucralose; (4) only sucrose, but not sucralose, stimulation engages dopaminergic midbrain areas in relation to the behavioral pleasantness response. Thus, brain response distinguishes the caloric from the non-caloric sweetener, although the conscious mind could not. This could have important implications on how effective artificial sweeteners are in their ability to substitute sugar intake.