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Insights into the biological basis for mammalian taste quality coding began with electrophysiological recordings from "taste" nerves and this technique continues to produce essential information today. Chorda tympani (geniculate ganglion) neurons, which are particularly involved in taste quality discrimination, are specialists or generalists. Specialists respond to stimuli characterized by a single taste quality as defined by behavioral cross-generalization in conditioned taste tests. Generalists respond to electrolytes that elicit multiple aversive qualities. Na(+)-salt (N) specialists in rodents and sweet-stimulus (S) specialists in multiple orders of mammals are well characterized. Specialists are associated with species' nutritional needs and their activation is known to be malleable by internal physiological conditions and contaminated external caloric sources. S specialists, associated with the heterodimeric G-protein coupled receptor T1R, and N specialists, associated with the epithelial sodium channel ENaC, are consistent with labeled line coding from taste bud to afferent neuron. Yet, S-specialist neurons and behavior are less specific than T1R2-3 in encompassing glutamate and E generalist neurons are much less specific than a candidate, PDK TRP channel, sour receptor in encompassing salts and bitter stimuli. Specialist labeled lines for nutrients and generalist patterns for aversive electrolytes may be transmitting taste information to the brain side by side. However, specific roles of generalists in taste quality coding may be resolved by selecting stimuli and stimulus levels found in natural situations. T2Rs, participating in reflexes via the glossopharynygeal nerve, became highly diversified in mammalian phylogenesis as they evolved to deal with dangerous substances within specific environmental niches. Establishing the information afferent neurons traffic to the brain about natural taste stimuli imbedded in dynamic complex mixtures will ultimately "crack taste codes."

Among well-nourished populations, eating beyond homeostatic needs when presented with caloric-dense palatable food evidences the assertion that an increasing proportion of consumption is driven by pleasure, not just by the need for calories. This presents a major health crisis because the affective component of foods constitutes a behavioral risk factor that promotes over consumption [Sorensen, L.B., Moller, P., Flint, A., Martens, M., Raben, A., 2003. Effect of sensory perception of foods on appetite and food intake: a review of studies on humans. Int. J. Obes. Relat. Metab. Disord. 27, 1152-1166; Yeomans, M.R., Blundell, J.E., Leshem, M., 2004. Palatability: response to nutritional need or need-free stimulation of appetite? Br. J. Nutr. 92 (Suppl. 1), S3-S14]. Overweight or obese individuals have an increased risk of developing hypertension, stroke, heart disease, chronic musculoskeletal problems, type-2 diabetes, and certain types of cancers [Hill, J.O., Catenacci, V., Wyatt, H.R., 2005. Obesity: overview of an epidemic. Psychiatr. Clin. N. Am. 28, 1-23, vii]. The etiology of obesity is complex involving genetic, metabolic, and behavioral factors, but ultimately results from long-term energy imbalance. Evidence indicates that learned and some forms of unlearned control of ingestive behavior driven by palatability (i.e. hedonic value) are critically dependent on reciprocal interactions between brainstem gustatory nuclei and the ventral forebrain. This review discusses the current understanding of centrifugal control of taste processing in subcortical gustatory nuclei and the potential role of such modulation in hedonic responding.

For humans and rodents, ingesting sucrose is rewarding. This experiment tested the prediction that the neural activity produced by sapid sucrose reaches reward systems via projections from the pons through the limbic system. Gastric cannulas drained ingested fluid before absorption. For 10 days, the rats alternated an hour of this sham ingestion between sucrose and water. On the final test day, half of them sham drank water and the other half 0.6 M sucrose. Thirty minutes later, the rats were killed and their brains immunohistochemically stained for Fos. The groups consisted of controls and rats with excitotoxic lesions in the gustatory thalamus (TTA), the medial (gustatory) parabrachial nucleus (PBN), or the lateral (visceral afferent) parabrachial nucleus. In controls, compared with water, sham ingesting sucrose produced significantly more Fos-positive neurons in the nucleus of the solitary tract, PBN, TTA, and gustatory cortex (GC). In the ventral forebrain, sucrose sham licking increased Fos in the bed nucleus of the stria terminalis, central nucleus of amygdala, and the shell of nucleus accumbens. Thalamic lesions blocked the sucrose effect in GC but not in the ventral forebrain. After lateral PBN lesions, the Fos distributions produced by distilled H(2)O or sucrose intake did not differ from controls. Bilateral medial PBN damage, however, eliminated the sucrose-induced Fos increase not only in the TTA and GC but also in the ventral forebrain. Thus ventral forebrain areas associated with affective responses appear to be activated directly by PBN gustatory neurons rather than via the thalamocortical taste system.

The efficacy of two different unconditioned stimuli (US) in producing conditioned taste aversion (CTA) was tested in rats after bilateral ibotenic acid (IBO) lesions of the gustatory nucleus of thalamus (TTAx) and the medial and lateral parabrachial nuclei (mPBNx, lPBNx). An initial study determined an equivalent dose for the two USs, LiCl and cyclophosphamide (CY), using non-lesioned rats. Subsequently, using a separate set of lesioned animals and their sham controls (SHAM), injections of CY were paired 3 times with one of two taste stimuli (CSs), 0.1 M NaCl for half the rats in each group, 0.2 M sucrose for the other half. After these conditioning trials, the CS was presented twice more without the US, first in a 1-bottle test, then in a 2-bottle choice with water. The acquisition and test trials had 2 intervening water-only days to assure complete rehydration. Two weeks later, the same rats were tested again for acquisition of a CTA using LiCl as the US and the opposite CS as that used during the CY trials. The SHAM and TTAx groups learned to avoid consuming the taste associated with either CY or LiCl treatment. The two PBNx groups failed to learn an aversion regardless of the US.

Furosemide (Furo) is a potent natriuretic drug that is often used experimentally to investigate the brain mechanisms underlying salt appetite. Within this experimental paradigm, however, Furo also has anorectic activity that has received only modest attention. In Experiment 1 we varied two things-administering a 10-mg dose of Furo in a single or a divided dose and preinjection exposure to a Na-free diet. In the 24 h after Furo, all four groups of rats reduced ingestion of Na-free diet. Both the division of the Furo dose and the preexposure to Na-free diet reduced the amount of food consumed even more than a single dose or continuous access to normal chow did. The fact that preexposure to Na-free diet increased the post-Furo anorexia implied an associative component to the phenomenon. Experiments 2 and 3 investigated the ability of Furo (2 and 10 mg) to serve as an unconditioned stimulus in taste aversion learning using 0.2 M sucrose as the conditioned stimulus. A saline (Sal) injection group served as control in both experiments. The results show that animals avoided sucrose when its ingestion was immediately followed by 10 mg Furo but not with 2 mg Furo or Sal. An aversion to sucrose did not develop when 10 mg Furo was administered the day prior to sucrose access. Thus, the suppressive effects of high-dose Furo on food intake might be due to a conditioned response.

Evidence suggests that centrifugal modulation of brain stem gustatory cells might play a role in the elaboration of complex taste-guided behaviors like conditioned taste aversion and sodium appetite. We previously showed that activity in one forebrain area, the central nucleus of the amygdala (CeA), increased the chemical selectivity of taste cells in the parabrachial nucleus (PBN). The present study investigates how activity in 2 other similarly interconnected forebrain sites, the lateral hypothalamus (LH) and gustatory cortex (GC), might influence PBN gustatory processing in rats. The potential convergence of descending inputs from these sites, as well as the CeA, was also evaluated. After anesthesia (35 mg/kg Nembutal ip), 70 PBN gustatory neurons were tested before, during, and after electrical stimulation of these forebrain sites, while responding to 0.3 M sucrose, 0.1 M NaCl, 0.01 M citric acid, and 0.003 M QHCl. Although each forebrain site modulated taste-evoked responses, more PBN neurons were influenced by stimulation of the GC (67%) and CeA (73%) than of the LH (48%). Activation of cortex (71%) and amygdala (85%) most often produced inhibition, whereas inhibition and excitation occurred equally often during hypothalamic stimulation. Of the neurons tested for convergence (n = 60), 88% were influenced by > or =1 of the 3 sites. Twenty were modulated by stimulation at all 3 sites and another 17 by 2 of the 3 sites. The net effect of centrifugal modulation was to sharpen the across-stimulus response profiles of PBN cells, particular with regard to the NaCl- and citric acid-best cells.

Sodium appetite is often produced experimentally by using the diuretic furosemide (Furo) to induce a rapid loss of urinary sodium. The present experiments were designed to investigate the dose-dependent relationship between renal and behavioral responses to Furo. We compared the effects of five different Furo doses (0.5, 1, 2, 6, and 10 mg) on 3% NaCl intake, water intake, Na(+)-free chow intake, urine quantity, electrolyte balance, and weight gain in rats. The Na(+) loss produced by Furo injection was dose dependent from 0.5 to 10 mg and did not change across repeated depletions. There was only a weak correspondence, however, between these dose-dependent changes in renal function and subsequent sodium appetite. This suggests that net Na(+) loss is not the only determinant of sodium intake. Moreover, at the two higher doses of Furo, both food intake and weight dropped significantly, but these did not change following the three lower ones. Given these substantial side effects, the preferred dose of Furo for inducing a salt appetite should not exceed 2.0 mg.

Visceral signals and experience modulate the responses of brain stem neurons to gustatory stimuli. Both behavioral and anatomical evidence suggests that this modulation may involve descending input from the forebrain. The present study investigates the centrifugal control of gustatory neural activity in the parabrachial nucleus (PBN). Extracellular responses were recorded from 51 single PBN neurons during application of sucrose, NaCl, NaCl mixed with amiloride, citric acid, and QHCl with or without concurrent electrical stimulation in the ipsilateral central nucleus of the amygdala (CeA). Based on the sapid stimulus that evoked the greatest discharge, 3 neurons were classified as sucrose-best, 32 as NaCl-best, and 16 as citric acid-best. In most of the neurons sampled, response rates to an effective stimulus were either inhibited or unchanged during electrical stimulation of the CeA. Stimulation in the CeA was without effect in two sucrose-best neurons, nine NaCl-best neurons, and one citric acid-best neuron. Suppression was evident in 1 sucrose-best neuron, 18 NaCl-best neurons, and 15 citric acid-best neurons. In NaCl-best neurons inhibited by CeA stimulation, the magnitude of the effect was similar for spontaneous activity and responses to the five taste stimuli. Nonetheless, the inhibitory modulation of gustatory sensitivity increased the relative effectiveness of NaCl resulting in narrower chemical selectivity. For citric acid-best neurons, the magnitude of inhibition produced by CeA activation increased with an increase in stimulus effectiveness. The responses to citric acid were inhibited significantly more than the responses to all other stimuli with the exception of NaCl mixed with amiloride. The overall effect was to change these CA-best neurons to CA/NaCl-best neurons. In a smaller subset of NaCl-best neurons (n = 5), CeA stimulation augmented the responsiveness to NaCl but was without effect on the other stimuli or on baseline activity. It appears that electrical stimulation in the CeA modulates response intensity, as well as the type of gustatory information that is transmitted in a subset of NaCl-best neurons. These findings provide an additional link between the amygdala and the PBN in the control of NaCl intake, modulating the response and the chemical selectivity of an amiloride-sensitive Na+ detecting input pathway.

We used extracellular single-cell recording procedures to characterize the chemical and thermal sensitivity of the rat geniculate ganglion to lingual stimulation, and to examine the effects of specific ion transport antagonists on salt transduction mechanisms. Hierarchical cluster analysis of the responses from 73 single neurons to 3 salts (0.075 and 0.3 M NaCl, KCl, and NH(4) Cl), 0.5 M sucrose, 0.01 M HCl, and 0.02 M quinine HCl (QHCl) indicated 3 main groups that responded best to either sucrose, HCl, or NaCl. Eight narrowly tuned neurons were deemed sucrose-specialists and 33 broadly tuned neurons as HCl-generalists. The NaCl group contained three identifiable subclusters: 18 NaCl-specialists, 11 NaCl-generalists, and 3 QHCl-generalists. Sucrose- and NaCl-specialists responded specifically to sucrose and NaCl, respectively. All generalist neurons responded to salt, acid, and alkaloid stimuli to varying degree and order depending on neuron type. Response order was NaCl > HCl = QHCl > sucrose in NaCl-generalists, HCl > NaCl > QHCl > sucrose in HCl-generalists, and QHCl = NaCl = HCl > sucrose in QHCl-generalists. NaCl-specialists responded robustly to low and high NaCl concentrations, but weakly, if at all, to high KCl and NH(4) Cl concentrations after prolonged stimulation. HCl-generalist neurons responded to all three salts, but at twice the rate to NH(4) Cl than to NaCl and KCl. NaCl- and QHCl-generalists responded equally to the three salts. Amiloride and 5-(N,N-dimethyl)-amiloride (DMA), antagonists of Na(+) channels and Na(+)/H(+) exchangers, respectively, inhibited the responses to 0.075 M NaCl only in NaCl-specialist neurons. The K(+) channel antagonist, 4-aminopyridine (4-AP), was without a suppressive effect on salt responses, but, when applied alone in solution, it evoked a response in many HCl-generalists and one QHCl-generalist neuron so tested. Of the 39 neurons tested for their sensitivity to temperature, 23 responded to cooling and chemical stimulation, and 20 of these neurons were HCl-generalists. Moreover, the responses to the four standard stimuli were reduced progressively at lower temperatures in HCl- and QHCl-generalist neurons, but not in NaCl-specialists. Thus sodium channels and Na(+)/H(+) exchangers appear to be expressed exclusively on the membranes of receptor cells that synapse with NaCl-specialist neurons. In addition, cooling sensitivity and taste-temperature interactions appear to be prominent features of broadly tuned neuron groups, particularly HCl-generalists. Taken all together, it appears that lingual taste cells make specific connections with afferent fibers that allow gustatory stimuli to be parceled into different input pathways. In general, these neurons are organized physiologically into specialist and generalist types. The sucrose- and NaCl-specialists alone can provide sufficient information to distinguish sucrose and NaCl from other stimuli, respectively.

Sodium is an essential nutrient for life, and its level in the body is tightly regulated. When sodium deficient, some mammals alter their behavior towards salt by avidly consuming it, even at concentrations animals typically choose to avoid. This change in acceptance is accompanied by a reduction in the response of the gustatory chorda tympani nerve to sodium solutions. More specifically, the response rate of the sodium-specialist units to NaCl stimulation is reduced following sodium deficiency or adrenalectomy. The initial transduction of the chemical signal is mediated, in part, by Na+ influx through epithelial Na+ channels in the apical membrane of taste cells that synapse with the specialist neurons. Circulating hormones like angiotensin II and adrenocorticotropin hormone, which are released in response to sodium deficiency and adrenalectomy, could regulate the activity of Na+ channels through G-protein linked second-messenger systems. These putative pathways are of interest because they have been described in mammalian taste receptor cells. The present review will summarize evidence linking some hormones of fluid homeostasis with the apparent attenuation of input from sodium-specialist neurons.

The effects of the epithelial Na+ channel antagonists amiloride and benzamil and the Na+/H+ exchange antagonist 5-(N,N-dimethyl)-amiloride (DMA)-Cl on the integrated responses of the chorda tympani nerve to 30, 75, 150, 300, and 500 mM concentrations of NaCl, KCl, and NH4Cl were assessed in male Sprague-Dawley rats. Based on evidence from other systems, 1 and 25 microM amiloride and benzamil were chosen to selectively inhibit epithelial Na+ channels and 1 microM DMA was chosen to selectively inhibit Na+/H+ exchange. When added to stimulating salt solutions, amiloride, benzamil, and DMA were each effective in inhibiting responses to all three salts. The degree of inhibition varied with drug, salt, and salt concentration, but not drug dose. Amiloride suppressed NaCl responses to a greater degree than KCl and NH4Cl responses, whereas DMA suppressed NH4Cl responses to a greater degree than NaCl and KCl responses. In all but one case (25 microM amiloride added to KCl), drug suppression of taste nerve responses decreased with an increase in salt concentration. The present results suggest that 1) epithelial Na+ channels in rat taste receptor cells may play a role in KCl and NH4Cl taste transduction; 2) a Na+/H+ exchange protein may be present in taste receptor cells, representing a putative component, in addition to epithelial Na+ channels, in salt taste transduction; and 3) salt taste detection and transduction may depend on the utilization of a combination of common and distinct transcellular pathways.

The effects of adaptation/stimulus temperature (25 degrees C vs. 35 degrees C) on taste nerve responses to salt stimulation and amiloride suppression were assessed in rats. We measured the integrated responses of the chorda tympani nerve to 500 mM concentrations of NaCl, Na2SO4, sodium acetate (NaAc), KCl, K2SO4, potassium acetate (KAc), NH4Cl, (NH4)2SO4, and ammonium acetate (NH4Ac) mixed with or without 100 microM amiloride hydrochloride at 35 degrees C. Taste nerve responses to all Na+ and NH4+ salts, but not K/ salts, were significantly smaller at 25 degrees C than at 35 degrees C. Amiloride significantly suppressed taste nerve responses to all salts (Na+ salts > K+ salts > NH4+ salts); amiloride suppression of Na+ and NH4+ salts was significantly greater at 25 degrees C than at 35 degrees C. Benzamil-HCl, a more potent Na+ channel blocker compared to amiloride, strongly suppressed taste nerve responses to NaCl and KCl, but not to NH4Cl. Amiloride and benzamil suppression of NaCl responses were similar; however, amiloride suppressed KCl responses more than did benzamil. The results suggest that: (1) amiloride-sensitive Na+ channels are involved to varying degrees in the transduction of sodium and potassium salt taste, and (2) amiloride may inhibit membrane proteins other than passive Na+ channels during stimulation with potassium and ammonium salts.

In a two-bottle test, Sprague-Dawley rats preferentially consume a greater amount of hypotonic and isotonic NaCl solutions relative to water, whereas inbred Fischer 344 (F344) rats fail to prefer NaCl solutions at any concentration relative to water. To determine whether taste contributes to this strain difference, we measured the integrated neural responses of the chorda tympani nerve to a concentration range of NaCl and KCl solutions. The amiloride-sensitive component of the taste nerve response was assessed by adding amiloride during salt stimulation in Experiment 1, and by pretreating the taste receptors with amiloride prior to salt stimulation in Experiment 2. Adding amiloride to NaCl during sustained neural activity suppressed chorda tympani nerve responses more than pretreating the tongue with amiloride. Adding amiloride during salt stimulation also partially suppressed chorda tympani neuron responses to KCl, a presumed control stimulus. The neural responses of the chorda tympani nerve to NaCl and KCl were similar for salt-avoiding F344 and salt-preferring Sprague-Dawley rats. However, amiloride pretreatment suppressed the taste nerve responses to NaCl significantly less in F344 rats than in Sprague-Dawley rats. The strain difference in the amiloride-sensitive component of the taste response may contribute to the difference in NaCl preference.

Menthol, a tangible substance present in many orally administered products, can produce a powerful influence on the perceived intensity of subsequent thermal stimulation in humans as well as the response magnitudes of thermally sensitive neurons in rats. However, there are no prior studies examining the influence of adaptation temperature on perceived intensity and/or response magnitudes of thermally sensitive neurons to subsequent menthol stimulation. We identified 32 thermally sensitive neurons that increased their discharge rate to a gradual temperature decrement beginning from 35 degrees C and dropping to 10 degrees C at 1 degree C/s. Based on their response threshold, time-to-peak, and range of sensitivity, these thermally sensitive lingual neurons were found to be divisible into two distinct groups. Group 1 neurons (n = 21) responded best to the upper cool range (34-15 degrees C) of the temperature decrement, whereas Group 2 neurons (n = 11) responded to the lower cold range (32-10 degrees C) of the temperature decrement. Our Group 1 and Group 2 neurons may be analogous to low threshold and high threshold cold receptors identified previously in primates. We also examined the responses of lingual neurons to 0%, 25%, 50% and 75% dilution's of a stock menthol concentration (1.28 mM) at 25 and 35 degrees C adaptation temperatures. Menthol responses across all concentrations were far larger after adaptation to 35 degrees C compared to 25 degrees C. Furthermore, only during 35 degrees C adaptation did responses to menthol stimulation persist during the ensuing 20 s after menthol off-set and water on-set.(ABSTRACT TRUNCATED AT 250 WORDS)

The addition of the coolant menthol to several oral and facial products is to increase their attractiveness and commercial value. Little is, however, known about the physiological basis of menthol's sensory effects. We studied the electrophysiological responses of 45 thermal-sensitive lingual fibers to anterior tongue stimulation (10 s) with menthol in male Sprague-Dawley rats. Menthol responses were unlike the responses to cold water. Cold water (6 degrees C, 15 degrees C) elicited an immediate sustained increase in impulse frequencies of thermal-sensitive fibers adapted to room temperature water (22-24 degrees C). Inhibitory off-responses followed cold water stimulation. Depending on the concentration and time of measurement, menthol stimulation either excited, inhibited, or had no effect on impulse frequencies of thermal-sensitive fibers. Strong menthol (0.64 mM, 1.28 mM) unequivocally excited thermal-sensitive fibers with a response latency of 4-6 s. In most cases after menthol stimulation, the impulse frequencies returned to baseline; there were no off-responses. Weak menthol (0.0128 mM, 0.064 mM, 0.128 mM) inhibited impulse frequencies of 14 thermal-sensitive fibers and excited impulse frequencies of 6 fibers primarily during the first 2 s of stimulation. Menthol responses were also unlike responses to stimulation with taste solutions. Most taste solutions (30 and 100 mM NaCl, 0.3 and 1 mM quinine-HCl, 0.3 mM citric acid) significantly inhibited impulse frequencies but only during the first 2-5 s of stimulation. The effect of NaCl was biphasic with the initial inhibitory phase followed by an excitatory phase during the second 5 s of stimulation. An excitatory off-response followed quinine stimulation. While considered principally a coolant, menthol elicits a unique pattern of responses from trigeminal and taste nerve endings quite unlike those of conventional thermal and taste stimuli.

Electrophysiological recordings of the summated response of the chorda tympani nerve to menthol stimulation of the tongue were obtained from 15 adult Sprague-Dawley rats. The chorda tympani nerve response to menthol was of short duration, ending within 2.5 s after stimulus onset, leaving the receptors in a state of insensitivity to subsequent menthol stimulation. Rinse durations with deionized-distilled water up to 10 min failed to bring the receptors back to their original prestimulus state. Although stimulation with menthol prevented taste receptors from responding to subsequent presentations of menthol, the chorda tympani nerve would respond normally to NaCl, NH4Cl, KCl, sodium acetate, glucose, citric acid, and quinine-HCl solutions. Prior stimulation with one of these taste solutions resulted in the recovery of the menthol response. The magnitude of the recovered menthol response depended on the magnitude of the phasic response elicited by the preceding taste stimulus. A general explanation involving possible reception and transduction mechanisms was offered to account for menthol's unexpected stimulatory effects on the chorda tympani nerve.