High salt recruits aversive taste pathways

Howard Hughes Medical Institute and Department of Biochemistry and Molecular Biophysics, Columbia College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Nature (Impact Factor: 41.46). 02/2013; 494(7438):472-5. DOI: 10.1038/nature11905
Source: PubMed


In the tongue, distinct classes of taste receptor cells detect the five basic tastes; sweet, sour, bitter, sodium salt and umami. Among these qualities, bitter and sour stimuli are innately aversive, whereas sweet and umami are appetitive and generally attractive to animals. By contrast, salty taste is unique in that increasing salt concentration fundamentally transforms an innately appetitive stimulus into a powerfully aversive one. This appetitive-aversive balance helps to maintain appropriate salt consumption, and represents an important part of fluid and electrolyte homeostasis. We have shown previously that the appetitive responses to NaCl are mediated by taste receptor cells expressing the epithelial sodium channel, ENaC, but the cellular substrate for salt aversion was unknown. Here we examine the cellular and molecular basis for the rejection of high concentrations of salts. We 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 behavioural aversion to concentrated salt, without impairing salt attraction. Notably, mice devoid of salt-aversion pathways show unimpeded, continuous attraction even to very 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 behavioural rejection, thus preventing its potentially detrimental effects on health.

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    • "However, when denied a choice (involuntary drinking), naïve rats consumed large volumes of both IS and HS (Fig. 1D, E). The increase in HS intake likely results from a suppression of the taste response to HS, overriding the normal aversive behaviour, making salty solutions more palatable [13], [32]. This capacity to drink HS in an involuntary situation is vital for survival. "
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    ABSTRACT: 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.
    PLoS ONE 08/2014; 9(8):e104802. DOI:10.1371/journal.pone.0104802 · 3.23 Impact Factor
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    • "Previous reports suggest that the peripheral sensitivity to bitter and phagostimulatory compounds play a role in evoking an aversive or appetitive feeding behaviour, both in invertebrates and vertebrates, including humans [14], [16], [46]. In a comparative study between two related species of Heliothis (Lepidoptera: Noctuidae), one generalist and one specialist, Bernays et al. [1] examined behaviourally the sensitivity of caterpillars to several bitter compounds and they found that all compounds reduced feeding, but the generalist was less affected than the specialist. "
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    ABSTRACT: In herbivorous insects, food selection depends on sensitivity to specific chemical stimuli from host-plants as well as to secondary metabolites (bitter) and to sugars (phagostimulatory). Bitter compounds are noxious, unpalatable or both and evoke an aversive feeding response. Instead, sugars and sugar alcohols play a critical role in determining and enhancing the palatability of foods. We assumed that peripheral taste sensitivity may be related to the width of the host selection. Our model consists of two closely phylogenetically related Papilionid species exhibiting a difference in host plant choice: Papilio hospiton and Papilio machaon. The spike activity of the lateral and medial maxillary styloconic taste sensilla was recorded following stimulation with several carbohydrates, nicotine and NaCl, with the aim of characterizing their gustatory receptor neurons and of comparing their response patterns in the light of their different acceptability in feeding behaviour. The results show that: a) each sensillum houses phagostimulant and phagodeterrent cells; b) the spike activity of the gustatory neurons in response to different taste stimuli is higher in P. hospiton than in P. machaon; c) sugar solutions inhibit the spike activity of the deterrent and salt cells, and the suppression is higher in P. machaon than in P. hospiton. In conclusion, we propose that the different balance between the phagostimulant and phagodeterrent inputs from GRNs of maxillary sensilla may contribute in determining the difference in food choice and host range.
    PLoS ONE 06/2014; 9(6):e100675. DOI:10.1371/journal.pone.0100675 · 3.23 Impact Factor
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    • "These results provide additional support for a link between TRPV1t and salt taste in humans. At high concentration NaCl is aversive (>500 mM) and is sensed by two aversive pathways localized in bitter and sour sensing TRCs [24]. "
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    ABSTRACT: 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 Ca(2+)-flux signaling assay in cultured cells. NGCC enhanced Ca(2+) influx in hTRPV1-expressing cells in a dose-dependent manner (EC50 = 115 µM). NGCC-induced Ca(2+) 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 Ca(2+) influx in hTRPA1-expressing cells (EC50 = 83.65 µM). The NGCC-induced Ca(2+) 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.
    PLoS ONE 02/2014; 9(2):e89062. DOI:10.1371/journal.pone.0089062 · 3.23 Impact Factor
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