Sour Sensing from the Tongue to the Brain.

The ability to sense sour provides an important sensory signal to prevent the ingestion of unripe, spoiled, or fermented foods. Taste and somatosensory receptors in the oral cavity trigger aversive behaviors in response to acid stimuli. Here, we show that the ion channel Otopetrin-1, a proton-selective channel normally involved in the sensation of gravity in the vestibular system, is essential for sour sensing in the taste system. We demonstrate that knockout of Otop1 eliminates acid responses from sour-sensing taste receptor cells (TRCs). In addition, we show that mice engineered to express otopetrin-1 in sweet TRCs have sweet cells that also respond to sour stimuli. Next, we genetically identified the taste ganglion neurons mediating each of the five basic taste qualities and demonstrate that sour taste uses its own dedicated labeled line from TRCs in the tongue to finely tuned taste neurons in the brain to trigger aversive behaviors.

A Taste Circuit that Regulates Ingestion by Integrating Food and Hunger Signals.

Ingestion is a highly regulated behavior that integrates taste and hunger cues to balance food intake with metabolic needs. To study the dynamics of ingestion in the vinegar fly Drosophila melanogaster, we developed Expresso, an automated feeding assay that measures individual meal-bouts with high temporal resolution at nanoliter scale. Flies showed discrete, temporally precise ingestion that was regulated by hunger state and sucrose concentration. We identify 12 cholinergic local interneurons (IN1, for "ingestion neurons") necessary for this behavior. Sucrose ingestion caused a rapid and persistent increase in IN1 interneuron activity in fasted flies that decreased proportionally in response to subsequent feeding bouts. Sucrose responses of IN1 interneurons in fed flies were significantly smaller and lacked persistent activity. We propose that IN1 neurons monitor ingestion by connecting sugar-sensitive taste neurons in the pharynx to neural circuits that control the drive to ingest. Similar mechanisms for monitoring and regulating ingestion may exist in vertebrates.

Physiology of the tongue with emphasis on taste transduction.

The tongue is a complex multifunctional organ that interacts and senses both interoceptively and exteroceptively. Although it is easily visible to almost all of us, it is relatively understudied and what is in the literature is often contradictory or is not comprehensively reported. The tongue is both a motor and a sensory organ: motor in that it is required for speech and mastication, and sensory in that it receives information to be relayed to the central nervous system pertaining to the safety and quality of the contents of the oral cavity. Additionally, the tongue and its taste apparatus form part of an innate immune surveillance system. For example, loss or alteration in taste perception can be an early indication of infection as became evident during the present global SARS-CoV-2 pandemic. Here, we particularly emphasize the latest updates in the mechanisms of taste perception, taste bud formation and adult taste bud renewal, and the presence and effects of hormones on taste perception, review the understudied lingual immune system with specific reference to SARS-CoV-2, discuss nascent work on tongue microbiome, as well as address the effect of systemic disease on tongue structure and function, especially in relation to taste.

Multisensory flavor perception.

The perception of flavor is perhaps the most multisensory of our everyday experiences. The latest research by psychologists and cognitive neuroscientists increasingly reveals the complex multisensory interactions that give rise to the flavor experiences we all know and love, demonstrating how they rely on the integration of cues from all of the human senses. This Perspective explores the contributions of distinct senses to our perception of food and the growing realization that the same rules of multisensory integration that have been thoroughly explored in interactions between audition, vision, and touch may also explain the combination of the (admittedly harder to study) flavor senses. Academic advances are now spilling out into the real world, with chefs and food industry increasingly taking the latest scientific findings on board in their food design.

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 possible role for taste receptor cells in surveying the oral microbiome.

Taste receptor cells are sensory specialists that detect chemicals in food and drink. An exciting new report in PLOS Biology suggests that some taste cells could also be involved in immune surveillance like counterparts in the intestine.

A singular shark bitter taste receptor provides insights into the evolution of bitter taste perception.

Many animal and plant species synthesize toxic compounds as deterrent; thus, detection of these compounds is of vital importance to avoid their ingestion. Often, such compounds are recognized by taste 2 receptors that mediate bitter taste in humans. Until now, bitter taste receptors have only been found in bony vertebrates, where they occur as a large family already in coelacanth, a "living fossil" and the earliest-diverging extant lobe-finned fish. Here, we have revisited the evolutionary origin of taste 2 receptors (T2Rs) making use of a multitude of recently available cartilaginous fish genomes. We have identified a singular T2R in 12 cartilaginous fish species (9 sharks, 1 sawfish, and 2 skates), which represents a sister clade to all bony fish T2Rs. We have examined its ligands for two shark species, a catshark and a bamboo shark. The ligand repertoire of bamboo shark represents a subset of that of the catshark, with roughly similar thresholds. Amarogentin, one of the most bitter natural substances for humans, also elicited the highest signal amplitudes with both shark receptors. Other subsets of ligands are shared with basal bony fish T2Rs indicating an astonishing degree of functional conservation over nearly 500 mya of separate evolution. Both shark receptors respond to endogenous steroids as well as xenobiotic compounds, whereas separate receptors exist for xenobiotics both in early- and late-derived bony vertebrates (coelacanth, zebrafish, and human), consistent with the shark T2R reflecting the original ligand repertoire of the ancestral bitter taste receptor at the evolutionary origin of this family.

A dedicate sensorimotor circuit enables fine texture discrimination by active touch.

Active touch facilitates environments exploration by voluntary, self-generated movements. However, the neural mechanisms underlying sensorimotor control for active touch are poorly understood. During foraging and feeding, Drosophila gather information on the properties of food (texture, hardness, taste) by constant probing with their proboscis. Here we identify a group of neurons (sd-L neurons) on the fly labellum that are mechanosensitive to labellum displacement and synapse onto the sugar-sensing neurons via axo-axonal synapses to induce preference to harder food. These neurons also feed onto the motor circuits that control proboscis extension and labellum spreading to provide on-line sensory feedback critical for controlling the probing processes, thus facilitating ingestion of less liquified food. Intriguingly, this preference was eliminated in mated female flies, reflecting an elevated need for softer food. Our results propose a sensorimotor circuit composed of mechanosensory, gustatory and motor neurons that enables the flies to select ripe yet not over-rotten food by active touch.

Multisensory Integration Underlies the Distinct Representation of Odor-Taste Mixtures in the Gustatory Cortex of Behaving Rats.

The perception of food relies on the integration of olfactory and gustatory signals originating from the mouth. This multisensory process generates robust associations between odors and tastes, significantly influencing the perceptual judgment of flavors. However, the specific neural substrates underlying this integrative process remain unclear. Previous electrophysiological studies identified the gustatory cortex as a site of convergent olfactory and gustatory signals, but whether neurons represent multimodal odor-taste mixtures as distinct from their unimodal odor and taste components is unknown. To investigate this, we recorded single-unit activity in the gustatory cortex of behaving female rats during the intraoral delivery of individual odors, individual tastes, and odor-taste mixtures. Our results demonstrate that chemoselective neurons in the gustatory cortex are broadly responsive to intraoral chemosensory stimuli, exhibiting time-varying multiphasic changes in activity. In a subset of these chemoselective neurons, odor-taste mixtures elicit nonlinear cross-modal responses that distinguish them from their olfactory and gustatory components. These findings provide novel insights into multimodal chemosensory processing by the gustatory cortex, highlighting the distinct representation of unimodal and multimodal intraoral chemosensory signals. Overall, our findings suggest that olfactory and gustatory signals interact nonlinearly in the gustatory cortex to enhance the identity coding of both unimodal and multimodal chemosensory stimuli.

LiCl-induced sickness modulates rat gustatory cortical responses.

Gustatory cortex (GC), a structure deeply involved in the making of consumption decisions, presumably performs this function by integrating information about taste, experiences, and internal states related to the animal's health, such as illness. Here, we investigated this assertion, examining whether illness is represented in GC activity, and how this representation impacts taste responses and behavior. We recorded GC single-neuron activity and local field potentials (LFPs) from healthy rats and rats made ill (via LiCl injection). We show (consistent with the extant literature) that the onset of illness-related behaviors arises contemporaneously with alterations in 7 to 12 Hz LFP power at approximately 12 min following injection. This process was accompanied by reductions in single-neuron taste response magnitudes and discriminability, and with enhancements in palatability-relatedness-a result reflecting the collapse of responses toward a simple "good-bad" code visible in the entire sample, but focused on a specific subset of GC neurons. Overall, our data show that a state (illness) that profoundly reduces consumption changes basic properties of the sensory cortical response to tastes, in a manner that can easily explain illness' impact on consumption.

Meeting a threat of the Anthropocene: Taste avoidance of metal ions by Drosophila.

The Anthropocene Epoch poses a critical challenge for organisms: they must cope with new threats at a rapid rate. These threats include toxic chemical compounds released into the environment by human activities. Here, we examine elevated concentrations of heavy metal ions as an example of anthropogenic stressors. We find that the fruit fly Drosophila avoids nine metal ions when present at elevated concentrations that the flies experienced rarely, if ever, until the Anthropocene. We characterize the avoidance of feeding and egg laying on metal ions, and we identify receptors, neurons, and taste organs that contribute to this avoidance. Different subsets of taste receptors, including members of both Ir (Ionotropic receptor) and Gr (Gustatory receptor) families contribute to the avoidance of different metal ions. We find that metal ions activate certain bitter-sensing neurons and inhibit sugar-sensing neurons. Some behavioral responses are mediated largely through neurons of the pharynx. Feeding avoidance remains stable over 10 generations of exposure to copper and zinc ions. Some responses to metal ions are conserved across diverse dipteran species, including the mosquito Aedes albopictus. Our results suggest mechanisms that may be essential to insects as they face challenges from environmental changes in the Anthropocene.

Coupled Dynamics of Stimulus-Evoked Gustatory Cortical and Basolateral Amygdalar Activity.

Gustatory cortical (GC) single-neuron taste responses reflect taste quality and palatability in successive epochs. Ensemble analyses reveal epoch-to-epoch firing-rate changes in these responses to be sudden, coherent transitions. Such nonlinear dynamics suggest that GC is part of a recurrent network, producing these dynamics in concert with other structures. Basolateral amygdala (BLA), which is reciprocally connected to GC and central to hedonic processing, is a strong candidate partner for GC, in that BLA taste responses evolve on the same general clock as GC and because inhibition of activity in the BLA→GC pathway degrades the sharpness of GC transitions. These facts motivate, but do not test, our overarching hypothesis that BLA and GC act as a single, comodulated network during taste processing. Here, we provide just this test of simultaneous (BLA and GC) extracellular taste responses in female rats, probing the multiregional dynamics of activity to directly test whether BLA and GC responses contain coupled dynamics. We show that BLA and GC response magnitudes covary across trials and within single responses, and that changes in BLA-GC local field potential phase coherence are epoch specific. Such classic coherence analyses, however, obscure the most salient facet of BLA-GC coupling: sudden transitions in and out of the epoch known to be involved in driving gaping behavior happen near simultaneously in the two regions, despite huge trial-to-trial variability in transition latencies. This novel form of inter-regional coupling, which we show is easily replicated in model networks, suggests collective processing in a distributed neural network.SIGNIFICANCE STATEMENT There has been little investigation into real-time communication between brain regions during taste processing, a fact reflecting the dominant belief that taste circuitry is largely feedforward. Here, we perform an in-depth analysis of real-time interactions between GC and BLA in response to passive taste deliveries, using both conventional coherence metrics and a novel methodology that explicitly considers trial-to-trial variability and fast single-trial dynamics in evoked responses. Our results demonstrate that BLA-GC coherence changes as the taste response unfolds, and that BLA and GC specifically couple for the sudden transition into (and out of) the behaviorally relevant neural response epoch, suggesting (although not proving) that: (1) recurrent interactions subserve the function of the dyad as (2) a putative attractor network.

Effect of salivary gland removal on taste preference in mice.

To evaluate the effect of decreased salivary secretion on taste preference, we investigated taste preference for five basic tastes by a 48 h two-bottle preference test using a mouse model (desalivated mice) that underwent surgical removal of three major salivary glands: the parotid, submandibular, and sublingual glands. In the desalivated mice, the avoidance behaviors for bitter and salty tastes and the attractive behaviors for sweet and umami tastes were significantly decreased. We confirmed that saliva is necessary to maintain normal taste preference. To estimate the cause of the preference changes, we investigated the effects of salivary gland removal on the expression of taste-related molecules in the taste buds. No apparent changes were observed in the expression levels or patterns of taste-related molecules after salivary gland removal. When the protein concentration and composition in the saliva were compared between the control and desalivated mice, the protein concentration decreased and its composition changed after major salivary gland removal. These results suggest that changes in protein concentration and composition in the saliva may be one of the factors responsible for the changes in taste preferences observed in the desalivated mice.

Sniffing out meaning: Chemosensory and semantic neural network changes in sommeliers.

Wine tasting is a very complex process that integrates a combination of sensation, language, and memory. Taste and smell provide perceptual information that, together with the semantic narrative that converts flavor into words, seem to be processed differently between sommeliers and naïve wine consumers. We investigate whether sommeliers' wine experience shapes only chemosensory processing, as has been previously demonstrated, or if it also modulates the way in which the taste and olfactory circuits interact with the semantic network. Combining diffusion-weighted images and fMRI (activation and connectivity) we investigated whether brain response to tasting wine differs between sommeliers and nonexperts (1) in the sensory neural circuits representing flavor and/or (2) in the neural circuits for language and memory. We demonstrate that training in wine tasting shapes the microstructure of the left and right superior longitudinal fasciculus. Using mediation analysis, we showed that the experience modulates the relationship between fractional anisotropy and behavior: the higher the fractional anisotropy the higher the capacity to recognize wine complexity. In addition, we found functional differences between sommeliers and naïve consumers affecting the flavor sensory circuit, but also regions involved in semantic operations. The former reflects a capacity for differential sensory processing, while the latter reflects sommeliers' ability to attend to relevant sensory inputs and translate them into complex verbal descriptions. The enhanced synchronization between these apparently independent circuits suggests that sommeliers integrated these descriptions with previous semantic knowledge to optimize their capacity to distinguish between subtle differences in the qualitative character of the wine.

Responses of Chemosensory Perception to Stimulation of the Human Brain.

OBJECTIVE: Significant advances have been made in our understanding of the neural substrates of human chemosensory processing, involving the piriform cortex, insula, and orbitofrontal cortex. However, the important and challenging issues are to localize the brain regions with high anatomic precision that can causally produce chemosensory perception and further delineate the topography of different classifications of chemosensory perception. METHODS: We quantitatively measured subjective responses of chemosensory perception to intracranial electrical stimulation over the brain in neurosurgical patients (n = 302) with medically refractory epilepsy. RESULTS: The chemosensory perceptions including olfaction, gustation, and chemesthesis were elicited in 21 of 302 patients (7%). Chemosensory responses were evoked in 53 (0.2%) of 21,661 stimulated sites. The highest response rate (1.8%) was in the insula (37/2,051 stimulated sites from 15/163 patients). The chemosensory perception emerged predominantly during stimulation of the insula along the central sulcus axis. Notably, there existed a distinct pattern that the anteroventral insula predominately represented orthonasal olfaction, whereas different chemosensory modalities converged in the mid-dorsal insula. INTERPRETATION: This study provided a detailed characterization of chemosensory perception across the brain, especially in the insula. These results suggest that the cortex along the banks of the central sulcus of the insula may play a role in producing the supramodal sensation of flavor. It also indicates that dysfunction of the central insula should be considered during the evaluation of chemosensory-related epileptic seizures. ANN NEUROL 2023;93:175-183.

What are olfaction and gustation, and do all animals have them?

Different animals have distinctive anatomical and physiological properties to their chemical senses that enhance detection and discrimination of relevant chemical cues. Humans and other vertebrates are recognized as having 2 main chemical senses, olfaction and gustation, distinguished from each other by their evolutionarily conserved neuroanatomical organization. This distinction between olfaction and gustation in vertebrates is not based on the medium in which they live because the most ancestral and numerous vertebrates, the fishes, live in an aquatic habitat and thus both olfaction and gustation occur in water and both can be of high sensitivity. The terms olfaction and gustation have also often been applied to the invertebrates, though not based on homology. Consequently, any similarities between olfaction and gustation in the vertebrates and invertebrates have resulted from convergent adaptations or shared constraints during evolution. The untidiness of assigning olfaction and gustation to invertebrates has led some to recommend abandoning the use of these terms and instead unifying them and others into a single category-chemical sense. In our essay, we compare the nature of the chemical senses of diverse animal types and consider their designation as olfaction, oral gustation, extra-oral gustation, or simply chemoreception. Properties that we have found useful in categorizing chemical senses of vertebrates and invertebrates include the nature of peripheral sensory cells, organization of the neuropil in the processing centers, molecular receptor specificity, and function.

Taste of common prebiotic oligosaccharides: impact of molecular structure.

Prebiotic oligosaccharides are naturally occurring nondigestible carbohydrates with demonstrated health benefits. They are also a chemically diverse class of nutrients, offering an opportunity to investigate the impact of molecular structure on oligosaccharide taste perception. Accordingly, a relevant question is whether these compounds are detected by the human gustatory system, and if so, whether they elicit sweet or "starchy" taste. Here, in 3 psychophysical experiments, we investigated the taste perception of 3 commercially popular prebiotics [fructooligosaccharides (FOS), galactooligosaccharides (GOS), xylooligosaccharides (XOS)] in highly pure form. Each of these classes of prebiotics differs in the type of glycosyl residue, and position and type of bond between those residues. In experiments I and II, participants were asked to discriminate a total of 9 stimuli [FOS, GOS, XOS; degree of polymerization (DP) of 2, 3, 4] prepared at 75 mM in the presence and absence of lactisole, a sweet receptor antagonist. We found that all 9 compounds were detectable (P < 0.05). We also found that GOS and XOS DP 4 were discriminable even with lactisole, suggesting that their detection was not via the canonical sweet receptor. Accordingly, in experiment III, the taste of GOS and XOS DP 4 were directly compared with that of MOS (maltooligosaccharides) DP 4-6, which has been reported to elicit "starchy" taste. We found that GOS and MOS were perceived similarly although narrowly discriminable, while XOS was easily discriminable from both GOS and MOS. The current findings suggest that the molecular structure of oligosaccharides impacts their taste perception in humans.

TRPM4 and PLCß3 contribute to normal behavioral responses to an array of sweeteners and carbohydrates but PLCß3 is not needed for taste-driven licking for glucose.

The peripheral taste system is more complex than previously thought. The novel taste-signaling proteins TRPM4 and PLCß3 appear to function in normal taste responding as part of Type II taste cell signaling or as part of a broadly responsive (BR) taste cell that can respond to some or all classes of tastants. This work begins to disentangle the roles of intracellular components found in Type II taste cells (TRPM5, TRPM4, and IP3R3) or the BR taste cells (PLCß3 and TRPM4) in driving behavioral responses to various saccharides and other sweeteners in brief-access taste tests. We found that TRPM4, TRPM5, TRPM4/5, and IP3R3 knockout (KO) mice show blunted or abolished responding to all stimuli compared with wild-type. IP3R3 KO mice did, however, lick more for glucose than fructose following extensive experience with the 2 sugars. PLCß3 KO mice were largely unresponsive to all stimuli except they showed normal concentration-dependent responding to glucose. The results show that key intracellular signaling proteins associated with Type II and BR taste cells are mutually required for taste-driven responses to a wide range of sweet and carbohydrate stimuli, except glucose. This confirms and extends a previous finding demonstrating that Type II and BR cells are both necessary for taste-driven licking to sucrose. Glucose appears to engage unique intracellular taste-signaling mechanisms, which remain to be fully elucidated.

A Pharmacological perspective on the temporal properties of sweeteners.

Several non-caloric sweeteners exhibit a delay in sweetness onset and a sweetness linger after sampling. These temporal properties are thought to be the result of non-specific interactions with cell membranes and proteins in the oral cavity. Data and analysis presented in this report also support the potential involvement of receptor affinity and binding kinetics to this phenomenon. In general, affected sweeteners exhibit distinctly higher binding affinity compared to carbohydrate sweeteners, which do not have temporal issues. In addition, binding kinetic simulations illustrate much slower receptor binding association and dissociation kinetics for a set of non-caloric sweeteners presenting temporal issues, in comparison to carbohydrate sweeteners. So, the higher affinity of some non-caloric sweeteners, dictating lower use levels, and affecting binding kinetics, could contribute to their delay and linger in sweetness perception. Simple pharmacology principles could explain, at least in part, some of the temporal issues of sweeteners.

Temporal progression along discrete coding states during decision-making in the mouse gustatory cortex.

The mouse gustatory cortex (GC) is involved in taste-guided decision-making in addition to sensory processing. Rodent GC exhibits metastable neural dynamics during ongoing and stimulus-evoked activity, but how these dynamics evolve in the context of a taste-based decision-making task remains unclear. Here we employ analytical and modeling approaches to i) extract metastable dynamics in ensemble spiking activity recorded from the GC of mice performing a perceptual decision-making task; ii) investigate the computational mechanisms underlying GC metastability in this task; and iii) establish a relationship between GC dynamics and behavioral performance. Our results show that activity in GC during perceptual decision-making is metastable and that this metastability may serve as a substrate for sequentially encoding sensory, abstract cue, and decision information over time. Perturbations of the model's metastable dynamics indicate that boosting inhibition in different coding epochs differentially impacts network performance, explaining a counterintuitive effect of GC optogenetic silencing on mouse behavior.