The ability to discern nutritious food from harmful substances is critical for animal survival, with the gustatory system playing a pivotal role. In insects, including the genetic model Drosophila melanogaster, taste perception involves more than the established valence-based labeled line model, where distinct populations of taste neurons encode appetitive versus aversive stimuli and their activation promotes either attraction or rejection behaviors. A growing body of evidence reveals that sophisticated opponent coding mechanisms operate at multiple levels to modulate responses of taste neurons, enabling dynamic integration between competing taste modalities. These processes significantly expand the informational capacity and behavioral flexibility of the taste system, allowing animals to make appropriate feeding decisions in complex chemical environments where tastants of multiple modalities are simultaneously present.

The mechanisms that contribute to CRSwNP-related olfactory loss are poorly characterized. We have previously shown in middle meatus mucus that levels of C3, a component of the complement system, are elevated and correlate with worse disease severity. Excessive complement activation has been shown to impact the severity and progression of injury in the visual and auditory sensory systems but has yet to be investigated in the context of olfaction and thus is the focus of this study. Mucus from the olfactory cleft was sampled from CRSwNP patients (n=22) undergoing endoscopic sinus surgery. Olfactory status was determined by UPSIT. Patients were categorized into two groups: normosmic/mild microsmic (n=10) and moderate microsomia/total anosmia (n=12). Mucus concentrations of classical (C1q), lectin (MBL), alternative pathways (fB, Adipsin), complement proteins (C2, 4, 3, and 5), activation fragments (C4b, C3a, C3b, C5a), and soluble regulators (Factor I and H) were assessed by multiplex or ELISA. With regards to findings, CRSwNP patients with olfactory dysfunction had higher MBL, C4, C3, fB, and Adipsin levels, suggesting lectin and alternative pathway involvement. Complement activation was present and significantly increased in microsomia/total anosmia patients as determined by the presence C3a and C3b complement cleavage fragments. No differences in terminal pathway proteins, C5 or C5a, were noted. Fluid phase complement inhibitor, factor H, was elevated, representative of increased complement activity. In conclusion, Elevated complement activation is linked to more severe olfactory dysfunction. These findings highlight the potential role of complement pathways in the pathogenesis of olfactory impairment related to CRSwNP.

Taste in Drosophila melanogaster is crucial to survival, influencing feeding, mating, and egg-laying behaviors. Taste organs are located on various parts of the body, including the legs, proboscis, wings, and ovipositor. Taste neurons detect chemicals via receptors like GRs, IRs, and TRPs, with bitter and sweet tastes linked to specific neurons (Gr66a+ and Gr5a+). Bitter substances such as caffeine activate neurons, resulting in rejection behavior. TrpA1 channels, associated with aversive responses, are involved in complex behaviors and could interact with taste receptors. Our results show that caffeine mixed with sucrose reduces proboscis extension in flies compared to sucrose alone, a response that requires only the TrpA1-E isoform out of the five possible ones. Furthermore, our data demonstrate that this avoidance requires TrpA1 and signaling via PLC and IP3-receptors in adult Gr66a+ neurons.

Mechanosensory neurons play a crucial role in determining the location of stimuli on the receptor surface, movement, as well as the identification and discrimination of textures. To date, little is known about mechanosensory neuron types that innervate the oral cavity. Here, we recorded from mechanosensitive neurons innervating the oral cavity, to examine their diversity and function mediating touch. We first recorded a rough topographical map to aid in locating mechanosensory neuron types innervating the oral cavity. Electrophysiological mapping indicated that neurons innervating the tongue were located within and between maxillary (V2) and mandibular (V3) receptive fields, resembling a "strip" similar to the anatomical position of the tongue. We found that both rapidly adapting and slowly adapting neurons innervate the anterior tongue and lips. Conduction velocity experiments showed that all the lip-innervating neurons were classified as C-fibers, whereas there was a broader range for the tongue-innervating neurons, ranging from C-fibers to A-fast. Interestingly, we found that rapidly adapting and slowly adapting neurons were present at all 3 conduction velocity classifications. The majority of pressure-sensitive neurons also responded to brush stimulation (91%); however, there was a small subset of neurons that only responded to pressure stimulation (9%). The majority of the A-fibers had receptive fields on the anterior tip of the tongue. Furthermore, we found that when a mechanically sensitive neuron innervated a fungiform papilla, its receptive field did not include the surrounding filiform papillae. Our findings provide important contributions to understanding some of the coding features of mechanosensory neurons that innervate the oral cavity.

Gustatory dysfunction (GD), or taste dysfunction, is associated with poor quality of life. Recent literature has demonstrated an association between olfactory dysfunction (OD) and mortality in older adults. However, the association between GD and mortality has not been rigorously studied in a large national cohort. This study helps characterize this relationship and explore underlying mechanisms. Cross-sectional study of the 2013 to 2014 National Health and Nutrition Examination Survey linked to the National Death Index (NDI) through 2019. GD was assessed through self-report and psychometric recognition of quinine and salt, excluding participants with self-reported and psychometric OD. Cox proportional hazards regression models examined associations between GD and mortality, adjusting for demographics, history of cardiovascular comorbidities, diabetes, and malignancy, nutritional status, cognitive function, and depression. Subgroup analysis was also performed based on age and sex. The analytical cohort consisted of 1,136 adults aged 40 and older with complete data, subsequently weighted to create a nationally representative cohort. Isolated psychometric GD is associated with an 87% increased risk of 5-year all-cause mortality after adjusting for all covariates (HR = 1.87, 95% CI = 1.09 to 3.21, P = 0.023). This relationship remains robust among a subgroup of younger participants age 40 to 64 (HR = 18.89, 95% CI = 1.73 to 205.96, P = 0.016) and among male participants (HR = 2.53, 95% CI = 1.34 to 4.76, P = 0.004). Isolated self-reported GD is not statistically significantly associated with mortality. This is one of the first studies to demonstrate an association between GD and mortality, supporting the growing body of literature linking chemosensory dysfunction with unhealthy aging, a finding that warrants more clinical scrutiny.

Naming common odors can be an exceptionally challenging task even for young and healthy individuals. Due to this difficulty, tests of cued odor identification (OID) are used instead of free odor identification in cognitive, neuropsychological, or aging research. Consequently, our understanding of the cognitive demands of free OID is limited. In this study, we analyze the demographic and cognitive factors that influence OID responses of old adults. We utilize a uniquely large dataset (n = 2,479) from a population-based sample of healthy, older Swedish adults (ages 58-102) who participated in free and cued OID using the 16-item Sniffin' TOM test. The free OID naming responses were categorized as correct, misnamings, or omissions. The results revealed that omissions are surprisingly prevalent, constituting 66.4% of errors and accounting for 87.7% of the age-related differences in task performance. Additionally, we hypothesized that successful free OID would be more closely linked to nonolfactory cognitive abilities, such as verbal fluency, vocabulary, and episodic memory proficiency. This hypothesis was supported, as we found significant associations between free OID and these cognitive abilities, while cued OID identification only was associated with perceptual speed. Our findings suggest that the assessment of free OID may provide valuable insights into odor-based cognition, indicating a need for further research in this area.

Olfactory perception, mediated by G protein-coupled receptors (GPCRs) such as odorant receptors (ORs) and trace amine-associated receptors (TAARs), plays a pivotal role in human health, influencing behaviors like food choices and serving as early biomarkers for neurodegenerative diseases. Despite their importance, olfactory GPCRs are among the least understood members of the GPCR superfamily, and most ORs and TAARs are still orphan receptors. This review provides a comprehensive overview of recent advancements in the structural bioinformatics of olfactory GPCRs. We outline how computational, structure-based strategies have succeeded in identifying novel modulators for olfactory receptors. By discussing recent breakthroughs in GPCR structural biology, such as the first resolved experimental structures of ORs and TAARs, and the transformative impact of AI-driven structure prediction tools for olfactory receptors, this review offers a roadmap for future olfaction pharmacology research.

The mammalian olfactory system enables the detection of a wide variety of chemical compounds via the expression of a repertoire of olfactory receptors comprising the largest gene family in the mammalian genome. Olfactory sensory neurons (OSNs) each express only 1 odorant receptor (OR) gene. In mice, this requires activation of 1 OR gene and repression of over 1,400 other OR genes. In this review, we describe the mechanisms that support the transcription of OR genes and how these mechanisms impact which OR is expressed in each neuron. First, we discuss what is currently known about the role of transcription in OR choice. We then describe the role of specific features of OR genes and enhancers in the regulation of OR transcription. Finally, we discuss characteristics of OSNs which specify transcription of some OR genes while restricting the transcription of others.

Umami taste of L-glutamate can be synergistically amplified by the addition of some purine 5'-ribonucleotides, most notably inosine 5'-monophosphate and guanosine 5'-monophosphate (GMP). However, potential synergistic effects of other 5'-ribonucleotides, such as adenosine 5'-monophosphate (AMP), cytidine 5'-monophosphate (CMP), and uridine 5'-monophosphate (UMP), have not been well characterized. Most recently, CMP has been proposed to function as a negative modulator of glutamate taste in some US participants. Here, we examined the effects of mixing these five 5'-ribonucleotides with monopotassium L-glutamate (MPG) on MPG detection threshold and umami intensity using Japanese young female trained participants. Purine 5'-ribonucleotides (IMP, GMP, AMP) significantly decreased MPG detection threshold and enhanced umami taste intensity. UMP showed a weak but significant reduction of MPG detection threshold and a slight but significant enhancement of umami intensity. CMP, however, did not modify MPG detection threshold or umami intensity. The rank order of the effects was GMP ≧IMP > AMP > UMP. Therefore, these results did not support the hypothesis that "CMP functions as a negative modulator of glutamate taste", at least in the Japanese young female trained participants.

Many species of animals rely on their chemical senses to detect tastants and odorants to guide dietary selection, avoid danger, and modulate social interactions, all of which ultimately enhance survival and fitness. Significant progress has been made in our understanding of the 2 major chemosensory systems, taste and smell, through studies in model organisms such as flies and mice, ranging from receptor identification to sensory coding mechanisms. These topics have been extensively reviewed elsewhere. Here, we will instead focus on less commonly used model systems and companion animals, examining how taste receptors have been shaped by feeding ecology over the course of evolution to illustrate the concept that each species lives in its own sensory world, finely tuned to its ecological niche.

In terrestrial mammals, odorant receptors and associated sensory transduction machinery in olfactory sensory neurons (OSNs) are compartmentalized in the cilia, a critically important organelle for odor detection. The large number and length of olfactory cilia provide an extensive receptive surface for odor detection. The stability of these organelles is critical for olfactory function, as damage to olfactory cilia due to environmental factors, age, or disease impairs odor detection. However, it is unclear if there are innate structural or functional features of olfactory cilia that vary between OSN subtypes and affect the fidelity of the odorant receptive field. Using ciliary-targeted fluorescent probes, we analyzed cilia morphology in live, intact OSNs in situ from mice and rats. This unbiased approach revealed a previously unappreciated constancy of average cilia length and number in OSNs across the olfactory epithelium, measures that were also independent of animal age, sex, genetic background, and even rodent species. However, average OSN cilia length did vary with the cyclic nucleotide they use to transduce olfactory stimuli: OSNs expressing the non-canonical olfactory receptor guanylate cyclase-D, which use cGMP as the second messenger, had dramatically shorter cilia than the canonical odorant receptors M71 or I7 or the trace amine-associated receptor TAAR3, each of which instead employs the second messenger cAMP. These findings suggest that differences in cyclic nucleotide signaling are associated with cilia length in OSNs. Together, the data provide a basis for understanding structure-function relationship between cilia morphology and odorant transduction as a foundation for building a high-fidelity chemosensory organ.

Odor perception is a complex, multimodal experience mainly shaped by the interaction between the olfactory and trigeminal systems. Descriptors such as warm, fresh, or spicy reflect the contribution of chemosensory input from the trigeminal nerve, which adds thermal and tactile dimensions to odor perception. The trigeminal nerve innervates the head, including the nasal cavity; its fibers express several transient receptor potential channels to which odorant molecules can bind. Despite its sensory function and its putative impact on olfactory processing, the chemosensory ability of the trigeminal system has received comparatively little attention. This review examines the molecular and physiological foundations of trigeminal chemosensation, highlighting transient receptor potential channels broad sensitivity, their perceptual roles, and their interactions with the olfactory system. Assessing nasal trigeminal chemosensory function presents several methodological challenges. Here, we explore the tools available for studying the complexity of trigeminal chemosensory encoding ex vivo and in vivo in animal and human models. These techniques have demonstrated that, although the trigeminal and olfactory systems are distinct sensory modalities, they converge at multiple processing stages within the nervous system, including the olfactory epithelium (OE), the olfactory bulb, and other brain regions. In humans, this convergence leads to the activation of overlapping brain regions, resulting in perceptual modulation where information from the trigeminal system enhances or suppresses the response of the olfactory system. As a consequence of this intimate connection, olfactory dysfunction is often accompanied by reduced trigeminal sensitivity. Therefore, we examine the involvement of the trigeminal system in conditions of olfactory dysfunction.

The mechanisms involved in the discrimination of basic tastes have been previously studied. However, the mechanisms that differentiate between various substances within the same taste quality remain largely unexplored. This study aimed to determine whether individuals can distinguish 5 different sweet substances and whether this ability can be improved through taste recall training, serving as an entry point for elucidating the underlying mechanism. Forty healthy individuals were divided into 2 groups: a training group (10 males and 10 females) and a control group (10 males and 10 females). The taste recall training involved 5 sweet substances: glucose, fructose, sucrose, maltose, and lactose. Using the filter paper disc method, participants recalled the taste of the 5 sweet substances at a concentration one level below their taste thresholds and then matched the 5 substances. This training was conducted for 3 consecutive days. There were no significant differences in the number of participants, sex, age, body mass index, oral moisture, or baseline taste sensitivity between the training and control groups. The training group showed a significant improvement in the taste thresholds for all 5 sweet substances compared to the control group (glucose: P < 0.001, fructose: P < 0.001, sucrose: P < 0.001, maltose: P < 0.005, lactose: P < 0.001). These findings suggest that taste recall training enhances taste sensitivity for all 5 sweet substances and may improve both taste thresholds and discrimination performance within the same taste quality.

Several forebrain areas project to the rostral gustatory portion of the nucleus of the solitary tract (rNST), where they modulate processing of oral gustatory signals. Among them, the central nucleus of the amygdala (CeA) provides descending input via somatostatin-expressing (Sst) neurons, where suppression of CeA/Sst-to-rNST neural activity alters ingestion of the bitter tastant quinine. Together, these results indicate that the regulation of ingestive behavior involves descending neuromodulatory processes. Yet, the postsynaptic targets of CeA/Sst and non-Sst-expressing neurons in rNST, as well as the projection targets of rNST neurons receiving CeA input, remain unknown. Using a combination of transmission electron microscopy and transsynaptic viral tracing in transgenic mice, we show that CeA axon terminals in the rNST are GABAergic and form synapses with Phox2b-, glutamate-, calretinin-, and GABA-expressing neurons in distinct proportions. rNST neurons receiving CeA input were distributed across the medial, central, and ventral subdivisions and projected primarily to the ipsilateral reticular formation and parabrachial nucleus. These findings suggest that CeA input to rNST neurons influences both ascending gustatory information and orosensory motor functions, including licking, mastication, and salivation.

Lyncodon patagonicus (Patagonian weasel), Galictis cuja (lesser grison), and Galictis vittata (greater grison) are the only extant species of Lyncodontini, a relatively poorly known Neotropical tribe of the mustelid subfamily Ictonychinae within the mammalian order Carnivora. Here, we report molecular evidence indicating that the TAS1R1-TAS1R3 umami (savory) taste receptor lost its function in the Lyncodontini's stem lineage (∼3 to 9.5 million years ago) and is therefore nonfunctional in all crown Lyncodontini. This finding is unexpected and intriguing because all extant Lyncodontini apparently need this receptor (they are terrestrial carnivores with diets high in umami-eliciting compounds, including purine 5'-monophosphate ribonucleotides, the main agonists of TAS1R1-TAS1R3 in carnivorans). We argue that the common ancestor of extant Lyncodontini that first lost TAS1R1-TAS1R3 function was semiaquatic and predated mainly on fish and/or aquatic invertebrates (tissues of living or recently dead fish and aquatic invertebrates are low in purine 5'-monophosphate ribonucleotides). This hypothesis is consistent with the idea that loss of taste receptor function is caused by feeding specializations that restrict access to the compounds that a particular receptor detects. Our hypothesis effectively suggests a prolonged semiaquatic episode in the evolutionary history of the Lyncodontini's stem lineage because loss of TAS1R1-TAS1R3 function is achieved by a stochastic process continuing over evolutionary time. Whether the extant Lyncodontini evolved a mechanism to compensate for the loss of TAS1R1-TAS1R3 function is currently unknown and requires further research.

Early childhood is a critical developmental period for the establishment of flavor preferences that in turn affect food and beverage consumption and health into adulthood. Flavor is a multisensory experience, combining taste and retronasal odor signals. However, while early life development of taste perception has received ample attention, there is limited knowledge of retronasal odor perception in early life. In the present cross-sectional study, we tested the hypothesis that hedonic perception of retronasal smell differs between children and adults. We used video analysis of facial expressions to taste and retronasal odor solutions in children and adults. Children ages 3 to 6 and one of their parents (n = 112 dyads) were asked to sample solutions containing either a taste or an odor compound. A subset of subjects (n = 84 dyads) also explicitly rated each solution on a pictorial liking scale. No differences between the 2 age groups were observed in responses to taste solutions. In contrast, responses to retronasal odor stimuli were less stimulus-specific in children compared with adults. Children showed fewer negative facial expressions to broccoli and pumpkin odors, and more negative facial expressions to apple and mango odors. Similar differences between the 2 age groups were observed in explicit hedonic ratings. These findings support our hypothesis that the hedonic value of retronasal odor components of flavor is not innate but differ between young children and adults.

Across the animal kingdom, a remarkable diversity of chemoreceptors has evolved, reflecting the ecological and evolutionary pressures that shape species-specific sensory demands. Insects, the most biodiverse class of animals, play crucial roles in ecosystems and have an extensive chemosensory repertoire. At the heart of insect gustation lie the gustatory receptors (GRs), a large and remarkably diverse family of proteins characterized by their seven-transmembrane domain structure and tetrameric stoichiometry. These receptors are phylogenetically distinct from the taste receptors present in most other animal groups, including mammals. Functionally, GRs operate as ligand-gated cation channels. Upon binding to specific chemical compounds (tastants), these receptors undergo conformational changes that lead to the opening of ion-conducting channels in the neuronal membrane, ultimately triggering neuronal activation and initiating the perception of taste. Recent advancements in structural biology, particularly the use of cryo-electron microscopy, have enabled the visualization of the three-dimensional structure of several insect GRs that detect sugars. These structures, in unbound and ligand-bound states, have begun to reveal the principles of sugar recognition and discrimination. Here, we highlight recent advances in our understanding of insect GRs.

In the nasal cavity, olfactory receptor neurons are situated in the sensory epithelium and act to transduce odor signals, whereas the respiratory epithelium is responsible for removing unwanted particles from inhaled air. Although several molecular markers have been identified to define multiple specific cell types in the sensory epithelium, less is known to indicate cells in the respiratory domain. We have recently shown that the non-visual photoreceptor opsin 3 (Opn3) is expressed in the developing olfactory region. This raised the question as to which functional role/s Opn3 might play in the nasal epithelium, as well as whether other non-visual photoreceptors may be expressed in this region. By using Opn3-eGFP and Opn5-tdTomato reporter mice in combination with Foxj1, Ker8, OMP, Sox2, and Tubb3 immunohistochemistry analyzes, our findings show that Opn3 is restricted to the olfactory sensory domain from early embryonic stages, whereas Opn5 is up-regulated in the respiratory epithelium at later developmental stages. In adulthood, Opn3 is expressed in Sox2/Ker8-positive sustentacular cells in the sensory epithelium, whereas Opn5 expression remains in the respiratory epithelium, thus indicating that these molecular markers could be used to distinguish the sensory versus respiratory epithelia. Studies of morphology and expression patterns of Foxj1, Ker8, OMP, Sox2, and Tubb3 in adult Opn3-/- and Opn5-/- mice did not reveal differences from wild-type mice. In addition, neither Opn3-/- nor Opn5-/- mice exhibited a disturbance in olfaction compared to wild-type littermates when performing a buried food test.

In mammals, odors are encoded by a combinatorial code determined by the pattern of responses across hundreds of odorant receptors expressed monogenically and monoallelically in olfactory sensory neurons. The compositions of these receptor response patterns are largely unknown and overlap between them has yet to be explored. Activity-dependent reporter gene expression in freely behaving S100a5-tauGFP mice allowed capture of activated olfactory sensory neurons and identified 168 receptors responsive to moderate concentrations of 1 or more of 12 aliphatic (5 to 8 carbons) ketones, alcohols, and carboxylic acids. These 12 response patterns are remarkably different, with only 19% of the receptors responding to more than 1 of these odorants. This distinctiveness corresponds with the ease of discrimination of these odorants and may help maintain perceptual constancy in the face of response pattern variability, such as across odorant concentrations. This set of 168 receptors is not specific to aliphatic odorants but instead has 16% overlap with the receptors responsive to 7 odors tested previously in vivo, consistent with a receptor repertoire evolved to produce combinatorial codes. Aliphatic odorant response pattern similarity depends more upon odorant functional group than carbon chain length but the impact of chain length increases with the number of carbons. The response patterns to these aliphatic odorants are mostly composed of unrelated receptors, except some patterns contain minor subsets of closely related receptors. These findings argue that the major selective forces driving OR evolution are expansion of the odorant receptor gene family and the production of distinct response patterns.

Animals, including humans, exhibit caution when encountering novel foods, a phenomenon known as food neophobia. This hesitancy decreases with repeated exposures, provided the food is perceived as safe. While extensive research has established rodent models of food neophobia using fluid consumption tasks, studies using solid foods, particularly in mice, are relatively limited. We investigated food neophobia in mice using an olfactory-based task in which the mice were given chow odorized with isoamyl acetate. We quantified several behaviors associated with novelty response and found that the time to begin eating is the most reliable measure of neophobia. Similar levels of neophobia were found using other monomolecular odorants, suggesting that the effect is not odor specific. Further, as some reports of food neophobia in humans have suggested sex differences, we compared food neophobia behaviors in male and female mice. We observed no significant differences between the 2 groups, suggesting that the behavioral expression of food neophobia is similar across sexes. Finally, we found that food neophobia is attenuated upon a second exposure, as mice consume the odorized food as quickly as nonodorized food. Overall, our findings highlight a simple, single-test session approach for exploring olfactory-driven food neophobia.