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Striking taste disturbances are reported in cancer patients treated with Hedgehog (HH)-pathway inhibitor drugs, including sonidegib (LDE225), which block the HH pathway effector Smoothened (SMO). We tested the potential for molecular, cellular, and functional recovery in mice from the severe disruption of taste-organ biology and taste sensation that follows HH/SMO signaling inhibition. Sonidegib treatment led to rapid loss of taste buds (TB) in both fungiform and circumvallate papillae, including disruption of TB progenitor-cell proliferation and differentiation. Effects were selective, sparing nontaste papillae. To confirm that taste-organ effects of sonidegib treatment result from HH/SMO signaling inhibition, we studied mice with conditional global or epithelium-specific Smo deletions and observed similar effects. During sonidegib treatment, chorda tympani nerve responses to lingual chemical stimulation were maintained at 10 d but were eliminated after 16 d, associated with nearly complete TB loss. Notably, responses to tactile or cold stimulus modalities were retained. Further, innervation, which was maintained in the papilla core throughout treatment, was not sufficient to sustain TB during HH/SMO inhibition. Importantly, treatment cessation led to rapid and complete restoration of taste responses within 14 d associated with morphologic recovery in about 55% of TB. However, although taste nerve responses were sustained, TB were not restored in all fungiform papillae even with prolonged recovery for several months. This study establishes a physiologic, selective requirement for HH/SMO signaling in taste homeostasis that includes potential for sensory restoration and can explain the temporal recovery after taste dysgeusia in patients treated with HH/SMO inhibitors.

In addition to the taste receptors corresponding to the six basic taste qualities—sweet, salty, sour, bitter, umami, and fatty—another type of taste receptor, calcium-sensing receptor (CaSR), is found in taste-bud cells. CaSR is called the ‘kokumi’ receptor because its agonists increase sweet, salty and umami tastes to induce ‘koku’, a Japanese word meaning the enhancement of flavor characters such as thickness, mouthfulness, and continuity. Koku is an important factor for enhancing food palatability. However, it is not well known whether other kokumi-receptors and substances exist. Here, we show that ornithine (L-ornithine but not D-ornithine) at low concentrations that do not elicit a taste of its own, enhances preferences to sweet, salty, umami, and fat taste solutions in mice. Increased preference to monosodium glutamate (MSG) was the most dominant effect. Antagonists of G-protein-coupled receptor family C group 6 subtype A (GPRC6A) abolished the additive effect of ornithine on MSG solutions. The additive effects of ornithine on taste stimuli are thought to occur in the oral cavity, and are not considered post-oral events because ornithine’s effects were confirmed in a brief-exposure test. Moreover, the additive effects of ornithine and the action of the antagonist were verified in electrophysiological taste nerve responses. Immunohistochemical analysis implied that GPRC6A was expressed in subsets of type II and type III taste cells of mouse circumvallate papillae. These results are in good agreement with those reported for taste modulation involving CaSR and its agonists. The present study suggests that ornithine is a kokumi substance and GPRC6A is a newly identified kokumi receptor.

Objectives The facial recess, an essential landmark for the posterior tympanotomy approach, is limited by the facial nerve and the chorda tympani, with a complicated relationship. This study tried to find the most appropriate radiological method to evaluate the chorda-facial angle (CFA). We also checked the effect of this angle on the round window accessibility during cochlear implantation. Methods It was a retrospective study that included cochlear implant surgeries of 237 pediatric patients, from September 2016 to April 2021. Two physicians evaluated the CFA in the para-sagittal cut of the preoperative HRCT. The round window accessibility was assessed in the unedited surgery videos. Results The CFA ranged from 21° to 35° with a mean of 27.14 ± 3.5°. It was detected in all cases with a high agreement between the two CT reviewers’ measurements. The CFA differed significantly between the accessible group and the group with difficult accessibility ( p value < 0.001). Spearman’s correlation coefficient revealed a strong correlation between the CFA and the intraoperative round accessibility. 25.5° was the best cutoff point; below this angle, difficult accessibility into the RW was expected, with high sensitivity, specificity, and accuracy Conclusions Our study on a relatively large number of cases provided a precise, valid, reliable, and applicable method to evaluate the CFA in the HRCT scan. We found a significant-close relation between the CFA and the round window accessibility; the difficulty increased with a need for posterior tympanotomy modification when the angle decreased. Key Points • Radiological detection of the chorda-facial angle was always problematic, without a previous straightforward method in the literature. • We used the para-sagittal cut of the high-resolution CT scans to evaluate the CFA. This cut was beneficial to seeing the chorda tympani nerve in every examined case. There was a high agreement between the two CT reviewers’ measurements. • Preoperative evaluation of the CFA in the HRCT accurately predicted the round window accessibility. Patients with CFA less than 25.5 ° were expected to have difficult accessibility into the round window during cochlear implantation.

The concept of ‘kokumi’, which refers to an enhanced and more delicious flavor of food, has recently generated considerable interest in food science. However, kokumi has not been well studied in gustatory physiology, and the underlying neuroscientific mechanisms remain largely unexplored. Our previous research demonstrated that ornithine (L-ornithine), which is abundant in shijimi clams, enhanced taste preferences in mice. The present study aimed to build on these findings and investigate the mechanisms responsible for kokumi in rats. In two-bottle preference tests, the addition of ornithine, at a low concentration that did not increase the favorability of this substance alone, enhanced the animals’ preferences for umami, sweet, fatty, salty, and bitter solutions, with the intake of monosodium glutamate showing the most significant increase. Additionally, a mixture of umami and ornithine synergistically induced significant responses in the chorda tympani nerve, which transmits taste information to the brain from the anterior part of the tongue. The observed preference enhancement and increase in taste-nerve response were abolished by antagonists of the G-protein-coupled receptor family C group 6 subtype A (GPRC6A). Furthermore, immunohistochemical analysis indicated that GPRC6A was expressed in a subset of type II taste cells in rat fungiform papillae. These results provide new insights into flavor-enhancement mechanisms, confirming that ornithine is a kokumi substance and GPRC6A is a novel kokumi receptor.

The chorda tympani nerve (CTN) is a mixed nerve, which carries sensory and parasympathetic fibres. The sensory component supplies the taste sensation of the anterior two-thirds of the ipsilateral side of the tongue. During middle ear surgery the CTN is exposed and frequently stretched or sacrificed, because it lacks a bony covering as it passes through the middle ear. Injury may cause hypogeusia, ageusia or altered taste sensation of the ipsilateral side of the tongue. To date, there is no consensus regarding which type of CTN injury (sacrificing or stretching), during middle ear surgery, leads to the least burden for the patient. A double-blind prospective prognostic association study was designed in a single medical centre in the Netherlands to determine the effect of CTN injury on postoperative taste disturbance and quality of life. 154 patients, who will undergo primary stapes surgery or cochlear implantation will be included. The taste sensation, food preferences and quality of life of these patients will be evaluated preoperatively and at one week, six weeks and six months postoperatively using the Taste Strip Test, Electrogustometry, supplementary questionnaire on taste disturbance, Macronutrient and Taste Preference Ranking Task, Appetite, Hunger and Sensory Perception questionnaire and Questionnaire of Olfactory Disorders to assess the association of these outcomes with CTN injury. Evaluation of olfactory function will only take place preoperatively and at one week postoperatively using the Sniffin' Sticks. The patient and outcome assessor are blinded to the presence or absence of CTN injury. This study is the first to validate and quantify the effect of chorda tympani nerve injury on taste function. The findings of this study may lead to evidence-based proof of the effect of chorda tympani injury on taste function with consequences for surgical strategies. Netherlands Trial Register NL9791. Registered on 10 October 2021.

Objectives The aim of this study was to compare the incidence of chorda tympani nerve (CTN) injury between endoscopic and microscopic stapes surgery. Methods This randomized controlled clinical trial included 88 patients who were randomly divided into two groups: endoscopic stapedotomy group ( n  = 44) and microscopic stapedotomy group ( n  = 44). The incidence of chorda tympani nerve (CTN) injury after surgery was determined by both subjective taste testing and chemical taste tests, before and after surgery. The results were compared between the two groups. Results The total number of patients who were identified as having CTN affection (based on the chemical testing) was 16 out of 88 (18.2%). The incidence was significantly lower in the endoscopic group ( n  = 2) than the microscopic group ( n  = 14) ( p  = 0.019). Conclusion Altered taste as a result of iatrogenic CTN injury can affect the patients’ quality of life. Endoscopic ear surgery offers better visualization, less need for extensive manipulation of the chorda tympani, and consequently decreased incidence of CTN injury.

Taste preference, a key component of food choice, changes with aging. However, it remains unclear how this occurs. To determine differences in taste preference between rats in different life stages, we examined the consumption of taste solutions and water using a two-bottle test. Male Sprague-Dawley rats of different ages were used: juvenile (3-6 weeks), young adult (8-11 weeks), adult (17-20 weeks), middle-aged (34-37 weeks), and old-aged (69-72 weeks). The intakes of the high and low concentration solutions presented simultaneously were measured. We observed that the old-aged group had lower preference ratios for 0.3 M sucrose and 0.1 M MSG in comparison with other groups. The preference ratio for 0.03 mM QHCl was higher in the middle-aged group than in the three younger groups and higher in the old-aged group than the juvenile group. The taste preferences for HCl and NaCl did not significantly differ among the age groups. The old-aged group tended to prefer high concentrations of sucrose, QHCl, NaCl, and MSG to low concentrations, indicating age-related decline in taste sensitivity. We also aimed to investigate differences between life stages in the electrophysiological responses of the chorda tympani nerve, one of the peripheral gustatory nerves, to taste stimuli. The electrophysiological recordings showed that aging did not alter the function of the chorda tympani nerve. This study showed that aging induced alterations in taste preference. It is likely that these alterations are a result of functional changes in other peripheral taste nerves, the gastrointestinal system, or the central nervous system.

Salivary gland acinar cells are routinely destroyed during radiation treatment for head and neck cancer that results in a lifetime of hyposalivation and co‐morbidities. A potential regenerative strategy for replacing injured tissue is the reactivation of endogenous stem cells by targeted therapeutics. However, the identity of these cells, whether they are capable of regenerating the tissue, and the mechanisms by which they are regulated are unknown. Using in vivo and ex vivo models, in combination with genetic lineage tracing and human tissue, we discover a SOX2 + stem cell population essential to acinar cell maintenance that is capable of replenishing acini after radiation. Furthermore, we show that acinar cell replacement is nerve dependent and that addition of a muscarinic mimetic is sufficient to drive regeneration. Moreover, we show that SOX2 is diminished in irradiated human salivary gland, along with parasympathetic nerves, suggesting that tissue degeneration is due to loss of progenitors and their regulators. Thus, we establish a new paradigm that salivary glands can regenerate after genotoxic shock and do so through a SOX2 nerve‐dependent mechanism. Synopsis Salivary glands regenerate after radiation injury through SOX2‐mediated secretory acinar cell replacement as shown using genetic lineage tracing and ablation methods, in combination with in vivo and ex vivo gamma radiation‐induced damage models. SOX2 + stem cells are essential to acinar cell replacement in the sublingual gland (SLG) during homeostasis and after radiation‐induced damage. SOX2‐mediated acinar cell replacement is contingent on neuronal muscarinic signalling. In the absence of nerves, a muscarinic mimetic can drive SOX2‐mediated regeneration. SOX2 function is essential for SLG regeneration following radiation‐induced injury. SOX2 along with parasympathetic nerves are diminished in human salivary gland biopsies following irradiation therapy and SOX2 and the acinar lineage are upregulated in response to muscarinic activation. Graphical Abstract Salivary glands regenerate after radiation injury through SOX2‐mediated secretory acinar cell replacement as shown using genetic lineage tracing and ablation methods, in combination with in vivo and ex vivo gamma radiation‐induced damage models.

Cholesteatoma often presents with persistent otorrhoea, conductive hearing loss or vestibular dysfunction. Rarely, cholesteatoma can cause dysgeusia if the lesion invades into the chorda tympani nerve. This paper presents an individual with cholesteatoma whose dysgeusia resolved following a mastoidectomy in which the chorda tympani was sacrificed. The current literature was reviewed for explanations behind this phenomenon. A previously fit 57-year-old man presented with a 3-month history of persistent otorrhoea and the complaint of a metallic taste in the mouth, and was diagnosed with cholesteatoma. The patient underwent radical mastoidectomy and the chorda tympani nerve was sacrificed. On post-operative review, he reported complete resolution of dysgeusia. The sense of taste is mediated by a complex neural network. It is possible that once the diseased chorda tympani is transected, compensation arises from other parts of the network. Sectioning of the chorda tympani could lead to a beneficial outcome in selected patients.

Taste buds contain 2 types of GABA-producing cells: sour-responsive Type III cells and glial-like Type I cells. The physiological role of GABA, released by Type III cells is not fully understood. Here, we investigated the role of GABA released from Type III cells using transgenic mice lacking the expression of GAD67 in taste bud cells (Gad67-cKO mice). Immunohistochemical experiments confirmed the absence of GAD67 in Type III cells of Gad67-cKO mice. Furthermore, no difference was observed in the expression and localization of cell type markers, ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2), gustducin, and carbonic anhydrase 4 (CA4) in taste buds between wild-type (WT) and Gad67-cKO mice. Short-term lick tests demonstrated that both WT and Gad67-cKO mice exhibited normal licking behaviors to each of the five basic tastants. Gustatory nerve recordings from the chorda tympani nerve demonstrated that both WT and Gad67-cKO mice similarly responded to five basic tastants when they were applied individually. However, gustatory nerve responses to sweet–sour mixtures were significantly smaller than the sum of responses to each tastant in WT mice but not in Gad67-cKO mice. In summary, elimination of GABA signalling by sour-responsive Type III taste cells eliminates the inhibitory cell–cell interactions seen with application of sour–sweet mixtures.