Neurotransmitter Acetylcholine Research Articles

Cortical Acetylcholine Response to Deep Brain Stimulation of the Basal Forebrain in Mice.

Deep brain stimulation (DBS) using electrical stimulation of neuronal tissue in the basal forebrain to enhance release of the neurotransmitter acetylcholine is under consideration to improve executive function in patients with dementia. While some small studies indicate a positive response in the clinical setting, the relationship between DBS and acetylcholine pharmacokinetics is incompletely understood. We examined the cortical acetylcholine response to different stimulation parameters of the basal forebrain. 2-photon in vivo imaging was combined with deep brain stimulation in C57BL/6J mice. Stimulating electrodes were implanted in the subpallidal basal forebrain, and the ipsilateral somatosensory cortex was imaged. Acetylcholine activity was determined using the GRABACh-3.0 acetylcholine receptor sensor, and blood vessels were visualized with Texas red. Experiments manipulating stimulation frequency demonstrated that integrated acetylcholine induced fluorescence was insensitive to frequency with the same number of pulses, and that maximum peak levels were achieved with frequencies from 60 to 130 Hz. Altering pulse train length indicated that longer stimulation resulted in higher peaks and more activation with sublinear summation. The acetylcholinesterase inhibitor, donepezil, increased the peak response to 10s of stimulation at 60Hz, and the integrated response increased 57% with the 2 mg/kg dose, and 126% with the 4 mg/kg dose. Acetylcholine levels returned to baseline with a time constant of 14 to 18 seconds. Donepezil increases total acetylcholine receptor activation associated with DBS but did not change temporal kinetics. The long time constants observed in the cerebral cortex add to the evidence supporting volume and synaptic neurotransmission.

11C]MK-6884 PET imaging reveals lower M4 muscarinic acetylcholine receptor availability following cocaine self-administration in male rats.

Cocaine Use Disorder (CUD) remains a significant problem in the United States, with high rates of relapse and no present FDA-approved treatment. The acetylcholine neurotransmitter system, specifically through modulation of muscarinic acetylcholine receptor (mAChR) function, has shown promise as a therapeutic target for multiple aspects of CUD. Enhancement of the M4 mAChR subtype via positive allosteric modulation has been shown to inhibit the behavioral and neurochemical effects of cocaine across several rodent models of CUD. However, it is unclear how cocaine exposure affects M4 mAChR expression or distribution. To evaluate the effects of cocaine self-administration on M4 mAChR availability using [11C]MK-6884 in vivo PET imaging in rats that self-administered cocaine (cocaine SA) or sucrose pellets (control). Sprague-Dawley rats self-administered cocaine or sucrose pellets for 15 days under 2-h or 4-h sessions followed by PET imaging with [11C]MK-6884, a radiolabeled M4 selective positive allosteric modulator to determine the effects of cocaine on [11C]MK-6884 standard uptake values with cerebellum as reference (SUVr). Cumulative cocaine intake ranged between 324 and 776mg/kg. Cocaine self-administration was associated with significantly lower [11C]MK-6884 SUVrs in the cortex, hippocampus, and striatum compared to cocaine-naive rats, with a negative correlation between radiotracer SUVrs and cocaine intake in the hippocampus. These results suggest that cocaine self-administration decreases M4 mAChR availability, providing further support for pursuing activation/enhancement of M4 mAChR function as a viable pharmacotherapeutic approach for CUD.

Postprandial parasympathetic signals promote lung type 2 immunity.

Lung type 2 immunity protects against pathogenic infection, but its dysregulation causes asthma. Although it has long been observed that symptoms of asthmatic patients often become exaggerated following food intake, the pathophysiological mechanism underlying this postprandial phenomenon is incompletely understood. Here, we report that lung type 2 immunity in mice is enhanced after feeding, which correlates with parasympathetic activation. Also, local parasympathetic innervations exhibit spatial engagement with such immune responses mediated by group 2 innate lymphoid cells (ILC2s). Pharmacologic or surgical blockage of parasympathetic signals diminishes lung type 2 immunity. Conversely, chemogenetic manipulation of parasympathetic inputs and their upstream neurocircuit is sufficient to modulate those immune responses. We then show that the cholinergic receptor muscarinic 4 (Chrm4) for the parasympathetic neurotransmitter acetylcholine is expressed in mouse or human lung ILC2s, and the Chrm4 deletion mitigates ILC2-mediated lung inflammation. These results have revealed a critical neuroimmune function of the gut-brain-lung reflex.

Acetylcholinesterase Activity Evaluated in Molluscs – A Bibliometric Analysis

Acetylcholinesterase (AChE) is determined as an enzyme linked to the action of the neurotransmitter acetylcholine (ACh) and is classified as a marker of neurotoxicity. Mollusks have been widely used as sentinels in monitoring programs, especially bivalve mollusks, as evaluators of contaminants in aquatic environments. This article aims to use bibliometric analysis techniques to detect trends in methods used to evaluate AChE activity in mollusks and investigate the current status and frontiers of publications. The present study was used as a basis for performing the bibliometric analysis data obtained through a bibliographic search in the CAPES Portal (Web of Science) database; for this analysis, 25 articles were used, including after selection and exclusion. Based on the results obtained with this research, although quite old, the Ellman method (1961) is still the most widely used due to its effectiveness in determining AChE activity. The species Mytilus galloprovincialis Lam. is quite susceptible to assessing this activity and the Bivalve mollusk group is the most used for such study, on the other hand, the Cephalopod group is very little used. The bibliometric analysis revealed gaps that reflect enormous missed opportunities in improving the health of aquatic ecosystems and highlight the urgency of the scientific community to intensify efforts in scientific studies, helping to promote the health of aquatic ecosystems.

Polystyrene microplastics induce depression-like behavior in zebrafish via neuroinflammation and circadian rhythm disruption.

Polystyrene microplastics (PS-MPs) are widespread pollutants in aquatic environments that accumulate in various organs, including the brain, raising concerns about their neurotoxic effects. This study exposed zebrafish to environmentally relevant concentrations (25 and 250μg/L) of PS-MPs for 40days to investigate their impact on neurobehavior and underlying mechanisms. Results revealed that PS-MPs induced depression-like behaviors in zebrafish, characterized by reduced exploration, decreased locomotor activity, and altered social interaction. Histological analyses of brain tissue demonstrated PS-MPs-induced neuropathological changes, including perinuclear vacuolation and reduced Nissl bodies. Additionally, PS-MPs triggered neuroinflammation, evidenced by upregulated pro-inflammatory cytokines (il-6, il-1β), and disrupted the circadian rhythm, leading to altered expression of key clock genes (per1b, per2, per3) and cryptochrome genes (cry1a, cry2). Furthermore, PS-MPs exposure significantly altered neurotransmitter levels, decreasing dopamine, serotonin, norepinephrine, acetylcholine, tyrosine, and tryptophan. In vitro experiments using HMC3 microglia cells confirmed that PS-MPs induced microglial activation, morphological changes, and dysregulated gene expression related to inflammation and circadian rhythm. These findings provide compelling evidence that PS-MPs induce depression-like behaviors in zebrafish through mechanisms involving neuroinflammation, circadian rhythm disruption, and neurotransmitter imbalances, highlighting the potential ecological risks of PS-MPs and contributing to our understanding of the neurotoxicity of microplastics.

Biological Implications of the Intrinsic Deformability of Human Acetylcholinesterase Induced by Diverse Compounds: A Computational Study.

The enzyme acetylcholinesterase (AChE) plays a crucial role in the termination of nerve impulses by hydrolyzing the neurotransmitter acetylcholine (ACh). The inhibition of AChE has emerged as a promising therapeutic approach for the management of neurological disorders such as Lewy body dementia and Alzheimer's disease. The potential of various compounds as AChE inhibitors was investigated. In this study, we evaluated the impact of natural compounds of interest on the intrinsic deformability of human AChE using computational biophysical analysis. Our approach incorporates classical dynamics, elastic networks (ENM and NMA), statistical potentials (CUPSAT and SWOTein), energy frustration (Frustratometer), and volumetric cavity analyses (MOLE and PockDrug). The results revealed that cyanidin induced significant changes in the flexibility and rigidity of AChE, especially in the distribution and volume of internal cavities, compared to model inhibitors such as TZ2PA6, and through a distinct biophysical-molecular mechanism from the other inhibitors considered. These findings suggest that cyanidin could offer potential mechanistic pathways for future research and applications in the development of new treatments for neurodegenerative diseases.

A Novel Galantamine–Curcumin Hybrid Inhibits Butyrylcholinesterase: A Molecular Dynamics Study

Cholinesterases are enzymes that break down the neurotransmitter acetylcholine in the nervous system. The two main types are acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). AChE inhibitors are used to treat Alzheimer’s disease by increasing acetylcholine levels. BChE activity increases in later stages of Alzheimer’s, suggesting it might contribute to the disease. In previous experiments, it was found that a newly designed hybrid of galantamine (GAL) and curcumin (CCN) (compound 4b) decreases the activity of BChE in murine brain homogenates. Here, we explore this observation using molecular dynamics simulations. GAL and CCN were also studied for comparison. The structures of the complexes between the BChE and the ligands were predicted by molecular docking. Then, molecular dynamics simulations were performed to evaluate the stability of the complexes and the interactions between the ligands and the enzyme over a simulated time of 1 μs. All three ligands formed stable complexes with BChE. Compound 4b formed more hydrogen bonds and other interactions with BChE compared to GAL and CCN, suggesting a stronger binding affinity. The stronger binding of 4b to BChE might explain its superior anti-BChE activity observed in previous experiments.

Paraxanthine enhances memory and neuroplasticity more than caffeine in rats

Paraxanthine (PXN) is the main metabolite of caffeine (CAF). PXN supplementation has been shown to increase measures of cognition, memory, reasoning, response time, and sustained attention; however, no preclinical study has compared the effects of PXN with those of CAF. The aim of this study was to compare the effects of PXN and CAF on memory and related biomarkers in rats. The effects of two different doses of PXN (PXN LOW, PXN HIGH), CAF (CAF HIGH), and a control group on cognition (escape latency in the Morris water maze test), neurotransmitters (acetylcholine, dopamine, and gamma-aminobutyric acid), and neurochemicals (BDNF, catalase, glutathione, and cyclic GMP) were analyzed from whole brain samples in young (8 weeks old) and aged (16 months old) rats. Compared to the control group, escape latency improved in PXN LOW, PXN HIGH, and CAF HIGH (all P < 0.05) in young animals, and in PXN HIGH and CAF HIGH in older animals (P < 0.001). PXN HIGH improved escape latency compared to CAF HIGH in both young (P < 0.001) and old animals (P = 0.003). BDNF levels increased in PXN LOW, PXN HIGH, and CAF HIGH (all P < 0.001), with PXN HIGH increasing BDNF to a greater extent compared to CAF HIGH (P = 0.03). PXN HIGH also significantly increased BDNF levels compared to PXN LOW (P < 0.001). All other neurotransmitters and neurochemicals significantly increased in the PXN HIGH and CAF HIGH groups compared to the control. In conclusion, PXN showed greater improvements in cognition and BDNF levels compared to CAF, further substantiating PXN as a nootropic with greater benefits compared to CAF.

Catalytic mechanism, computational design, and crystal structure of a highly specific and efficient benzoylecgonine hydrolase.

Enzyme therapy for cocaine detoxification should break down both cocaine and its primary toxic metabolite, benzoylecgonine (BZE), which is also the main form of cocaine contaminant in the environment. An ideal BZE-metabolizing enzyme (BZEase) is expected to be highly efficient and selective in BZE hydrolysis. Here, BZEase4 was engineered from bacterial cocaine esterase (CocE) by our reactant state-based enzyme design theories (RED), which has a 34,977-fold improved substrate discrimination between BZE and the neurotransmitter acetylcholine (ACh), compared with wild-type CocE. Under the physiological concentrations of BZE and ACh, the reaction velocity of BZEase4 against BZE is 2.25×106-fold higher than it against ACh, suggesting BZEase4 has extremely high substrate selectivity for BZE over ACh to minimize the potential cholinergic side-effects. This study provides additional evidence supporting the further development of BZEase4 toward a promising therapeutic for cocaine overdose, a potentially effective and eco-friendly enzymatic method for BZE degradation in the environment.

Ion coupling and inhibitory mechanisms of the human presynaptic high-affinity choline transporter CHT1.

In cholinergic neurons, choline is the precursor of the excitatory neurotransmitter acetylcholine (ACh), which plays a fundamental role in the brain. The high-affinity choline transporter, CHT1, mediates the efficient recycling of choline to facilitate ACh synthesis in the presynapse. Here, we report high-resolution cryoelectron microscopic (cryo-EM) structures of CHT1 in complex with the inhibitors HC-3 and ML352, the substrate choline, and a substrate-free state. Our structures show distinct binding modes of the inhibitors with different chemical structures, revealing their inhibition mechanisms. Additionally, we observed a chloride ion that directly interacts with the substrate choline, thereby stabilizing its binding with CHT1. Two sodium ions, Na2 and Na3, were clearly identified, which we speculate might be involved in substrate binding and conformational transitions, respectively. Our structures provide molecular insights into the coupling mechanism of ion binding with substrate binding and conformational transitions, promoting our understanding of the ion-coupled substrate transport mechanism.

Lactiplantibacillus plantarum KABP051: Stability in Fruit Juices and Production of Bioactive Compounds During Their Fermentation.

The lactic fermentation of fruit and vegetable juices by well-characterised probiotics remains relatively underexplored. We have investigated the stability and impact of Lactiplantibacillus plantarum KABP051 fermentation on orange, apple, and peach juices by microbiological, physicochemical, and sensory evaluation means. For each fruit juice, three different samples were analysed: original fruit juice without probiotic as blank (B), fruit juice inoculated with 107 CFU/mL of probiotic without fermentation (P), and fruit juice inoculated with 107 CFU/mL of probiotic and fermented at 37 °C for 24 h (PF). P samples displayed good stability throughout the study, and PF samples showed an initial increase in CFUs accompanied by a change in pH, confirming the ability of the probiotic to ferment these juices. After 60 days of refrigeration, PF samples contained >107 CFU/mL. Total phenolic content and antioxidant capacity were equivalent in F, P, and PF. Remarkably, deep metabolomic analyses confirmed malolactic fermentation and revealed the production of several bioactive compounds including the antimicrobial substance phenyllactic acid, the immunomodulatory and anti-fatigue amino acid N-acetyl glutamine, the vitamin B3 form nicotinic acid, the monoterpene (-)-β-pinene, and the neurotransmitter acetylcholine, among others, during probiotic fermentation. Finally, a hedonic analysis involving 51 participants showed that probiotic fermented orange juice is well accepted by panellists, with scores comparable to those of the control juice. Overall, we here show that fruit juices are excellent carriers for the delivery of the probiotic L. plantarum KABP051 and its non-alcoholic fermentation can result in tasty functional fruit juices enriched with health-promoting compounds.

2D-SnS-Embedded Schottky Device with Neurotransmitter-Like Functionality Produced Using Proximity Vapor Transfer Method for Photonic Neurocomputing.

Neuromorphic computing, which involves the creation of artificial synapses capable of mimicking biological brain activity, has intrigued researchers in the field of artificial intelligence (AI). To advance neuromorphic computing, a highly efficient 2D material-based artificial synapse capable of performing logical and arithmetic operations must be developed. However, fabricating large, uniform films or high-quality structures of 2D materials remains challenging because of their multistep and complex fabrication processes. In the present study, to produce large (Ø ≈ 3 in.), uniform, transparent neuromorphic devices, a novel single-step approach called proximity vapor transfer (PVT) that utilizes van der Waals (vdW) materials is employed. This single-step technique, which involves the fabrication of vdW materials on various substrates (glass, ITO, AZO, Mo, and Cu), allows control of the thickness and bandgap tunability. The Schottky device developed via the PVT method using vdW SnS with neurotransmitter (acetylcholine)-like functionality emulates biological synapses and exhibits photoelectronic synaptic behavior with wide-field-of-view synaptic plasticity. In addition, logic gate operations (NOT, OR, AND), reward-cascade neurotransmission, and imaging can be performed using 3 × 3 arrays of the device. This study represents a significant step toward the development of transparent and large-area synaptic devices, which are crucial for advancing AI applications.

Trends in dietary choline and betaine intake among Chinese adults: the China Health and Nutrition Survey 1991-2011.

Choline and its derivative betaine are important methyl donors, components of cell membrane phospholipids, or precursors of the neurotransmitter acetylcholine and the gut microbial metabolite trimethylamine-N-oxide. We aimed to investigate trends in dietary intake and food sources of total choline, individual choline forms, and betaine in Chinese adults using data from the China Health and Nutrition Survey (CHNS) 1991-2011. The sample was drawn from urban and rural communities in 12 provinces or autonomous regions with a multistage, random cluster design. Dietary intake was estimated using three consecutive 24-hour dietary recalls in combination with a household food inventory. Linear mixed-effect models were constructed to calculate adjusted mean intake values and 95% confidence intervals (CIs) using R version 4.2.2. A total of 11,188 men and 12,279 women aged 18 years or older were included. Between 1991 and 2011, total choline intake increased from 219.3 (95% CI: 215.1-223.4) mg/d to 269.0 (95% CI: 265.6-272.5) mg/d in men and from 195.6 (95% CI: 191.8-199.4) mg/d to 240.4 (95% CI: 237.4-243.5) mg/d in women (both P-trends <0.001). Phosphatidylcholine was the major form of dietary choline and its contribution to total choline increased from 46.9% in 1991 to 58.8% in 2011. Cereals were the primary food source of total choline before 2000 while eggs had ranked at the top since 2004. Dietary betaine intake was relatively steady over time with a range of 134.0-151.5 mg/d in men (P-trend <0.001) and 111.7-125.3 mg/d in women (P-trend >0.05). In conclusion, Chinese adults experienced a significant increase in dietary intake of choline, particularly phosphatidylcholine during 1991-2011 and animal-derived foods have replaced plant-based foods as the main food sources of choline. Betaine intake remained relatively stable over time. Future efforts should address the health effects of these changes.

Biological Evaluation of Cucumis trigonus (Roxb.) for Memory Enhancing Activity in Scopolamine-induced Amnesia in Mice

Introduction: Plants have been employed for centuries to enhance human health due to their cost-effectiveness and minimal adverse effects. Numerous plants exhibit a wide spectrum of pharmacological activities, and various herbal medicines are currently being investigated for their memory-enhancing properties. Method: Cucumis trigonus (Roxb.), commonly known as Kachari or Bitter gourd, is one such plant with diverse pharmacological attributes. Historically, the fruits of C. trigonus have been utilized for addressing various conditions like leprosy, pyrexia, icterus, hyperglycemia, chronic cough, bronchitis, abdominal fluid accumulation, anemia, obstipation, diverse gastrointestinal disease, and cognitive impairment. The current investigation aims to explore the memory enhancement properties of C. trigonus, rooted in its traditional applications, particularly against scopolamine-induced amnesia in mice. Morris water maze and elevated plus maze paradigms were employed to evaluate cognitive performance. Furthermore, the research examined acetylcholine neurotransmission, oxidative stress markers, and cerebral histopathology. Result: The results showed that C. trigonus ethanol extract (dose- 150 or 300 mg/kg., p.o.), markedly (p&lt;0.05) improved memory in scopolamine-induced amnesia in mice and significantly (p&lt;0.05) elevated hippocampus acetylcholine concentration. These findings revealed that the ethanol extract of C. trigonus fruits mitigates memory deficits and demonstrates neuroprotective efficacy analogous to the reference drug Piracetam. Additionally, the extract showed notable in vivo antioxidant activity. The occurrence of flavonoids and phenols is likely to be responsible for its memory-enhancing effects due to their antioxidant properties, which help to prevent the loss of neurons. Conclusion: These results support the efficacy and potential of C. trigonus ethanol extract as an affordable alternative form of herbal medicine for the treatment of Amnesia.

A Comprehensive Analysis on Galantamine Based Hybrids for the Management of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive chronic age-related neurodegenerative brain disorder characterized by the loss of memory and other cognitive functions. The exact etiology of AD is still under investigation, however several factors such as low level of neurotransmitter acetylcholine (ACh), aggregation of amyloid beta (Aβ) in the form of Aβ plaques, hyperphosphorylation of tau protein into neurofibrillary tangles (NFTs), oxidative stress, and metal ion imbalance are the major hallmarks of this disease. Of the multiple hypotheses for AD, the amyloid-β (Aβ) and cholinergic hypothesis are the main targeting hypotheses for AD. Some researchers hypothesized that the primary event associated with the cholinergic neurotransmitter (acetylcholine) is memory loss and cognitive impairment. Due to the disease's complicated pathogenesis, long-term therapy with a single target candidate is futile. As a result, multitargeted and multifunctional therapies have emerged. Various research teams are concentrating on addressing multiple disease factors through hybridization techniques. Consequently, this hybridization approach has been applied to all core scaffolds, including galantamine. In this article, we tried to provide a thorough overview of the most recent developments on galantamine, a prospective AChE inhibitor, and its hybrid analogs as possible therapeutic agents for treating AD. Furthermore, we also provided the design, synthesis, and SAR analysis of the galantamine-based compounds used in the last decades for the management of AD.

Vagus Nerve Stimulation for Neurologic Recovery

Neural plasticity, a potential mode of managing various neurologic diseases, can be modulated via bursts of neurotransmitter release, including norepinephrine and acetylcholine. One method to do so is by electrically stimulating the vagus nerve while performing a specific task. Vagus nerve stimulation (VNS) has proven to be a viable intervention for conditions, including treatment-resistant epilepsy, depression, and, more recently, motor recovery after ischemic stroke. This article aims to explain the neurobiologic mechanism of VNS-induced cortical plasticity. It highlights both animal and human studies of VNS therapy, with a primary focus on recovery after stroke, traumatic brain injury, and spinal cord injury recovery. Furthermore, we discuss the long-term effects of VNS therapy, suggest potential solutions to overcome challenges encountered in previous studies, and elaborate on future directions in the field.

The Importance of Gut Microbiota on Choline Metabolism in Neurodegenerative Diseases.

The gut microbiota is a complex ecosystem that influences digestion, immune response, metabolism, and has been linked to health and well-being. Choline is essential for neurotransmitters, lipid transport, cell-membrane signaling, methyl-group metabolism and is believed to have neuroprotective properties. It is found in two forms, water-soluble and lipid-soluble, and its metabolism is different. Long-term choline deficiency is associated with many diseases, and supplements are prescribed for improved health. Choline supplements can improve cognitive function in adults but not significantly. Choline is a precursor of phospholipids and an acetylcholine neurotransmitter precursor and can be generated de novo from phosphatidylcholine via phosphatidylethanolamine-N-methyltransferase and choline oxidase. Choline supplementation has been found to have a beneficial effect on patients with neurodegenerative diseases, such as Alzheimer's disease (AD), by increasing amyloid-β, thioflavin S, and tau hyper-phosphorylation. Choline supplementation has been shown to reduce amyloid-plaque load and develop spatial memory in an APP/PS1 mice model of AD. Choline is necessary for normative and improved function of brain pathways and can reduce amyloid-β deposition and microgliosis. Clinical research suggests that early neurodegenerative diseases (NDs) can benefit from a combination of choline supplements and the drugs currently used to treat NDs in order to improve memory performance and synaptic functioning.

The memory-improving effect of Hizikia forsiforme functional oil microcapsule (HFFOM) prepared by subcritical extraction and complex coacervational embedding

Functional foods are prospective in improving memory decline caused by Alzheimer’s disease and aging. The Edible seaweed Hizikia fusiforme functional oil (HFFO) inhibited acetylcholinesterase, prevented cellular neuroinflammation, and improved memory deficits in zebrafish models in the previous studies. To realize its greener preparation and lipid oxidation mitigation and study its effects on higher animals, more investigations are necessary. Herein, sub-critical fluid extraction of HFFO and successive complex coacervation embedding yielded a water-soluble and anti-oxidative microcapsule HFFOM, which displayed in vivo memory-improving effects on LPS-injured zebrafish and normal rodents in different behavior tests. HFFOM can elevate the level of the neurotransmitter acetylcholine while decreasing the levels of MDA, IL-1β, and TNF-α in the zebrafish brain. LC-MS/MS and lipidomic analysis suggested its predominant memory-improving ingredients to be linolenic, erucic, nervonic, arachidonic, linoleic, eicosatrienoic, docosahexaenoic, and docosapentaenoic acids. This study enlightens the potential of HFFOM in developing memory-enhancing functional foods or drugs.

The neural regulation and impact of posterior nasal neurectomy on nasal ciliary motion in vivo in a murine allergic rhinitis model.

Posterior nasal neurectomy (PNN) is a commonly employed surgical approach for the treatment of allergic rhinitis (AR). Due to its denervation effect on the nasal mucosa, PNN may potentially alter the motion and defensive capability of cilia. Previous research on the effects of neural regulation and denervation on cilia has been limited by the absence of a feasible in vivo evaluation method for assessing ciliary function. Utilizing a new system developed by our team for visualizing and analyzing ciliary motion in vivo, we analysed ciliary beat frequency and distance in vivo and histomorphological changes in a murine PNN and AR model. Ovalbumin, histamine and neurotransmitters (acetylcholine chloride, α receptor agonist and β receptor agonist) were applied to investigate the responsiveness and neural regulation of the nasal mucosa. Denervation resulting from PNN led to a reduction in nasal ciliary beat frequency (CBF) to 78% of the control, as well as diminished response towards allergens and histamine. Among neurotransmitters examined, α receptor agonists exhibited inhibitory effects on in vivo ciliary motion while acetylcholine and β receptor agonists demonstrated stimulatory effects. PNN did not affect the reactivity of in vivo cilia towards these neurotransmitters. PNN-induced denervation can reduce ciliary motion, potentially compromising the defensive capability of nasal mucosa. Neural regulation and the neurotransmitters involved have significant effect on ciliary motion.

Tuft cells in the intestine, immunity and beyond.

Tuft cells have gained substantial attention over the past 10 years due to numerous reports linking them with type 2 immunity and microorganism-sensing capacity in many mucosal tissues. This heightened interest is fuelled by their unique ability to produce an array of biological effector molecules, including IL-25, allergy-related eicosanoids, and the neurotransmitter acetylcholine, enabling downstream responses in diverse cell types. Operating through G protein-coupled receptor-mediated signalling pathways reminiscent of type II taste cells in oral taste buds, tuft cells emerge as chemosensory sentinels that integrate luminal conditions, eliciting appropriate responses in immune, epithelial and neuronal populations. How tuft cells promote tissue alterations and adaptation to the variety of stimuli at mucosal surfaces has been explored in multiple studies in the past few years. Since the initial recognition of the role of tuft cells, the discovery of diverse tuft cell effector functions and associated feedback loops have also revealed the complexity of tuft cell biology. Although earlier work largely focused on extraintestinal tissues, novel genetic tools and recent mechanistic studies on intestinal tuft cells established fundamental concepts of tuft cell activation and functions. This Review is an overview of intestinal tuft cells, providing insights into their development, signalling and interaction modules in immunity and other states.