The vestibular system is a critical sensory modality required for coordinated movement, balance and our ability to interact with the surrounding environment. Vestibular sensory neurons provide the nervous system with information about head rotation and acceleration. However, the nervous system can also modify the activity of sensory neurons and hair cells via the actions of the efferent vestibular system (EVS). The function of the EVS has remained unknown partly because of an inability to target efferent vestibular neurons in a selective manner to understand their synaptic inputs and function during behaviour. Here, we present a novel method for the selective targeting and expression of flp-recombinase in EVS neurons. We take advantage of the dual expression of choline acetyl transferase (ChAT) and calcitonin gene related peptide (CGRP) in these neurons to develop an adeno-associated virus (AAV) that expresses a gene only in neurons with this intersectional expression. We use this system to map the monosynaptic inputs to EVS neurons and show inputs from distinct populations of brainstem and midbrain regions indicating a functional role as a multimodal processing center and integrator for the vestibular periphery. To demonstrate the applicability of our technology in behavioural assays, we performed a preliminary behaviour analysis (treadmill running and open field) in mice with disrupted EVS function. While more bespoke assays are required to ascertain EVS function/s, our viral method presents a novel tool for investigators examining the role of the vestibular system and its central circuits.

Cholinergic modulation of hippocampal CA1 pyramidal cell excitability in ArxGCG+7 mice.

Carnitine acetyltransferase acts as a unidirectional compensatory enzyme for choline acetyltransferase activity in Nilaparvata lugens.

Compound heterozygous CHAT gene mutations, a missense and a splice site variant, in two siblings with congenital myasthenic syndrome.

The purpose of this study was to assess the effects of a 60% ethanolic extract of Aster yomena (EAY) on chronic unpredictable mild stress (CUMS)-induced depressive cognitive dysfunction. The results showed that EAY mitigated CUMS-induced depressive-like behaviors, as confirmed by the sucrose preference test (SPT), open field test (OFT), tail suspension test (TST), and forced swimming test (FST). In addition, EAY showed protective effects on cognitive function in the Y-maze and the Morris water maze (MWM) tests. In this regard, EAY alleviated hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis through regulation of corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), and cytochrome P450 family 11 subfamily B member 1 (CYP11B1), thereby improving the levels of serum cortisol. It suppressed neuroinflammation, oxidative stress, and mitochondrial dysfunction by inhibiting the Toll-like receptor 4 (TLR4)/nuclear factor κ-light-chain-enhancer of the activated B cells (NF-κB) pathway. As a result, cognitive dysfunction was ameliorated through modulation of the cholinergic system, including acetylcholinesterase (AChE), acetylcholine (ACh), and choline acetyltransferase (ChAT), and synaptic plasticity-related factors such as postsynaptic density protein 95 (PSD-95) and growth-associated protein 43 (GAP-43). Based on these results, EAY could potentially be used as a natural therapeutic for prevention of major depressive cognitive impairment.

Choline acetyltransferase as a marker for Merkel cells in mucosal and skin tissues.

Reprogramming of astrocytes into motoneuron-like cells by a Ascl1-Myt1l-Pou3f2-Isl1 cocktail.

Neuroprotective effects of aegeline against LPS-induced memory dysfunction: involvement of hippocampal cholinergic/proinflammatory cytokines receptor modulation and insilico insight.

Lactobacillus helveticus R0052-derived membrane vesicles ameliorate DSS-induced inflammatory bowel disease by modulating the gut microbiota and activating the cholinergic anti-inflammatory pathway.

Striatal output is dynamically modulated by cholinergic interneurons (CINs), the primary source of acetylcholine in the striatum. CINs have been classically viewed as a random and homogeneous population, but recent evidence suggests heterogeneity in their anatomical and functional organization. Here, using systematic mapping and quantitative spatial analyses, we found that-contrary to current dogma-CINs exhibited striking enrichment and nonrandom clustering in the striosome compartment, particularly in the lateral striatum. Similar analyses carried out for parvalbumin- and somatostatin-expressing interneurons revealed that compartmental organization is interneuron specific. The strong "striosome preference" exhibited by CINs was confined within striosome borders, not extending to the surrounding matrix. We further found that striosome and matrix CINs differed in their expression levels of phospho-S6 ribosomal protein-Ser240/244 and choline acetyltransferase, suggesting functional differences, and clustered CINs differed from unclustered CINs in their intrinsic membrane properties. Finally, CINs expressing Lhx6, which defines a distinct γ-aminobutyric acid (GABA) coreleasing population, were notably absent from regions where highly clustered striosomal CINs appeared. Collectively, our findings uncover important dimensions of CIN organization, suggesting that modulation of regional and compartmental striatal output may depend upon the spatial-functional heterogeneity of CINs.

Lactococcus formosensis and its metabolite 4-acetamidobutanoic acid induced caspase-11 dependent myenteric neuronal pyroptosis in intractable functional constipation.

Fine particulate matter (PM2.5), which contains heavy metals such as Al, Fe, Mg, and Mn, among others, induces cognitive dysfunction through oxidative stress, neuroinflammation, and impaired mitochondria. This study evaluated the neuroprotective effects of a 40% ethanol extract of Polygonum multiflorum (EPM) on PM2.5-induced cognitive dysfunction in a mouse model. Behavioral assessments demonstrated attenuated learning and memory impairment following EPM treatment. Redox homeostasis was restored through increased expression of superoxide dismutase (SOD) and glutathione (GSH) and decreased levels of malondialdehyde (MDA) and mitochondrial reactive oxygen species (mtROS) in the EPM group. Mitochondrial function was attenuated, as indicated by recovery of mitochondrial membrane potential and ATP levels. EPM inhibited neuroinflammation by downregulating the TLR4-MyD88-NF-κB pathway and maintaining blood-brain barrier integrity through the upregulation of tight junction proteins. It modulated neuronal apoptosis through the JNK pathway, reducing the accumulation of amyloid-beta and phosphorylated tau. Synaptic plasticity was preserved through upregulation of BDNF/TrkB signaling and cholinergic neurotransmission via regulation of acetylcholine (ACh), acetylcholinesterase (AChE), and choline acetyltransferase (ChAT). To standardize EPM, high-performance liquid chromatography (HPLC) confirmed the presence of the bioactive compound, tetrahydroxystilbene glucoside (TSG). These findings suggest that EPM may be a promising functional food candidate for mitigating PM2.5-related cognitive impairments.

This study aimed to explore the effects and molecular mechanisms of 8-week treadmill exercise on constipation symptoms in mice with chronic Parkinson's disease (PD). Forty C57BL/6 mice were randomly divided into four groups: control group, model (PD) group, 8-week treadmill exercise (PD+Ex) group, and 8-week treadmill exercise+3-methyladenine (3MA) (PD+Ex+3MA) group, with n = 10 in each group. A chronic PD mouse model was prepared using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) combined with probenecid (MPTP/p). The PD+Ex group underwent 8 weeks of treadmill exercise training, while the PD+Ex+3MA group received an additional 5 weeks of 3MA intraperitoneal injection (simultaneously with modeling). Constipation symptoms were evaluated using indicators such as defecation parameters, colon length, and colon to body weight ratio. Immunofluorescence staining was used to detect α-synuclein (α-syn) deposition in the colon. RT-qPCR was used to detect the mRNA expression levels of key enzymes of neurotransmitters in the colon, and Western blot was used to detect pathological and autophagy-related protein expression levels. The results showed that, compared with the control group, the PD group mice exhibited motor dysfunction and significant constipation symptoms. In the PD group, the protein expression of tyrosine hydroxylase (TH) in the striatum was significantly downregulated, while α-syn deposition in the colon was significant and its protein expression was significantly up-regulated. The mRNA expression of neuronal nitric oxide synthase (nNOS) was up-regulated, while the expression levels of TH protein and choline acetyltransferase (ChAT) mRNA were down-regulated in the colon. The protein expression of p62 was up-regulated, and the protein expression levels of Beclin1 and LC3II were down-regulated in the colon. After treadmill exercise intervention, all the above changes in the PD group were significantly improved, and autophagy inhibitor 3MA could counteract these improving effects of treadmill exercise intervention. These results suggest that 8-week treadmill exercise can improve constipation symptoms in MPTP/p-induced chronic PD mice, and its protective effect may be achieved by activating autophagy.

Background/Objectives: Facial nerve injury from conditions such as Bell’s palsy, trauma, surgery, and infection leads to facial asymmetry and motor deficits. Axotomy models reproduce peripheral nerve disruption and consequent motor impairment. To compare the effects of forward versus reverse autologous nerve suturing on neural regeneration and motor recovery within the facial nucleus after axotomy. Methods: In rats subjected to facial nerve axotomy, motor recovery was assessed at 8 weeks using whisker movement and blink reflex tests. Immunohistochemistry quantified choline acetyltransferase (ChAT), sirtuin 1 (SIRT1), and Iba-1 as indices of cholinergic function, cellular stress/inflammation modulation, and microglial activation in the facial nucleus. Results: Axotomy significantly reduced whisker and blink scores compared with sham. Both forward and reverse suturing significantly improved these behavioral outcomes versus axotomy. Within the facial nucleus, axotomy decreased ChAT- and SIRT1-positive cells and increased Iba-1 expression, while both suturing techniques increased ChAT and SIRT1 and reduced Iba-1. These changes suggest enhanced cholinergic function, mitigation of stress/inflammatory responses, and attenuation of microglial activation following repair. Conclusions: Forward and reverse suturing were each associated with improved motor function and favorable molecular and cellular changes in the facial nucleus after facial nerve axotomy. These findings support the utility of surgical repair irrespective of graft orientation and highlight involvement of key pathways—cholinergic signaling, SIRT1-related regulation, and microglial activity—in nerve restoration. This work extends our previous study, which focused on peripheral nerve regeneration after forward and reverse suturing, by elucidating how graft orientation affects central facial nucleus responses. By integrating behavioral outcomes with ChAT, Iba-1, and SIRT1 expression, the present study provides novel insight into the central mechanisms underlying motor recovery after facial nerve repair and helps explain why comparable functional outcomes are achieved regardless of graft polarity.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder predominantly affecting the elderly and characterized by dementia. AD pathology involves impaired cholinergic neurotransmission, largely due to β-amyloid (Aβ) plaque accumulation, which inhibits choline acetyltransferase (ChAT) and reduces acetylcholine (ACh) levels. Acetylcholinesterase (AChE) contributes to AD progression by hydrolyzing ACh and promoting Aβ plaque formation, making it a key therapeutic target. This study investigated natural compounds from black tea (Camellia sinensis) as potential AChE inhibitors. Molecular docking analyses assessed interactions between bioactive compounds from aqueous black tea extracts and AChE, followed by evaluation of bioavailability, biological activity, toxicity, stability, and reactivity. Epigallocatechin gallate exhibited the strongest binding affinity (∆Gbind = –12.2740 kcal/mol), forming extensive interactions with the catalytic active site located at the bottom of a deep and narrow gorge (~20 Å). Density Functional Theory (DFT) analysis confirmed its high stability and favorable reactivity in complex with AChE. In vitro validation using black tea extracts from Bogor, Indonesia, showed significant AChE inhibition with an IC50 value of 44.85 ± 1.48 µg/mL. These findings highlight the promising potential of Indonesian black tea as a natural alternative for Alzheimer’s disease therapy.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is the leading cause of dementia globally. First-line AD therapy using cholinesterase inhibitors such as donepezil, galantamine, and rivastigmine shows interindividual variation in effectiveness, indicating the involvement of genetic factors. This study aims to identify genetic variants that influence response to AD therapy through bioinformatics and pharmacogenomic approaches. Data were retrieved from PharmGKB and analyzed based on therapy efficacy, allele frequencies across populations (1000 Genomes), and gene expression (GTEx). Four SNP variants were found to be relevant: rs6494223 (CHRNA7), rs3793790 and rs2177370 (CHAT), and rs1803274 (BCHE). Specific genotypes such as CC (rs6494223), GG and AA (CHAT), and TT (rs1803274) showed better therapy response. Expression analysis showed that the CHAT gene is highly expressed in the brain, reinforcing its pharmacogenetic relevance. In contrast, CHRNA7 and BCHE showed high expression in non-neuronal tissues, yet still play a systemic role in acetylcholine metabolism. Variations in allele frequencies between populations were also identified, underscoring the importance of population-based therapeutic approaches. These results support the importance of simple genetic screening in the development of precision therapies for Alzheimer’s. This study demonstrates that integrating pharmacogenomic and gene expression data can provide a better understanding of the heterogeneity of AD therapy response and open the possibility of personalized treatment based on the patient’s genetic profile.

Chlorogenic acid (CGA) is a dietary polyphenol with well-documented anti-inflammatory property. However, its effects on cholinergic signaling during inflammation remain under-explored. To investigate the role of CGA in modulating lipopolysaccharide (LPS) induced inflammation and epithelial barrier dysfunction in human intestinal cells, with a focus on cholinergic pathways involving acetylcholinesterase (AChE) and muscarinic receptors. Caco-2 cell monolayers were treated with LPS, with or without CGA. Inflammatory markers, tight junction proteins, mucin secretion, and cholinergic gene expression were assessed via qRT-PCR, ELISA, immunofluorescence, and Alcian Blue staining. AChE activity was measured in cell supernatants. Kinetic studies were done with pure human and electric eel enzymes. Inhibition kinetics and molecular docking was performed. Darifenacin was used to probe the role of muscarinic receptors. CGA significantly suppressed LPS-induced expression of TNF-α, IL-6, and COX-2, and restored tight junction protein expression (ZO-1, occludin) and sucrase-isomaltase mRNA levels. CGA attenuated LPS-induced mucin hypersecretion without affecting MUC2 gene or protein expression. It also reversed LPS-induced upregulation of α7 nicotinic ACh receptors and further elevated choline acetyltransferase (ChAT) and M3 muscarinic receptor (mAChR3) expression. These effects were abolished by muscarinic receptor antagonism, indicating CGA's dependence on mAChR signaling. CGA reduced cholinesterase activity in supernatants. Kinetic studies revealed that CGA competitively inhibited HuAChE (IC₅₀ = 225 nM; Ki = 30.7 nM) and EeAChE (IC₅₀ = 150 µM; Ki = 15.5 µM). Molecular docking showed strong interactions with HuAChE catalytic residues and the mAChR3 orthosteric site, supporting its dual role as an AChE inhibitor and muscarinic receptor agonist. Bioavailability radar analysis confirmed CGA's potential as a drug-like molecule. CGA protects intestinal epithelial cells from inflammatory damage by enhancing cholinergic anti-inflammatory signaling through specific AChE inhibition and regulation. Future studies should validate these effects in vivo and confirm functional receptor activation and bioavailability.

BackgroundAlzheimer's disease (AD), the leading cause of dementia, is characterized by β‐amyloid plaques, tau tangles, and early cholinergic dysfunction. This meta analysis examines changes in Butyrylcholinesterase (BChE), Acetylcholinesterase (AChE), Choline Acetyltransferase (ChAT), and choline levels in brain regions and cerebrospinal fluid (CSF) of AD patients versus healthy controls, highlighting their association with cognitive impairment.MethodWe searched MEDLINE, EMBASE, Cochrane, and Scopus for studies on BChE, AChE, ChAT activity, and choline levels in CSF and brain regions of AD patients, following PRISMA guidelines. Meta‐analysis used R's 'meta' package with inverse variance weighting to calculate mean concentrations and Standardized Mean Differences (SMDs). Heterogeneity was assessed using I2 and T2, with T2 estimated via restricted maximum‐likelihood and Q‐profile methods.ResultAChE showed significant SMD of ‐1.00 (95% CI: ‐1.79 to ‐0.22, I2 = 95.1%) in 22 studies (AD 414, 434 controls) in CSF. For brain regions, AChE showed significant SMD of ‐1.20 (95% CI: ‐1.58 to ‐0.83, I2 = 63.9%) in 6 studies (AD 253, 180 controls), with the most significant SMDs of ‐1.70 (temporal), ‐1.87 (frontal), ‐1.48 (parietal), and ‐1.27 (hippocampal). BChE showed significant SMD of ‐0.55 (95% CI: ‐1.04 to ‐0.06, I2 = 70.5%) in 8 studies (AD 159, 157 controls) in CSF. ChAT showed significant SMD of ‐2.21 (95% CI: ‐2.80 to ‐1.63, I2 = 90.1%) in 13 studies (AD 471, 434 controls), with the most significant SMDs of ‐3.24 (frontal), ‐2.55 (hippocampal), ‐2.28 (temporal), and ‐1.81 (occipital). Choline showed a significant SMD of ‐0.87 (95% CI: ‐1.52 to ‐0.23, I2 = 91.8%) in 5 studies (AD 311, 298 controls).ConclusionAChE showed significantly reduced activity in CSF and particularly in the temporal, frontal, hippocampal, and parietal brain regions. BChE exhibited significant reduction in CSF activity, and choline levels were significantly decreased in brain regions. ChAT showed significant reduction in the frontal, temporal, hippocampal, and occipital brain regions. Further research is required to validate these findings.

BackgroundAlzheimer's disease (AD), the leading cause of dementia, is characterized by β‐amyloid plaques, tau tangles, and early cholinergic dysfunction. This meta analysis examines changes in Butyrylcholinesterase (BChE), Acetylcholinesterase (AChE), Choline Acetyltransferase (ChAT), and choline levels in brain regions and cerebrospinal fluid (CSF) of AD patients versus healthy controls, highlighting their association with cognitive impairment.MethodWe searched MEDLINE, EMBASE, Cochrane, and Scopus for studies on BChE, AChE, ChAT activity, and choline levels in CSF and brain regions of AD patients, following PRISMA guidelines. Meta‐analysis used R's 'meta' package with inverse variance weighting to calculate mean concentrations and Standardized Mean Differences (SMDs). Heterogeneity was assessed using I² and τ², with τ² estimated via restricted maximum‐likelihood and Q‐profile methods.ResultAChE showed significant SMD of ‐1.00 (95% CI: ‐1.79 to ‐0.22, I² = 95.1%) in 22 studies (AD 414, 434 controls) in CSF. For brain regions, AChE showed significant SMD of ‐1.20 (95% CI: ‐1.58 to ‐0.83, I² = 63.9%) in 6 studies (AD 253, 180 controls), with the most significant SMDs of ‐1.70 (temporal), ‐1.87 (frontal), ‐1.48 (parietal), and ‐1.27 (hippocampal). BChE showed significant SMD of ‐0.55 (95% CI: ‐1.04 to ‐0.06, I² = 70.5%) in 8 studies (AD 159, 157 controls) in CSF. ChAT showed significant SMD of ‐2.21 (95% CI: ‐2.80 to ‐1.63, I² = 90.1%) in 13 studies (AD 471, 434 controls), with the most significant SMDs of ‐3.24 (frontal), ‐2.55 (hippocampal), ‐2.28 (temporal), and ‐1.81 (occipital). Choline showed a significant SMD of ‐0.87 (95% CI: ‐1.52 to ‐0.23, I² = 91.8%) in 5 studies (AD 311, 298 controls).ConclusionAChE showed significantly reduced activity in CSF and particularly in the temporal, frontal, hippocampal, and parietal brain regions. BChE exhibited significant reduction in CSF activity, and choline levels were significantly decreased in brain regions. ChAT showed significant reduction in the frontal, temporal, hippocampal, and occipital brain regions. Further research is required to validate these findings.

A comparison of transduction efficiency of medial septal neurons by adeno-associated viruses with three promoters.