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Altered interaction between striatonigral dopaminergic (DA) inputs and local acetylcholine (ACh) in striatum has long been hypothesized to play a central role in the pathophysiology of dystonia and dyskinesia. Indeed, previous research using several genetic mouse models of human isolated dystonia identified a shared endophenotype with paradoxical excitation of striatal cholinergic interneuron (ChIs) activity in response to activation of dopamine D2 receptors (D2R). These mouse models lack a dystonic motor phenotype, which leaves a critical gap in comprehending the role of DA and ACh transmission in the manifestations of dystonia. To tackle this question, we used a combination of ex vivo slice physiology and in vivo monitoring of striatal ACh dynamics in the inducible, phenotypically penetrant, transgenic mouse model of paroxysmal non-kinesiogenic dyskinesia (PNKD), an animal with both dystonic and dyskinetic features. We found that, similarly to genetic models of isolated dystonia, the PNKD mouse displays D2R-induced paradoxical excitation of ChI firing in ex vivo striatal brain slices. In vivo, caffeine triggers dystonic symptoms while reversing the D2R-mediated excitation of ChIs and desynchronizing ACh release in PNKD mice. In WT littermate controls, caffeine stimulates spontaneous locomotion through a similar but reversed mechanism involving an excitatory switch of the D2R control of ChI activity, associated with enhanced synchronization of ACh release. These observations suggest that the "paradoxical excitation" of cholinergic interneurons described in isolated dystonia models could represent a compensatory or protective mechanism that prevents manifestation of movement abnormalities and that phenotypic dystonia is possible only when this is absent. These findings also suggest that D2Rs may play an important role in synchronizing the ChI network leading to rhythmic ACh release during heightened movement states. Dysfunction of this interaction and corresponding desynchrony of ACh release may contribute to aberrant movements., Competing Interests: Declaration of competing interest Mariangela Scarduzio reports financial support was provided by Dystonia Medical Research Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Recently, we have observed an increasing focus on myocardial infarction (MI) with non-obstructive coronary arteries (MINOCA) patients. MINOCA incidence is estimated to be within the range of 5-15% of all MI cases. Unfortunately, MINOCA relates to various conditions that are not rarely hard to identify, including coronary microcirculation dysfunction, epicardial coronary spasm, or plaque erosion. Our systematic review aimed to identify and appraise previous studies which characterized acute complications, with particular focus on mechanical complications, in patients with MINOCA. Methods: Applying the MeSH strategy in PubMed and Embase, two operators independently and systematically reviewed published studies on patients diagnosed with MINOCA and in whom acute complications were described. Papers published in the last 10 years (June 2012-June 2022) to reflect the introduction of the MINOCA definition as well as the current clinical practice were analyzed. The research was conducted in July 2022. Results: The search yielded 192 records. After abstract review, 79 papers were left, and after full-text analysis, we finally included 20 studies. Among 20 studies, there were: one randomized controlled trial, one prospective study, five retrospective studies, 1 case series, and 12 case reports with a total number of 337,385 patients. In the identified literature, we revealed 7 cases of intraventricular septal rupture, 3 cases of free wall rupture with pericardial effusion or cardiac tamponade, and 3 cases of bleeding complications (intracerebral or intestinal bleeding). Moreover, the ventricular arrhythmia incidence ranged from 2% to 13.8%, and the in-hospital death rate ranged from 0.9% to 6.4%. Conclusions: These findings suggest that MINOCA patients should be treated as standard MI patients with watchful monitoring, especially in the first few days. [ABSTRACT FROM AUTHOR]

Objective: ASCL1, a pioneer transcription factor, is essential for neural cell differentiation and function. Previous studies have shown that Ascl1 expression is increased in pancreatic β-cells lacking functional K ATP channels or after feeding of a high fat diet (HFD) suggesting that it may contribute to the metabolic stress response of β-cells., Methods: We generated β-cell-specific Ascl1 knockout mice (Ascl1 βKO ) and assessed their glucose homeostasis, islet morphology and gene expression after feeding either a normal diet or HFD for 12 weeks, or in combination with a genetic disruption of Abcc8, an essential K ATP channel component., Results: Ascl1 expression is increased in response to both a HFD and membrane depolarization and requires CREB-dependent Ca 2+ signaling. No differences in glucose homeostasis or islet morphology were observed in Ascl1 βKO mice fed a normal diet or in the absence of K ATP channels. However, male Ascl1 βKO mice fed a HFD exhibited decreased blood glucose levels, improved glucose tolerance, and increased β-cell proliferation. Bulk RNA-seq analysis of islets from Ascl1 βKO mice from three studied conditions showed alterations in genes associated with the secretory function. HFD-fed Ascl1 βKO mice showed the most extensive changes with increased expression of genes necessary for glucose sensing, insulin secretion and β-cell proliferation, and a decrease in genes associated with β-cell dysfunction, inflammation and dedifferentiation. HFD-fed Ascl1 βKO mice also displayed increased expression of parasympathetic neural markers and cholinergic receptors that was accompanied by increased insulin secretion in response to acetylcholine and an increase in islet innervation., Conclusions: Ascl1 expression is induced by stimuli that cause Ca 2+ -signaling to the nucleus and contributes in a multifactorial manner to the loss of β-cell function by promoting the expression of genes associated with cellular dedifferentiation, attenuating β-cells proliferation, suppressing acetylcholine sensitivity, and repressing parasympathetic innervation of islets. Thus, the removal of Ascl1 from β-cells improves their function in response to metabolic stress., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Introduction: Hirschsprung disease (HD) manifests as a developmental anomaly affecting the enteric nervous system, where there is an absence of ganglion cells in the lower part of the intestine. This deficiency leads to functional blockages within the intestines. HD is usually confirmed or ruled out through rectal biopsy. The identification of any ganglion cells through hematoxylin and eosin (H&E) staining rules out HD. If ganglion cells are absent, further staining with acetylcholine-esterase (AChE) histochemistry or calretinin immunohistochemistry (IHC) forms part of the standard procedure for determining a diagnosis of HD. In 2017, our Institute of Pathology at University Hospital of Heidelberg changed our HD diagnostic procedure from AChE histochemistry to calretinin IHC. In this paper, we report the impact of the diagnostic procedure change on surgical HD therapy procedures and on the clinical outcome of HD patients. Methods: We conducted a retrospective review of the diagnostic procedures, clinical data, and postoperative progress of 29 patients who underwent surgical treatment for HD in the Department of Pediatric Surgery, University of Heidelberg, between 2012 and 2021. The patient sample was divided into two groups, each covering a treatment period of 5 years. In 2012–2016, HD diagnosis was performed exclusively using AChE histochemistry (AChE group, n = 17). In 2017–2021, HD diagnosis was performed exclusively using calretinin IHC (CR group, n = 12). Results: There were no significant differences between the groups in sex distribution, weeks of gestation, birth weight, length of the aganglionic segment, or associated congenital anomalies. Almost half of the children in the AChE group, twice as many as in the CR group, required an enterostomy before transanal endorectal pull-through procedure (TERPT). In the AChE group, 4 patients (23.5%) required repeat bowel sampling to confirm the diagnosis. Compared to the AChE group, more children in the CR group suffered from constipation post TERPT. Discussion: Elevated AChE expression is linked to hypertrophied extrinsic cholinergic nerve fibers in the aganglionic segment in the majority of patients with HD. The manifestation of increased AChE expression develops over time. Therefore, in neonatal patients with HD, especially those in the first 3 weeks of life, an increase in AChE reaction is not detected. Calretinin IHC reliably identifies the presence or absence of ganglion cells and offers multiple benefits over AChE histochemistry. These include the ability to perform the test on paraffin-embedded tissue sections, a straightforward staining pattern, a clear binary interpretation (negative or positive), cost-effectiveness, and utility regardless of patient age. Conclusions: The ability of calretinin IHC to diagnose HD early and time-independently prevented repeated intestinal biopsies in our patient population and allowed us to perform a one-stage TERPT in the first months of life, reducing the number of enterostomies and restoring colonic continuity early. Patients undergoing transanal pull-through under the age of 3 months require a close follow-up to detect cases with bowel movement problems. [ABSTRACT FROM AUTHOR]

The thymus is a lymphoid organ involved in the differentiation of T cells, and has a central role in the physiopathogenesis of Myasthenia Gravis (MG). This connection is proved by a series of changes in the level of neuromuscular junctions, which leads to a decrease in the amplitude of the action potential in the post-synaptic membrane. Because of this, the presence of anti-cholinergic receptor antibodies (AChR), characteristic of MG, is found, which causes the progressive regression of the effect of acetylcholine at the level of neuromuscular junctions, with the appearance of muscle weakness. The thymectomy is a surgical variant of drug therapy administered to patients with MG. In the case of patients with nonthymomatous MG, thymectomy has become a therapeutic standard, despite the fact that there is no solid scientific evidence to explain its positive effect. Videothoracoscopic surgery or robotic surgery led to a decrease in the length of hospital stay for these patients. This paper aims to synthesize the information presented in the literature in order to create a background for the perspectives of thymectomy. [ABSTRACT FROM AUTHOR]

Speer allergic tension-fatigue syndrome (SATFS) is a classic allergy syndrome characterized by allergy-like symptoms, muscle tension, headaches, chronic fatigue, and other particular behaviors that were initially described in the fifties. The particular behaviors displayed include symptoms such as hyperkinesis, hyperesthesia (i.e., insomnia), restlessness, and distractibility, among others. Interestingly, these symptoms are very similar to descriptions of attention deficit hyperactivity disorder (ADHD), the most prevalent neurodevelopmental disorder worldwide, which is characterized by inattention, hyperactivity, and impulsivity. The clinical description of SATFS precedes the nomination of ADHD in 1960 by Stella Chess. In this conceptual paper, we stress that there is a gap in the research on the relationship between ADHD and allergic pathologies. The hypotheses of this conceptual paper are (1) SATFS is probably one of the first and best historical descriptions of ADHD alongside a common comorbidity (allergy) displayed by these patients; (2) SATFS (ADHD) is a systemic disease that includes both somatic and behavioral manifestations that may influence each other in a bidirectional manner; (3) The role of neuroinflammation and histamine is key for understanding the pathophysiology of ADHD and its frequent somatic comorbidities; (4) The deficiency of the diamine oxidase (DAO) enzyme, which metabolizes histamine extracellularly, may play a role in the pathophysiology of ADHD. Decreased DAO activity may lead to an accumulation of histamine, which could contribute to core ADHD symptoms and comorbid disorders. Further empirical studies are needed to confirm our hypotheses. [ABSTRACT FROM AUTHOR]

Background: Heterogeneity in diagnostic criteria and provocation protocols has posed challenges in understanding the safety of coronary provocation testing with intracoronary acetylcholine (ACh) for the contemporary diagnosis of epicardial and microvascular spasm., Objectives: We examined the safety of testing and subgroup differences in procedural risks based on ethnicity, diagnostic criteria, and provocation protocols., Methods: PubMed and Embase were searched in November 2021 to identify original articles reporting procedural complications associated with intracoronary ACh administration. The primary outcome was the pooled estimate of the incidence of major complications including death, myocardial infarction, ventricular tachycardia/fibrillation, and shock., Results: A total of 16 studies with 12,585 patients were included in the meta-analysis. The overall pooled estimate of the incidence of major complications was 0.5% (95% CI: 0.0%-1.3%) without any reports of death. Exploratory subgroup analyses revealed that the pooled incidence of major complications was significantly higher in the studies that followed the contemporary diagnosis criteria for epicardial spasm defined as ≥90% diameter reduction (1.0%; 95% CI: 0.3%-2.0%) but significantly lower in Western populations (0.0%; 95% CI: 0.0%-0.45%). The rate of positive epicardial spasm and the incidence of major complications were similar between provocation protocols using the maximum ACh doses of 100 μg and 200 μg., Conclusions: Intracoronary ACh administration for the contemporary diagnosis of epicardial and microvascular spasm is a safe procedure. Moreover, excellent safety records are observed in Western populations primarily presenting with myocardial ischemia and/or infarction with nonobstructive coronary arteries. This study will help standardize ACh testing to improve clinical diagnosis and ensure procedural safety., Competing Interests: Funding Support and Author Disclosures Dr Samuels has a consulting agreement with Abbott Vascular; and serves as a consultant and on the Speakers Bureau for Abbott Vascular and Philips. Dr Parikh has a consulting agreement with Abbott Vascular; and serves on the advisory boards of Abbott Vascular, Boston Scientific, and Medtronic. Dr Wei has a consulting agreement with and serves on the advisory board of Abbott Vascular. Drs Moses, Fearon, Henry, Tremmel, and Kobayashi have consulting agreements with Abbott Vascular. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The aim of this paper was to investigate the influence of four different external factors (acetylcholine, ethanol, temperature and lidocaine hydrochloride) on PC12 quasi-neuronal networks by multielectrode-array-based Voltage Threshold Measurement Method (VTMM). At first, VTMM was employed to measure the lowest amplitude of the voltage stimulating pulses that could just trigger the action potential from PC12 quasi-neuronal networks under normal conditions, and the amplitude was defined as the normal voltage threshold (VTh). Then the changes of the VTh of PC12 quasi-neuronal networks treated by the four external factors were tested respectively. The results showed the normal VTh of PC12 quasi-neuronal networks was 36 mV. The VTh has negative correlation with the concentration of acetylcholine and has positive correlation with the concentration of ethanol. The curves of the correlation of the VTh with temperature and the concentration of lidocaine hydrochloride were U-shaped and Λ-shaped respectively. Comparing with our earlier studies on hippocampal neuronal networks and hippocampal slices, PC12 quasi-neuronal networks not only had the same typical voltage threshold characteristic, but also had similar changes on electrical excitability when treated by the four external factors mentioned above. Therefore, the rapid-formed PC12 quasi-neuronal networks could replace neuronal networks in proper conditions, and VTMM could be used to analyze the influence of external factors on the electrical excitability of PC12 quasi-neuronal networks., Competing Interests: The authors have declared that no competing interests exist.

Objectives: The present study aimed to assess the feasibility and clinical value of acetylcholine (ACh) rechallenge for the detection of coexisting epicardial and microvascular spasm and to determine the efficacy of nitroglycerin in these spasm endotypes., Background: The coexistence of epicardial and microvascular spasm is difficult to identify; thus, its frequency is unknown. Nitroglycerin treatment is equally recommended for both epicardial and microvascular coronary spasm despite contradictory data., Methods: In this multicenter study, 95 patients with coronary spasm were included to undergo ACh rechallenge, which consisted of repeated ACh provocation 3 minutes after intracoronary nitroglycerin administration using the same dose that previously induced spasm., Results: In total, 95 patients (age 61 ± 12 years, 69% female) were included. Fifty-five patients (58%) had microvascular spasm, and 40 patients (42%) had epicardial spasm during initial ACh provocation. In 48% of patients with epicardial spasm, ACh rechallenge revealed coexisting nitroglycerin-persistent microvascular spasm. Nitroglycerin administration before ACh rechallenge prevented reinducibility of epicardial spasm in all patients with focal spasm and in 80% of patients with diffuse spasm. Microvascular spasm was prevented in only 20% by prior nitroglycerin administration but was attenuated in another 49% of patients., Conclusions: This study demonstrates a high frequency of epicardial spasm with coexisting nitroglycerin-persistent microvascular spasm. Intracoronary nitroglycerin was very effective in preventing reinducibility of epicardial spasm, whereas it prevented microvascular spasm in only 20% of patients. ACh rechallenge is a novel method that facilitates the detection of coexisting spasm endotypes and may pave the way towards tailored treatment of vasospastic angina., Competing Interests: Funding Support and Author Disclosures This study was supported by the Robert Bosch Foundation, Stuttgart, Germany, and the Berthold Leibinger Foundation, Ditzingen, Germany. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Neuromodulators act on multiple timescales to affect neuronal activity and behavior. They function as synaptic fine-tuners and master coordinators of neuronal activity across distant brain regions and body organs. While much research on neuromodulation has focused on roles in promoting features of wakefulness and transitions between sleep and wake states, the precise dynamics and functions of neuromodulatory signaling during sleep have received less attention. This review discusses research presented at our minisymposium at the 2024 Society for Neuroscience meeting, highlighting how norepinephrine, dopamine, and acetylcholine orchestrate brain oscillatory activity, control sleep architecture and microarchitecture, regulate responsiveness to sensory stimuli, and facilitate memory consolidation. The potential of each neuromodulator to influence neuronal activity is shaped by the state of the synaptic milieu, which in turn is influenced by the organismal or systemic state. Investigating the effects of neuromodulator release across different sleep substates and synaptic environments offers unique opportunities to deepen our understanding of neuromodulation and explore the distinct computational opportunities that arise during sleep. Moreover, since alterations in neuromodulatory signaling and sleep are implicated in various neuropsychiatric disorders and because existing pharmacological treatments affect neuromodulatory signaling, gaining a deeper understanding of the less-studied aspects of neuromodulators during sleep is of high importance. [ABSTRACT FROM AUTHOR]

Humans are exposed to significant amounts of blue light from computers and smartphones. However, the effects of blue light on ulcerative colitis remain unclear. In this study, we assessed blue-light-irradiation-induced alterations in colonic symptoms using a dextran sodium sulfate (DSS)-induced ulcerative colitis model mice. Both male and female institute of cancer research (ICR) mice were administered DSS (5%) ad libitum for 5 days while irradiated with 40 kJ/m2 blue light daily. Additionally, tranexamic acid (TA) was administered daily throughout the study. Male mice treated with DSS/blue light exhibited exacerbated colitis compared to those treated with DSS alone. In contrast, female mice treated with DSS/blue light exhibited enhanced symptoms compared to those treated with DSS alone. Additionally, in male mice exposed to blue light, the clock/brain and muscle Arndt-like 1 (Bma1)/noradrenaline/macrophage or beta2-adrenergic receptor (β2-AR) pathways were activated. In female mice, the Bmal1/acetylcholine/macrophage/nicotinic acetylcholine receptor alpha 7 (α7nAChR) pathway was activated. These findings highlight sex differences in the effects of blue light on DSS-induced ulcerative colitis. Moreover, the worsening of symptoms in males was ameliorated through TA administration. [ABSTRACT FROM AUTHOR]

Acetylcholine (ACh) is thought to control arousal, attention, and learning by slowly modulating cortical excitability and plasticity. Recent studies, however, discovered that cholinergic neurons emit precisely timed signals about the aversive outcome at millisecond precision. To investigate the functional relevance of such phasic cholinergic signaling, we manipulated and monitored cholinergic terminals in the mPFC while male mice associated a neutral conditioned stimulus (CS) with mildly aversive eyelid shock (US) over a short temporal gap. Optogenetic inhibition of cholinergic terminals during the US promoted the formation of the CS--US association. On the contrary, optogenetic excitation of cholinergic terminals during the US blocked the association formation. The bidirectional behavioral effects paralleled the corresponding change in the expression of an activity-regulated gene, c-Fos in the mPFC. In contrast, optogenetic inhibition of cholinergic terminals during the CS impaired associative learning, whereas their excitation had marginal effects. In parallel, photometric recording from cholinergic terminals in the mPFC revealed strong innate phasic responses to the US. With subsequent CS--US pairings, cholinergic terminals weakened the responses to the US while developing strong responses to the CS. The across-session changes in the CS- and US-evoked terminal responses were correlated with associative memory strength. These findings suggest that phasic cholinergic signaling in the mPFC exerts opposite effects on aversive associative learning depending on whether it is emitted by the outcome or the cue. [ABSTRACT FROM AUTHOR]

Acetylcholine regulates various cognitive functions through broad cholinergic innervation. However, specific cholinergic subpopulations, circuits and molecular mechanisms underlying recognition memory remain largely unknown. Here we show that Ngfr+ cholinergic neurons in the substantia innominate (SI)/nucleus basalis of Meynert (nBM)-medial prefrontal cortex (mPFC) circuit selectively underlies recency judgements. Loss of nerve growth factor receptor (Ngfr−/− mice) reduced the excitability of cholinergic neurons in the SI/nBM-mPFC circuit but not in the medial septum (MS)-hippocampus pathway, and impaired temporal order memory but not novel object and object location recognition. Expression of Ngfr in Ngfr−/− SI/nBM restored defected temporal order memory. Fiber photometry revealed that acetylcholine release in mPFC not only predicted object encounters but also mediated recency judgments of objects, and such acetylcholine release was absent in Ngfr−/− mPFC. Chemogenetic and optogenetic inhibition of SI/nBM projection to mPFC in ChAT-Cre mice diminished mPFC acetylcholine release and deteriorated temporal order recognition. Impaired cholinergic activity led to a depolarizing shift of GABAergic inputs to mPFC pyramidal neurons, due to disturbed KCC2-mediated chloride gradients. Finally, potentiation of acetylcholine signaling upregulated KCC2 levels, restored GABAergic driving force and rescued temporal order recognition deficits in Ngfr−/− mice. Thus, NGFR-dependent SI/nBM-mPFC cholinergic circuit underlies temporal order recognition memory. Functional roles of the diverse cholinergic subpopulations such as those in the substantia innominate (SI) and the nucleus basalis of Meynert (nBM) are not fully understood. Here the authors show that Ngfr+ cholinergic neurons in the SI/nBM-mPFC circuit selectively regulates recency judgement in recognition memory. [ABSTRACT FROM AUTHOR]

This study focused on α -synuclein (α -syn) aggregation in the dorsomedial striatum (DMS) so as to investigate its role in the cognitive flexibility of Parkinson's disease (PD). Here, we investigated the cognitive flexibility by assessing reversal learning abilities in MPTP-induced subacute PD model mice and in C57BL/6J mice with α -syn aggregation in the DMS induced by adenovirus (AAV-SNCA) injection, followed by an analysis of the target protein's expression and distribution. PD mice exhibited impairments in reversal learning, positively correlated with the expression of phosphorylated α -syn in the DMS. Furthermore, the mice in the AAV-SNCA group exhibited reversal learning deficits and a reduction in acetylcholine levels, accompanied by protein alterations within the DMS. Notably, the administration of a muscarinic receptor 1 (M1R) agonist was able to alleviate the aforementioned phenomenon. These findings suggest that the impaired cognitive flexibility in PD may be attributed to the diminished activation of acetylcholine to M1R caused by α -syn aggregation. [ABSTRACT FROM AUTHOR]

Rhythmic brain activity is critical to many brain functions and is sensitive to neuromodulation, but so far very few studies have investigated this activity on the cellular level in vitro in human brain tissue samples. This study reveals and characterizes a novel rhythmic network activity in the human neocortex. Using intracellular patch-clamp recordings of human cortical neurons, we identify large rhythmic depolarizations (LRDs) driven by glutamate release but not by GABA. These LRDs are intricate events made up of multiple depolarizing phases, occurring at ~0.3 Hz, have large amplitudes and long decay times. Unlike human tissue, rat neocortex layers 2/3 exhibit no such activity under identical conditions. LRDs are mainly observed in a subset of L2/3 interneurons that receive substantial excitatory inputs and are likely large basket cells based on their morphology. LRDs are highly sensitive to norepinephrine (NE) and acetylcholine (ACh), two neuromodulators that affect network dynamics. NE increases LRD frequency through β-adrenergic receptor activity while ACh decreases it via M4 muscarinic receptor activation. Multi-electrode array recordings show that NE enhances and synchronizes oscillatory network activity, whereas ACh causes desynchronization. Thus, NE and ACh distinctly modulate LRDs, exerting specific control over human neocortical activity. A study discovered in vitro-maintained network activity in human neocortex, with large rhythmic depolarizations mainly in layer 2/3 basket cells, modulated by norepinephrine and acetylcholine. [ABSTRACT FROM AUTHOR]

In everyday life, we encounter situations that require tradeoffs between potential rewards and associated costs, such as time and (physical) effort. The literature indicates a prominent role for dopamine in discounting of both delay and effort, with mixed findings for delay discounting in humans. Moreover, the reciprocal antagonistic interaction between dopaminergic and cholinergic transmission in the striatum suggests a potential opponent role of acetylcholine in these processes. We found opposing effects of dopamine D2 (haloperidol) and acetylcholine M1 receptor (biperiden) antagonism on specific components of effort-based decision-making in healthy humans: haloperidol decreased, whereas biperiden increased the willingness to exert physical effort. In contrast, delay discounting was reduced under haloperidol, but not affected by biperiden. Together, our data suggest that dopamine, acting at D2 receptors, modulates both effort and delay discounting, while acetylcholine, acting at M1 receptors, appears to exert a more specific influence on effort discounting only. Tradeoffs between potential rewards and associated costs involves the dopaminergic system, which antagonistically interacts with the cholinergic system. This study describes that dopamine and acetylcholine have opposing effects on the modulation of specific components of cost-benefit decision making in humans. [ABSTRACT FROM AUTHOR]

Dysregulation of oligodendrocyte progenitor cell (OPC) recruitment and oligodendrocyte differentiation contribute to failure of remyelination in human demyelinating diseases such as multiple sclerosis (MS). Deletion of muscarinic receptor enhances OPC differentiation and remyelination. However, the role of ligand-dependent signaling versus constitutive receptor activation is unknown. We hypothesized that dysregulated acetylcholine (ACh) release upon demyelination contributes to ligand-mediated activation hindering myelin repair. Following chronic cuprizone (CPZ)-induced demyelination (male and female mice), we observed a 2.5-fold increase in ACh concentration. This increase in ACh concentration could be attributed to increased ACh synthesis or decreased acetylcholinesterase-/butyrylcholinesterase (BChE)-mediated degradation. Using choline acetyltransferase (ChAT) reporter mice, we identified increased ChAT-GFP expression following both lysolecithin and CPZ demyelination. ChAT-GFP expression was upregulated in a subset of injured and uninjured axons following intraspinal lysolecithin-induced demyelination. In CPZ-demyelinated corpus callosum, ChAT-GFP was observed in Gfap+ astrocytes and axons indicating the potential for neuronal and astrocytic ACh release. BChE expression was significantly decreased in the corpus callosum following CPZ demyelination. This decrease was due to the loss of myelinating oligodendrocytes which were the primary source of BChE. To determine the role of ligand-mediated muscarinic signaling following lysolecithin injection, we administered neostigmine, a cholinesterase inhibitor, to artificially raise ACh. We identified a dose-dependent decrease in mature oligodendrocyte density with no effect on OPC recruitment. Together, these results support a functional role of ligand-mediated activation of muscarinic receptors following demyelination and suggest that dysregulation of ACh homeostasis directly contributes to failure of remyelination in MS. [ABSTRACT FROM AUTHOR]

Goal-directed tasks involve acquiring an internal model, known as a predictive map, of relevant stimuli and associated outcomes to guide behavior. Here, we identified neural signatures of a predictive map of task behavior in perirhinal cortex (Prh). Mice learned to perform a tactile working memory task by classifying sequential whisker stimuli over multiple training stages. Chronic two-photon calcium imaging, population analysis, and computational modeling revealed that Prh encodes stimulus features as sensory prediction errors. Prh forms stable stimulus-outcome associations that can progressively be decoded earlier in the trial as training advances and that generalize as animals learn new contingencies. Stimulus-outcome associations are linked to prospective network activity encoding possible expected outcomes. This link is mediated by cholinergic signaling to guide task performance, demonstrated by acetylcholine imaging and systemic pharmacological perturbation. We propose that Prh combines error-driven and map-like properties to acquire a predictive map of learned task behavior. The neural mechanisms underlying how the brain generates internal models of the environment is not fully understood. Here authors show that mouse perirhinal cortex is involved in forming stable stimulus-outcome associations, possibly via cholinergic signaling. [ABSTRACT FROM AUTHOR]

Introduction: Pollution harms the health of people with asthma. The effect of the anti-inflammatory cholinergic pathway in chronic allergic inflammation associated to pollution is poorly understood. Methods: One hundred eight animals were divided into 18 groups (6 animals). Groups included: wild type mice (WT), genetically modified with reduced VAChT (VAChTKD), and those sensitized with ovalbumin (VAChTKDA), exposed to metal powder due to iron pelletizing in mining company (Local1) or 3.21 miles away from a mining company (Local2) in their locations for 2 weeks during summer and winter seasons. It was analyzed for hyperresponsivity, inflammation, remodeling, oxidative stress responses and the cholinergic system. Results: During summer, animals without changes in the cholinergic system revealed that Local1 exposure increased the hyperresponsiveness (%Rrs, %Raw), and inflammation (IL-17) relative to vivarium animals, while animals exposed to Local2 also exhibited elevated IL-17. During winter, animals without changes in the cholinergic system revealed that Local2 exposure increased the hyperresponsiveness (%Rrs) relative to vivarium animals. Comparing the exposure local of these animals during summer, animals exposed to Local1 showed elevated %Rrs, Raw, and IL-5 compared to Local 2, while in winter, Local2 exposure led to more IL-17 than Local1. Animals with VAChT attenuation displayed increased %Rrs, NFkappaB, IL-5, and IL-13 but reduced alpha-7 compared to animals without changes in the cholinergic system WT. Animals with VAChT attenuation and asthma showed increased the hyperresponsiveness, all inflammatory markers, remodeling and oxidative stress compared to animals without chronic lung inflammation. Exposure to Local1 exacerbated the hyperresponsiveness, oxidative stressand inflammation in animals with VAChT attenuation associated asthma, while Local2 exposure led to increased inflammation, remodeling and oxidative stress. Conclusions: Reduced cholinergic signaling amplifies lung inflammation in a model of chronic allergic lung inflammation. Furthermore, when associated with pollution, it can aggravate specific responses related to inflammation, oxidative stress, and remodeling. [ABSTRACT FROM AUTHOR]

The behavioral and neural effects of the endogenous release of acetylcholine following stimulation of the nucleus basalis (NB) of Meynert have been recently examined in two male monkeys (Qi et al., 2021). Counterintuitively, NB stimulation enhanced behavioral performance while broadening neural tuning in the prefrontal cortex (PFC). The mechanism by which a weaker mnemonic neural code could lead to better performance remains unclear. Here, we show that increased neural excitability in a simple continuous bump attractor model can induce broader neural tuning and decrease bump diffusion, provided neural rates are saturated. Increased memory precision in the model overrides memory accuracy, improving overall task performance. Moreover, we show that bump attractor dynamics can account for the nonuniform impact of neuromodulation on distractibility, depending on distractor distance from the target. Finally, we delve into the conditions under which bump attractor tuning and diffusion balance in biologically plausible heterogeneous network models. In these discrete bump attractor networks, we show that reducing spatial correlations or enhancing excitatory transmission can improve memory precision. Altogether, we provide a mechanistic understanding of how cholinergic neuromodulation controls spatial working memory through perturbed attractor dynamics in the PFC. [ABSTRACT FROM AUTHOR]

Background: Recently, we have observed an increasing focus on myocardial infarction (MI) with non-obstructive coronary arteries (MINOCA) patients. MINOCA incidence is estimated to be within the range of 5–15% of all MI cases. Unfortunately, MINOCA relates to various conditions that are not rarely hard to identify, including coronary microcirculation dysfunction, epicardial coronary spasm, or plaque erosion. Our systematic review aimed to identify and appraise previous studies which characterized acute complications, with particular focus on mechanical complications, in patients with MINOCA. Methods: Applying the MeSH strategy in PubMed and Embase, two operators independently and systematically reviewed published studies on patients diagnosed with MINOCA and in whom acute complications were described. Papers published in the last 10 years (June 2012–June 2022) to reflect the introduction of the MINOCA definition as well as the current clinical practice were analyzed. The research was conducted in July 2022. Results: The search yielded 192 records. After abstract review, 79 papers were left, and after full-text analysis, we finally included 20 studies. Among 20 studies, there were: one randomized controlled trial, one prospective study, five retrospective studies, 1 case series, and 12 case reports with a total number of 337,385 patients. In the identified literature, we revealed 7 cases of intraventricular septal rupture, 3 cases of free wall rupture with pericardial effusion or cardiac tamponade, and 3 cases of bleeding complications (intracerebral or intestinal bleeding). Moreover, the ventricular arrhythmia incidence ranged from 2% to 13.8%, and the in-hospital death rate ranged from 0.9% to 6.4%. Conclusions: These findings suggest that MINOCA patients should be treated as standard MI patients with watchful monitoring, especially in the first few days.

Several studies have shown an inverse correlation between the likelihood of developing a neurodegenerative disorder and cancer. We previously reported that the levels of amyloid beta (Aβ), at the center of Alzheimer's disease pathophysiology, are regulated by acetylcholinesterase (AChE) in non-small cell lung cancer (NSCLC). Here, we examined the effect of Aβ or its fragments on the levels of ACh in A549 (p53 wild-type) and H1299 (p53-null) NSCLC cell media. ACh levels were reduced by cell treatment with Aβ 1–42, Aβ 1–40, Aβ 1–28, and Aβ 25–35. AChE and p53 activities increased upon A549 cell treatment with Aβ, while knockdown of p53 in A549 cells increased ACh levels, decreased AChE activity, and diminished the Aβ effects. Aβ increased the ratio of phospho/total p38 MAPK and decreased the activity of PKC. Inhibiting p38 MAPK reduced the activity of p53 in A549 cells and increased ACh levels in the media of both cell lines, while opposite effects were found upon inhibiting PKC. ACh decreased the activity of p53 in A549 cells, decreased p38 MAPK activity, increased PKC activity, and diminished the effect of Aβ on those activities. Moreover, the negative effect of Aβ on cell viability was diminished by cell co-treatment with ACh. [ABSTRACT FROM AUTHOR]

Although the dopamine hypothesis of schizophrenia explains the effects of all the available antipsychotics in clinical use, there is an increasing need for developing new drugs for the treatment of the positive, negative, and cognitive symptoms of chronic psychoses. Xanomeline–trospium (KarXT) is a drug combination that is based on the essential role played by acetylcholine in the regulation of cognitive processes and the interactions between this neurotransmitter and other signaling pathways in the central nervous system, with a potential role in the onset of schizophrenia, Alzheimer's disease, and substance use disorders. A systematic literature review that included four electronic databases (PubMed, Cochrane, Clarivate/Web of Science, and Google Scholar) and the US National Library of Medicine database for clinical trials detected twenty-one sources referring to fourteen studies focused on KarXT, out of which only four have available results. Based on the results of these trials, the short-term efficacy and tolerability of xanomeline–trospium are good, but more data are needed before this drug combination may be recommended for clinical use. However, on a theoretical level, the exploration of KarXT is useful for increasing the interest of researchers in finding new, non-dopaminergic, antipsychotics that could be used either as monotherapy or as add-on drugs. [ABSTRACT FROM AUTHOR]

Acetylcholine (ACh) is released from basal forebrain cholinergic neurons in response to salient stimuli and engages brain states supporting attention and memory. These high ACh states are associated with theta oscillations, which synchronize neuronal ensembles. Theta oscillations in the basolateral amygdala (BLA) in both humans and rodents have been shown to underlie emotional memory, yet their mechanism remains unclear. Here, using brain slice electrophysiology in male and female mice, we show large ACh stimuli evoke prolonged theta oscillations in BLA local field potentials that depend upon M3 muscarinic receptor activation of cholecystokinin (CCK) interneurons (INs) without the need for external glutamate signaling. Somatostatin (SOM) INs inhibit CCK INs and are themselves inhibited by ACh, providing a functional SOM→CCK IN circuit connection gating BLA theta. Parvalbumin (PV) INs, which can drive BLA oscillations in baseline states, are not involved in the generation of ACh-induced theta, highlighting that ACh induces a cellular switch in the control of BLA oscillatory activity and establishes an internally BLA-driven theta oscillation through CCK INs. Theta activity is more readily evoked in BLA over the cortex or hippocampus, suggesting preferential activation of the BLA during high ACh states. These data reveal a SOM→CCK IN circuit in the BLA that gates internal theta oscillations and suggest a mechanism by which salient stimuli acting through ACh switch the BLA into a network state enabling emotional memory. [ABSTRACT FROM AUTHOR]

Inflammation is a physiological condition characterized by a complex interplay between different cells handled by metabolites and specific inflammatory-related molecules. In some pathological situations, inflammation persists underlying and worsening the pathological state. Over the years, two membrane transporters namely OCTN1 (SLC22A4) and OCTN2 (SLC22A5) have been shown to play specific roles in inflammation. These transporters form the OCTN subfamily within the larger SLC22 family. The link between these proteins and inflammation has been proposed based on their link to some chronic inflammatory diseases such as asthma, Crohn's disease (CD), and rheumatoid arthritis (RA). Moreover, the two transporters show the ability to mediate the transport of several compounds including carnitine, carnitine derivatives, acetylcholine, ergothioneine, and gut microbiota by-products, which have been specifically associated with inflammation for their anti- or proinflammatory action. Therefore, the absorption and distribution of these molecules rely on the presence of OCTN1 and OCTN2, whose expression is modulated by inflammatory cytokines and transcription factors typically activated by inflammation. In the present review, we wish to provide a state of the art on OCTN1 and OCTN2 transport function and regulation in relationships with inflammation and inflammatory diseases focusing on the metabolic signature collected in different body districts and gene polymorphisms related to inflammatory diseases. [ABSTRACT FROM AUTHOR]

Gonadotropin-releasing hormone (GnRH)-synthesizing neurons orchestrate reproduction centrally. Early studies have proposed the contribution of acetylcholine (ACh) to hypothalamic control of reproduction, although the causal mechanisms have not been clarified. Here, we report that in vivo pharmacogenetic activation of the cholinergic system increased the secretion of luteinizing hormone (LH) in orchidectomized mice. 3DISCO immunocytochemistry and electron microscopy revealed the innervation of GnRH neurons by cholinergic axons. Retrograde viral labeling initiated from GnRH-Cre neurons identified the medial septum and the diagonal band of Broca as exclusive sites of origin for cholinergic afferents of GnRH neurons. In acute brain slices, ACh and carbachol evoked a biphasic effect on the firing rate in GnRH neurons, first increasing and then diminishing it. In the presence of tetrodotoxin, carbachol induced an inward current, followed by a decline in the frequency of miniature postsynaptic currents (mPSCs), indicating a direct influence on GnRH cells. RT-PCR and whole-cell patch-clamp studies revealed that GnRH neurons expressed both nicotinic (a4ß2, a3ß4, and a7) and muscarinic (M1-M5) AChRs. The nicotinic AChRs contributed to the nicotine-elicited inward current and the rise in firing rate. Muscarine via M1 and M3 receptors increased, while via M2 and M4 reduced the frequency of both mPSCs and firing. Optogenetic activation of channelrhodopsin-2-tagged cholinergic axons modified GnRH neuronal activity and evoked cotransmission of ACh and GABA from a subpopulation of boutons. These findings confirm that the central cholinergic system regulates GnRH neurons and activates the pituitary-gonadal axis via ACh and ACh/GABA neurotransmissions in male mice. [ABSTRACT FROM AUTHOR]

Coronary vasomotor disorders (CVD) are characterized by transient hypercontraction of coronary vascular smooth muscle cells, leading to hypercontraction of epicardial and/or microvascular coronary circulation. CVDs play a relevant role in the pathogenesis of ischemia, angina and myocardial infarction with non-obstructive coronary arteries. Invasive provocative testing with intracoronary Acetylcholine (ACh) administration is the gold standard tool for addressing CVD, providing relevant therapeutic and prognostic implications. However, safety concerns preclude the widespread incorporation of the ACh test into clinical practice. The purpose of this review is to shed light on the pathophysiology underlying CVD and on the clinical role of the ACh test, focusing on safety profile and prognostic implications. We will also discuss contemporary evidence on the management of CVD and the role of the ACh test in driving a personalized approach of patients with CVD. [ABSTRACT FROM AUTHOR]

Human brain imaging research using functional MRI (fMRI) has uncovered flexible variations in the functional connectivity between brain regions. While some of this variability likely arises from the pattern of information flow through circuits, it may also be influenced by rapid changes in effective synaptic strength at the molecular level, a phenomenon called Dynamic Network Connectivity (DNC) discovered in non-human primate circuits. These neuromodulatory molecular mechanisms are found in layer III of the macaque dorsolateral prefrontal cortex (dlPFC), the site of the microcircuits shown by GoldmanRakic to be critical for working memory. This research has shown that the neuromodulators acetylcholine, norepinephrine, and dopamine can rapidly change the strength of synaptic connections in layer III dlPFC by (1) modifying the depolarization state of the post-synaptic density needed for NMDA receptor neurotransmission and (2) altering the open state of nearby potassium channels to rapidly weaken or strengthen synaptic efficacy and the strength of persistent neuronal firing. Many of these actions involve increased cAMP-calcium signaling in dendritic spines, where varying levels can coordinate the arousal state with the cognitive state. The current review examines the hypothesis that some of the dynamic changes in correlative strength between cortical regions observed in human fMRI studies may arise from these molecular underpinnings, as has been seen when pharmacological agents or genetic alterations alter the functional connectivity of the dlPFC consistent with the macaque physiology. These DNC mechanisms provide essential flexibility but may also confer vulnerability to malfunction when dysregulated in cognitive disorders. [ABSTRACT FROM AUTHOR]

The intricate functionality of the vertebrate retina relies on the interplay between neurotransmitter activity and calcium (Ca2+) dynamics, offering important insights into developmental processes, physiological functioning, and disease progression. Neurotransmitters orchestrate cellular processes to shape the behavior of the retina under diverse circumstances. Despite research to elucidate the roles of individual neurotransmitters in the visual system, there remains a gap in our understanding of the holistic integration of their interplay with Ca2+ dynamics in the broader context of neuronal development, health, and disease. To address this gap, the present review explores the mechanisms used by the neurotransmitters glutamate, gamma-aminobutyric acid (GABA), glycine, dopamine, and acetylcholine (ACh) and their interplay with Ca2+ dynamics. This conceptual outline is intended to inform and guide future research, underpinning novel therapeutic avenues for retinal-associated disorders. [ABSTRACT FROM AUTHOR]

Alpha-synuclein (α-syn) has gained significant attention due to its involvement in neurodegenerative diseases, particularly Parkinson's disease. However, its normal function in the human brain is equally fascinating. The α-syn protein is highly dynamic and can adapt to various conformational stages, which differ in their interaction with synaptic elements, their propensity to drive pathological aggregation, and their toxicity. This review will delve into the multifaceted role of α-syn in different types of synapses, shedding light on contributions to neurotransmission and overall brain function. We describe the physiological role of α-syn at central synapses, including the bidirectional interaction between α-syn and neurotransmitter systems. [ABSTRACT FROM AUTHOR]

In atrial fibrillation (AF), the ECG P-wave, which represents atrial depolarization, is replaced with chaotic and irregular fibrillation waves (f waves). The fwave frequency, Ff, shows significant variations over time. Cardiorespiratory interactions regulated by the autonomic nervous system have been suggested to play a role in such variations. We conducted a simulation study to test whether the spatiotemporal release pattern of the parasympathetic neurotransmitter acetylcholine (ACh) modulates the frequency of atrial reentrant circuits. Understanding parasympathetic involvement in AF may guide more effective treatment approaches and could help to design autonomic markers alternative to heart rate variability (HRV), which is not available in AF patients. 2D tissue and 3D whole-atria models of human atrial electrophysiology in persistent AF were built. Different ACh release percentages (8% and 30%) and spatial ACh release patterns, including spatially random release and release from ganglionated plexi (GPs) and associated nerves, were considered. The temporal pattern of ACh release, ACh(t), was simulated following a sinusoidal waveform of frequency 0.125 Hz to represent the respiratory frequency. Different mean concentrations (ACh) and peak-to-peak ranges of ACh (ΔACh)were tested. We found that temporal variations in Ff, Ff(t), followed the simulated temporal ACh(t) pattern in all cases. The temporal mean of Ff(t), Ff, depended on the fibrillatory pattern (number and location of rotors), the percentage of ACh release nodes and ACh. The magnitude of Ff (t) modulation, ΔFf, depended on the percentage of ACh release nodes and ΔACh. The spatial pattern of ACh release did not have an impact on Ffand only a mild impact on ΔFf. The f-wave frequency, being indicative of vagal activity, has the potential to drive autonomic-based therapeutic actions and could replace HRV markers not quantifiable from AF patients. [ABSTRACT FROM AUTHOR]

Acetylcholine (ACh) promotes neocortical output to the thalamus and brainstem by preferentially enhancing the postsynaptic excitability of layer 5 pyramidal tract (PT) neurons relative to neighboring intratelencephalic (IT) neurons. Less is known about how ACh regulates the excitatory synaptic drive of IT and PT neurons. To address this question, spontaneous excitatory postsynaptic potentials (sEPSPs) were recorded in dual recordings of IT and PT neurons in slices of prelimbic cortex from adult female and male mice. ACh (20 µM) enhanced sEPSP amplitudes, frequencies, rise-times, and half-widths preferentially in PT neurons. These effects were blocked by the muscarinic receptor antagonist atropine (1 µM). When challenged with pirenzepine (1 µM), an antagonist selective for M1-type muscarinic receptors, ACh instead reduced sEPSP frequencies, suggesting that ACh may generally suppress synaptic transmission in the cortex via non-M1 receptors. Cholinergic enhancement of sEPSPs in PT neurons was not sensitive to antagonism of GABA receptors with gabazine (10 µM) and CGP52432 (2.5 µM) but was blocked by tetrodotoxin (1 µM), suggesting that ACh enhances action-potential-dependent excitatory synaptic transmission in PT neurons. ACh also preferentially promoted the occurrence of synchronous sEPSPs in dual recordings of PT neurons relative to IT-PT and IT-IT parings. Finally, selective chemogenetic silencing of hM4Di-expressing PT, but not commissural IT, neurons blocked cholinergic enhancement of sEPSP amplitudes and frequencies in PT neurons. These data suggest that, in addition to selectively enhancing the postsynaptic excitability of PT neurons, M1 receptor activation promotes corticofugal output by amplifying recurrent excitation within networks of PT neurons. [ABSTRACT FROM AUTHOR]

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Metoclopramide is a treatment for gastroenteritis accompanied by vomiting. Hyoscine-n-butyl bromide as an anticholinergic agent causes inhibition of the acetylcholine (Ach) by acting on muscarinic receptors. The study aims to ascertain how metoclopramide affects Ach-induced cortical motility and also investigates the effects of metoclopramide alone and in combination with hyoscine-n-butyl bromide drug effects on colon motility. In this study, 1 cm of colon tissue width was cut, 2 cm long strips were made, and both sides of the tissue were secured with surgical silk at both ends of isolated bath tissues of isolated organs with (1 g) tension to the suspended instrument that recorded isometric contractions. Tissue fixation is followed by drug addiction: Ach, metoclopramide, and hyoscine-N-butyl bromide. The tissue was treated with metoclopramide and hyoscine-n-butyl bromide and excess Caine for 10 min. The results show changes in colon frequency, peak-to-peak, and amplitude levels for metoclopramide, hyoscine-N-butyl, and metoclopramide and hyoscine. A paired T-test statistically analyzes the results. Metoclopramide by itself, as well as in combination with hyoscine-n-butyl bromide, increases colon motility and induces Ach release. In addition, an analysis of the physicochemical characteristics of hyoscine-n-butyl bromide and metoclopramide molecules is conducted. The study includes theoretical calculations of electronic parameters for both protonated and unprotonated forms of these molecules in both gaseous and aqueous environments. These results show the potential use of metoclopramide as a therapeutic option for gastroenteritis with vomiting, warranting additional study, and clinical evaluation. The research also reveals hyoscine-n-butyl bromide and metoclopramide's molecular features by their physicochemical properties. [ABSTRACT FROM AUTHOR]

Simple Summary: Nicotine, a highly addictive component in cigarette smoke, facilitates tumorigenesis and the accelerated development of non-small cell lung cancer (NSCLC), which is known to account for ~80% of all lung cancer cases. This study sheds light on how the nicotine treatment of NSCLC cells regulates vascular endothelial growth factor (VEGF) signaling, known to be important in the progression of vascular disease and cancer, by acting through nicotinic acetylcholine receptors and by leading to the activation of β-adrenergic receptors through increased levels of the stress neurotransmitters, norepinephrine/noradrenaline, and epinephrine/adrenaline. Nicotine-induced activation of VEGF promoted the function of proteins involved in increased cell survival and suppressed the function of a crucial tumor suppressor, blocking cell death. This work expands our scientific knowledge of mechanisms employed by nicotine in regulating VEGF signaling in a manner dependent on the acetylcholine and/or β-adrenergic receptors, leading to lung cancer cell survival, and also provides significant insights into novel future therapeutic strategies to combat lung cancer. In addition to binding to nicotinic acetylcholine receptors (nAChRs), nicotine is known to regulate the β-adrenergic receptors (β-ARs) promoting oncogenic signaling. Using A549 (p53 wild-type) and H1299 (p53-null) lung cancer cells, we show that nicotine treatment led to: increased adrenaline/noradrenaline levels, an effect blocked by treatment with the α7nAChR inhibitor (α-BTX) but not by the β-blocker (propranolol) or the α4β2nAChR antagonist (DhβE); decreased GABA levels in A549 and H1299 cell media, an effect blocked by treatment with DhβE; increased VEGF levels and PI3K/AKT activities, an effect diminished by cell co-treatment with α-BTX, propranolol, and/or DhβE; and inhibited p53 activity in A549 cells, that was reversed, upon cell co-treatment with α-BTX, propranolol, and/or DhβE or by VEGF immunodepletion. VEGF levels increased upon cell treatment with nicotine, adrenaline/noradrenaline, and decreased with GABA treatment. On the other hand, the p53 activity decreased in A549 cells treated with nicotine, adrenaline/noradrenaline and increased upon cell incubation with GABA. Knockdown of p53 led to increased VEGF levels in the media of A549 cells. The addition of anti-VEGF antibodies to A549 and H1299 cells decreased cell viability and increased apoptosis; blocked the activities of PI3K, AKT, and NFκB in the absence or presence of nicotine; and resulted in increased p53 activation in A549 cells. We conclude that VEGF can be upregulated via α7nAChR and/or β-ARs and downregulated via GABA and/or p53 in response to the nicotine treatment of NSCLC cells. [ABSTRACT FROM AUTHOR]

In volume transmission (or neuromodulation) neurons do not make one-to-one connections to other neurons, but instead simply release neurotransmitter into the extracellular space from numerous varicosities. Many well-known neurotransmitters including serotonin (5HT), dopamine (DA), histamine (HA), Gamma-Aminobutyric Acid (GABA) and acetylcholine (ACh) participate in volume transmission. Typically, the cell bodies are in one volume and the axons project to a distant volume in the brain releasing the neurotransmitter there. We introduce volume transmission and describe mathematically two natural homeostatic mechanisms. In some brain regions several neurotransmitters in the extracellular space affect each other's release. We investigate the dynamics created by this comodulation in two different cases: serotonin and histamine; and the comodulation of 4 neurotransmitters in the striatum and we compare to experimental data. This kind of comodulation poses new dynamical questions as well as the question of how these biochemical networks influence the electrophysiological networks in the brain. [ABSTRACT FROM AUTHOR]

Realtime monitoring of neurotransmitters is of great interest for understanding their fundamental role in a wide range of biological processes in the central and peripheral nervous system, as well as their role, in several degenerative brain diseases. The measurement of acetylcholine in the brain is particularly challenging due to the complex environment of the brain and the low concentration and short lifetime of acetylcholine. In this paper, we demonstrated a novel, label-free biosensor for the detection of Ach using a single enzyme, acetylcholinesterase (ACHE), and electrochemical impedance spectroscopy (EIS). Acetylcholinesterase was covalently immobilized onto the surface of gold microelectrodes through an amine-reactive crosslinker dithiobis(succinimidyl propionate) (DSP). Passivation of the gold electrode with SuperBlock eliminated or reduced any non-specific response to other major interfering neurotransmitter molecules such as dopamine (DA), norepinephrine (NE) and epinephrine (EH). The sensors were able to detect acetylcholine over a wide concentration range (5.5–550 μM) in sample volumes as small as 300 μL by applying a 10 mV AC voltage at a frequency of 500 Hz. The sensors showed a linear relationship between Ach concentration and ΔZmod(R2 = 0.99) in PBS. The sensor responded to acetylcholine not only when evaluated in a simple buffer (PBS buffer) but in several more complex environments such as rat brain slurry and rat whole blood. The sensor remained responsive to acetylcholine after being implanted ex vivo in rat brain tissue. These results bode well for the future application of these novel sensors for real time in vivo monitoring of acetylcholine. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is associated with amyloidosis and dysfunction of the cholinergic system, which is crucial for learning and memory. However, the nature of acetylcholine signaling within regions of cholinergic-dependent plasticity and how it changes with experience is poorly understood, much less the impact of amyloidosis on this signaling. Therefore, we optically measure the release profile of acetylcholine to unexpected, predicted, and predictive events in visual cortex (VC)--a site of known cholinergic-dependent plasticity--in a preclinical mouse model of AD that develops amyloidosis. We find that acetylcholine exhibits reinforcement signaling qualities, reporting behaviorally relevant outcomes and displaying release profiles to predictive and predicted events that change as a consequence of experience. We identify three stages of amyloidosis occurring before the degeneration of cholinergic synapses within VC and observe that cholinergic responses in amyloid-bearing mice become impaired over these stages, diverging progressively from age- and sex-matched littermate controls. In particular, amyloidosis degrades the signaling of unexpected rewards and punishments, and attenuates the experience-dependent (1) increase of cholinergic responses to outcome predictive visual cues, and (2) decrease of cholinergic responses to predicted outcomes. Hyperactive spontaneous acetylcholine release occurring transiently at the onset of impaired cholinergic signaling is also observed, further implicating disrupted cholinergic activity as an early functional biomarker in AD. Our findings suggest that acetylcholine acts as a reinforcement signal that is impaired by amyloidosis before pathologic degeneration of the cholinergic system, providing a deeper understanding of the effects of amyloidosis on acetylcholine signaling and informing future interventions for AD. [ABSTRACT FROM AUTHOR]

Cortical layer 6b is considered by many to be a remnant of the subplate that forms during early stages of neocortical development, but its role in the adult is not well understood. Its neuronal complement has only recently become the subject of systematic studies, and its axonal projections and synaptic input structures have remained largely unexplored despite decades of research into neocortical function. In recent years, however, layer 6b (L6b) has attracted increasing attention and its functional role is beginning to be elucidated. In this review, I will attempt to provide an overview of what is currently known about the excitatory and inhibitory neurons in this layer, their pre- and postsynaptic connectivity, and their functional implications. Similarities and differences between different cortical areas will be highlighted. Finally, layer 6b neurons are highly responsive to several neuropeptides such as orexin/hypocretin, neurotensin and cholecystokinin, in some cases exclusively. They are also strongly controlled by neurotransmitters such as acetylcholine and norepinephrine. The interaction of these neuromodulators with L6b microcircuitry and its functional consequences will also be discussed. [ABSTRACT FROM AUTHOR]

Females increase aggression for mating opportunities and for acquiring reproductive resources. Although the close relationship between female aggression and mating status is widely appreciated, whether and how female aggression is regulated by mating-related cues remains poorly understood. Here we report an interesting observation that Drosophila virgin females initiate high-frequency attacks toward mated females. We identify 11-cis-vaccenyl acetate (cVA), a male-derived pheromone transferred to females during mating, which promotes virgin female aggression. We subsequently reveal a cVA-responsive neural circuit consisting of four orders of neurons, including Or67d, DA1, aSP-g, and pC1 neurons, that mediate cVA-induced virgin female aggression. We also determine that aSP-g neurons release acetylcholine (ACh) to excite pC1 neurons via the nicotinic ACh receptor nAChRα7. Together, beyond revealing cVA as a mating-related inducer of virgin female aggression, our results identify a neural circuit linking the chemosensory perception of mating-related cues to aggressive behavior in Drosophila females. [ABSTRACT FROM AUTHOR]

The special issue on Multiple Sclerosis: Diagnosis and Treatment II, reflects advances and discoveries in the molecular and cellular mechanisms of disease, and novel laboratory techniques providing more sensitivity to diagnostic techninques and the understanding of neuroinflammation. Mitochondrial-mediated apoptosis in isolated peripheral blood mononuclear cells and the role of reactive oxygen species are studied as indicators of activity of MS. In these cells, downregulation of circular and linera RNAs are reported as markers of highly active disease in MS. Progress and importance of Neurofilaments determinations in early diagnosis and as a marker of disease activity, and the analysis of the complex mechanisms and therapeutic potential of Sphingosine-1-phosphate receptor modulator are discussed. Epidemiologic observations from a highly diversified area of the world provide more insights into this important aspect of MS; discussions on the clinical challenges posed by spinal cord involvement in demyelinatind disorders and the latest aspects of pediatric onset MS, complement this fine collection of scientific papers. [ABSTRACT FROM AUTHOR]

Neurotoxic pesticides are a group of chemicals that pose a severe threat to both human health and the environment. These molecules are also known to accumulate in the food chain and persist in the environment, which can lead to long-term exposure and adverse effects on non-target organisms. The detrimental effects of these pesticides on neurotransmitter levels and function can lead to a range of neurological and behavioral symptoms, which are closely associated with neurodegenerative diseases. Hence, the accurate and reliable detection of these neurotoxic pesticides and associated neurotransmitters is essential for clinical applications, such as diagnosis and treatment. Over the past few decades, acetylcholinesterase (AchE) biosensors have emerged as a sensitive and reliable tool for the electrochemical detection of neurotoxic pesticides and acetylcholine. These biosensors can be tailored to utilize the high specificity and sensitivity of AchE, enabling the detection of these chemicals. Additionally, enzyme immobilization and the incorporation of nanoparticles have further improved the detection capabilities of these biosensors. AchE biosensors have shown tremendous potential in various fields, including environmental monitoring, clinical diagnosis, and pesticide residue analysis. This review summarizes the advancements in AchE biosensors for electrochemical detection of neurotoxic pesticides and acetylcholine over the past two decades. • This paper reviews the research status of acetylcholinesterase (AchE) biosensors. • Pesticides influence the neurotransmitters linked to neurodegenerative diseases. • AchE biosensors used for detecting pesticides and acetylcholine are reviewed. • Immobilizing AchE enhances biosensor performance, sensitivity, and selectivity. • AchE biosensor was used for environmental monitoring and clinical diagnosis. [ABSTRACT FROM AUTHOR]

The cholinergic system is essential for memory. While degradation of cholinergic pathways characterizes memory-related disorders such as Alzheimer's disease, the neurophysiological mechanisms linking the cholinergic system to human memory remain unknown. Here, combining intracranial brain recordings with pharmacological manipulation, we describe the neurophysiological effects of a cholinergic blocker, scopolamine, on the human hippocampal formation during episodic memory. We found that the memory impairment caused by scopolamine was coupled to disruptions of both the amplitude and phase alignment of theta oscillations (2–10 Hz) during encoding. Across individuals, the severity of theta phase disruption correlated with the magnitude of memory impairment. Further, cholinergic blockade disrupted connectivity within the hippocampal formation. Our results indicate that cholinergic circuits support memory by coordinating the temporal dynamics of theta oscillations across the hippocampal formation. These findings expand our mechanistic understanding of the neurophysiology of human memory and offer insights into potential treatments for memory-related disorders. Memory loss is a known result of cholinergic dysfunction, yet the neural basis for this effect remains unknown. Here, the authors demonstrate that the way cholinergic blockade disrupts memory is by impairing the amplitude and timing of theta oscillations. [ABSTRACT FROM AUTHOR]

Neurotransmission is shaped by extracellular pH. Alkalization enhances pH-sensitive transmitter release and receptor activation, whereas acidification inhibits these processes and can activate acid-sensitive conductances in the synaptic cleft. Previous work has shown that the synaptic cleft can either acidify because of synaptic vesicular release and/or alkalize because of Ca2+ extrusion by the plasma membrane ATPase (PMCA). The direction of change differs across synapse types. At the mammalian neuromuscular junction (NMJ), the direction and magnitude of pH transients in the synaptic cleft during transmission remain ambiguous. We set out to elucidate the extracellular pH transients that occur at this cholinergic synapse under nearphysiological conditions and identify their sources. We monitored pH-dependent changes in the synaptic cleft of the mouse levator auris longus using viral expression of the pseudoratiometric probe pHusion-Ex in the muscle. Using mice from both sexes, a significant and prolonged alkalization occurred when stimulating the connected nerve for 5 s at 50 Hz, which was dependent on postsynaptic intracellular Ca2+ release. Sustained stimulation for a longer duration (20 s at 50 Hz) caused additional prolonged net acidification at the cleft. To investigate the mechanism underlying cleft alkalization, we used muscleexpressed GCaMP3 to monitor the contribution of postsynaptic Ca2+. Activity-induced liberation of intracellular Ca2+ in muscle positively correlated with alkalization of the synaptic cleft, whereas inhibiting PMCA significantly decreased the extent of cleft alkalization. Thus, cholinergic synapses of the mouse NMJ typically alkalize because of cytosolic Ca2+ liberated in muscle during activity, unless under highly strenuous conditions where acidification predominates. [ABSTRACT FROM AUTHOR]

The functional heterogeneity of hippocampal CA3 pyramidal neurons has emerged as a key aspect of circuit function. Here, we explored the effects of long-term cholinergic activity on the functional heterogeneity of CA3 pyramidal neurons in organotypic slices obtained from male rat brains. Application of agonists to either AChRs generally, or mAChRs specifically, induced robust increases in network activity in the low-gamma range. Prolonged AChR stimulation for 48 h uncovered a population of hyperadapting CA3 pyramidal neurons that typically fired a single, early action potential in response to current injection. Although these neurons were present in control networks, their proportions were dramatically increased following long-term cholinergic activity. Characterized by the presence of a strong M-current, the hyperadaptation phenotype was abolished by acute application of either M-channel antagonists or the reapplication of AChR agonists. We conclude that long-term mAChR activation modulates the intrinsic excitability of a subset of CA3 pyramidal cells, uncovering a highly plastic cohort of neurons that are sensitive to chronic ACh modulation. Our findings provide evidence for the activity-dependent plasticity of functional heterogeneity in the hippocampus. [ABSTRACT FROM AUTHOR]

Communication between the ovaries and the central nervous system occurs by peripheral innervation through the celiac plexus, superior ovarian nerve, and ovarian plexus nerve. The vagus nerve is involved in regulating the ovaries, but the neuroanatomical pathway that links them is not clear. Adult female rats were used for gross anatomy, acetylcholinesterase histochemistry, and the immunofluorescence analysis of tyrosine hydroxylase (TH), choline acetyltransferase (ChAT), and tryptophan hydroxylase 2 (TPH). The results obtained indicate that the right vagus nerve (RVN) travels parallel and caudal to the esophagus, where three nerve branches were identified. Also, a right vagal plexus (RVP) formed by microganglia was described, establishing communication with the celiac plexus, and was mainly reactive to tyrosine hydroxylase (TH); some serotoninergic and cholinergic neurons were also found. The left vagus nerve (LVN) travels over the esophagus, bifurcates before its insertion into the stomach and enters the RCG. This neuroanatomical and biochemical description of the RVN and LVN in the rat suggests the RVP is formed by presynaptic catecholaminergic terminals and cholinergic neurons. This information could support detailed studies of communication between the vagus nerve and the ovaries and identify the type of neural signaling involved in abdominal control of the vagus nerve. [ABSTRACT FROM AUTHOR]

Salvia officinalis is a perennial plant commonly used in culinary and medical preparations. Its large intake is usually related to psychiatric disorders (such as pica) and might induce different symptoms (e.g. vomiting, nausea, diarrhoea, salivation, arterial hypertension, tachycardia, vertigo, flushes, cyanosis and convulsions) likely ascribable to pro-cholinergic effects of various constituents. The identification of this toxicity is challenging because of its rarity and possible underlying psychiatric comorbidities. Herein we describe the case of a schizophrenic 56-year-old male admitted to the Emergency Department for abdominal pain and diarrhea resulted in a rare case of acute toxicity by Salvia officinalis. [ABSTRACT FROM AUTHOR]