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Central cholinergic system and endocannabinoid, anandamide exhibits anti-compulsive-like behavior in mice. However, the role of the central cholinergic system in the anandamide-induced anti-compulsive-like behavior is still unexplored. Therefore, the present study assessed the role of central cholinergic transmission in the anandamide-induced anti-compulsive activity using a marble-burying behavior (MBB) model in mice. Thus, the modulation in the anandamide-induced effect on MBB was evaluated using mice with altered central cholinergic transmission achieved by pretreatment (i.c.v.) with various cholinergic agents like acetylcholine (ACh), acetylcholinesterase inhibitor (AChEI), neostigmine, nicotine, mAChR antagonist, atropine, and nAChR antagonist, mecamylamine. The influence of anandamide treatment on the brain AChE activity was also evaluated. The results revealed that i.c.v. injection of anandamide (10, 20µg/mouse, i.c.v.) dose-dependently reduced MBB in mice. Moreover, anandamide in all the tested doses inhibited the brain AChE activity indicating an anti-compulsive-like effect probably via an enhanced central cholinergic transmission. Furthermore, the anti-compulsive-like effect of anandamide (20µg/mouse, i.c.v.) was found to be enhanced in mice centrally pre-treated with, ACh (0.1µg/mouse, i.c.v.) or AChEI, neostigmine (0.3µg/mouse, i.c.v.). In addition, the anandamide-induced anti-compulsive-like effect was significantly increased in mice pre-treated with a low dose of nicotine (0.1µg/mouse, i.c.v.) while, it was attenuated by the higher dose of nicotine (2µg/mouse, i.c.v.). On the other hand, the anandamide (20µg/mouse, i.c.v.) induced anti-compulsive-like effect was found to be diminished in mice pre-treated with mAChR antagonist, atropine (0.1, 0.5µg/mouse, i.c.v.) and pre-injection of nAChR antagonist, mecamylamine (0.1, 0.5µg/mouse, i.c.v.) potentiated the anandamide induced anti-compulsive-like response in mice. Thus, the present investigation delineates the modulatory role of an enhanced central cholinergic transmission in the anandamide-induced anti-compulsive-like behavior in mice by inhibition of brain AChE or via muscarinic and nicotinic receptors mediated mechanism.

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The classic enzymatic function of acetylcholinesterase (AChE) is the hydrolysis of acetylcholine (ACh) in the neuronal synapse. However, AChE is also present in nonneuronal cells such as lymphocytes. Various studies have proposed the participation of AChE in the development of cancer. The ACHE gene produces three mRNAs (T, H and R). AChE-T encodes amphiphilic monomers, dimers, tetramers (G1 A, G2 A and G4 A) and hydrophilic tetramers (G4 H). AChE-H encodes amphiphilic monomers and dimers (G1 A and G2 A). AChE-R encodes a hydrophilic monomer (G1 H). The present study considered the differences in the mRNA expression (T, H and R) and protein levels of AChE, as well as the molecular forms of AChE, the glycosylation pattern and the enzymatic activity of AChE present in normal T lymphocytes and leukemic Jurkat E6-1 cells. The results revealed that AChE enzymatic activity was higher in normal T lymphocytes than in Jurkat cells. Normal T cells expressed AChE-H transcripts, whereas Jurkat cells expressed AChE-H and AChE-T. The molecular forms identified in normal T cells were G2 A (5.2 S) and G1 A (3.5 S), whereas those in Jurkat cells were G2 A (5.2 S), G1 A (3.5 S) and G4 H (10.6S). AChE in Jurkat cells showed altered posttranslational maturation since a decrease in the incorporation of galactose and sialic acid into its structure was observed. In conclusion, the content and composition of AChE were altered in Jurkat cells compared with those in normal T lymphocytes. The present study opened new avenues for exploring the development of novel therapeutic strategies against T-cell leukemia and for identifying potential molecular targets for the early detection of this type of cancer.

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The cholinergic system has been implicated in postural deficits, in particular falls, in Parkinson's disease (PD). Falls and freezing of gait typically occur during dynamic and challenging balance and gait conditions, such as when initiating gait, experiencing postural perturbations, or making turns. However, the precise cholinergic neural substrate underlying dynamic postural and gait changes remains poorly understood. The aim of this study was to investigate whether brain vesicular acetylcholine transporter binding, as measured with [18F]-fluoroethoxybenzovesamicol binding PET, correlates with dynamic gait and balance impairments in 125 patients with PD (mean age 66.89 ± 7.71 years) using the abbreviated balance evaluation systems test total and its four functional domain sub-scores (anticipatory postural control, reactive postural control, dynamic gait, and sensory integration). Whole brain false discovery-corrected (P < 0.05) correlations for total abbreviated balance evaluation systems test scores included the following bilateral or asymmetric hemispheric regions: gyrus rectus, orbitofrontal cortex, anterior part of the dorsomedial prefrontal cortex, dorsolateral prefrontal cortex, cingulum, frontotemporal opercula, insula, fimbria, right temporal pole, mesiotemporal, parietal and visual cortices, caudate nucleus, lateral and medial geniculate bodies, thalamus, lingual gyrus, cerebellar hemisphere lobule VI, left cerebellar crus I, superior cerebellar peduncles, flocculus, and nodulus. No significant correlations were found for the putamen or anteroventral putamen. The four domain-specific sub-scores demonstrated overlapping cholinergic topography in the metathalamus, fimbria, thalamus proper, and prefrontal cortices but also showed distinct topographic variations. For example, reactive postural control functions involved the right flocculus but not the upper brainstem regions. The anterior cingulum associated with reactive postural control whereas the posterior cingulum correlated with anticipatory control. The spatial extent of associated cholinergic system changes were least for dynamic gait and sensory orientation functional domains compared to the anticipatory and reactive postural control functions. We conclude that specific aspects of dynamic balance and gait deficits in PD associate with overlapping but also distinct patterns of cerebral cholinergic system changes in numerous brain regions. Our study also presents novel evidence of cholinergic topography involved in dynamic balance and gait in PD that have not been typically associated with mobility disturbances, such as the right anterior temporal pole, right anterior part of the dorsomedial prefrontal cortex, gyrus rectus, fimbria, lingual gyrus, flocculus, nodulus, and right cerebellar hemisphere lobules VI and left crus I.

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Familial Alzheimer's disease (FAD) is a chronic neurological condition that progresses over time. Currently, lacking a viable treatment, the use of multitarget medication combinations has generated interest as a potential FAD therapy approach. In this study, we examined the effects of 4-phenylbutyric acid (4-PBA) and methylene blue (MB) either separately or in combination on PSEN1 I416T cholinergic-like neuron cells (ChLNs), which serve as a model for FAD. We found that MB was significantly efficient at reducing the accumulation of intracellular Aß, phosphorylation of TAU Ser202/Thr205, and increasing Δψm, whereas 4-PBA was significantly efficient at diminishing oxidation of DJ-1Cys106-SH, expression of TP53, and increasing ACh-induced Ca2+ influx. Both agents were equally effective at blunting phosphorylated c-JUN at Ser63/Ser73 and activating caspase 3 (CASP3) into cleaved caspase 3 (CC3) on mutant cells. Combination of MB and 4-PBA at middle (0.1, 1) concentration significantly reduced iAß, p-TAU, and oxDJ-1 and augmented the ACh-induced Ca2+ influx compared to combined agents at low (0.05, 0.5) or high (0.5, 5) concentration. However, combined MB and 4-PBA were efficient only at dropping DJ-1Cys106-SO3 and increasing ACh-induced Ca2+ inward in mutant ChLNs. Our data show that the reagents MB and 4-PBA alone possess more than one action (e.g., antiamyloid, antioxidant, anti-TAU, antiapoptotic, and ACh-induced Ca2+ influx enhancers), that in combination might cancel or diminish each other. Together, these results strongly argue that MB and 4-PBA might protect PSEN1 I416T ChLNs from Aß-induced toxicity by working intracellularly as anti-Aß and anti-Tau agents, improving Δψm and cell survival, and extracellularly, by increasing ACh-induced Ca2+ ion influx. MB and 4-PBA are promising drugs with potential for repurposing in familial AD.

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This review is an attempt to compile existing hypotheses on the mechanisms underlying the initiation and progression of Alzheimer's disease (AD), starting from sensory impairments observed in AD and concluding with molecular events that are typically associated with the disease. These events include spreading of amyloid plaques and tangles of hyperphosphorylated tau and formation of Hirano and Biondi bodies as well as the development of oxidative stress. We have detailed the degenerative changes that occur in several neuronal populations, including the cholinergic neurons in the nucleus basalis of Meynert, the histaminergic neurons in the tuberomammillary nucleus, the serotonergic neurons in the raphe nuclei, and the noradrenergic neurons in the locus coeruleus. Furthermore, we discuss the potential role of iron accumulation in the brains of subjects with AD in the disease progression which served as a basis for the idea that iron chelation in the brain may mitigate oxidative stress and decelerate disease development. We also draw attention to possible role of sympathetic system and, more specifically, noradrenergic neurons of the superior cervical ganglion in triggering of the disease. We also explore the alternative possibility of compensatory protective changes that may occur in these neurons to support cholinergic function in the forebrain of subjects with AD.

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The identification of acute cardioprotective strategies against myocardial ischemia/reperfusion (I/R) injury that can be applied in the catheterization room is currently an unmet clinical need and several interventions evaluated in the past at the pre-clinical level have failed in translation. Autonomic imbalance, sustained by an abnormal afferent signalling, is a key component of I/R injury. Accordingly, there is a strong rationale for neuromodulation strategies, aimed at reducing sympathetic activity and/or increasing vagal tone, in this setting. In this review we focus on cervical vagal nerve stimulation (cVNS) and on transcutaneous auricular vagus nerve stimulation (taVNS); the latest has the potential to overcome several of the issues of invasive cVNS, including the possibility of being used in an acute setting, while retaining its beneficial effects. First, we discuss the pathophysiology of I/R injury, that is mostly a consequence of the overproduction of reactive oxygen species. Second, we describe the functional anatomy of the parasympathetic branch of the autonomic nervous system and the most relevant principles of bioelectronic medicine applied to electrical vagal modulation, with a particular focus on taVNS. Then, we provide a detailed and comprehensive summary of the most relevant pre-clinical studies of invasive and non-invasive VNS that support its strong cardioprotective effect whenever there is an acute or chronic cardiac injury and specifically in the setting of myocardial I/R injury. The potential benefit in the emerging field of post cardiac arrest syndrome (PCAS) is also mentioned. Indeed, electrical cVNS has a strong anti-adrenergic, anti-inflammatory, antioxidants, anti-apoptotic and pro-angiogenic effect; most of the involved molecular pathways were already directly confirmed to take place at the cardiac level for taVNS. Pre-clinical data clearly show that the sooner VNS is applied, the better the outcome, with the possibility of a marked infarct size reduction and almost complete left ventricular reverse remodelling when VNS is applied immediately before and during reperfusion. Finally, we describe in detail the limited but very promising clinical experience of taVNS in I/R injury available so far.

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BACKGROUND: Skin reaction patterns vary across patients with cholinergic urticaria (CholU), but their definition, prevalence, and clinical significance remain ill characterized. METHODS: Patients with CholU underwent pulse-controlled ergometry provocation testing to analyze skin reaction patterns and their correlation with location, onset, severity, sweating behaviour, clinical features, disease control, and quality of life (QoL) impairment. RESULTS: Based on the size, color, spacing, and shape of wheals as well as their surrounding skin responses, we identified six distinct types of CholU skin reactions, which differed in prevalence, from 83% (Type I) to 11% (Type VI) of patients affected. Almost all patients (94%) had ≥1 type of skin reaction pattern. Sweating was reduced in the majority of CholU patients and most prominently reduced in patients with Type VI skin signs (very small, round, red, widely spaced wheals with surrounding anemic halo), which emerged exclusively on the extremities. Type V skin signs (large, irregular, anemic, widely spaced wheals with moderate size erythema) were associated with the most severe clinical presentation and poorest QoL. CONCLUSIONS: Our analysis showed that most patients have more than one type of skin reaction patterns and that different skin signs are linked to distinct features. Future studies should determine any links between treatment response and types of skin signs in CholU.

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The neurokinin-1 receptors (NK1Rs) in the forebrain medial septum (MS) region are localized exclusively on cholinergic neurons that partly project to the hippocampus and the cingulate cortex (Cg), regions implicated in nociception. In the present study, we explored the hypothesis that neurotransmission at septal NK1R and hippocampal cholinergic mechanisms mediate experimental neuropathic pain in the rodent chronic constriction injury model (CCI). Our investigations showed that intraseptal microinjection of substance P (SP) in rat evoked a peripheral hypersensitivity (PH)-like response in uninjured animals that was attenuated by systemic atropine sulphate, a muscarinic-cholinergic receptor antagonist. Conversely, pre-emptive destruction of septal cholinergic neurons attenuated the development of PH in the CCI model that also prevented the expression of cellular markers of nociception in the spinal cord and the forebrain. Likewise, anti-nociception was evoked on intraseptal microinjection of L-733,060, an antagonist at NK1Rs, and on bilateral or unilateral microinjection of the cholinergic receptor antagonists, atropine or mecamylamine, into the different regions of the dorsal hippocampus (dH) or on bilateral microinjection into the Cg. Interestingly, the effect of L-733,060 was accompanied with a widespread decreased in levels of CCI-induced nociceptive cellular markers in forebrain that was not secondary to behaviour, suggesting an active modulation of nociceptive processing by transmission at NK1R in the medial septum. The preceding suggest that the development and maintenance of neuropathic nociception is facilitated by septal NK1R-dH cholinergic mechanisms which co-ordinately affect nociceptive processing in the dH and the Cg. Additionally, the data points to a potential strategy for pain modulation that combines anticholinergics and anti-NKRs.

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Individuals with DS develop Alzheimer's disease (AD) neuropathology, including endosomal-lysosomal system abnormalities and degeneration of basal forebrain cholinergic neurons (BFCNs). We investigated whether maternal choline supplementation (MCS) affects early endosome pathology within BFCNs using the Ts65Dn mouse model of DS/AD. Ts65Dn and disomic (2N) offspring from dams administered MCS were analyzed for endosomal pathology at 3-4 months or 10-12 months. Morphometric analysis of early endosome phenotype was performed on individual BFCNs using Imaris. The effects of MCS on the endosomal interactome were interrogated by relative co-expression (RCE) analysis. MCS effectively reduced age- and genotype-associated increases in early endosome number in Ts65Dn and 2N offspring, and prevented increases in early endosome size in Ts65Dn offspring. RCE revealed a loss of interactome cooperativity among endosome genes in Ts65Dn offspring that was restored by MCS. These findings demonstrate MCS rescues early endosome pathology, a driver of septohippocampal circuit dysfunction. The genotype-independent benefits of MCS on endosomal phenotype indicate translational applicability as an early-life therapy for DS as well as other neurodevelopmental/neurodegenerative disorders involving endosomal pathology.

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Imidacloprid (IMI), the most widely used worldwide neonicotinoid biocide, produces cognitive disorders after repeated and single treatment. However, little was studied about the possible mechanisms that produce this effect. Cholinergic neurotransmission regulates cognitive function. Most cholinergic neuronal bodies are present in the basal forebrain (BF), regulating memory and learning process, and their dysfunction or loss produces cognition decline. BF SN56 cholinergic wild-type or acetylcholinesterase (AChE), ß-amyloid-precursor-protein (ßAPP), Tau, glycogen-synthase-kinase-3-beta (GSK3ß), beta-site-amyloid-precursor-protein-cleaving enzyme 1 (BACE1), and/or nuclear-factor-erythroid-2-related-factor-2 (NRF2) silenced cells were treated for 1 and 14 days with IMI (1 µM-800 µM) with or without recombinant heat-shock-protein-70 (rHSP70), recombinant proteasome 20S (rP20S) and with or without N-acetyl-cysteine (NAC) to determine the possible mechanisms that mediate this effect. IMI treatment for 1 and 14 days altered cholinergic transmission through AChE inhibition, and triggered cell death partially through oxidative stress generation, AChE-S overexpression, HSP70 downregulation, P20S inhibition, and Aß and Tau peptides accumulation. IMI produced oxidative stress through reactive oxygen species production and antioxidant NRF2 pathway downregulation, and induced Aß and Tau accumulation through BACE1, GSK3ß, HSP70, and P20S dysfunction. These results may assist in determining the mechanisms that produce cognitive dysfunction observed following IMI exposure and provide new therapeutic tools.

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TRPM4 is a calcium activated non-selective cation channel, impermeable to Ca2+, in neurons it has been implicated in the regulation of the excitability and in the persistent firing. Cholinergic stimulation is also implicated in changes in excitability that leads neurons to an increased firing frequency, however it is not clear whether TRPM4 is involved in the cholinergic-induced increase in firing frequency. Here using a combination of patch clamp electrophysiology, Ca2+ imaging, immunofluorescence, fluorescence recovery after photobleaching (FRAP) and pharmacological approach, we demonstrate that carbachol (Cch) increases firing frequency, intracellular Ca2+ and that TRPM4 inhibition using 9-Ph and CBA reduces firing frequency and decreases the peak in intracellular Ca2+ induced by Cch in cortical pyramidal neurons in culture. Moreover, we determined that cholinergic stimulation reduces TRPM4 recycling and stabilizes TRPM4 in the plasma membrane. Together our results indicate that cholinergic stimulation increases firing in a TRPM4 dependent manner, and also increases the TRPM4 stability in the membrane, suggesting that TRPM4 is locked in microdomains in the membrane, possibly signaling or cytoskeleton proteins complexes.

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PURPOSE: To evaluate if self-administered bladder neuromodulation with transcutaneous tibial nerve stimulation can safely replace overactive bladder medications in people with spinal cord injury. MATERIALS AND METHODS: We performed a 3-month, randomized, investigator-blinded, tibial nerve stimulation vs sham-control trial in adults with spinal cord injury and neurogenic bladder performing intermittent catheterization and taking overactive bladder medications. The primary outcome was a reduction in bladder medications while maintaining stable bladder symptoms and quality of life based on pre-post Neurogenic Bladder Symptom Score and the Incontinence-QOL questionnaire, respectively. Secondary outcomes included changes in pre-post cystometrogram, 2-day voiding diaries, and an anticholinergic medication side effect survey. RESULTS: Fifty people consented to the study, with 42 completing the trial. No dropouts were due to stimulation issues. All baseline demographics and surveys were comparable at baseline. Cystometrogram parameters were also comparable at baseline, except the stimulation group had a higher proportion of loss of bladder compliance compared to the control group. At the end of the trial, a significantly greater percentage of the tibial nerve stimulation group were able to reduce medications (95% v 68%), by a 26.2% difference in medication reduction (95% confidence interval 1.17%-51.2%). Function and quality of life surveys and cystometrograms at the end of the trial were alike between groups. Transcutaneous tibial nerve stimulation satisfaction surveys and adherence to protocol were high. CONCLUSIONS: In people with chronic spinal cord injury performing intermittent catheterization, transcutaneous tibial nerve stimulation can be an option to reduce or replace overactive bladder medications.

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Organophosphate (OP) poisoning is a critical public health issue, particularly in agricultural regions where these compounds are extensively used as pesticides. The toxic effects of OP compounds arise from their inhibition of acetylcholinesterase, leading to an accumulation of acetylcholine and a subsequent cholinergic crisis, which can be fatal if not promptly treated. Traditional management of OP poisoning includes the administration of atropine and pralidoxime; however, these treatments often fall short of reducing the high morbidity and mortality associated with severe cases. Recent research has highlighted the potential of magnesium sulfate as an adjunctive treatment for OP poisoning. Magnesium sulfate exerts its beneficial effects through mechanisms such as calcium channel blockade and stabilization of neuromuscular junctions, which help mitigate the cholinergic hyperactivity induced by OP compounds. Clinical studies have shown that magnesium sulfate can significantly reduce the duration of intensive care unit (ICU) stays and improve overall patient outcomes. This narrative review aims to comprehensively analyze current insights into using magnesium sulfate to manage OP poisoning. It discusses the pathophysiology of OP poisoning, the pharmacological action of magnesium sulfate, and the clinical evidence supporting its use. Furthermore, the review will address the safety profile of magnesium sulfate and its potential role in current treatment guidelines. By synthesizing available evidence, this review seeks to establish magnesium sulfate as a game-changer in the management of OP poisoning, ultimately contributing to better clinical practices and patient outcomes.

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Cortical neurons encode both sensory and contextual information, yet it remains unclear how experiences modulate these cortical representations. Here, we demonstrate that trace eyeblink conditioning (TEC), an aversive associative-learning paradigm linking conditioned (CS) with unconditioned stimuli (US), finely tunes cortical coding at both population and single-neuron levels. Initially, we show that the primary somatosensory cortex (S1) is necessary for TEC acquisition, as evidenced by local muscimol administration. At the population level, TEC enhances activity in a small subset (∼20%) of CS- or US-responsive primary neurons (rPNs) while diminishing activity in non-rPNs, including locomotion-tuned or unresponsive PNs. Crucially, TEC learning modulates the encoding of sensory versus contextual information in single rPNs: CS-responsive neurons become less responsive, while US-responsive neurons gain responses to CS. Moreover, we find that the cholinergic pathway, via nicotinic receptors, underlies TEC-induced modulations. These findings suggest that experiences dynamically tune cortical representations through cholinergic pathways.

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Overactive bladder (OAB) is a common urological disease with a high prevalence in older adult populations. Antimuscarinic drugs have been the most common treatment for OAB for more than a decade, but their anticholinergic side-effects and potential impact on cognitive function among older patients are usually underestimated. This consensus aimed to provide practical recommendations concerning OAB management, with a particular emphasis on older patients. A joint consensus panel was formed by representatives of the Hong Kong Urological Association and the Hong Kong Geriatrics Society. Literature searches regarding OAB and its management were performed in PubMed and Ovid. Several working meetings were held to present and discuss available evidence, develop consensus statements, and vote for the statements. A modified Delphi method was used in this consensus process. To address questions regarding various aspects of OAB, 29 consensus statements were proposed covering the following areas: diagnosis, initial assessment, non-pharmacological treatments, considerations before administration of pharmacological treatments, various pharmacological treatments, combination therapy, and surgical treatment. Twenty-five consensus statements were accepted.

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Cholinergic projection neurons of the nucleus basalis and substantia innominata (NBM/SI) densely innervate the basolateral amygdala (BLA) and have been shown to contribute to the encoding of fundamental and life-threatening experiences. Given the vital importance of these circuits in the acquisition and retention of memories that are essential for survival in a changing environment, it is not surprising that the basic anatomical organization of the NBM/SI is well conserved across animal classes as diverse as teleost and mammal. What is not known is the extent to which the physiology and morphology of NBM/SI neurons have also been conserved. To address this issue, we made patch-clamp recordings from NBM/SI neurons in ex vivo slices of two widely divergent mammalian species, mouse and rhesus macaque, focusing our efforts on cholinergic neurons that project to the BLA. We then reconstructed most of these recorded neurons post hoc to characterize neuronal morphology. We found that rhesus macaque BLA-projecting cholinergic neurons were both more intrinsically excitable and less morphologically compact than their mouse homologs. Combining measurements of 18 physiological features and 13 morphological features, we illustrate the extent of the separation. Although macaque and mouse neurons both exhibited considerable within-group diversity and overlapped with each other on multiple individual metrics, a combined morpho-electric analysis demonstrates that they form two distinct neuronal classes. Given the shared purpose of the circuits in which these neurons participate, this finding raises questions about (and offers constraints on) how these distinct classes result in similar behavior.

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Cerebral perfusion is functionally regulated by neural mechanisms in addition to the systemic hemodynamic variation, vascular reactivity and cerebral metabolism. Although anesthesia is generally esteemed to suppress the overall brain neural activity and metabolism, a few inhalation anesthetics, such as isoflurane, can increase cerebral perfusion, thus heightening the risks of higher intracranial pressure, bleeding, and brain edema during surgery. With the aid of laser speckle contrast imaging, we observed a transient yet limited effect of cerebral perfusion enhancement in mice from awake to anesthetized conditions with different concentration of isoflurane. Retrograde and antegrade tracing revealed a higher proportion of parasympathetic control more than sympathetic innervation for the blood vessels. Surprisingly, isoflurane directly activated pterygopalatine ganglion (PPG) explants and induced FOS expression in the cholinergic neurons. Chemogenetic activation of cholinergic PPG neurons reduced isoflurane-related cerebral perfusion. On the contrary, ablation of the cholinergic PPG neurons resulted in further enhancement of cerebral perfusion induced by isoflurane. While blocking muscarinic cholinergic receptors resulted in the overall reduction upon isoflurane stimulation, the blockage of nicotinic cholinergic receptors enhanced the isoflurane-induced cerebral perfusion only when PPG neurons exist. Collectively, these results suggest that PPG play important roles in regulating cerebral perfusion under isoflurane inhalation.

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Resistance exercise training (RET) is considered an excellent tool for preventing diseases with an inflammatory background. Its neuroprotective, antioxidant, and anti-inflammatory properties are responsible for positively modulating cholinergic and oxidative systems, promoting neurogenesis, and improving memory. However, the mechanisms behind these actions are largely unknown. In order to investigate the pathways related to these effects of exercise, we conducted a 12-week long-term exercise training protocol and used lipopolysaccharide (LPS) to induce damage to the cortex and hippocampus of male Wistar rats. The cholinergic system, oxidative stress, and histochemical parameters were analyzed in the cerebral cortex and hippocampus, and memory tests were also performed. It was observed that LPS: (1) caused memory loss in the novel object recognition (NOR) test; (2) increased the activity of acetylcholinesterase (AChE) and Iba1 protein density; (3) reduced the protein density of brain-derived neurotrophic factor (BDNF) and muscarinic acetylcholine receptor M1 (CHRM1); (4) elevated the levels of lipid peroxidation (TBARS) and reactive species (RS); and (5) caused inflammatory damage to the dentate gyrus. RET, on the other hand, was able to prevent all alterations induced by LPS, as well as increase per se the protein density of the alpha-7 nicotinic acetylcholine receptor (nAChRα7) and Nestin, and the levels of protein thiols (T-SH). Overall, our study elucidates some mechanisms that support resistance physical exercise as a valuable approach against LPS-induced neuroinflammation and memory loss.

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Sleep deprivation has been shown to exacerbate pain sensitivity and may contribute to the onset of chronic pain, yet the precise neural mechanisms underlying this association remain elusive. In our study, we explored the contribution of cholinergic neurons within the medial habenula (MHb) to hyperalgesia induced by sleep deprivation in rats. Our findings indicate that the activity of MHb cholinergic neurons diminishes during sleep deprivation and that chemogenetic stimulation of these neurons can mitigate the results. Interestingly, we did not find a direct response of MHb cholinergic neurons to pain stimulation. Further investigation identified the interpeduncular nucleus (IPN) and the paraventricular nucleus of the thalamus (PVT) as key players in the pro-nociceptive effect of sleep deprivation. Stimulating the pathways connecting the MHb to the IPN and PVT alleviated the hyperalgesia. These results underscore the important role of MHb cholinergic neurons in modulating pain sensitivity linked to sleep deprivation, highlighting potential neural targets for mitigating sleep deprivation-induced hyperalgesia.

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BACKGROUND: The cholinergic neurotransmitter system is crucial to cognitive function, with the basal forebrain (BF) being particularly susceptible to Alzheimer's disease (AD) pathology. However, the interaction of white matter hyperintensities (WMH) in cholinergic pathways and BF atrophy without amyloid pathology remains poorly understood. METHODS: We enrolled patients who underwent neuropsychological tests, magnetic resonance imaging, and 18F-florbetaben positron emission tomography due to cognitive impairment at the teaching university hospital from 2015 to 2022. Among these, we selected patients with negative amyloid scans and additionally excluded those with Parkinson's dementia that may be accompanied by BF atrophy. The WMH burden of cholinergic pathways was quantified by the Cholinergic Pathways Hyperintensities Scale (CHIPS) score, and categorized into tertile groups because the CHIPS score did not meet normal distribution. Segmentation of the BF on volumetric T1-weighted MRI was performed using FreeSurfer, then was normalized for total intracranial volume. Multivariable regression analysis was performed to investigate the association between BF volumes and CHIPS scores. RESULTS: A total of 187 patients were enrolled. The median CHIPS score was 12 [IQR 5.0; 24.0]. The BF volume of the highest CHIPS tertile group (mean ± SD, 3.51 ± 0.49, CHIPSt3) was significantly decreased than those of the lower CHIPS tertile groups (3.75 ± 0.53, CHIPSt2; 3.83 ± 0.53, CHIPSt1; P = 0.02). In the univariable regression analysis, factors showing significant associations with the BF volume were the CHIPSt3 group, age, female, education, diabetes mellitus, smoking, previous stroke history, periventricular WMH, and cerebral microbleeds. In multivariable regression analysis, the CHIPSt3 group (standardized beta [ßstd] = -0.25, P = 0.01), female (ßstd = 0.20, P = 0.04), and diabetes mellitus (ßstd = -0.22, P < 0.01) showed a significant association with the BF volume. Sensitivity analyses showed a negative correlation between CHIPS score and normalized BF volume, regardless of WMH severity. CONCLUSIONS: We identified a significant correlation between strategic WMH burden in the cholinergic pathway and BF atrophy independently of amyloid positivity and WMH severity. These results suggest a mechanism of cholinergic neuronal loss through the dying-back phenomenon and provide a rationale that strategic WMH assessment may help identify target groups that may benefit from acetylcholinesterase inhibitor treatment.

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