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The vagus nerve (VN) belongs to the parasympathetic nervous system, which is well known to be involved in the regulation of the functions of organs in the body. The neurotransmitter acetylcholine, released from the cholinergic system including VN, has been known to play an anti-inflammatory role through the efferent pathways in regulating peripheral inflammatory responses profoundly involved in the pathogenesis of diseases. In contrast, anatomically, it connects the central nervous system (CNS) and peripheral organs, including the heart and gastrointestinal (GI) tract. Therefore, it has been recently reported that the VN also plays an important role in the pathogenesis of psychological disorders since it confers varied signals from the GI tract to the CNS, and alteration of microbiota residing in GI definitely influences the condition of neuropsychiatric disorders. Furthermore, the CNS includes microglia, a neuroinflammatory effector in the brain, which is also influenced by the VN to modulate its inflammatory status. Based on significant findings of the VN, the VN stimulation (VNS) has recently drawn attention from many scientific fields. VNS was initially applied to patients with refractory epilepsy, followed by patients with refractory depression. Subsequently, VNS was also attempted to be introduced to other diseases. However, against whichever disease, central or peripheral, detailed underlying mechanisms of VNS involved in neuropsychiatric disorders as well as VNS target molecules in the GI tract and the CNS remains to be studied. In this review, we discuss the mechanisms and predicted responsible factors of VNS in terms of neuropsychiatric disorders., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Neurological signs and symptoms are the most common complications of Ebola virus disease. However, the mechanisms underlying the neurologic manifestations in Ebola patients are not known. In this study, peripheral ganglia were collected from 12 rhesus macaques that succumbed to Ebola virus (EBOV) disease from 5 to 8 days post exposure. Ganglionitis, characterized by neuronal degeneration, necrosis, and mononuclear leukocyte infiltrates, was observed in the dorsal root, autonomic, and enteric ganglia. By immunohistochemistry, RNAscope in situ hybridization, transmission electron microscopy, and confocal microscopy, we confirmed that CD68+ macrophages are the target cells for EBOV in affected ganglia. Further, we demonstrated that EBOV can induce satellite cell and neuronal apoptosis and microglial activation in infected ganglia. Our results demonstrate that EBOV can infect peripheral ganglia and results in ganglionopathy in rhesus macaques, which may contribute to the neurological signs and symptoms observed in acute and convalescent Ebola virus disease in human patients., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Aims: Parasympathetic nerve (PN) signaling plays a crucial role in the maintenance of pancreatic β-cell volume density (V β ). PN may be pathologically affected in diabetic polyneuropathy (DPN). However, the association between the reduction of PNs in islets and V β and the therapeutic effects of a DPP4 inhibitor (DPP4i) and an SGLT2 inhibitor (SGLT2i) in nonobese type 2 diabetes mellitus (T2DM) Goto-Kakizaki rats (GK) have not been investigated., Materials and Methods: We divided 5-week old male GK and Wistar rats (W) into a DPP4i-treated group (GKTe), SGLT2i-treated group (GKCa), and combination-treated group (GKCaTe). After 25 weeks, the pancreata was pathologically evaluated., Results: V β in GK was significantly decreased (p < 0.01 vs. W), whereas V β was the most well preserved in GKCaTe (p < 0.05 vs. GKTe), followed by GKTe (p < 0.05 vs. GK). The decreased amount of PNs in the islets and intraepidermal nerve fiber density (IENFD) in GK was significantly improved in the treated groups compared with GK (p < 0.05 vs. GKCa and GKTe and p < 0.01 vs. GKCaTe). PN density and IENFD were significantly correlated with V β (r = 0.55, p < 0.01 and r = 0.54, p < 0.01, respectively). IENFD was identified as a surrogate marker for the prediction of V β (cutoff value, 16.39)., Conclusions: The combination therapy of DPP4i and SGLT2i improved V β accompanied by PNs density and IENFD. IENFD was proportionally correlated with V β . Therefore, the prevention of DPN development may be concurrently beneficial for the preservation of V β in nonobese T2DM., Competing Interests: Declaration of competing interest There is no potential conflict of interest for all authors except for HM. Teneligliptin and canagliflozin were kindly gifted from Tanabe Mitsubishi Pharmacological Inc. Research grant was given to HM by Tanabe Mitsubishi Pharmacological Inc, Japan., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To investigate whether baseline concentrations of plasma total tau (t-tau) and neurofilament light (NfL) chain proteins are associated with annual percent change (APC) of the basal forebrain cholinergic system (BFCS) in cognitively intact older adults at risk for Alzheimer disease (AD)., Methods: This was a large-scale study of 276 cognitively intact older adults from the monocentric INSIGHT-preAD (Investigation of Alzheimer's Predictors in Subjective Memory Complainers) cohort. Participants underwent baseline assessment of plasma t-tau and NfL concentrations as well as baseline and 24-month follow-up MRI scans. Linear models with and without influential observations (calculated using the Cook distance) were carried out to investigate the effect of plasma NfL and t-tau concentrations, and their interaction effect with β-amyloid status and APOE genotype, on the APC of the whole BFCS and its anterior (Ch1/2) and posterior (Ch4) subdivisions separately., Results: Higher plasma t-tau concentrations at baseline were associated with higher BFCS rate of atrophy (model without influencers: n = 251, F value = 4.6815; p value = 0.031). Subregional analyses showed similar results for both the APC of the Ch1/2 (model without influencers: n = 256, F value = 3.9535, p corrected = 0.047) and Ch4 BFCS sectors (model without influencers: n = 253, F value = 4.9090, p corrected = 0.047). Baseline NfL, β-amyloid load, and APOE ε4 carrier status did not affect APC of the BFCS., Conclusion: Increased concentrations of baseline plasma t-tau may predict in vivo structural BFCS atrophy progression in older adults at risk for AD, independently of β-amyloid status and APOE genotype., (© 2019 American Academy of Neurology.)

Background and Purpose: The brain's cholinergic network has various interconnections with the cortical and subcortical structures. Disruption of cholinergic pathways by white matter hyperintensities (WMH) may cause pathologic changes within brain regions. Thus, WMH may represent an important pathological contributor to subcortical vascular cognitive impairment (scVCI). We aimed to investigate associations between the magnitude of WMH and volumetric changes in cortical and subcortical regions innervated by cholinergic neurons in patients with scVCI., Methods: We enrolled patients with scVCI, defined as moderate to severe WMH or multiple (>2) lacunar infarcts outside the brainstem. Cholinergic Pathway HyperIntensities Scale (CHIPS) scores were used to quantify the magnitude of cholinergic pathway disruptions by WMH. We measured cortical thickness and subcortical volumes of 11 brain regions innervated by cholinergic neurons. Partial correlation of brain region volumes with total CHIPS scores was obtained using multiple linear regression., Results: In total, 80 patients were enrolled. The mean age was 78.4 ± 6.5 years, median Mini-Mental State Examination score was 17 (interquartile range, 13-20) and median CHIPS score was 11 (interquartile range, 7-17). CHIPS scores were positively correlated with subcortical volumes of the putamen (r' = 0.46, P = 0.002) and pallidum (r' = 0.45, P = 0.002), and were negatively associated with inferior temporal (r' = -0.35, P = 0.002) and medial orbitofrontal (r' = -0.32, P = 0.002) cortical thickness., Conclusion: Our study suggested that WMH in cholinergic pathways may contribute to volumetric structural changes in cortical and subcortical structures innervated by cholinergic neurons., (© 2019 European Academy of Neurology.)

The effects of autonomic innervation of tumors on tumor growth remain unclear. Here we developed a series of genetic techniques to manipulate autonomic innervation in a tumor- and fiber-type-specific manner in mice with human breast cancer xenografts and in rats with chemically induced breast tumors. Breast cancer growth and progression were accelerated following stimulation of sympathetic nerves in tumors, but were reduced following stimulation of parasympathetic nerves. Tumor-specific sympathetic denervation suppressed tumor growth and downregulated the expression of immune checkpoint molecules (programed death-1 (PD-1), programed death ligand-1 (PD-L1), and FOXP3) to a greater extent than with pharmacological α- or β-adrenergic receptor blockers. Genetically induced simulation of parasympathetic innervation of tumors decreased PD-1 and PD-L1 expression. In humans, a retrospective analysis of breast cancer specimens from 29 patients revealed that increased sympathetic and decreased parasympathetic nerve density in tumors were associated with poor clinical outcomes and correlated with higher expression of immune checkpoint molecules. These findings suggest that autonomic innervation of tumors regulates breast cancer progression.

Exposure to lead is a threat factor for neurodegenerative disorders progress as it could trigger dopaminergic deficiency. We aimed herein to assess the effect of acute lead exposure (25mg/kg B.W i.p.) during three continuous days on the dopaminergic and noradrenergic systems together with locomotor performance in Meriones shawi (M. shawi), then the neuroprotective potential of curcumin-III (30mg/kg B.W) by oral gavage. Pb-exposed M. shawi exhibited increased tyrosine hydroxylase (TH) immunoreactivity in substantia nigra compacta (SNc), ventral tegmental area (VTA), locus coeruleus (LC), and dorsal striatum (DS), unlike the controls. This was correlated with decreased locomotor performance. A noticeable protective effect by co-treatment with curcumin-III was observed; in consequence, TH-immunoreactivity and locomotor disturbance were restored in Pb-treated Meriones. Our data results proved, on the one hand, an evident neurotoxic effect of acute Pb exposure and, on the other hand, a potent therapeutic effect of curcumin-III. Thereby, this compound may be recommended as a neuroprotective molecule for neurodegenerative disorders involving catecholaminergic impairment initiated by metallic elements., (Copyright © 2019. Published by Elsevier Masson SAS.)

Background: Toxoplasma gondii infection can occur through the ingestion of raw meat that contains tissue cysts or food that contains oocysts. Through the ingestion of oocysts, the parasite crosses the intestinal barrier, where the enteric nervous system is located. The objective was to investigate the kinetics of neuronal and glial responses during acute T. gondii infection., Methods: We used 45 Wistar rats that were divided into a control group and infected groups that were evaluated at 6, 12, 24, 48, 72 hours, 7 days, 10 days, and 15 days after infection. The rats received 5000 sporulated oocysts of the parasite orally. To detect neurons and enteric glia cells, the myenteric and submucosal plexuses of the duodenum underwent double-labeling immunohistochemical techniques to evaluate HuC/HuD and S100, HuC/HuD and ChAT, and HuC/HuD and nNOS., Key Results: We observed a reduction of the total neuron population in the submucosal plexus 72 hours after infection. Cholinergic neurons decreased in the submucosal plexus 15 days after infection, and nitrergic neurons decreased in the myenteric plexus 72 hours after infection. A decrease in the number of glial cells was observed 7 days after infection in the submucosal plexus, and an increase in the enteric glial cell (EGC)/neuron ratio was found in both plexuses 48 hours after infection., Conclusions and Inferences: We found decrease of neurons and increase in the EGC/neuron ratio in both plexuses caused by acute T. gondii infection, with major alterations 72 hours after oral infection. The number of cholinergic neurons decreased in the submucosal plexus, and the number of nitrergic neurons decreased in the myenteric plexus. A decrease in the number of enteric glial cells was observed in the submucosal plexus, and an increase in the enteric glial cell/neuron ratio was observed in both ganglionate plexuses of the duodenum., (© 2018 John Wiley & Sons Ltd.)

Cardiac sympathetic tone overdrive is a key mechanism of arrhythmia. Cardiac sympathetic nerves denervation, such as LSG ablation or renal sympathetic denervation, suppressed both the prevalence of VAs and the incidence of SCD. Accumulating evidence demonstrates the ligament of Marshall (LOM) is a key component of the sympathetic conduit between the left stellate ganglion (LSG) and the ventricles. The present study aimed to investigate the roles of the distal segment of LOM (LOMLSPV) denervation in ischemia and reperfusion (IR)-induced VAs, and compared that LSG denervation. Thirty-three canines were randomly divided into group 1 (IR group, n = 11), group 2 (LOMLSPV Denervation + IR, n = 9), and group 3 (LSG Denervation + IR, n = 13). Hematoxylin-Eosin (HE) and Immunohistochemistry staining revealed that LOMLSPV contained bundles of sympathetic but not parasympathetic nerves. IR increased the cardiac sympathetic tone [serum concentrations of noradrenaline (NE) and epinephrine (E)] and induced the prevalence of VAs [ventricular premature beat (VPB), salvo of VPB, ventricular tachycardia (VT), VT duration (VTD) and ventricular fibrillation (VF)]. Both LOMLSPV denervation and LSG denervation could reduce the cardiac sympathetic tone in Baseline (BS) [heart rate variability (HRV)]. Compared with group 1, LOMLSPV denervation and LSG denervation similarly reduced sympathetic tone [NE (1.39±0.068 ng/ml in group 2, 1.29±0.081 ng/ml in group 3 vs 2.32±0.17 ng/ml in group 1, P<0.05) and E (114.64±9.22 pg/ml in group 2, 112.60±9.69 pg/ml in group 3 vs 166.18±15.78 pg/ml in group 1, P<0.05),] and VAs [VT (0±3.00 in group 2, 0±1.75 in group 3 vs 8.00±11.00 in group 1, P<0.05) and VTD (0 ± 4 s in group 2, 0±0.88s in group 3 vs 10.0 ± 22.00s in group 1, P<0.05)] after 2h reperfusion. These findings indicated LOMLSPV denervation reduced the prevalence of VT by suppressing SNS activity. These effects are comparable to those of LSG denervation. In myocardial IR, the anti-arrhythmic effects of LOMLSPV Denervation may be related to the inhibition of the expression of NE and E., Competing Interests: The authors have declared that no competing interests exist.

It is a well-established fact that the sympathetic, parasympathetic and enteric nervous systems are affected at early stages in Parkinson's disease (PD). However, it is not yet clarified whether the earliest pathological events preferentially occur in any of these three divisions of the autonomic nervous system (ANS). Significant involvement of the peripheral autonomic nervous system of the heart and gastrointestinal tract has been documented in PD. Accumulating evidence suggests that the PD pathology spreads centripetally from the peripheral to central nervous system through autonomic nerve fibers, implicating the ANS as a major culprit in PD pathogenesis and a potential target for therapy. This study begins with a brief overview of the structures of the central and peripheral autonomic nervous system and then outlines the major clinicopathological manifestations of cardiovascular and gastrointestinal disturbances in PD.

Rationale: Slow transit constipation (STC) is a common disease of which the etiology is still not clear. Multiple hypotheses have been proposed to explain STC, including autonomic neuropathy, disorders of the enteric nervous system and so forth. Morphological abnormalities of the enteric nerves of the colon in patients with STC have been extensively reported, while there have been no morphological reports focusing on extrinsic extramural fibers from the pelvic plexus to the distal colon (i.e., pelvic parasympathetic colonic nerve) in patients with STC., Patient Concerns: Whether morphological changes of pelvic parasympathetic colonic nerve coexist with abnormalities of the enteric nerves of the colon in the patient with STC., Diagnosis: Slow transit constipation (STC)., Interventions: The patient with STC underwent a partial colectomy (sigmoid colon and partial descending colon). The fibers of the myenteric plexuses within the removed colon and the myelinated fibers of the pelvic parasympathetic colonic nerve were observed under optical and electron-microscope., Outcomes: The fibers of the myenteric plexuses showed vacuolated degeneration between the muscularis propria layer under optical microscope. Myelinated fibers of the pelvic parasympathetic colonic nerve showed obvious vacuolated degeneration under electron-microscopic examination., Lessons: Such a simultaneous neuropathy in both myenteric plexuses and extrinsic extramural nerves has not been documented previously. Our finding supports the notion that neuropathy remains the most plausible explanation for STC, in which nerve dysfunction might occur by way of a degenerative process.

In recent years the identification of regulatory mechanisms of the general adaptation syndrome, manifesting itself as the response of an organism to drastic changes in the environment and leading to emotional stress, acquires a special significance. The control over visceral functions plays a particular role in stress reactions because of emerging threat of violation of neurodynamic balance of sympathetic-para- sympathetic relationships with their most sensitive element - the heart. Quick adaptation to stress helps to restore not only the sympathetic-parasympathetic homeostasis but also the energy metabolism. One of the essential components, activating metabolic processes, is taurine. This paper considers the descending influence of the paraventricular nucleus (PVN) on neuronal reactions of the solitary tract nucleus (NTS), the first linking pathways of visceral sensitivity, the mechanisms of central control over visceral reactions by mathematical model analysis of heart rate variability (MMA HRV) as well as morpho-histochemical changes in brain structures integrating and regulating the visceral sphere (PVN of the hypothalamus and the amygdala) under psycho-emotional stress without and with intraperitoneal injection of taurine (50 mg/kg). Acute and semichronic experiments were conducted on white nonlinear rats under 5-hour- long immobilization psycho-emotional stress. A highly defined centralization of vegetative HRV parame- ters (HR, IVR, INRS) was revealed, these parameters being normalized on days 7 and 14 at the background of taurine injections. The interaction and interdependence of the central regulatory mechanisms of cardiovascular reactions are shown as well as a considerable protective effect of taurine on promoting early restoration of adaptive properties of the central and peripheral segments of visceral sensitivity under development of long-term psycho-emotional stress.

Vagally mediated heart rate variability (vmHRV), defined as the beat-to-beat fluctuations in a heart series mediated by the vagus nerve, serves as a non-invasive index of parasympathetic nervous system (PNS) activity. Lower resting state vmHRV is associated with greater body mass index (BMI), providing a psychophysiological pathway linking obesity with health and disease. However little research has been conducted to examine how BMI may influence PNS reactivity to orthostatic stress. The present study sought to explore this in a sample of 59 individuals (44 females, mean age = 24.37 years, age range 19-65 years). VmHRV was measured throughout the 5-minute baseline (sitting), orthostatic (standing), and recovery (sitting) conditions. Individuals were stratified into low (BMI < 20), moderate (BMI 20-25), and high (BMI > 25) BMI groups. Results indicate that the high BMI group had a greater decrease in vmHRV from baseline to standing in comparison to the moderate BMI group. Furthermore, the low BMI group showed lower vmHRV during recovery compared to baseline, suggesting that these individuals did not fully recover from the standing position. Taken together, these results extend previous literature showing that those with low and high BMI can show different yet maladaptive patterns of vmHRV in response to orthostatic stress., Competing Interests: The authors did not receive funding for the work presented. The authors declare no conflict of interests, all authors are listed, and all have contributed substantially to the manuscript.

Sudden unexpected death occurs in one quarter of deaths in Rett Syndrome (RTT), a neurodevelopmental disorder caused by mutations in Methyl-CpG-binding protein 2 (MECP2). People with RTT show a variety of autonomic nervous system (ANS) abnormalities and mouse models show similar problems including QTc interval prolongation and hypothermia. To explore the role of cardiac problems in sudden death in RTT, we characterized cardiac rhythm in mice lacking Mecp2 function. Male and female mutant mice exhibited spontaneous cardiac rhythm abnormalities including bradycardic events, sinus pauses, atrioventricular block, premature ventricular contractions, non-sustained ventricular arrhythmias, and increased heart rate variability. Death was associated with spontaneous cardiac arrhythmias and complete conduction block. Atropine treatment reduced cardiac arrhythmias in mutant mice, implicating overactive parasympathetic tone. To explore the role of MeCP2 within the parasympathetic neurons, we selectively removed MeCP2 function from cholinergic neurons (MeCP2 ChAT KO), which recapitulated the cardiac rhythm abnormalities, hypothermia, and early death seen in RTT male mice. Conversely, restoring MeCP2 only in cholinergic neurons rescued these phenotypes. Thus, MeCP2 in cholinergic neurons is necessary and sufficient for autonomic cardiac control, thermoregulation, and survival, and targeting the overactive parasympathetic system may be a useful therapeutic strategy to prevent sudden unexpected death in RTT.

Fabry disease is a glycosphingolipid storage disorder that is caused by a genetic deficiency of the enzyme alpha-galactosidase A (AGA, EC 3.2.1.22). It is a multisystem disease that affects the vascular, cardiac, renal, and nervous systems. One of the hallmarks of this disorder is neuropathic pain and sympathetic and parasympathetic nervous dysfunction. The exact mechanism by which changes in AGA activity result in change in neuronal function is not clear, partly due to of a lack of relevant model systems. In this study, we report the development of an in vitro model system to study neuronal dysfunction in Fabry disease by using short-hairpin RNA to create a stable knock-down of AGA in the human cholinergic neuronal cell line, LA-N-2. We show that gene-silenced cells show specifically reduced AGA activity and store globotriaosylceramide. In gene-silenced cells, release of the neurotransmitter acetylcholine is significantly reduced, demonstrating that this model may be used to study specific neuronal functions such as neurotransmitter release in Fabry disease., (Published by Elsevier Inc.)

Purpose: Giant axonal neuropathy (GAN) is an inherited severe sensorimotor neuropathy. The aim of this research was to investigate the neuropathologic features and clinical autonomic nervous system (ANS) phenotype in two GAN knockout (KO) mouse models. Little is known about ANS involvement in GAN in humans, but autonomic signs and symptoms are commonly reported in early childhood., Methods: Routine histology and immunohistochemistry was performed on GAN KO mouse specimens taken at various ages. Enteric dysfunction was assessed by quantifying the frequency, weight, and water content of defecation in GAN KO mice., Results: Histological examination of the enteric, parasympathetic and sympathetic ANS of GAN KO mice revealed pronounced and widespread neuronal perikaryal intermediate filament inclusions. These neuronal inclusions served as an easily identifiable, early marker of GAN in young GAN KO mice. Functional studies identified an age-dependent alteration in fecal weight and defecation frequency in GAN KO mice., Conclusions: For the first time in the GAN KO mouse model, we described the early, pronounced and widespread neuropathologic features involving the ANS. In addition, we provided evidence for a clinical autonomic phenotype in GAN KO mice, reflected in abnormal gastrointestinal function. These findings in GAN KO mice suggest that consideration should be given to ANS involvement in human GAN, especially when considering treatments and patient care.

Traumatic brain injury (TBI) results in varying degrees of disability in a significant number of persons annually. The mechanisms of cognitive dysfunction after TBI have been explored in both animal models and human clinical studies for decades. Dopaminergic, serotonergic, and noradrenergic dysfunction has been described in many previous reports. In addition, cholinergic dysfunction has also been a familiar topic among TBI researchers for many years. Although pharmacological agents that modulate cholinergic neurotransmission have been used with varying degrees of success in previous studies, improving their function and maximizing cognitive recovery is an ongoing process. In this article, we review the previous findings on the biological mechanism of cholinergic dysfunction after TBI. In addition, we describe studies that use both older agents and newly developed agents as candidates for targeting cholinergic neurotransmission in future studies.

Developmental mechanisms leading to lung hypoplasia in congenital diaphragmatic hernia (CDH) remain poorly defined. Pulmonary innervation is defective in the human disease and in the rodent models of CDH. We hypothesize that defective parasympathetic innervation may contribute to airway branching abnormalities and, therefore, lung hypoplasia, during lung development in CDH. The murine nitrofen model of CDH was utilized to study the effect of the cholinergic agonist carbachol on embryonic day 11.5 (E11.5) lung explant cultures. Airway branching and contractions were quantified. In a subset of experiments, verapamil was added to inhibit airway contractions. Sox9 immunostaining and 5-bromo-2-deoxyuridine incorporation were used to identify and quantify the number and proliferation of distal airway epithelial progenitor cells. Intra-amniotic injections were used to determine the in vivo effect of carbachol. Airway branching and airway contractions were significantly decreased in nitrofen-treated lungs compared with controls. Carbachol resulted in increased airway contractions and branching in nitrofen-treated lungs. Nitrofen-treated lungs exhibited an increased number of proliferating Sox9-positive distal epithelial progenitor cells, which were decreased and normalized by treatment with carbachol. Verapamil inhibited the carbachol-induced airway contractions in nitrofen-treated lungs but had no effect on the carbachol-induced increase in airway branching, suggesting a direct carbachol effect independent of airway contractions. In vivo treatment of nitrofen-treated embryos via amniotic injection of carbachol at E10.5 resulted in modest increases in lung size and branching at E17.5. These results suggest that defective parasympathetic innervation may contribute to airway branching abnormalities in CDH., (Copyright © 2015 the American Physiological Society.)

Diabetic cardiac autonomic neuropathy (DCAN) may cause fatal ventricular arrhythmias and increase mortality in diabetics. However, limited data are available with regard to the precise changes in cardiac autonomic denervation after diabetes onset. In this study, we dynamically observed the progression of DCAN and its relationship with the inducibility of ventricular arrhythmias in diabetic rats. Rats were randomly divided into normal control and diabetes mellitus (DM) groups. The rats were sacrificed at 3 or 6 months post-treatment. Heart rate variability and programmed electrical stimulation were used to assess the electrophysiological characteristics and the inducibility of ventricular arrhythmias in the animals. Immunohistochemistry and real-time RT-PCR were used to measure choline acetyltransferase and tyrosine hydroxylase-positive nerve fibers and the corresponding mRNA expression levels in the proximal and distal regions of the left ventricle. Short-term diabetes resulted in distal myocardial parasympathetic denervation with sparing of the proximal myocardium. By 6 months, both parasympathetic and sympathetic denervation were further aggravated. Moreover, electrophysiological experiments demonstrated a sympatho-parasympathetic imbalance and an increase in ventricular arrhythmia inducibility in the diabetic rats. These results suggest that DM causes cardiac nerve denervation, relative sympathetic hyperinnervation and inhomogeneous neural innervations, which may be associated with an increase in the induction of ventricular arrhythmia in diabetic rats., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Unlabelled: Brain cholinergic function has been previously studied with PET but little effort has been devoted to imaging peripheral organs. Many disorders, including diabetes and Parkinson disease, are associated with autonomic dysfunction including parasympathetic denervation. Nonneuronal cholinergic signaling is also involved in immune responses to infections and in cancer pathogenesis. 5-(11)C-methoxy-donepezil, a noncompetitive acetylcholinesterase ligand, was previously validated for imaging cerebral levels of acetylcholinesterase. In the present study, we explored the utility of (11)C-donepezil for imaging acetylcholinesterase densities in peripheral organs, including the salivary glands, heart, stomach, intestine, pancreas, liver, and spleen., Methods: With autoradiography, we determined binding affinities and levels of nonspecific (11)C-donepezil binding to porcine tissues. Radiation dosimetry was estimated by whole-body PET of a single human volunteer. Biodistribution and kinetic analyses of (11)C-donepezil time-activity curves were assessed with dynamic PET scans of 6 healthy human volunteers. A single pig with bacterial abscesses was PET-scanned to explore (11)C-donepezil uptake in infections., Results: Autoradiography showed high (11)C-donepezil binding (dissociation constant, 6-39 nM) in pig peripheral organs with low nonspecific signal. Radiation dosimetry was favorable (effective dose, 5.2 μSv/MBq). Peripheral metabolization of (11)C-donepezil was low (>90% unchanged ligand at 60 min). Slow washout kinetics were seen in the salivary glands, heart, intestines, pancreas, and prostate. A linear correlation was seen between (11)C-donepezil volumes of distribution and standardized uptake values, suggesting that arterial blood sampling may not be necessary for modeling uptake kinetics in future (11)C-donepezil PET studies. High standardized uptake values and slow washout kinetics were seen in bacterial abscesses., Conclusion: (11)C-donepezil PET is suitable for imaging acetylcholinesterase densities in peripheral organs. Its uptake may potentially be quantitated with static whole-body PET scans not requiring arterial blood sampling. We also demonstrated high (11)C-donepezil binding in bacterial abscesses. We propose that (11)C-donepezil PET imaging may be able to quantify the parasympathetic innervation of organs but also detect nonneuronal cholinergic activity in infections., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Background: Chronic atrial fibrillation (AF) leads to heterogeneous autonomic nerve innervation termed neural remodeling. The quantitative changes in neural density as a function of autonomic remodeling and its association with sustained AF has not been previously determined., Method and Results: Seven dogs (paced group) were chronically paced with electrodes sutured to the epicardium of left atrial appendages. Seven dogs (control animals) were not paced. All paced dogs developed sustained AF by 5 weeks of pacing. The fat pads on the atrial epicardium containing ganglionated plexuses (GP) were separated along with underlying myocardial tissue. Immunocytochemical techniques were used to identify the neurons immunoreactive to anti-tyrosine hydroxylase (TH) and anti-acetylcholine antibodies. After chronic AF, sympathetic and parasympathetic neurons in the atrial intrinsic cardiac ganglia increased significantly. In paced dogs, the density of sympathetic neurons was 3,022 ± 507 μm(2) /mm(2) in the right atrial GP (vs control P < 0.01), 8,571 ± 476 μm(2) /mm(2) in the ventral left atrial GP (vs control P < 0.0001)， 6,422 ± 464 μm(2) /mm(2) in the dorsal atrial GP (vs control P < 0.0001) and 5,392 ± 595 μm(2) /mm(2) in the inferior vena cava-inferior atrial GP (vs control P <0.0001), respectively. The density of parasympathetic neurons was 4,396 ± 877 μm(2) /mm(2) in the right atrial GP, 7,769 ± 465 μm(2) /mm(2) in the ventral left atrial GP， 7,016.47 ± 687 μm(2) /mm(2) in the dorsal atrial GP and 5,485 ± 554 μm(2) /mm(2) in the inferior vena cava-inferior atrial GP, respectively, which was higher than control cohorts in corresponding GP (P < 0.05)., Conclusions: This study provides evidence for the remodeling in atrial intrinsic cardiac ganglia in the dogs with pacing induced AF. A significant increase of sympathetic and parasympathetic neurons was present in atrial intrinsic cardiac ganglia., (©2014 Wiley Periodicals, Inc.)

Degeneration of basal forebrain (BF) cholinergic neurons is one of the early pathological events in Alzheimer's disease (AD) and is thought to be responsible for the cholinergic and cognitive deficits in AD. The functions of this group of neurons are highly influenced by glutamatergic inputs from neocortex. We found that activation of metabotropic glutamate receptor 7 (mGluR7) decreased NMDAR-mediated currents and NR1 surface expression in rodent BF neurons via a mechanism involving cofilin-regulated actin dynamics. In BF cholinergic neurons, β-amyloid (Aβ) selectively impaired mGluR7 regulation of NMDARs by increasing p21-activated kinase activity and decreasing cofilin-mediated actin depolymerization through a p75(NTR)-dependent mechanism. Cell viability assays showed that activation of mGluR7 protected BF neurons from NMDA-induced excitotoxicity, which was selectively impaired by Aβ in BF cholinergic neurons. It provides a potential basis for the Aβ-induced disruption of calcium homeostasis that might contribute to the selective degeneration of BF cholinergic neurons in the early stage of AD., (Copyright © 2014 the authors 0270-6474/14/3413614-15$15.00/0.)

Neuropathy and cystopathy are two common conditions in patients with chronic diabetes. Despite obvious bladder sensory and motor nerve dysfunction in diabetes, no studies have selectively explored whether sensory or motor innervation is affected in the bladder. In the present study, we tested the hypothesis that loss of bladder sensory and motor fibers is responsible for bladder sensory and motor dysfunction. Parasympathetic and sensory innervation of the bladder dome and neck were examined using immunohistochemistry (IHC) and stereology in adult female rats 12weeks after induction of diabetes by streptozotocin. Naïve and age matched rats were evaluated as controls. Diabetic rats had mean blood glucose level of >400mg/dl, and bladder weights and thicknesses that were more than doubled compared to naïve rats. In naïve rats, parasympathetic vesicular acetylcholine transporter (VAT) and sensory calcitonin gene-related peptide (CGRP) immunopositive nerve fibers were located in bladder smooth muscle and were more densely distributed in the neck compared to the dome. Within the urothelial region, CGRP nerve fibers were densely distributed while VAT nerve fibers were sparsely distributed in the bladder neck and both were virtually absent in the bladder dome. Streptozotocin induced diabetes did not change the total nerve fiber length of either VAT or CGRP stained fibers in either the neck or dome. These studies indicate that hyperglycemia, induced by streptozotocin treatment, does not result in a loss of parasympathetic VAT or CGRP sensory nerve fibers, per se, but the doubling of bladder weight and mass does indicate a decrease in innervation density., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Intracellular glucose signalling pathways control the secretion of glucagon and insulin by pancreatic islet α- and β-cells, respectively. However, glucose also indirectly controls the secretion of these hormones through regulation of the autonomic nervous system that richly innervates this endocrine organ. Both parasympathetic and sympathetic nervous systems also impact endocrine pancreas postnatal development and plasticity in adult animals. Defects in these autonomic regulations impair β-cell mass expansion during the weaning period and β-cell mass adaptation in adult life. Both branches of the autonomic nervous system also regulate glucagon secretion. In type 2 diabetes, impaired glucose-dependent autonomic activity causes the loss of cephalic and first phases of insulin secretion, and impaired suppression of glucagon secretion in the postabsorptive phase; in diabetic patients treated with insulin, it causes a progressive failure of hypoglycaemia to trigger the secretion of glucagon and other counterregulatory hormones. Therefore, identification of the glucose-sensing cells that control the autonomic innervation of the endocrine pancreatic and insulin and glucagon secretion is an important goal of research. This is required for a better understanding of the physiological control of glucose homeostasis and its deregulation in diabetes. This review will discuss recent advances in this field of investigation., (© 2014 John Wiley & Sons Ltd.)

The islets of Langerhans receive signals from the circulation and nerves to modulate hormone secretion in response to physiological cues. Although the rich islet innervation has been documented in the literature dating as far back as Paul Langerhans' discovery of islets in the pancreas, it remains a challenging task for researchers to acquire detailed islet innervation patterns in health and disease due to the dispersed nature of the islet neurovascular network. In this article, we discuss the recent development of 3-dimensional (3D) islet neurohistology, in which transparent pancreatic specimens were prepared by optical clearing to visualize the islet microstructure, vasculature and innervation with deep-tissue microscopy. Mouse islets were used as an example to illustrate how to apply this 3D imaging approach to characterize (i) the islet parasympathetic innervation, (ii) the islet sympathetic innervation and its reinnervation after transplantation under the kidney capsule and (iii) the reactive cellular response of the Schwann cell network in islet injury. While presenting and characterizing the innervation patterns, we also discuss how to apply the signals derived from transmitted light microscopy, vessel painting and immunostaining of neural markers to verify the location and source of tissue information. In summary, the systematic development of tissue labelling, clearing and imaging methods to reveal the islet neuroanatomy offers insights to help study the neural-islet regulatory mechanisms and the role of neural tissue remodelling in the development of diabetes., (© 2014 John Wiley & Sons Ltd.)

A powerful interaction between the autonomic and the immune systems plays a prominent role in the initiation and maintenance of hypertension and significantly contributes to cardiovascular pathology, end-organ damage and mortality. Studies have shown consistent association between hypertension, proinflammatory cytokines and the cells of the innate and adaptive immune systems. The sympathetic nervous system, a major determinant of hypertension, innervates the bone marrow, spleen and peripheral lymphatic system and is proinflammatory, whereas the parasympathetic nerve activity dampens the inflammatory response through α7-nicotinic acetylcholine receptors. The neuro-immune synapse is bidirectional as cytokines may enhance the sympathetic activity through their central nervous system action that in turn increases the mobilization, migration and infiltration of immune cells in the end organs. Kidneys may be infiltrated by immune cells and mesangial cells that may originate in the bone marrow and release inflammatory cytokines that cause renal damage. Hypertension is also accompanied by infiltration of the adventitia and perivascular adipose tissue by inflammatory immune cells including macrophages. Increased cytokine production induces myogenic and structural changes in the resistance vessels, causing elevated blood pressure. Cardiac hypertrophy in hypertension may result from the mechanical afterload and the inflammatory response to resident or migratory immune cells. Toll-like receptors on innate immune cells function as sterile injury detectors and initiate the inflammatory pathway. Finally, abnormalities of innate immune cells and the molecular determinants of their activation that include toll-like receptor, adrenergic, cholinergic and AT1 receptors can define the severity of inflammation in hypertension. These receptors are putative therapeutic targets.

Ozone exposure causes airway hyperreactivity and increases hospitalizations resulting from pulmonary complications. Ozone reacts with the epithelial lining fluid and airway epithelium to produce reactive oxygen species and lipid peroxidation products, which then activate cell signaling pathways, including the mitogen activated protein kinase (MAPK) pathway. Both p38 and c-Jun NH2 terminal kinase (JNK) are MAPK family members that are activated by cellular stress and inflammation. To test the contribution of both p38 and JNK MAPK to ozone-induced airway hyperreactivity, guinea pigs were pretreated with dual p38 and JNK MAPK inhibitors (30 mg/kg, i.p.) 60 minutes before exposure to 2 ppm ozone or filtered air for 4 hours. One day later airway reactivity was measured in anesthetized animals. Ozone caused airway hyperreactivity one day post-exposure, and blocking p38 and JNK MAPK completely prevented ozone-induced airway hyperreactivity. Blocking p38 and JNK MAPK also suppressed parasympathetic nerve activity in air exposed animals, suggesting p38 and JNK MAPK contribute to acetylcholine release by airway parasympathetic nerves. Ozone inhibited neuronal M2 muscarinic receptors and blocking both p38 and JNK prevented M2 receptor dysfunction. Neutrophil influx into bronchoalveolar lavage was not affected by MAPK inhibitors. Thus p38 and JNK MAPK mediate ozone-induced airway hyperreactivity through multiple mechanisms including prevention of neuronal M2 receptor dysfunction.

Purpose of Review: The purpose of this review is to briefly discuss methods for classifying Nonallergic rhinitis (NAR), the current understanding of its immunopathogenesis, scientific evidence-based treatment options along with anecdotal clinical experience for selecting different treatment regimens for these challenging patients., Recent Findings: NAR also known as idiopathic rhinitis, irritant-induced rhinitis and vasomotor rhinitis is a heterogeneous condition that has been classified many different ways, but currently there is no consensus on definition for this condition due to its poorly elucidated mechanism(s) of action. A typical patient presents with nasal congestion, postnasal drainage with or without a cough associated with, to a lesser extent, some degree of sneezing, itching, and rhinorrhea. Recent studies have proposed more specific approaches for characterizing rhinitis subtypes. It is speculated that this condition is due to an autonomic imbalance resulting in an overactive parasympathetic and perhaps an underactive sympathetic nervous system. Our poor understanding of NAR mechanism(s) of action has significantly hindered progress in developing novel therapies for this condition., Summary: Further investigation is required to understand the neurogenic signaling pathways that lead to this aberrant response. Until we have selective therapies for NAR, treatment requires selecting the medication or combination of medications best suited to the symptomatic needs of the patient.

Background and Purpose: Nasal sensory nerves play an important role in symptoms associated with rhinitis triggered by environmental stimuli. Here, we propose that TRPV1 is pivotal in nasal sensory nerve activation and assess the potential of SB-705498 as an intranasal therapy for rhinitis., Experimental Approach: The inhibitory effect of SB-705498 on capsaicin-induced currents in guinea pig trigeminal ganglion cells innervating nasal mucosa was investigated using patch clamp electrophysiology. A guinea pig model of rhinitis was developed using intranasal challenge of capsaicin and hypertonic saline to elicit nasal secretory parasympathetic reflex responses, quantified using MRI. The inhibitory effect of SB-705498, duration of action and potency comparing oral versus intranasal route of administration were examined., Key Results: SB-705498 concentration-dependently inhibited capsaicin-induced currents in isolated trigeminal ganglion cells (pIC50 7.2). In vivo, capsaicin ipsilateral nasal challenge (0.03-1 mM) elicited concentration-dependent increases in contralateral intranasal fluid secretion. Ten per cent hypertonic saline initiated a similar response. Atropine inhibited responses to either challenge. SB-705498 inhibited capsaicin-induced responses by ∼50% at 10 mg·kg⁻¹ (oral), non-micronized 10 mg·mL⁻¹ or 1 mg·mL⁻¹ micronized SB-705498 (intranasal) suspension. Ten milligram per millilitre intranasal SB-705498, dosed 24 h prior to capsaicin challenge produced a 52% reduction in secretory response. SB-705498 (10 mg·mL⁻¹, intranasal) inhibited 10% hypertonic saline responses by 70%., Conclusions and Implications: The paper reports the development of a guinea pig model of rhinitis. SB-705498 inhibits capsaicin-induced trigeminal currents and capsaicin-induced contralateral nasal secretions via oral and intranasal routes; efficacy was optimized using particle-reduced SB-705498. We propose that TRPV1 is pivotal in initiating symptoms of rhinitis., (© 2013 GlaxoSmithKline. British Journal of Pharmacology © 2013 The British Pharmacological Society.)

Hypertensive heart disease (HHD) is the leading cause of mortality and morbidity in the United States. Despite the availability of medical therapy it remains a challenge to treat. Autonomic nervous system imbalance resulting in overactivity of the sympathetic nervous system and under activity of the parasympathetic nervous system is integral in the development of hypertension and ultimately the development of HHD. Emerging data suggest that neuromodulation device therapy for treatment of HHD is promising.

Background: Visual hallucinations (VH), which are common in patients with Parkinson's disease (PD), lead to increased disability and are a significant predictor of the development of dementia. However, the neuroanatomical basis for VH in non-demented PD patients remains controversial., Methods: A total of 110 patients with PD were classified into PD with VH (n=46) and PD without VH (n=64) groups, depending on the presence of VH assessed by the caregiver-based structured interview of the Neuropsychiatric Inventory. We performed voxel-based morphometry (VBM) for grey matter (GM) volume and a region-of-interest-based volumetric analysis of the substantia innominata (SI) between two groups., Results: The comprehensive neuropsychological assessment showed that PD patients with VH showed more severe cognitive deficits in delayed visual memory and frontal executive functions compared with those without VH. A VBM analysis revealed that PD patients with VH had significantly lower GM volume in the right orbitofrontal, left temporal and left thalamic areas compared with those without VH. The normalised SI volume was significantly reduced in PD patients with VH compared with those without VH (1.28 ± 0.22 vs 1.41 ± 0.25, p=0.005)., Conclusions: The present study demonstrates that non-demented PD patients with VH exhibited a smaller volume in the frontal, temporal and thalamic areas as well as the SI, suggesting that PD hallucinators may have distinctive neuroanatomical bases relative to PD non-hallucinators.

Objectives: Endothelial dysfunction and alterations in heart rate variability (HRV) as well as sleep deprivation and shift work have been associated with cardiovascular disease. The aim of this study was to compare HRV and endothelial function among shift and matched non-shift workers in response to total sleep deprivation and recovery sleep under identical laboratory settings., Methods: Eleven experienced male shift workers (shift work ≥ 5 years) and 14 non-shift workers were matched for age, body mass index, and cholesterol. HRV parameters [eg, HR variance and low frequency/high frequency (LF/HF) ratio] were derived from 5-minute electrocardiogram bins at 0.25, 4.25, 11.5, 12.5, and 13.5 hours after habitual wake-up time and endothelial function was assessed by flow-mediated dilatation (FMD) using ultrasound at 0.75 and 10.75 hours after habitual wake-up time, following baseline sleep, total sleep deprivation, and recovery sleep (posture- and food-controlled throughout). Circadian phase was assessed before baseline sleep by salivary dim light melatonin onset., Results: There was no difference in circadian phase between shift and non-shift workers. HR variance was highest at 0.25 hours following total sleep deprivation and lowest after recovery sleep. A significantly higher LF/HF ratio, significantly lower HR variance, and a trend for a lower %FMD (P=0.08) were observed among shift compared to non-shift workers., Conclusion: Despite similar demographics, circadian phase, posture and food intake, differences in endothelial function and HRV were observed in the two groups, which may reflect higher sympathetic and/or lower parasympathetic activity, contributing to increased cardiovascular risk among the shift workers.

Congenital diaphragmatic hernia (CDH) is associated with significant mortality due to lung hypoplasia and pulmonary hypertension. The role of embryonic pulmonary innervation in normal lung development and lung maldevelopment in CDH has not been defined. We hypothesize that developmental defects of intrapulmonary innervation, in particular autonomic innervation, occur in CDH. This abnormal embryonic pulmonary innervation may contribute to lung developmental defects and postnatal physiological derangement in CDH. To define patterns of pulmonary innervation in CDH, human CDH and control lung autopsy specimens were stained with the pan-neural marker S-100. To further characterize patterns of overall and autonomic pulmonary innervation during lung development in CDH, the murine nitrofen model of CDH was utilized. Immunostaining for protein gene product 9.5 (a pan-neuronal marker), tyrosine hydroxylase (a sympathetic marker), vesicular acetylcholine transporter (a parasympathetic marker), or VIP (a parasympathetic marker) was performed on lung whole mounts and analyzed via confocal microscopy and three-dimensional reconstruction. Peribronchial and perivascular neuronal staining pattern is less complex in human CDH than control lung. In mice, protein gene product 9.5 staining reveals less complex neuronal branching and decreased neural tissue in nitrofen-treated lungs from embryonic day 12.5 to 16.5 compared with controls. Furthermore, nitrofen-treated embryonic lungs exhibited altered autonomic innervation, with a relative increase in sympathetic nerve staining and a decrease in parasympathetic nerve staining compared with controls. These results suggest a primary defect in pulmonary neural developmental in CDH, resulting in less complex neural innervation and autonomic imbalance. Defective embryonic pulmonary innervation may contribute to lung developmental defects and postnatal physiological derangement in CDH.

Autonomic dysregulation is a feature of chronic heart failure (HF) and is characterized by a sustained increase of sympathetic drive and by withdrawal of parasympathetic activity. Both sympathetic overdrive and increased heart rate are predictors of poor long-term outcome in patients with HF. Pharmacologic agents that partially inhibit sympathetic activity, such as beta-adrenergic receptor blockers, effectively reduce mortality and morbidity in patients with chronic HF. In contrast, modulation of parasympathetic activation as a potential therapy for HF has received only limited attention because of its inherent complex cardiovascular effects. This review examines results of experimental animal studies that provide support for the possible use of electrical vagus nerve stimulation (VNS) as a long-term therapy for the treatment of chronic HF. The review also addresses the effects of VNS on potential modifiers of the HF state, including proinflammatory cytokines, nitric oxide elaboration, and myocardial expression of gap junction proteins. Finally, the safety, feasibility, and efficacy trends of VNS in patients with advanced HF are reviewed.

Cardiac autonomic neuropathy is a frequent complication of diabetes and often presents as impaired cholinergic regulation of heart rate. Some have assumed that diabetics have degeneration of cardiac cholinergic nerves, but basic knowledge on this topic is lacking. Accordingly, our goal was to evaluate the structure and function of cardiac cholinergic neurons and nerves in C57BL/6 mice with streptozotocin-induced diabetes. Electrocardiograms were obtained weekly from conscious control and diabetic mice for 16 weeks. Resting heart rate decreased in diabetic mice, but intrinsic heart rate was unchanged. Power spectral analysis of electrocardiograms revealed decreased high frequency and increased low frequency power in diabetic mice, suggesting a relative reduction of parasympathetic tone. Negative chronotropic responses to right vagal nerve stimulation were blunted in 16-week diabetic mice, but postjunctional sensitivity of isolated atria to muscarinic agonists was unchanged. Immunohistochemical analysis of hearts from diabetic and control mice showed no difference in abundance of cholinergic neurons, but cholinergic nerve density was increased at the sinoatrial node of diabetic mice (16 weeks: 14.9±1.2% area for diabetics versus 8.9±0.8% area for control, P<0.01). We conclude that disruption of cholinergic function in diabetic mice cannot be attributed to a loss of cardiac cholinergic neurons and nerve fibers or altered cholinergic sensitivity of the atria. Instead, decreased responses to vagal stimulation might be caused by a defect of preganglionic cholinergic neurons and/or ganglionic neurotransmission. The increased density of cholinergic nerves observed at the sinoatrial node of diabetic mice might be a compensatory response., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The methods used to assess cardiac parasympathetic (cardiovagal) activity and its effects on the heart in both humans and animal models are reviewed. Heart rate (HR)-based methods include measurements of the HR response to blockade of muscarinic cholinergic receptors (parasympathetic tone), beat-to-beat HR variability (HRV) (parasympathetic modulation), rate of post-exercise HR recovery (parasympathetic reactivation), and reflex-mediated changes in HR evoked by activation or inhibition of sensory (afferent) nerves. Sources of excitatory afferent input that increase cardiovagal activity and decrease HR include baroreceptors, chemoreceptors, trigeminal receptors, and subsets of cardiopulmonary receptors with vagal afferents. Sources of inhibitory afferent input include pulmonary stretch receptors with vagal afferents and subsets of visceral and somatic receptors with spinal afferents. The different methods used to assess cardiovagal control of the heart engage different mechanisms, and therefore provide unique and complementary insights into underlying physiology and pathophysiology. In addition, techniques for direct recording of cardiovagal nerve activity in animals; the use of decerebrate and in vitro preparations that avoid confounding effects of anesthesia; cardiovagal control of cardiac conduction, contractility, and refractoriness; and noncholinergic mechanisms are described. Advantages and limitations of the various methods are addressed, and future directions are proposed.

Sympathetic-parasympathetic interaction plays a major role in the evolution and outcome of many cardiovascular disorders. Nonetheless, a thorough understanding of this relationship and of its potential implications for prognosis and management still escapes many cardiologists. This article reviews the background of sympathetic-parasympathetic interactions focusing on the best direct evidence available, namely direct neural recordings of the activity of single vagal and sympathetic fibers directed to the heart. It examines indirect but highly reliable markers of this interaction as they can be studied in the clinical setting of ischemic heart disease and of heart failure, focusing primarily on the experimental and clinical studies of baroreflex sensitivity. It concludes by drawing inferences likely to lead to a novel approach to the management of heart failure, resulting from the knowledge gained about the vagal control of the heart and based on electrical vagal stimulation.

Chronic heart failure (HF) is associated with autonomic dysregulation characterized by a sustained increase in sympathetic drive and by withdrawal of parasympathetic activity. Sympathetic overdrive and increased heart rate are predictors of poor long-term outcome in patients with HF. Considerable evidence exists that supports the use of pharmacologic agents that partially inhibit sympathetic activity as effective long-term therapy for patients with HF; the classic example is the wide use of selective and non-selective beta-adrenergic receptor blockers. In contrast, modulation of parasympathetic activation as potential therapy for HF has received only limited attention over the years given its complex cardiovascular effects. In this article, we review the results of recent experimental animal studies that provide support for the possible use of electrical Vagus nerve stimulation (VNS) as a long-term therapy for the treatment of chronic HF. In addition to exploring the effects of chronic VNS on left ventricular (LV) function, the review will also address the effects of VNS on potential modifiers of the HF state that include cytokine production and nitric oxide elaboration. Finally, we will briefly review other nerve stimulation approaches which is also currently under investigation as potential therapeutic modalities for treating chronic HF.

The authors studied features of vegetative regulation in patients with occupational cervical dorsopathy and specified differentiated rehabilitation programs proved to be more efficient than the conventional treatment.

Changes in airway nerves associated with chronic inflammation may underlie the pathogenesis and symptoms of lower airway diseases, such as asthma. The molecules most likely causing such alterations are neurotrophins (NTs) and/or related neurokines. In several species, including humans, lower airway parasympathetic postganglionic neurons that project axons to airway smooth muscle are either cholinergic or nonadrenergic noncholinergic (NANC), the latter synthesizing vasoactive intestinal peptide and nitric oxide, but not acetylcholine. In guinea pig trachealis smooth muscle, cholinergic nerve terminals arise from ganglionic neurons located near the tracheal smooth muscle, whereas the source of NANC nerve fibers is from neurons in ganglia located in the adjacent myenteric plexus of the esophagus, making this an ideal species to study regulation of parasympathetic neurotransmitter phenotypes. In the present study, we determined that, 48 hours after repeated allergen challenge, the NANC phenotype of airway parasympathetic ganglionic neurons changed to a cholinergic phenotype, and NT-3 mimicked this change. Nerve growth factor, brain-derived neurotrophic factor, leukemia inhibitory factor, or IL-1β had no effect on either phenotype, and they did not induce these neurons to synthesize substance P or tyrosine hydroxylase. These results indicate a role for inflammation and NT-3 in regulating biochemical and anatomical characteristics of principal neurons in adult airway parasympathetic ganglia.

1. Epidemiological and clinical studies suggest that women may obtain cognitive benefits from oestrogen-replacement therapy (ERT) during menopause transition rather than in the post-menopausal stages. However, the underlying mechanisms remain to be determined. 2. We propose that long-term oestrogen deficiency may result in abnormal distribution and localization of brain oestrogen receptors, brain mitochondrial dysfunction, septohippocampal cholinergic degeneration and reactive gliosis. These multiple pathogenic factors may account for the lack of any beneficial effects of ERT in post-menopausal women with or without Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation and aggregation of amyloid-β peptide and loss of forebrain cholinergic neurons, resulting in progressive loss of memory and irreversible impairment of higher cognitive functions. Several studies have accounted for the close relationship between AD and the central cholinergic system, suggesting that a dysfunction of acetylcholine containing neurons in the brain contributes significantly to the cognitive deficit of individuals with AD. The aim of the present review is to survey current literature on this topic in order to provide a clear understanding of the role of the cholinergic system in the development and neurodegenerative process of AD. The implications for anesthesia are also discussed. This knowledge could be valuable to improve anesthesia performance and patient safety.

In this chapter the imaging changes associated with non-motor aspects of Parkinson's disease (PD) are reviewed. The relationship between reduced monoaminergic and cholinergic function and cognitive difficulties, depression, fatigue, sleep disorders, and dysautonomia is discussed and the relevance of Alzheimer pathology to PD dementia debated. Finally the discordance between the development of functional changes in PD and Braak staging is highlighted., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Impaired abomasal motility and an increased accumulation of gas are prerequisites for displacement of the abomasum in the cow. Predisposing factors are the breed (e.g. Holstein-Friesian, Simmental-Red-Holstein cross breeds and Guernsey), genetic background, twin pregnancy, first weeks of lactation, metabolic disorders (ketosis, increased lipomobilisation, insulin resistance), high-concentrate and low-fibre diets, as well as other concomitant diseases, such as endometritis, mastitis and claw disorders. There does not appear to be a strong correlation between increased milk yield or endotoxaemia and abomasal displacement. Recent studies have focused on possible functional disorders of the enteric nervous system within the abomasal wall, since cattle with abomasal displacement have an increased activity of neuronal nitric oxide synthase, as well as decreased acetylcholine sensitivity. In addition, there appear to be significant differences between breeds in the levels of the neurotransmitters substance P (SP) and vasoactive intestinal peptide (VIP) in the abomasal wall. For example, SP (stimulatory) was significantly less in German Holsteins in comparison to the German Fleckvieh, whereas VIP (inhibitory) was markedly increased. These risk factors may explain why Holstein cows are more susceptible to abomasal displacement than other breeds.

Background and Purpose: Increased tumour necrosis factor-alpha (TNF-alpha) is associated with airway hyperreactivity in antigen-challenged animals. In human asthmatics, TNF-alpha is increased and blocking it prevents airway hyperreactivity in some asthmatic patients. However, the mechanisms by which TNF-alpha mediates hyperreactivity are unknown. Airway hyperreactivity can be caused by dysfunction of neuronal M(2) muscarinic receptors that normally limit acetylcholine release from parasympathetic nerves. Here we test whether blocking TNF-alpha receptors with etanercept prevents M(2) receptor dysfunction and airway hyperreactivity in antigen-challenged guinea pigs., Experimental Approach: Ovalbumin-sensitized guinea pigs were challenged by inhalation of antigen. Some animals received etanercept (3 mg kg(-1) i.p.) 3 h before challenge. 24 h after challenge, airway hyperreactivity and M(2) receptor function were tested. Inflammatory cells in bronchoalveolar lavage, blood and lung were counted. TNF-alpha and its receptors were detected by real-time RT-PCR and immunocytochemistry in parasympathetic nerves from humans and guinea pigs and in human neuroblastoma cells., Key Results: Antigen-challenged animals were hyperreactive to vagal stimulation and neuronal M(2) receptors were dysfunctional. Both M(2) receptor dysfunction and airway hyperreactivity were prevented by etanercept. Etanercept reduced eosinophils around airway nerves, and in blood, bronchoalveolar lavage and airway smooth muscle. Also, TNF-alpha decreased M(2) receptor mRNA in human and guinea pig parasympathetic neurons., Conclusions and Implications: Tumour necrosis factor-alpha may contribute to M(2) receptor dysfunction and airway hyperreactivity directly by decreasing receptor expression and indirectly by promoting recruitment of eosinophils, containing major basic protein, an M(2) antagonist. This suggests that etanercept may be beneficial in treatment of allergic asthma.

We evaluated changes of brain rhythmicity correlating with the cerebrovascular damage of long-range (capsular tract) and short-range (medial and perisylvian tracts) cholinergic pathways in subjects with mild cognitive impairment (MCI). Ninety-four MCI subjects underwent electroencephalographic (EEG) recordings and magnetic resonance imaging (MRI). The EEG relative power spectrum was computed in delta, theta, alpha1, alpha2, alpha3, beta1, beta2, gamma frequency bands. White matter hyperintensities along each cholinergic tract was segmented on MRI. Three MCI subgroups were identified based on increasing damage. A significant increase of delta and theta power band was found in patients with the highest total cholinergic burden as well as in patients with highest capsular pathway damage; total load of cholinergic damage was also associated with decreased gamma power band. Alpha frequency was differentially affected: decrease of alpha3 power band was associated with the greatest damage of the capsular pathway whereas increase of alpha3 power band was associated with the greatest damage of the perisylvian pathway. Multiple regression linear analysis showed independent association of cholinergic damage with delta, theta and gamma frequency, not with alpha frequency. In conclusion, the damage of long-range and short range cholinergic tracts has possible different implications for cognitive functions in MCI subjects.

The mammalian mesopontine tegmentum (MPT) contains two cholinergic nuclei, the pedunculopontine tegmental nucleus (PPTg) and the laterodorsal tegmental nucleus (LDTg). These provide the cholinergic innervation of, among other brain areas, the dopaminergic A9 and A10 cell groups. Their axons are thus the source of endogenous acetylcholine (ACh) acting on somato-dendritic acetylcholine receptors in the substantia nigra (SN) and ventral tegmental area (VTA). The anatomy, physiology, functional and pathological implications of these interactions with the nicotinic subtype of acetylcholine receptors (nAChRs) are discussed with a view of the important role of the MPT as a master regulator of nicotinic dopaminergic signalling in the brain, including for nicotine addiction.

Age-dependent accumulation of lead in brain has been implicated in the pathomechanisms of Alzheimer's disease. The aim of this work was to investigate whether cholinotoxic effects of lead may result from alterations in acetyl-CoA metabolism. One day exposure of differentiated SN56 cholinergic neuroblastoma cells to 0.5 micromol/L lead or 0.01 mmol/L amyloid-beta1-42, increased fraction of nonviable cells to about 2%. Suppression of choline acetyltransferase activity occurred only in the presence of fresh amyloid-beta1-42, whereas lead was ineffective. All agents in combination caused suppression of acetyl-CoA in cytoplasm and mitochondria down to 19% and 34% of controls, respectively. Inverse correlation was observed between whole cell acetyl-CoA level and fraction of nonviable cells at different combinations of lead and other neurotoxic compounds. It indicates that lead had no primary suppressive effect on cholinergic phenotype but, at least in part, exerted cytotoxic influence on cholinergic neurons through the decrease of their acetyl-CoA.