Significance of vagus nerve function in terms of pathogenesis of psychosocial disorders.

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.

Peripheral Neuronopathy Associated With Ebola Virus Infection in Rhesus Macaques: A Possible Cause of Neurological Signs and Symptoms in Human Ebola Patients.

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.

Beneficial effects of combination therapy of canagliflozin and teneligliptin on diabetic polyneuropathy and ß-cell volume density in spontaneously type 2 diabetic Goto-Kakizaki rats.

AIMS: Parasympathetic nerve (PN) signaling plays a crucial role in the maintenance of pancreatic ß-cell volume density (Vß). PN may be pathologically affected in diabetic polyneuropathy (DPN). However, the association between the reduction of PNs in islets and Vß 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: Vß in GK was significantly decreased (p < 0.01 vs. W), whereas Vß 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 Vß (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 Vß (cutoff value, 16.39). CONCLUSIONS: The combination therapy of DPP4i and SGLT2i improved Vß accompanied by PNs density and IENFD. IENFD was proportionally correlated with Vß. Therefore, the prevention of DPN development may be concurrently beneficial for the preservation of Vß in nonobese T2DM.

Effect of cholinergic pathway disruption on cortical and subcortical volumes in subcortical vascular cognitive impairment.

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.

Plasma tau correlates with basal forebrain atrophy rates in people at risk for Alzheimer disease.

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 ß-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, ß-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 ß-amyloid status and APOE genotype.

Altered nigrostriatal dopaminergic and noradrenergic system prompted by systemic lead toxicity versus a treatment by curcumin-III in the desert rodent Meriones shawi.

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.

Genetic manipulation of autonomic nerve fiber innervation and activity and its effect on breast cancer progression.

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 ß-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.

Acute Toxoplasma gondii infection alters the number of neurons and the proportion of enteric glial cells in the duodenum in Wistar rats.

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.

Selective ablation of the ligament of Marshall reduces ischemia and reperfusion-induced ventricular arrhythmias.

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.

Peripheral and central autonomic nervous system: does the sympathetic or parasympathetic nervous system bear the brunt of the pathology during the course of sporadic PD?

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.

Effects of Body Mass Index on Parasympathetic Nervous System Reactivity and Recovery Following Orthostatic 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.

Simultaneous degeneration of myenteric plexuses and pelvic parasympathetic colonic nerve in slow transit constipation: A case report.

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.

[THE ROLE OF TAURINE THE PROCESS OF ADAPTATION OF VISCERAL SYSTEMS UNDER PSYCHO-EMOTIONAL STRESS IN RAT].

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.

Development of a model system for neuronal dysfunction in Fabry disease.

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.

Autonomic nervous system involvement in the giant axonal neuropathy (GAN) KO mouse: implications for human disease.

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.

Methyl-CpG binding-protein 2 function in cholinergic neurons mediates cardiac arrhythmogenesis.

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.

Defective parasympathetic innervation is associated with airway branching abnormalities in experimental CDH.

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.

Alterations in Cholinergic Pathways and Therapeutic Strategies Targeting Cholinergic System after Traumatic Brain Injury.

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.

In rats the duration of diabetes influences its impact on cardiac autonomic innervations and electrophysiology.

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.

Aß selectively impairs mGluR7 modulation of NMDA signaling in basal forebrain cholinergic neurons: implication in Alzheimer's disease.

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, ß-amyloid (Aß) 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 Aß in BF cholinergic neurons. It provides a potential basis for the Aß-induced disruption of calcium homeostasis that might contribute to the selective degeneration of BF cholinergic neurons in the early stage of AD.