Evidence for vagal sensory neural involvement in influenza pathogenesis and disease.

Influenza A virus (IAV) is a common respiratory pathogen and a global cause of significant and often severe morbidity. Although inflammatory immune responses to IAV infections are well described, little is known about how neuroimmune processes contribute to IAV pathogenesis. In the present study, we employed surgical, genetic, and pharmacological approaches to manipulate pulmonary vagal sensory neuron innervation and activity in the lungs to explore potential crosstalk between pulmonary sensory neurons and immune processes. Intranasal inoculation of mice with H1N1 strains of IAV resulted in stereotypical antiviral lung inflammation and tissue pathology, changes in breathing, loss of body weight and other clinical signs of severe IAV disease. Unilateral cervical vagotomy and genetic ablation of pulmonary vagal sensory neurons had a moderate effect on the pulmonary inflammation induced by IAV infection, but significantly worsened clinical disease presentation. Inhibition of pulmonary vagal sensory neuron activity via inhalation of the charged sodium channel blocker, QX-314, resulted in a moderate decrease in lung pathology, but again this was accompanied by a paradoxical worsening of clinical signs. Notably, vagal sensory ganglia neuroinflammation was induced by IAV infection and this was significantly potentiated by QX-314 administration. This vagal ganglia hyperinflammation was characterized by alterations in IAV-induced host defense gene expression, increased neuropeptide gene and protein expression, and an increase in the number of inflammatory cells present within the ganglia. These data suggest that pulmonary vagal sensory neurons play a role in the regulation of the inflammatory process during IAV infection and suggest that vagal neuroinflammation may be an important contributor to IAV pathogenesis and clinical presentation. Targeting these pathways could offer therapeutic opportunities to treat IAV-induced morbidity and mortality.

Vagus nerve signal has an inhibitory influence on the development of peritoneal metastasis in murine gastric cancer.

The vagus nerve is the only pathway for transmitting parasympathetic signals between the brain and thoracoabdominal organs, thereby exhibiting anti-inflammatory functions through the cholinergic anti-inflammatory pathway. Despite often being resected during lymph node dissection in upper gastrointestinal cancer surgery, the impact of vagotomy on postoperative outcomes in gastric cancer patients remains unclear. Sub-diaphragmatic vagotomy was performed on C57BL/6 mice. Three weeks later, syngeneic murine gastric cancer cell line YTN16P was injected into the peritoneal cavity, and the number of peritoneal metastases (PM) on the mesentery and omentum compared with control mice. The phenotypes of immune cells in peritoneal lavage and omental milky spots one day after tumor inoculation were analyzed using flow cytometry and immunohistochemistry. Intraperitoneal transfer of 3 × 105 YTN16P significantly increased the number of metastatic nodules on the mesentery in the vagotomy group compared to the control group. The omental metastasis grade was also significantly higher in the vagotomy group. Phenotypic analysis of immune cells in peritoneal lavage did not reveal significant differences after vagotomy. However, vagotomized mice exhibited a notable increase in milky spot area, with a higher presence of cytokeratin(+) tumor cells, F4/80(+) macrophages, and CD3(+) T cells. Vagus nerve signaling appears to regulate the immune response dynamics within milky spots against disseminated tumor cells and inhibits the development of PM. Preserving the vagus nerve may offer advantages in advanced gastric cancer surgery to reduce peritoneal recurrence.

Preservation of the celiac branch of the vagus nerve reduces the incidence of postoperative diarrhea in gastric cancer: a cohort study.

BACKGROUND: To investigate the short-term and long-term outcomes of preserving the celiac branch of the vagus nerve during laparoscopic distal gastrectomy. METHODS: A total of 149 patients with prospective diagnosis of gastric cancer who underwent laparoscopic-assisted distal gastrectomy (LADG) combined with Billroth-II anastomosis and D2 lymph node dissection between 2017 and 2018 were retrospectively analyzed. The patients were divided into the preserved LADG group (P-LADG, n = 56) and the resected LADG group (R-LADG, n = 93) according to whether the vagus nerve celiac branch was preserved. We selected 56 patients (P-LADG, n = 56) with preservation of the celiac branch of the vagus nerve and 56 patients (R-LADG, n = 56) with removal of the celiac branch of the vagus nerve by propensity-matched score method. Postoperative nutritional status, weight change, short-term and long-term postoperative complications, and gallstone formation were evaluated in both groups at 5 years of postoperative follow-up. The status of residual gastritis and bile reflux was assessed endoscopically at 12 months postoperatively. RESULTS: The incidence of diarrhea at 5 years postoperatively was lower in the P-LADG group than in the R-LADG group (p < 0.05). In the multivariate logistic analysis, the removal of vagus nerve celiac branch was an independent risk factor for the occurrence of postoperative diarrhea (odds ratio = 3.389, 95% confidential interval = 1.143-10.049, p = 0.028). In the multivariate logistic analysis, the removal of vagus nerve celiac branch was an independent risk factor for the occurrence of postoperative diarrhea (odds ratio = 4.371, 95% confidential interval = 1.418-13.479, p = 0.010). CONCLUSIONS: Preservation of the celiac branch of the vagus nerve in LADG reduced the incidence of postoperative diarrhea postoperatively in gastric cancer. TRIAL REGISTRATION: This study was registered with the Ethics Committee of the First Affiliated Hospital of Dalian Medical University in 2014 under the registration number: LCKY2014-04(X).

Effectiveness of preserved vagal nerve in totally laparoscopy radical distal gastrectomy: a matched-paired cohort analysis.

BACKGROUND: The aim of this retrospective matched-paired cohort study was to clarify the effectiveness of preserving the vagus nerve in totally laparoscopic radical distal gastrectomy (TLDG). METHODS: One hundred eighty-three patients with gastric cancer who underwent TLDG between February 2020 and March 2022 were included and followed up. Sixty-one patients with preservation of the vagal nerve (VPG) in the same period were matched (1:2) to conventional sacrificed (CG) cases for demographics, tumor characteristics, and tumor node metastasis stage. The evaluated variables included intraoperative and postoperative indices, symptoms, nutritional status, and gallstone formation at 1 year after gastrectomy between the two groups. RESULTS: Although the operation time was significantly increased in the VPG compared with the CG (198.0 ± 35.2 vs. 176.2 ± 35.2 min, P < 0.001), the mean time of gas passage in the VPG was significantly lower than that in the CG (68.1 ± 21.7 h vs. 75.4 ± 22.6 h, P = 0.038). The overall postoperative complication rate was similar between the two groups (P = 0.794). There was no statistically significant difference between the two groups hospital stay, total number of harvested lymph nodes, and mean number of examined lymph nodes at each station. During follow-up, the morbidity of gallstones or cholecystitis (8.2% vs. 20.5%, P = 0.036), chronic diarrhea (3.3% vs. 14.8%, P = 0.022), and constipation (4.9% vs. 16.4%, P = 0.032) were significantly lower in the VPG than in the CG in this study. Moreover, injury to the vagus nerve was found to be an independent risk factor for gallstone formation or cholecystitis and chronic diarrhea in univariate analysis and multivariate analysis. CONCLUSION: The vagus nerve plays an imperative role in gastrointestinal motility, and hepatic and celiac branch preservation mainly exerts efficacy and safety in patients who undergo TLDG.

Case Report: Vagal Nerve Neuritis Associated with Pulmonary Melioidosis Provides Potential Insights into the Pathophysiology of Neuromelioidosis.

Encephalomyelitis is the most frequent manifestation of neuromelioidosis in Australia. It is hypothesized that Burkholderia pseudomallei causes encephalomyelitis after entering the brain directly, if complicating a scalp infection, or after traveling to the brain within peripheral or cranial nerves. A 76-year-old man presented with fever, dysphonia, and hiccups. Chest imaging demonstrated extensive bilateral pneumonia with mediastinal lymphadenopathy, blood cultures isolated B. pseudomallei, and nasendoscopy confirmed a left vocal cord palsy. Magnetic resonance imaging identified no intracranial abnormality but demonstrated an enlarged, enhancing left vagus nerve, consistent with neuritis. We hypothesize that B. pseudomallei invaded the vagus nerve in the thorax, was traveling proximally-involving the left recurrent laryngeal nerve and causing the left vocal cord palsy, but had not yet reached the brainstem. Given the frequency of pneumonia in cases of melioidosis, the vagus nerve may represent an alternative, and indeed common, route for B. pseudomallei to enter the brainstem in cases of melioidosis-related encephalomyelitis.

Glossopharyngeal, Vagus and Accessory Nerves: Anatomy and Pathology.

The glossopharyngeal, vagus, and accessory nerves are discussed in this article, given their intimate anatomical and functional associations. Abnormalities of these lower cranial nerves may be intrinsic or extrinsic due to various disease processes. This article aims to review these nerves' anatomy and demonstrates the imaging aspect of the diseases which most commonly affect them.

Electroacupuncture at Neiguan (PC6) attenuates cardiac dysfunction caused by cecal ligation and puncture via the vagus nerve.

PURPOSE: Previous studies proved the benefits of electroacupuncture (EA) on heart in ischemia reperfusion injury and chronic heart failure. However, the role of EA on sepsis-induced cardiac dysfunction has rarely been elucidated before. In this study, we aimed to investigate the effects of EA on cardiac dysfunction in a rat model of sepsis and to speculate the underlying mechanisms. METHODS: Sepsis was induced by cecum ligation and puncture in anesthetized rats. EA at the acupoint "Neiguan (PC6)" was applied 0.5 h after the induction of sepsis for 20 min. Heart rate variability was obtained immediately after EA to evaluate autonomic balance. Echocardiography was performed at 6 h and 24 h after sepsis induction in vivo. Measurements of hemodynamics, blood gases, cytokines and biochemistry were collected at 24 h. Cardiac tissue underwent immunofluorescence staining to determine the expression of α7 nicotinic acetylcholine receptor (α7nAChR) on macrophages. RESULTS: EA increased vagus nerve activity, prevented the development of hyperlactatemia, attenuated the decline of left ventricle ejection fraction, suppressed systemic and cardiac inflammation and alleviated the histopathological manifestations of heart in sepsis rats. Furthermore, the cardiac tissue from EA treated rats showed increased expressions of α7nAChR on macrophages. The cardio-protective and anti-inflammatory effects of EA were partly or completely prevented in rats with vagotomy. CONCLUSION: EA at PC6 attenuates left ventricle dysfunction and decreases inflammation in sepsis-induced cardiac dysfunction. The cardio-protective effects of EA are mediated through vagus nerve mediated cholinergic pathway.

Resection of a schwannoma originating from vagus nerve in the right superior mediastinum.

BACKGROUND: Schwannoma is the most common mediastinal neurogenic tumor, while schwannoma originating from mediastinal vagus nerve is rare. CASE PRESENTATION: This article reported one case of schwannoma originating from vagus nerve in the right superior mediastinum. The mediastinal schwannoma was completely resected through a right-sided video-assisted thoracoscopic thoracotomy. Histologic examination clarified the diagnosis as schwannoma. CONCLUSION: Chest CT scan and MRI can be used to determine the location of mediastinal schwannoma and its relationship with adjacent tissue. Histologic examination showing distinctive feature of Antoni A areas and Antoni B areas can help clarify the diagnosis. Complete surgical resection is the first-line treatment option for mediastinal schwannomas.

Intrastriatal injection of Parkinson's disease intestine and vagus lysates initiates α-synucleinopathy in rat brain.

Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons in the midbrain and the pathological accumulation of misfolded α-synuclein (α-syn) in the brain. A growing body of evidence suggests that the formation of misfolded α-syn and aggregation may begin in the peripheral nervous system, specifically the enteric nervous system, and then propagate to the central nervous system via the vagus nerve. However, the PD-like neuropathology induced by the intestine and vagus nerve extracts is rarely investigated. In this work, we injected lysates of the intestine and vagus obtained from a diagnosed PD patient, which contained abnormal α-syn aggregates, into the rat striatum unilaterally. Strikingly, such an injection induced dopaminergic neurodegeneration and α-syn depositions in the striatum, substantia nigra, and other brain regions, including the frontal cortex, somatosensory cortex, hypothalamus, brain stem, and cerebellum. Moreover, significant activation of microglia and the development of astrogliosis were observed in the substantia nigra pars compacta of the injected rats. These findings provide essential information for our understanding of PD pathogenesis, as we established for the first time that the α-syn aggregates in the intestine and vagus of a PD patient were sufficient to induce prion-like propagation of endogenous α-syn pathology in wild-type rats.

Vagus nerve stimulation exerts cardioprotection against doxorubicin-induced cardiotoxicity through inhibition of programmed cell death pathways.

The aberration of programmed cell death including cell death associated with autophagy/mitophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis can be observed in the development and progression of doxorubicin-induced cardiotoxicity (DIC). Vagus nerve stimulation (VNS) has been shown to exert cardioprotection against cardiomyocyte death through the release of the neurotransmitter acetylcholine (ACh) under a variety of pathological conditions. However, the roles of VNS and its underlying mechanisms against DIC have never been investigated. Forty adults male Wistar rats were divided into 5 experimental groups: (i) control without VNS (CSham) group, (ii) doxorubicin (3 mg/kg/day, i.p.) without VNS (DSham) group, (iii) doxorubicin + VNS (DVNS) group, (iv) doxorubicin + VNS + mAChR antagonist (atropine; 1 mg/kg/day, ip, DVNS + Atro) group, and (v) doxorubicin + VNS + nAChR antagonist (mecamylamine; 7.5 mg/kg/day, ip, DVNS + Mec) group. Our results showed that doxorubicin insult led to left ventricular (LV) dysfunction through impaired cardiac autonomic balance, decreased mitochondrial function, imbalanced mitochondrial dynamics, and exacerbated cardiomyocyte death including autophagy/mitophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis. However, VNS treatment improved cardiac mitochondrial and autonomic functions, and suppressed excessive autophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis, leading to improved LV function. Consistent with this, ACh effectively improved cell viability and suppressed cell cytotoxicity in doxorubicin-treated H9c2 cells. In contrast, either inhibitors of muscarinic (mAChR) or nicotinic acetylcholine receptor (nAChR) completely abrogated the favorable effects mediated by VNS and acetylcholine. These findings suggest that VNS exerts cardioprotective effects against doxorubicin-induced cardiomyocyte death via activation of both mAChR and nAChR.

[A case report of giant vagal schwannoma in the right neck and literature review].

Vagal nerve-derived schwannomas are rare, especially those with huge tumors. This paper reports a case of giant tumor in the right neck. The patient was misdiagnosed as pleomorphic adenoma before operation, and was diagnosed as schwannoma during operation. The clinical manifestations, diagnosis, differential diagnosis, treatment and prognosis are discussed in this paper based on the history and related literature.

IgG4-Related Hypertrophic Pachymeningitis with Skull Base Involvement Presenting with Isolated Glossopharyngeal and Vagus Nerve Palsy.

We herein report a 70-year-old man diagnosed with IgG4-related hypertrophic pachymeningitis with skull base involvement, who presented with isolated glossopharyngeal and vagus nerve palsy. Contrast-enhanced magnetic resonance imaging (MRI) showed enhanced dural thickening of the posterior clivus and skull base involvement. When a patient with hypertrophic pachymeningitis presents with isolated cranial neuropathy without systemic manifestations or definite MRI abnormalities, it is difficult to make a diagnosis, and the patient may be misdiagnosed. This case suggests that a detailed radiological evaluation including contrast enhancement of the skull base is very important in patients with isolated glossopharyngeal and vagus nerve palsy.

The first experience of ultrasound-guided percutaneous microwave ablation for extracranial schwannoma of the cervical vagus nerve in carotid space and treatment response evaluation with contrast-enhanced imaging: A case report.

Schwannoma is a benign tumor that originates from Schwann cells in the nerve sheathing of cranial, other peripheral, or autonomic nerves. Patients often present with painless mass as the chief complaint. The main symptoms of this tumor are related to its size and specific nerve origin. At present, the pretreatment diagnosis is mainly made by ultrasound, CT, MR, or biopsy, and the main treatment is surgical resection. We reported a new treatment method for cervical schwannoma in a 65-year-old woman with a history of non-small cell lung cancer (NSCLC). When the patient's neck mass was initially found with hoarseness and severe cough, it was considered as cervical lymph node metastasis of lung cancer due to her medical history. And she was diagnosed with schwannoma by core-needle biopsy after chemotherapy failed and the tumor shrank after the radiotherapy with no improvement of the clinical symptoms. After considering the physical condition, the patients were treated in our department for minimal invasiveness treatment. The patient was definitively diagnosed with cervical vagus schwannoma and was treated with ultrasound-guided microwave ablation of schwannoma under general anesthesia with systematic evaluation and improved preoperative examination. Her condition was stable, and the symptoms of severe cough disappeared after anesthesia resuscitation and the ablation. The tumor continued to shrink after the operation with no recurrence of cough symptoms. Ultrasound-guided percutaneous microwave ablation (MWA) for cervical vagus schwannomas might be a minimally invasive, effective, and relatively safe alternative to conventional treatment for those patients with severe symptoms.

Evaluation of Carotid Space Schwannoma Using Ultrasonography: Characteristics and Role in Defining the Nerve of Origin.

OBJECTIVES: We aimed to evaluate the ultrasonography (US) characteristics of carotid space schwannoma and their role in identifying the nerve of origin. METHODS: This prospective study enrolled patients with cervical carotid space schwannoma accessible by US. The US characteristics of vagus nerve schwannomas (VNSs) and sympathetic nerve schwannomas (SNSs) were assessed; a carotid space schwannoma was defined as a VNS if the tumor originated in the mid-vagal region and an SNS if it arose posterior to the intact vagus nerve, displacing the vagus nerve anteriorly. RESULTS: Twenty patients with carotid space schwannoma were enrolled. The vagus and sympathetic nerves were identified as the nerve of origin in 12 and 8 patients, respectively. VNSs were centered at levels II, III, and IV in 5, 3, and 4 patients, respectively, while SNSs were centered at levels II (7 patients) and IV (1 patient) (P = .105). The maximal diameters were 3.2 and 4.8 cm for VNSs and SNSs, respectively (P = .011). Internal vascularity was absent and low in 9 and 3 VNSs, respectively, and low and intermediate in 4 SNSs each (P = .002). Twelve patients with VNSs underwent active surveillance without immediate surgery; no adverse events occurred during the 55.2-month follow-up period. Eight patients with potential SNSs underwent surgery, confirming the sympathetic nerve as the nerve of origin. CONCLUSIONS: US facilitates identification of the nerve of origin in cervical carotid space schwannoma. VNSs are more frequent in infrahyoid locations and tend to be smaller in size with lower vascularity compared with SNSs on US.

The Wandering Nerve: Positional Variations of the Cervical Vagus Nerve and Neurosurgical Implications.

BACKGROUND: The vagus ("wandering") nerve is the longest cranial nerve with the largest territory of innervation in the human body. Injury during various operative procedures involving the anterior or lateral neck may lead to serious complications. Per "textbook" descriptions, the cervical vagus nerve (CVN) commonly locates within the carotid sheath, in between the common carotid artery (CCA) and internal jugular vein (IJV). However, anatomic variations in its positioning may occur more often than expected and intraoperative identification may anticipate potential surgical pitfalls. METHODS: A literature review was conducted per PRISMA guidelines for all studies describing positional variations of the CVN within the carotid sheath. A rare and potentially dangerous variation, occurring in only 0.7% of all reported cases, is illustrated with a cadaveric case. RESULTS: Overall, 10 anatomic CVN variations have been described across 971 specimens. The non-textbook variations (26.5%) consist of: lateral (4.7%), anterolateral (8.7%), posteromedial (0.2%), posterior (5.8%), anterior (3.1%), medial (0.7%), and anteromedial (0.4%) to the CCA, as well as posterolateral (0.3%) and posterior (2.6%) to IJV. The "textbook" anatomic location is posterolateral to CCA (73.5%). Moreover, an increase in variability is reported on the left side (17.1%) compared with the right (11.3%). Our cadaveric dissection revealed a right-sided CVN directly medial to the CCA. CONCLUSIONS: Positional variations of the CVN occur in over 26% of patients and may add difficulty to an array of surgical procedures. Knowledge of these variations and their prevalence may aid the surgeon in conducting a more precise dissection possibly preventing significant potential adverse sequelae.

Capsaicin-Sensitive Vagal Afferent Nerve-Mediated Interoceptive Signals in the Esophagus.

Heartburn and non-cardiac chest pain are the predominant symptoms in many esophageal disorders, such as gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), functional heartburn and chest pain, and eosinophilic esophagitis (EoE). At present, neuronal mechanisms underlying the process of interoceptive signals in the esophagus are still less clear. Noxious stimuli can activate a subpopulation of primary afferent neurons at their nerve terminals in the esophagus. The evoked action potentials are transmitted through both the spinal and vagal pathways to their central terminals, which synapse with the neurons in the central nervous system to induce esophageal nociception. Over the last few decades, progress has been made in our understanding on the peripheral and central neuronal mechanisms of esophageal nociception. In this review, we focus on the roles of capsaicin-sensitive vagal primary afferent nodose and jugular C-fiber neurons in processing nociceptive signals in the esophagus. We briefly compare their distinctive phenotypic features and functional responses to mechanical and chemical stimulations in the esophagus. Then, we summarize activation and/or sensitization effects of acid, inflammatory cells (eosinophils and mast cells), and mediators (ATP, 5-HT, bradykinin, adenosine, S1P) on these two nociceptive C-fiber subtypes. Lastly, we discuss the potential roles of capsaicin-sensitive esophageal afferent nerves in processing esophageal sensation and nociception. A better knowledge of the mechanism of nociceptive signal processes in primary afferent nerves in the esophagus will help to develop novel treatment approaches to relieve esophageal nociceptive symptoms, especially those that are refractory to proton pump inhibitors.

Vagus Nerve and Stomach Synucleinopathy in Parkinson's Disease, Incidental Lewy Body Disease, and Normal Elderly Subjects: Evidence Against the "Body-First" Hypothesis.

BACKGROUND: Braak and others have proposed that Lewy-type α-synucleinopathy in Parkinson's disease (PD) may arise from an exogenous pathogen that passes across the gastric mucosa and then is retrogradely transported up the vagus nerve to the medulla. OBJECTIVE: We tested this hypothesis by immunohistochemically staining, with a method specific for p-serine 129 α-synuclein (pSyn), stomach and vagus nerve tissue from an autopsy series of 111 normal elderly subjects, 33 with incidental Lewy body disease (ILBD) and 53 with PD. METHODS: Vagus nerve samples were taken adjacent to the carotid artery in the neck. Stomach samples were taken from the gastric body, midway along the greater curvature. Formalin-fixed paraffin-embedded sections were immunohistochemically stained for pSyn, shown to be highly specific and sensitive for α-synuclein pathology. RESULTS: Median disease duration for the PD group was 13 years. In the vagus nerve none of the 111 normal subjects had pSyn in the vagus, while 12/26 ILBD (46%) and 32/36 PD (89%) subjects were pSyn-positive. In the stomach none of the 102 normal subjects had pSyn while 5/30 (17%) ILBD and 42/52 (81%) of PD subjects were pSyn-positive. CONCLUSION: As there was no pSyn in the vagus nerve or stomach of subjects without brain pSyn, these results support initiation of pSyn in the brain. The presence of pSyn in the vagus nerve and stomach of a subset of ILBD cases indicates that synucleinopathy within the peripheral nervous system may occur, within a subset of individuals, at preclinical stages of Lewy body disease.

Peripheral Vascular Abnormalities in Anorexia Nervosa: A Psycho-Neuro-Immune-Metabolic Connection.

Immune, neuroendocrine, and autonomic nervous system dysregulation in anorexia nervosa lead to cardiovascular complications that can potentially result in increased morbidity and mortality. It is suggested that a complex non-invasive assessment of cardiovascular autonomic regulation-cardiac vagal control, sympathetic vascular activity, and cardiovascular reflex control-could represent a promising tool for early diagnosis, personalized therapy, and monitoring of therapeutic interventions in anorexia nervosa particularly at a vulnerable adolescent age. In this view, we recommend to consider in the diagnostic route, at least in the subset of patients with peripheral microvascular symptoms, a nailfold video-capillaroscopy as an easy not invasive tool for the early assessing of possible cardiovascular involvement.

Protective effect of electrical stimulation of the vagus nerve in lipopolysaccharide­induced acute lung injury in rats.

The present study investigated the role of electrical stimulation of the vagus nerve in the acute lung injury (ALI) inflammatory response induced by lipopolysaccharide (LPS) in rats. A rat model of ALI was established using LPS and by connecting an electrode to the left vagus nerve proximal to the heart in order to provide continuous electrical stimulation (1 mA; 1 msec; 10 Hz). After 120 min, the rat lung tissue was stained with hematoxylin and eosin and the expression of inflammatory factors was evaluated by reverse transcription­quantitative PCR and western blot analysis. The change in apoptosis rate in cells from bronchoalveolar lavage fluid (BALF) was analyzed using flow cytometry. The results of the present study demonstrated that inflammatory cell infiltration, alveolar wall and interstitial thickening, and lung hyperemia in rats with LPS­induced ALI were decreased following electrical stimulation of the vagus nerve. Electrical stimulation inhibited the expression levels of IL­1, IL­6, IL­10, IL-8 and TNF­α at both the mRNA and protein levels and decreased early and late apoptosis rates in inflammatory cells from BALF. The results indicated that vagus nerve stimulation can reverse the inflammatory response in lung injury, thereby exerting a pulmonary protective effect.

Optogenetic stimulation of cholinergic fibers for the modulation of insulin and glycemia.

Previous studies have demonstrated stimulation of endocrine pancreas function by vagal nerve electrical stimulation. While this increases insulin secretion, expected concomitant reductions in circulating glucose do not occur. A complicating factor is the non-specific nature of electrical nerve stimulation. Optogenetic tools, however, provide the potential for cell-type specific neural stimulation using genetic targeting and/or spatially shaped excitation light. Here, we demonstrate light-activated stimulation of the endocrine pancreas by targeting parasympathetic (cholinergic) axons. In a mouse model expressing ChannelRhodopsin2 (ChR2) in cholinergic cells, serum insulin and glucose were measured in response to (1) ultrasound image-guided optical stimulation of axon terminals in the pancreas or (2) optical stimulation of axons of the cervical vagus nerve. Measurements were made in basal-glucose and glucose-stimulated conditions. Significant increases in plasma insulin occurred relative to controls under both pancreas and cervical vagal stimulation, while a rapid reduction in glycemic levels were observed under pancreatic stimulation. Additionally, ultrasound-based measurements of blood flow in the pancreas were increased under pancreatic stimulation. Together, these results demonstrate the utility of in-vivo optogenetics for studying the neural regulation of endocrine pancreas function and suggest its therapeutic potential for the control of insulin secretion and glucose homeostasis.