Vagus nerve stimulation in cerebral stroke:biological mechanisms,therapeutic modalities,clinical applications,and future directions

Stroke is a major disorder of the central nervous system that poses a serious threat to human life and quality of life.Many stro ke victims are left with long-term neurological dysfunction,which adversely affects the well-being of the individual and the broader socioeconomic impact.Currently,poststroke brain dysfunction is a major and difficult area of treatment.Vagus nerve stimulation is a Food and Drug Administration-approved exploratory treatment option for autis m,refractory depression,epilepsy,and Alzheimer’s disease.It is expected to be a novel therapeutic technique for the treatment of stroke owing to its association with multiple mechanisms such as alte ring neurotransmitters and the plasticity of central neuro ns.In animal models of acute ischemic stroke,vagus nerve stimulation has been shown to reduce infarct size,reduce post-stroke neurological damage,and improve learning and memory capacity in rats with stroke by reducing the inflammatory response,regulating bloodbrain barrier permeability,and promoting angiogenesis and neurogenesis.At present,vagus nerve stimulation includes both invasive and non-invasive vagus nerve stimulation.Clinical studies have found that invasive vagus nerve stimulation combined with rehabilitation therapy is effective in im proving upper limb motor and cognitive abilities in stroke patients.Further clinical studies have shown that non-invasive vagus nerve stimulation,including ear/ce rvical vagus nerve stimulation,can stimulate vagal projections to the central nervous system similarly to invasive vagus nerve stimulation and can have the same effect.In this paper,we first describe the multiple effects of vagus nerve stimulation in stroke,and then discuss in depth its neuroprotective mechanisms in ischemic stroke.We go on to outline the res ults of the current major clinical applications of invasive and non-invasive vagus nerve stimulation.Finally,we provide a more comprehensive evaluation of the advantages and disadvantages of different types of vagus nerve stimulation in the treatment of cerebral ischemia and provide an outlook on the developmental trends.We believe that vagus nerve stimulation,as an effective treatment for stroke,will be widely used in clinical practice to promote the recovery of stroke patients and reduce the incidence of disability.

Gut-microbiome-brain axis:the crosstalk between the vagus nerve,alpha-synuclein and the brain in Parkinson's disease

This critical review of the literature shows that there is a close link between the microbiome,the gut,and the brain in Parkinson's disease.The vagus nerve,the main component of the parasympathetic nervous system,is involved in the regulation of immune response,digestion,heart rate,and control of mood.It can detect microbiota metabolites through its afferents,transferring this gut information to the central nervous system.Preclinical and clinical studies have shown the important role played by the gut microbiome and gut-related factors in disease development and progression,as well as treatment responses.These findings suggest that the gut microbiome may be a valuable target for new therapeutic strategies for Parkinson's disease.More studies are needed to better understand the underlying biology and how this axis can be modulated for the patient's benefit.

Vagus nerve stimulation is a potential treatment for ischemic stroke

Microglia are the brain’s primary innate immune cells,and they are activated and affect pro-inflammatory phenotype or regulatory phenotype after ischemic stroke.Vagus nerve stimulation was shown to activate microglial phenotypic changes and exhibit neuroprotective effects in ischemia/reperfusion injury.In this study,we established rat models of ischemic stroke by occlusion of the middle cerebral artery and performed vagus nerve stimulation 30 minutes after modeling.We found that vagus nerve stimulation caused a shift from a pro-inflammatory phenotype to a regulatory phenotype in microglia in the ischemic penumbra.Vagus nerve stimulation decreased the levels of pro-inflammatory phenotype markers inducible nitric oxide synthase and tumor necrosis factorαand increased the expression of regulatory phenotype markers arginase 1 and transforming growth factorβthrough activatingα7 nicotinic acetylcholine receptor expression.Additionally,α7 nicotinic acetylcholine receptor blockade reduced the inhibition of Toll-like receptor 4/nuclear factor kappa-B pathwayassociated proteins,including Toll-like receptor 4,myeloid differentiation factor 88,I kappa B alpha,and phosphorylated-I kappa B alpha,and also weakened the neuroprotective effects of vagus nerve stimulation in ischemic stroke.Vagus nerve stimulation inhibited Toll-like receptor 4/nuclear factor kappa-B expression through activatingα7 nicotinic acetylcholine receptor and regulated microglial polarization after ischemic stroke,thereby playing a role in the treatment of ischemic stroke.Findings from this study confirm the mechanism underlying vagus nerve stimulation against ischemic stroke.

Vagus nerve stimulation protects against cerebral injury after cardiopulmonary resuscitation by inhibiting inflammation through the TLR4/NF-κB and α7nAChR/JAK2 signaling pathways

BACKGROUND: Our previous research proved that vagus nerve stimulation(VNS) improved the neurological outcome after cardiopulmonary resuscitation(CPR) by activating α7 nicotinic acetylcholine receptor(α7nAChR) in a rat model, but the underlying mechanism of VNS in neuroprotection after CPR remains unclear.METHODS: In vivo, we established a mouse model of cardiac arrest(CA)/CPR to observe the survival rate, and the changes in inflammatory factors and brain tissue after VNS treatment. In vitro, we examined the effects of α7nAChR agonist on ischemia/reperfusion(I/R)-induced inflammation in BV2 cells under oxygen-glucose deprivation/reoxygenation(OGD/R) conditions. We observed the changes in cell survival rate, the levels of inflammatory factors, and the expressions of α7nAChR/Janus kinase 2(JAK2) and toll-like receptor 4(TLR4)/nuclear factor-κB(NF-κB).RESULTS: In vivo, VNS preconditioning enhanced functional recovery, improved the survival rate, and reduced hippocampal CA1 cell damage, and the levels of inflammatory mediators after CA/CPR. The application of α7nAChR agonists provided similar effects against cerebral injury after the return of spontaneous circulation(ROSC), while α7nAChR antagonists reversed these neuroprotective impacts. The in vitro results mostly matched the findings in vivo. OGD/R increased the expression of tumor necrosis factor-alpha(TNF-α), TLR4 and NF-κB p65. When nicotine was added to the OGD/R model, the expression of TLR4, NF-κB p65, and TNF-α decreased, while the phosphorylation of JAK2 increased, which was prevented by preconditioning with α7nAChR or JAK2 antagonists.CONCLUSION: The neuroprotective effect of VNS correlated with the activation of α7nAChR. VNS may alleviate cerebral IR injury by inhibiting TLR4/NF-κB and activating the α7nAChR/JAK2 signaling pathway.

GTCS-Vagus Nerve Stimulator Automation Using Private IoT-Blockchain Smartcontract

Generalized Tonic Clonic Seizure(GTCS)is a form of epileptic seizure in which a patient loses control over their entire body,ultimately leading to loss of consciousness.The Vagus Nerve Stimulator(VNS)is a tool/method for treating epileptic episodes that sends counter-electrical stimulations to the Vagus Nerve in order to mitigate epileptic signals from the brain.The machine is a stand-alone device that depends on human decision-making.The proposed framework uses an IoT and Blockchain oversight mechanism to augment the device's transparency.The system counteracts against false-activation by monitoring the patient's vitals through a smart watch and allows only legitimate use.The nominal operating threshold is determined by preprocessing inferences that include an 18-year-old GTCS epileptic patient and a data set of 281 non-GTCS epileptic patients.The proposed system functions as a dual control lock where the IoT system and the manually activation system work in tandem to activate the device.Based on the values sensed by the IoT device,the deployed system is able to make deci-sions and regulate the use of the VNS.The IoT-Blockchain framework is able to fully eradicate false activation by increasing accuracy and transparency,ensur-ing the device is used correctly and safely.

Modulatory effects of transcutaneous auricular vagus nerve stimulation (taVNS) on attentional processes

Background The modulatory effect of transcutaneous auricular vagus nerve stimulation(taVNS)on attention has varied in previous studies.This inconsistency might be attributed to the combined influence of the modulation effect on the different attentional functions,including alerting,orienting and executive control.Aims We aimed to preliminarily examine the modulatory effectsoftaVNS on differentattentionalfunctions.Methods Fifty-nine healthy participants were recruited and were randomly assigned to taVNS(receiving taVNS for 20 minutes)or control(receiving taVNS for 30 seconds)groups.All participants underwent a dot-probe task before and after the taVNS/control intervention.Their behavioural performance and electroencephalographic signals during pre-and post-tests were recorded,and different observed variables were extracted and analysed to characterise different attentional systems.Results We observed that active taVNS applied at the left ear significantly improved the overall behavioural performance,that is,shorter reaction time(RT)and lower intra-individual reaction time variability(lIRTV)for right-hand responses when compared with the control condition.In addition,active taVNS resulted in larger P3 and movement-related cortical potential(MRCP)amplitudes associated with right-hand reactions than the control condition.Active taVNS also decreased the difference between the pre-and post-tests in the power spectral density of spontaneous high-αband oscillations at C4 electrode.Importantly,parallel mediation models for right-hand responses showed that the change of P3 amplitude mediated the effects of taVNS on RT and lIRTV.In contrast,the change of MRCP amplitude suppressed the effect of taVNS on the lIRTV.Conclusions Our results provided behavioural and brain evidence supporting the effects of taVNS on different attentional systems,and their interaction further shaped behavioural performance,suggesting a promising role of taVNS in cognitive enhancement.

Advances of Research on Auricular Vagus Nerve Stimulation for Treatment of Nervous System Diseases

As a new type of nerve regulation technology, Vagus Nerve Stimulation is currently used in the treatment of nervous system diseases. Auricular Vagus Nerve Stimulation has become one of the research hotspots in this field, because there is no implantation risk. However, there is no unified standard for the treatment parameters of aVNS for nervous system diseases. In this paper, the research progress of the anatomical structure and parameters of the vagus nerve and its role in nervous system diseases are reviewed to provide basis for further research.

Electrical stimulation of the vagus nerve protects against cerebral ischemic injury through an anti-inflammatory mechanism

Vagus nerve stimulation exerts protective effects against ischemic brain injury; however, the underlying mechanisms remain unclear. In this study, a rat model of focal cerebral ischemia was established using the occlusion method, and the right vagus nerve was given electrical stimula-tion （constant current of 0.5 mA; pulse width, 0.5 ms; frequency, 20 Hz; duration, 30 seconds; every 5 minutes for a total of 60 minutes） 30 minutes, 12 hours, and 1, 2, 3, 7 and 14 days after surgery. Electrical stimulation of the vagus nerve substantially reduced infarct volume, improved neurological function, and decreased the expression levels of tumor necrosis factor-α and in-terleukin-6 in rats with focal cerebral ischemia. The experimental findings indicate that the neuroprotective effect of vagus nerve stimulation following cerebral ischemia may be associated with the inhibition of tumor necrosis factor-α and interleukin-6 expression.

Electroacupuncture modulates the activity of the hippocampus-nucleus tractus solitarius-vagus nerve pathway to reduce myocardial ischemic injury

The hippocampus is involved in the regulation of the autonomic nervous system,together with the hypothalamus and brainstem nuclei,such as the paraventricular nucleus and nucleus tractus solitarius.The vagus nerve-nucleus tractus solitarius pathway has an important role in cardiovascular reflex regulation.Myocardial ischemia has been shown to cause changes in the autonomic nervous system,affecting the dynamic equilibrium of the sympathetic and vagal nerves.However,it remains poorly understood how the hippocampus communicates with brainstem nuclei to regulate the autonomic nervous system and alleviate myocardial ischemic tissue damage.A rat model of acute myocardial ischemia（AMI） was made by ligating the left anterior descending branch of the coronary artery.Three days before ischemia,the hippocampal CA1 region was damaged.Then,3 days after ischemia,electroacupuncture（EA） at Shenmen（HT7）-Tongli（HT5） was performed（continuous wave,1 m A,2 Hz,duration of 30 minutes）.Cluster analysis of firing patterns showed that one type of neuron was found in rats in the sham and AMI groups.Three types of neurons were observed in the AMI ＋ EA group.Six types of neurons were found in the AMI ＋ EA ＋ Lesion group.Correlation analysis showed that the frequency of vagus nerve discharge in each group was negatively correlated with heart rate（HR）（P 〈 0.05,r =-0.424）,and positively correlated with mean arterial pressure（MAP）（P 〈 0.05,r = 0.40987） and the rate-pressure product（RPP）（P 〈 0.05,r = 0.4252）.The total frequency of the nucleus tractus solitarius discharge in each group was positively correlated with vagus nerve discharge（P 〈 0.01,r = 0.7021）,but not with hemodynamic index（HR： P 〉 0.05,r =-0.03263; MAP： P 〉 0.05,r =-0.08993; RPP： P 〉 0.05,r =-0.03263）.Some neurons（Neuron C） were negatively correlated with vagus nerve discharge,HR,MAP and RPP in the AMI ＋ EA group（vagus nerve discharge： P 〈 0.05,r =-0.87749; HR： P 〈 0.01,r =-0.91902; MAP： P 〈 0.05,r =-0.85691; RPP： P 〈 0.01,r =-0.91902）.Some neurons（Neurons C,D and E） were positively correlated with vagus nerve discharge,HR,MAP and RPP in the AMI ＋ EA ＋ Lesion group（vagus nerve discharge： P 〈 0.01,r = 0.8905,P 〈 0.01,r = 0.9725,P 〈 0.01,r = 0.9054; HR： P 〈 0.01,r = 0.9347,P 〈 0.01,r = 0.9089,P 〈 0.05,r = 0.8247; MAP： P 〈 0.05,r = 0.8474,P 〈 0.01,r = 0.9691,P 〈 0.01,r = 0.9027; RPP： P 〈 0.05,r = 0.8637,P 〈 0.01,r = 0.9407,P 〈 0.01,r = 0.9027）.These findings show that the hippocampus-nucleus tractus solitarius-vagus nerve pathway is involved in the cardioprotective effect of EA at the heart meridian.Some interneurons in the nucleus tractus solitarius may play a particularly important role in the cardiomodulatory process.

Wake-promoting effects of vagus nerve stimulation after traumatic brain injury: upregulation of orexin-A and orexin receptor type 1 expression in the prefrontal cortex

Orexins, produced in the lateral hypothalamus, are important neuropeptides that participate in the sleep/wake cycle, and their expres- sion coincides with the projection area of the vagus nerve in the brain. Vagus nerve stimulation has been shown to decrease the amounts of daytime sleep and rapid eye movement in epilepsy patients with traumatic brain injury. In the present study, we investigated whether vagus nerve stimulation promotes wakefulness and affects orexin expression. A rat model of traumatic brain injury was established using the free fall drop method. In the stimulated group, rats with traumatic brain injury received vagus nerve stimulation （frequency, 30 Hz, current, 1.0 mA; pulse width, 0.5 ms; total stimulation time, 15 minutes）. In the antagonist group, rats with traumatic brain injury were intracerebroventricularly injected with the orexin receptor type 1 （OXIR） antagonist SB334867 and received vagus nerve stimulation. Changes in consciousness were observed after stimulation in each group. Enzyme-linked immunosorbent assay, western blot assay and immunohistochemistry were used to assess the levels of orexin-A and OX1R expression in the prefrontal cortex. In the stimulated group, consciousness was substantially improved, orexin-A protein expression gradually increased within 24 hours after injury and OX1R expres- sion reached a peak at 12 hours, compared with rats subjected to traumatic brain injury only. In the antagonist group, the wake-promoting effect of vagus nerve stimulation was diminished, and orexin-A and OX1R expression were decreased, compared with that of the stim- ulated group. Taken together, our findings suggest that vagus nerve stimulation promotes the recovery of consciousness in comatose rats after traumatic brain injury. The upregulation of orexin-A and OXIR expression in the prefrontal cortex might be involved in the wake-promoting effects of vagus nerve stimulation.

Vagus efect on pylorus-preserving gastrectomy

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TRH microinjection into DVC enhances motility of rabbits gallbladder via vagus nerve

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Neuroprotective effects of vagus nerve stimulation on traumatic brain injury

Previous studies have shown that vagus nerve stimulation can improve the prognosis of trau- matic brain injury. The aim of this study was to elucidate the mechanism of the neuroprotective effects of vagus nerve stimulation in rabbits with brain explosive injury. Rabbits with brain ex- plosive injury received continuous stimulation （10 V, 5 Hz, 5 ms, 20 minutes） of the right cervical vagus nerve. Tumor necrosis factor-a, interleukin-l~ and interleukin-10 concentrations were detected in serum and brain tissues, and water content in brain tissues was measured. Results showed that vagus nerve stimulation could reduce the degree of brain edema, decrease tumor necrosis factor-a and interleukin-1β concentrations, and increase interleukin-10 concentration after brain explosive injury in rabbits. These data suggest that vagus nerve stimulation may exert neuroprotective effects against explosive injury via regulating the expression of tumor necrosis factor-a, interleukin-1 β and interleukin-10 in the serum and brain tissue.

The mechanisms through which auricular vagus nerve stimulation protects against cerebral ischemia/reperfusion injury

Previous studies have shown that vagus nerve stimulation can improve patients' locomotor function.The stimulation of the auricular vagus nerve,which is the only superficial branch of the vagus nerve,may have similar effects to vagus nerve stimulation.However,the precise mechanisms remain poorly understood.In this study,rat models of cerebral ischemia/reperfusion injury were established by modified Longa ligation.Twenty-four hours later,7-day auricular vagus nerve stimulation was performed.The results showed that auricular vagus nerve stimulation promoted the secretion of acetylcholine,inhibited the secretion of interleukin-1β,interleukin-6,and tumor necrosis factor-α,and reduced connexin 43 phosphorylation in the ischemic penumbra and motor cortex,promoting locomotor function recovery in rats with cerebral ischemia/reperfusion injury.These findings suggested that auricular vagus nerve stimulation promotes the recovery of locomotor function in rats with cerebral ischemia/reperfusion injury by altering the secretion of acetylcholine and inflammatory factors and the phosphorylation of connexin 43.This study was approved by the Animal Use and Management Committee of Shanghai University of Traditional Chinese Medicine on November 8,2019(approval No.PZSHUTCM191108014).

Left-sided vagus nerve stimulation improves cardiopulmonary resuscitation outcomes in rats as effectively as right-sided vagus nerve stimulation

BACKGROUND: Our group previously reported that right-sided vagus nerve stimulation(RVNS) significantly improved outcomes after cardiopulmonary resuscitation(CPR) in a rat model of cardiac arrest(CA). However, whether left-sided vagus nerve stimulation(LVNS) could achieve the same effect as RVNS in CPR outcomes remains unknown.METHODS: A rat model of CA was established using modified percutaneous epicardial electrical stimulation to induce ventricular fibrillation(VF). Rats were treated with LVNS or RVNS for 30 minutes before the induction of VF. All animals were observed closely within 72 hours after return of spontaneous circulation(ROSC), and their health and behavior were evaluated every 24 hours.RESULTS: Compared with those in the RVNS group, the hemodynamic measurements in the LVNS group decreased more notably. Vagus nerve stimulation(VNS) decreased the serum levels of tumor necrosis factor-alpha(TNF-α) and the arrhythmia score, and attenuated inflammatory infiltration in myocardial tissue after ROSC, regardless of the side of stimulation, compared with findings in the CPR group. Both LVNS and RVNS ameliorated myocardial function and increased the expression of α-7 nicotinic acetylcholine receptor in the myocardium after ROSC. Moreover, a clear improvement in 72-hour survival was shown with VNS pre-treatment, with no significant difference in efficacy when comparing the laterality of stimulation. CONCLUSIONS: LVNS may have similar effects as RVNS on improving outcomes after CPR.

Preliminary analysis of the effect of vagus nerve stimulation in the treatment of children with intractable epilepsy

BACKGROUND Implant vagus nerve stimulation is an adjunctive treatment for intractable epilepsy when patients are not suitable for resective surgery.AIM To identify the safety and efficacy of vagus nerve stimulation in children with intractable epilepsy and analyze the effects on different epilepsy syndromes.METHODS Eligible children with intractable epilepsy were admitted to the study.We collected data from preoperative assessments as the baseline.During the followup time,we recorded the process of seizures(frequency,duration,and seizure type),the changes of drugs or parameters,the complications,etc.The mean reduction rate of seizures,response rate,and McHugh scale were chosen as the outcomes.RESULTS A total of 213 patients were implanted with Tsinghua Pins vagus nerve stimulators,and the average age was 6.6 years.In the follow-up time of postoperative 3 mo,6 mo,12 mo,18 mo,and 24 mo,the average reduction rate was 30.2%,49.5%,56.3%,59.4%,and 63.2%,while the response rate was 21.8%,62.5%,57.1%,69.2%,and 70.7%.In addition,implanted vagus nerve stimulation had different effects on epilepsy syndromes.The reduction rate of West syndrome increased from 36.4%(postoperative 6 m)to 74.3%(postoperative 24 m).The reduction rate of Lennox-Gastaut syndrome improved from 25.4%to 73.1%in 24 mo.The chi-square test of the five efficacy grades showed P<0.05.The comparison between the 3-mo follow-up and the 6-mo follow-up showed P<0.05,and the comparison between the 6-mo follow-up and the 24-mo follow-up showed P>0.05.CONCLUSION Vagus nerve stimulation is safe and effective in children with intractable epilepsy,and the seizure reduction occurred in a time-dependent manner.Moreover,patients with West syndrome may get the most benefits.

Efficacy of Vagus Nerve Stimulation (VNS) after Multiple Subpial Transections (MST) for Extra-Temporal Seizure Foci

Background: The effect of Vagus nerve stimulation (VNS) therapy following major resective surgeries has been reported. However, the effect of VNS therapy following multiple-subpial-transections (MST) has not been reported. The objective of this paper is to examine the beneficial effect of VNS therapy following MST. Methods: There are 22 patients aged 10 - 55 years. Male/female distribution is 11/11 and follow-up is 24 - 148 months (median of 120 months). Seizure foci were bilateral in 9 patients, multi-lobar (unilateral) in 12 patients and single-lobar in 1 patient. MST was performed over broad areas in and around the seizure foci. VNS implantation was done when the response to MST procedure was poor (1 patients), or there was recurrence of seizures (21 patients). Interval between MST and VNS implanttation varied from one month to three years (median of 2 years). Results: Thirteen patients (59%) are seizure free (Engel’ Class I), 8 (36.5%) have greater than 90% reduction in seizure frequency (Class II), and 1 (4.5%) has between 50% - 90% reduction in seizure frequency (Class III). Conclusion: The results show that VNS therapy produced meaningful improvement in seizure outcome in all patients with extra-temporal seizures that had inadequate response to MST.

Pylorus- and vagus-nerve-preserving partial gastrectomy (D2 dissection)

Pylorus- and vagus nerve-preserving partial gastrectomy is important in improving the prognosis of early gastric cancer surgery, reducing surgical complications and improving the quality of life for such patients. In the present case, pylorus- and vagus nerve-preserving partial gastrectomy was performed using the bipolar electrocautery dissection technique combined with D2 dissection along the lesser sac.

Auricular vagus nerve acupressure for patients with emotional distress under the COVID-19 pandemic:A smartphone-based,randomized controlled trial

Objective: To confirm whether self-administered AVNA treatment is effective in improving emotional distressunder the COVID-19 pandemic.Methods: A smartphone-based online, randomized, controlled trial was designed from 26 February 2020 to 28April 2020 in four study sites, including Wuhan, Beijing, Shenyang, and Guangzhou of China. Local residentswho had considerable emotional distress with a score of the Hospital Anxiety and Depression Scale (HADS) ≥9 were recruited. Participants were randomly assigned to three times of AVNA (n = 191) per day, in morning,around noon, and in evening or usual care (UC, n = 215) once daily for 14 days. The primary outcome was theresponse rate, which was the proportion of participants whose Hospital Anxiety and Depression Scale (HADS)score reduced from baseline by ≥ 50%. The assessment was conducted at baseline, 3 days, and 14 days.Results: The AVNA group had a markedly higher response rate than the UC group at 3 days (35.6% vs. 24.9%,P = 0.02) and at 14 days (70.7% vs. 60.6%, P = 0.02). The AVNA group showed significantly greater reductionin scores of HADS at the two measurement points and BAI at 3 days (P ≤ 0.03), with average respective effectsize of 0.217 and 0.195. Participants with AVNA spent less time falling asleep and rated their sleep qualitybeing remarkably higher than those with UC at endpoint.Conclusion: During COVID-19 pandemic period, treatment with self-administrated AVNA was more effectivethan UC in reducing emotional distress of isolated populations. These findings support self-administered AVNAas a treatment option for patients with emotional distress under the COVID-19 pandemic or other emergentevents.

Hippocampal plasticity after a vagus nerve injury in the rat

Stimulation of the vagus nerve has been previously reported to promote neural plasticity and neurogenesis in the brain. Several studies also revealed plastic changes in the spinal cord after injuries to somatosensory nerves originating from both the brachial and lumbo-sacral plexuses. However, the neurogenic responses of the brain to the injury of the viscerosensory innervation are not as yet well understood. In the present study, we investigated whether cells in the dentate gyrus of the hippocampus respond to a chemical and physical damage to the vagus nerve in the adult rat. Intraperitoneal capsaicin administration was used to damage non-myelinated vagal afferents while subdiaphragmatic vagotomy was used to damage both the myelinated and non-myelinated vagal afferents. The 5-bromo-2-deoxyuridine （BrdU） incorporation together with cell-specific markers was used to study neural proliferation in subgranular zone, granule cell layer, molecular layer and hilus of the dentate gyrus. Microglia activation was determined by quantifying changes in the intensity of fluorescent staining with a primary antibody against ionizing calcium adapter-binding molecule 1. Results revealed that vagotomy decreased BrdU incorporation in the hilus 15 days after injury compared to the capsaicin group. Capsaicin administration decreased BrdU incorporation in the granular cell layer 60 days after the treatment. Capsaicin decreased the number of doublecortin-expressing cells in the dentate gyrus, whereas vagotomy did not alter the expression of doublecortin in the hippocampus. Both the capsaicin- and the vagotomy-induced damage to the vagus nerve decreased microglia activation in the hippocampus at 15 days after the injury. At 30 days post injury, capsaicin-treated and vagotomized rats revealed significantly more activated microglia. Our findings show that damage to the subdiaphragmatic vagus in adult rats is followed by microglia activation and long-lasting changes in the dentate gyrus, leading to alteration of neurogenesis.