Genetic Identification of Vagal Sensory Neurons That Control Feeding.

Energy homeostasis requires precise measurement of the quantity and quality of ingested food. The vagus nerve innervates the gut and can detect diverse interoceptive cues, but the identity of the key sensory neurons and corresponding signals that regulate food intake remains unknown. Here, we use an approach for target-specific, single-cell RNA sequencing to generate a map of the vagal cell types that innervate the gastrointestinal tract. We show that unique molecular markers identify vagal neurons with distinct innervation patterns, sensory endings, and function. Surprisingly, we find that food intake is most sensitive to stimulation of mechanoreceptors in the intestine, whereas nutrient-activated mucosal afferents have no effect. Peripheral manipulations combined with central recordings reveal that intestinal mechanoreceptors, but not other cell types, potently and durably inhibit hunger-promoting AgRP neurons in the hypothalamus. These findings identify a key role for intestinal mechanoreceptors in the regulation of feeding.

Vagal pathways for systemic regulation of glucose metabolism.

Maintaining blood glucose at an appropriate physiological level requires precise coordination of multiple organs and tissues. The vagus nerve bidirectionally connects the central nervous system with peripheral organs crucial to glucose mobilization, nutrient storage, and food absorption, thereby presenting a key pathway for the central control of blood glucose levels. However, the precise mechanisms by which vagal populations that target discrete tissues participate in glucoregulation are much less clear. Here we review recent advances unraveling the cellular identity, neuroanatomical organization, and functional contributions of both vagal efferents and vagal afferents in the control of systemic glucose metabolism. We focus on their involvement in relaying glucoregulatory cues from the brain to peripheral tissues, particularly the pancreatic islet, and by sensing and transmitting incoming signals from ingested food to the brain. These recent findings - largely driven by advances in viral approaches, RNA sequencing, and cell-type selective manipulations and tracings - have begun to clarify the precise vagal neuron populations involved in the central coordination of glucose levels, and raise interesting new possibilities for the treatment of glucose metabolism disorders such as diabetes.

Vagal sensory pathway for the gut-brain communication.

The communication between the gut and brain is crucial for regulating various essential physiological functions, such as energy balance, fluid homeostasis, immune response, and emotion. The vagal sensory pathway plays an indispensable role in connecting the gut to the brain. Recently, our knowledge of the vagal gut-brain axis has significantly advanced through molecular genetic studies, revealing a diverse range of vagal sensory cell types with distinct peripheral innervations, response profiles, and physiological functions. Here, we review the current understanding of how vagal sensory neurons contribute to gut-brain communication. First, we highlight recent transcriptomic and genetic approaches that have characterized different vagal sensory cell types. Then, we focus on discussing how different subtypes encode numerous gut-derived signals and how their activities are translated into physiological and behavioral regulations. The emerging insights into the diverse cell types and functional properties of vagal sensory neurons have paved the way for exciting future directions, which may provide valuable insights into potential therapeutic targets for disorders involving gut-brain communication.

Molecular cell types as functional units of the efferent vagus nerve.

The vagus nerve vitally connects the brain and body to coordinate digestive, cardiorespiratory, and immune functions. Its efferent neurons, which project their axons from the brainstem to the viscera, are thought to comprise "functional units" - neuron populations dedicated to the control of specific vagal reflexes or organ functions. Previous research indicates that these functional units differ from one another anatomically, neurochemically, and physiologically but have yet to define their identity in an experimentally tractable way. However, recent work with genetic technology and single-cell genomics suggests that genetically distinct subtypes of neurons may be the functional units of the efferent vagus. Here we review how these approaches are revealing the organizational principles of the efferent vagus in unprecedented detail.

Vagal Regulation of Group 3 Innate Lymphoid Cells and the Immunoresolvent PCTR1 Controls Infection Resolution.

Uncovering mechanisms that control immune responses in the resolution of bacterial infections is critical for the development of new therapeutic strategies that resolve infectious inflammation without unwanted side effects. We found that disruption of the vagal system in mice delayed resolution of Escherichia coli infection. Dissection of the right vagus decreased peritoneal group 3 innate lymphoid cell (ILC3) numbers and altered peritoneal macrophage responses. Vagotomy resulted in an inflammatory peritoneal lipid mediator profile characterized by reduced concentrations of pro-resolving mediators, including the protective immunoresolvent PCTR1, along with elevated inflammation-initiating eicosanoids. We found that acetylcholine upregulated the PCTR biosynthetic pathway in ILC3s. Administration of PCTR1 or ILC3s to vagotomized mice restored tissue resolution tone and host responses to E. coli infections. Together these findings elucidate a host protective mechanism mediated by ILC3-derived pro-resolving circuit, including PCTR1, that is controlled by local neuronal output to regulate tissue resolution tone and myeloid cell responses.

Molecular Characterization of Nodose Ganglia Development Reveals a Novel Population of Phox2b+ Glial Progenitors in Mice.

The vagal ganglia, comprised of the superior (jugular) and inferior (nodose) ganglia of the vagus nerve, receive somatosensory information from the head and neck or viscerosensory information from the inner organs, respectively. Developmentally, the cranial neural crest gives rise to all vagal glial cells and to neurons of the jugular ganglia, while the epibranchial placode gives rise to neurons of the nodose ganglia. Crest-derived nodose glial progenitors can additionally generate autonomic neurons in the peripheral nervous system, but how these progenitors generate neurons is unknown. Here, we found that some Sox10+ neural crest-derived cells in, and surrounding, the nodose ganglion transiently expressed Phox2b, a master regulator of autonomic nervous system development, during early embryonic life. Our genetic lineage-tracing analysis in mice of either sex revealed that despite their common developmental origin and extreme spatial proximity, a substantial proportion of glial cells in the nodose, but not in the neighboring jugular ganglia, have a history of Phox2b expression. We used single-cell RNA-sequencing to demonstrate that these progenitors give rise to all major glial subtypes in the nodose ganglia, including Schwann cells, satellite glia, and glial precursors, and mapped their spatial distribution by in situ hybridization. Lastly, integration analysis revealed transcriptomic similarities between nodose and dorsal root ganglia glial subtypes and revealed immature nodose glial subtypes. Our work demonstrates that these crest-derived nodose glial progenitors transiently express Phox2b, give rise to the entire complement of nodose glial cells, and display a transcriptional program that may underlie their bipotent nature.

Vago-splenic signal transduction of cardioprotection in humans.

BACKGROUND AND AIMS: The spleen serves as an important relay organ that releases cardioprotective factor(s) upon vagal activation during remote ischaemic conditioning (RIC) in rats and pigs. The translation of these findings to humans was attempted. METHODS: Remote ischaemic conditioning or electrical auricular tragus stimulation (ATS) were performed in 10 healthy young volunteers, 10 volunteers with splenectomy, and 20 matched controls. Venous blood samples were taken before and after RIC/ATS or placebo, and a plasma dialysate was infused into isolated perfused rat hearts subjected to global ischaemia/reperfusion. RESULTS: Neither left nor right RIC or ATS altered heart rate and heart rate variability in the study cohorts. With the plasma dialysate prepared before RIC or ATS, respectively, infarct size (% ventricular mass) in the recipient rat heart was 36 ± 6% (left RIC), 34 ± 3% (right RIC) or 31 ± 5% (left ATS), 35 ± 5% (right ATS), and decreased with the plasma dialysate from healthy volunteers after RIC or ATS to 20 ± 4% (left RIC), 23 ± 6% (right RIC) or to 19 ± 4% (left ATS), 26 ± 9% (right ATS); infarct size was still reduced with plasma dialysate 4 days after ATS and 9 days after RIC. In a subgroup of six healthy volunteers, such infarct size reduction was abrogated by intravenous atropine. Infarct size reduction by RIC or ATS was also abrogated in 10 volunteers with splenectomy, but not in their 20 matched controls. CONCLUSIONS: In humans, vagal innervation and the spleen as a relay organ are decisive for the cardioprotective signal transduction of RIC and ATS.

MrgprC11+ Jugular Neurons Control Airway Hyperresponsiveness in Allergic Airway Inflammation.

The lung is densely innervated by sensory nerves, the majority of which are derived from the vagal sensory neurons. Vagal ganglia consist of two different ganglia, termed nodose and jugular ganglia, with distinct embryonic origins, innervation patterns, and physiological functions in the periphery. Since nodose neurons constitute the majority of the vagal ganglia, our understanding of the function of jugular nerves in the lung is very limited. This study aims to investigate the role of MrgprC11+ jugular sensory neurons in a mouse allergic asthma model. Our previous study has shown that MrgprC11+ jugular neurons mediate cholinergic bronchoconstriction. In this study, we found that in addition to MrgprC11, several other Mrgpr family members including MrgprA3, MrgprB4, and MrgprD are also specifically expressed in the jugular sensory neurons. MrgprC11+ jugular neurons exhibit dense innervation in the respiratory tract including the larynx, trachea, proximal, and distal bronchus. We also found that receptors for IL-4 and oncostatin M, two critical cytokines promoting allergic airway inflammation, are mainly expressed in jugular sensory neurons. Both IL-4 and oncostatin M can sensitize the neuronal responses of MrgprC11+ jugular neurons. Moreover, ablation of MrgprC11+ neurons significantly inhibited airway hyperresponsiveness in the asthmatic lung, demonstrating the critical role of MrgprC11+ neurons in controlling airway constriction. Our results emphasize the critical role of jugular sensory neurons in respiratory diseases.

Transcutaneous vagal nerve stimulation for treating gastrointestinal symptoms in individuals with diabetes: a randomised, double-blind, sham-controlled, multicentre trial.

AIMS/HYPOTHESIS: Diabetic gastroenteropathy frequently causes debilitating gastrointestinal symptoms. Previous uncontrolled studies have shown that transcutaneous vagal nerve stimulation (tVNS) may improve gastrointestinal symptoms. To investigate the effect of cervical tVNS in individuals with diabetes suffering from autonomic neuropathy and gastrointestinal symptoms, we conducted a randomised, sham-controlled, double-blind (participants and investigators were blinded to the allocated treatment) study. METHODS: This study included adults (aged 20-86) with type 1 or 2 diabetes, gastrointestinal symptoms and autonomic neuropathy recruited from three Steno Diabetes Centres in Denmark. Participants were randomly allocated 1:1 to receive active or sham stimulation. Active cervical tVNS or sham stimulation was self-administered over two successive study periods: 1 week of four daily stimulations and 8 weeks of two daily stimulations. The primary outcome measures were gastrointestinal symptom changes as measured using the gastroparesis cardinal symptom index (GCSI) and the gastrointestinal symptom rating scale (GSRS). Secondary outcomes included gastrointestinal transit times and cardiovascular autonomic function. RESULTS: Sixty-eight participants were randomised to the active group, while 77 were randomised to the sham group. Sixty-three in the active and 68 in the sham group remained for analysis in study period 1, while 62 in each group were analysed in study period 2. In study period 1, active and sham tVNS resulted in similar symptom reductions (GCSI: -0.26 ± 0.64 vs -0.17 ± 0.62, p=0.44; GSRS: -0.35 ± 0.62 vs -0.32 ± 0.59, p=0.77; mean ± SD). In study period 2, active stimulation also caused a mean symptom decrease that was comparable to that observed after sham stimulation (GCSI: -0.47 ± 0.78 vs -0.33 ± 0.75, p=0.34; GSRS: -0.46 ± 0.90 vs -0.35 ± 0.79, p=0.50). Gastric emptying time was increased in the active group compared with sham (23 min vs -19 min, p=0.04). Segmental intestinal transit times and cardiovascular autonomic measurements did not differ between treatment groups (all p>0.05). The tVNS was well-tolerated. CONCLUSIONS/INTERPRETATION: Cervical tVNS, compared with sham stimulation, does not improve gastrointestinal symptoms among individuals with diabetes and autonomic neuropathy. TRIAL REGISTRATION: ClinicalTrials.gov NCT04143269 FUNDING: The study was funded by the Novo Nordisk Foundation (grant number NNF180C0052045).

Development of autonomic heart rate modulations during childhood and adolescence.

Autonomic control of heart rate is well known in adult subjects, but limited data are available on the development of the heart rate control during childhood and adolescence. Continuous 12-lead electrocardiograms were recorded in 1045 healthy children and adolescents (550 females) aged 4 to 19 years during postural manoeuvres involving repeated 10-min supine, unsupported sitting, and unsupported standing positions. In each position, heart rate was measured, and heart rate variability indices were evaluated (SDNN, RMSSD, and high (HF) and low (LF) frequency components were obtained). Quasi-normalized HF frequency components were defined as qnHF = HF/(HF + LF). These measurements were, among others, related to age using linear regressions. In supine position, heart rate decreases per year of age were significant in both sexes but lower in females than in males. In standing position, these decreases per year of age were substantially lowered. RMSSD and qnHF indices were independent of age in supine position but significantly decreased with age in sitting and standing positions. Correspondingly, LF/HF proportions showed steep increases with age in sitting and standing positions but not in the supine position. The study suggests that baseline supine parasympathetic influence shows little developmental changes during childhood and adolescence but that in young children, sympathetic branch is less responsive to vagal influence. While vagal influences modulate cardiac periods in young and older children equally, they are less able to suppress the sympathetic influence in younger children.

Cardiac vagal activity changes moderated the association of cognitive and cerebral hemodynamic variations in the prefrontal cortex.

Phasic cardiac vagal activity (CVA), reflecting ongoing, moment-to-moment psychophysiological adaptations to environmental changes, can serve as a predictor of individual difference in executive function, particularly executive performance. However, the relationship between phasic CVA and executive function demands requires further validation because of previous inconsistent findings. Moreover, it remains unclear what types of phasic changes of CVA may be adaptive in response to heightened executive demands. This study used the standard N-back task to induce different levels of working memory (WM) load and combined functional Near-Infrared Spectroscopy (fNIRS) with a multipurpose polygraph to investigate the variations of CVA and its interactions with cognitive and prefrontal responses as executive demands increased in fifty-two healthy young subjects. Our results showed phasic decreases in CVA as WM load increased (t (51) = -3.758, p < 0.001, Cohen's d = 0.526). Furthermore, phasic changes of CVA elicited by increased executive demands moderated the association of cognitive and cerebral hemodynamic variations in the prefrontal cortex (B = 0.038, SE = 0.014, p < 0.05). Specifically, as executive demands increased, individuals with larger phasic CVA withdrawal showed a positive relationship between cognitive and hemodynamic variations in the prefrontal cortex (ß = 0.281, p = 0.031). No such significant relationship was observed in individuals with smaller phasic CVA withdrawal. The current findings demonstrate a decrease in CVA with increasing executive demands and provide empirical support for the notion that a larger phasic CVA withdrawal can be considered adaptive in situations requiring high executive function demands.

The immunomodulatory effect of oral NaHCO3 is mediated by the splenic nerve: multivariate impact revealed by artificial neural networks.

Stimulation of the inflammatory reflex (IR) is a promising strategy for treating systemic inflammatory disorders. Recent studies suggest oral sodium bicarbonate (NaHCO3) as a potential activator of the IR, offering a safe and cost-effective treatment approach. However, the mechanisms underlying NaHCO3-induced anti-inflammatory effects remain unclear. We investigated whether oral NaHCO3's immunomodulatory effects are mediated by the splenic nerve. Female rats received NaHCO3 or water (H2O) for four days, and splenic immune markers were assessed using flow cytometry. NaHCO3 led to a significant increase (p < 0.05, and/or partial eta squared > 0.06) in anti-inflammatory markers, including CD11bc + CD206 + (M2-like) macrophages, CD3 + CD4 + FoxP3 + cells (Tregs), and Tregs/M1-like ratio. Conversely, proinflammatory markers, such as CD11bc + CD38 + TNFα + (M1-like) macrophages, M1-like/M2-like ratio, and SSChigh/SSClow ratio of FSChighCD11bc + cells, decreased in the spleen following NaHCO3 administration. These effects were abolished in spleen-denervated rats, suggesting the necessity of the splenic nerve in mediating NaHCO3-induced immunomodulation. Artificial neural networks accurately classified NaHCO3 and H2O treatment in sham rats but failed in spleen-denervated rats, highlighting the splenic nerve's critical role. Additionally, spleen denervation independently influenced Tregs, M2-like macrophages, Tregs/M1-like ratio, and CD11bc + CD38 + cells, indicating distinct effects from both surgery and treatment. Principal component analysis (PCA) further supported the separate effects. Our findings suggest that the splenic nerve transmits oral NaHCO3-induced immunomodulatory changes to the spleen, emphasizing NaHCO3's potential as an IR activator with therapeutic implications for a wide spectrum of systemic inflammatory conditions.

Identification of vagal afferent nerve endings in the mouse colon and their spatial relationship with enterochromaffin cells.

Understanding how the gut communicates with the brain, via sensory nerves, is of significant interest to medical science. Enteroendocrine cells (EEC) that line the mucosa of the gastrointestinal tract release neurochemicals, including the largest quantity of 5-hydroxytryptamine (5-HT). How the release of substances, like 5-HT, from enterochromaffin (EC) cells activates vagal afferent nerve endings is unresolved. We performed anterograde labelling from nodose ganglia in vivo and identified vagal afferent axons and nerve endings in the mucosa of whole-mount full-length preparations of mouse colon. We then determined the spatial relationship between mucosal-projecting vagal afferent nerve endings and EC cells in situ using 3D imaging. The mean distances between vagal afferent nerve endings in the mucosa, or nearest varicosities along vagal afferent axon branches, and the nearest EC cell were 29.6 ± 19.2 µm (n = 107, N = 6) and 25.7 ± 15.2 µm (n = 119, N = 6), respectively. No vagal afferent endings made close contacts with EC cells. The distances between EC cells and vagal afferent endings are many hundreds of times greater than known distances between pre- and post-synaptic membranes (typically 10-20 nm) that underlie synaptic transmission in vertebrates. The absence of any close physical contacts between 5-HT-containing EC cells and vagal afferent nerve endings in the mucosa leads to the inescapable conclusion that the mechanism by which 5-HT release from ECs in the colonic mucosa occurs in a paracrine fashion, to activate vagal afferents.

Stimulatory effect of methylglyoxal on capsaicin-sensitive lung vagal afferents in rats: role of TRPA1.

Methylglyoxal (MG), a reactive metabolic byproduct of glycolysis, is a causative of painful diabetic neuropathy. Patients with diabetes are associated with more frequent severe asthma exacerbation. Stimulation of capsaicin-sensitive lung vagal (CSLV) afferents may contribute to the pathogenesis of hyperreactive airway diseases such as asthma. However, the possibility of the stimulatory effect of MG on CSLV afferents and the underlying mechanisms remain unknown. Our results showed that intravenous injection of MG (25 mg/kg, MG25) in anesthetized, spontaneously breathing rats elicited pulmonary chemoreflexes characterized by apnea, bradycardia, and hypotension. The MG-induced apneic response was reproducible and dose dependent. MG25 no longer evoked these reflex responses after perineural capsaicin treatment of both cervical vagi to block C-fibers' conduction, suggesting that the reflexes were mediated through the stimulation of CSLV afferents. Pretreatment with HC030031 [an antagonist of transient receptor potential ankyrin subtype 1 protein (TRPA1)] or AP18 (another TRPA1 antagonist), but not their vehicle, markedly attenuated the apneic response induced by MG25. Consistently, electrophysiological results showed that pretreatment with HC030031 largely attenuated the intense discharge in CSLV afferents induced by injection of MG25 in open-chest and artificially ventilated rats. In isolated CSLV neurons, the perfusion of MG evoked an abrupt and pronounced increase in calcium transients in a concentration-dependent manner. This stimulatory effect on CSLV neurons was also abolished by HC030031 treatment but not by its vehicle. In conclusion, these results suggest that MG exerts a stimulatory effect on CSLV afferents, inducing pulmonary chemoreflexes, and such stimulation is mediated through the TRPA1 activation.NEW & NOTEWORTHY Methylglyoxal (MG) is implicated in the development of painful diabetic neuropathy. A retrospective cohort study revealed an increased incidence of asthma exacerbations in patients with diabetes. This study demonstrated that elevated circulating MG levels stimulate capsaicin-sensitive lung vagal afferents via activation of TRPA1, which in turn triggers respiratory reflexes. These findings provide new information for understanding the pathogenic mechanism of diabetes-associated hyperreactive airway diseases and potential therapy.

Gaps in our understanding of how vagal afferents to the small intestinal mucosa detect luminal stimuli.

Vagal afferents to the gastrointestinal tract are crucial for the regulation of food intake, signaling negative feedback that contributes to satiation and positive feedback that produces appetition and reward. Vagal afferents to the small intestinal mucosa contribute to this regulation by sensing luminal stimuli and reporting this information to the brain. These afferents respond to mechanical, chemical, thermal, pH, and osmolar stimuli, as well as to bacterial products and immunogens. Surprisingly, little is known about how these stimuli are transduced by vagal mucosal afferents or how their transduction is organized among these afferents' terminals. Furthermore, the effects of stimulus concentration ranges or physiological stimuli on vagal activity have not been examined for some of these stimuli. Also, detection of luminal stimuli has rarely been examined in rodents, which are most frequently used for studying small intestinal innervation. Here we review what is known about stimulus detection by vagal mucosal afferents and illustrate the complexity of this detection using nutrients as an exemplar. The accepted model proposes that nutrients bind to taste receptors on enteroendocrine cells (EECs), which excite them, causing the release of hormones that stimulate vagal mucosal afferents. However, evidence reviewed here suggests that although this model accounts for many aspects of vagal signaling about nutrients, it cannot account for all aspects. A major goal of this review is therefore to evaluate what is known about nutrient absorption and detection and, based on this evaluation, identify candidate mucosal cells and structures that could cooperate with EECs and vagal mucosal afferents in stimulus detection.

Pulsed-field ablation does not induce esophageal and periesophageal injury-A new esophageal safety paradigm in catheter ablation of atrial fibrillation.

INTRODUCTION: Esophageal injury is one of the most serious complications of pulmonary vein isolation (PVI) with thermic energy sources. Better tissue selectivity of primarily non-thermic pulsed field ablation (PFA) may eliminate collateral injury, particularly the risk of atrio-esophageal fistula (AEF). OBJECTIVE: To compare the incidence of any (peri)-esophageal injury following PVI using PFA to thermic energy sources. METHODS: Using endoscopy, endoscopic ultrasound, and electrogastrography before and after PVI, esophageal and periesophageal injury (mucosal lesions, food retention, periesophageal edema, or vagal nerve injury) were assessed following PFA and radiofrequency (RF)- or cryoballoon (CB)-PVI. RESULTS: Between December 2022 and February 2023, 20 patients (67 ± 10 years, 53% male) undergoing PFA (Farapulse, Boston Scientific) for atrial fibrillation (AF) were studied and compared with a previous cohort of 57 patients who underwent thermic PVI (CB: n = 33; RF: n = 24). Following PFA-PVI, none of the patients had mucosal lesions, food retention, or ablation-induced vagal nerve injury; four patients showed periesophageal edema. Following thermic ablation, 33/57 patients (58%) showed esophageal and/or periesophageal injury (CB: 21/33 [64%], RF: 12/24 [50%]), in detail 4/57 mucosal lesions, 18/57 food retention, 17/57 vagal nerve injury, and 20/52 edema. Midterm success rates were similar for all energy sources. CONCLUSION: In contrast to thermic ablation tools, PFA is not associated with relevant esophageal and periesophageal injury, and might, therefore, reduce or eliminate the risk of potentially lethal AEF in interventional treatment of AF. The etiology of ablation-induced periesophageal edema is unknown but has not been shown to be related to lesion progression.

Increased cardiac vagal tone in childhood-only, adolescent-only, and persistently antisocial teenagers: the mediating role of low heart rate.

BACKGROUND: Cardiac vagal tone is an indicator of parasympathetic nervous system functioning, and there is increasing interest in its relation to antisocial behavior. It is unclear however whether antisocial individuals are characterized by increased or decreased vagal tone, and whether increased vagal tone is the source of the low heart rate frequently reported in antisocial populations. METHODS: Participants consisted of four groups of community-dwelling adolescent boys aged 15.7 years: (1) controls, (2) childhood-only antisocial, (3) adolescent-only antisocial, and (4) persistently antisocial. Heart rate and vagal tone were assessed in three different conditions: rest, cognitive stressor, and social stressor. RESULTS: All three antisocial groups had both lower resting heart rates and increased vagal tone compared to the low antisocial controls across all three conditions. Low heart rate partially mediated the relationship between vagal tone and antisocial behavior. CONCLUSIONS: Results indicate that increased vagal tone and reduced heart rate are relatively broad risk factors for different developmental forms of antisocial behavior. Findings are the first to implicate vagal tone as an explanatory factor in understanding heart rate - antisocial behavior relationships. Future experimental work using non-invasive vagus nerve stimulation or heart rate variability biofeedback is needed to more systematically evaluate this conclusion.

No consistent evidence for the anti-inflammatory effect of vagus nerve stimulation in humans: A systematic review and meta-analysis.

Vagus nerve stimulation (VNS) has been identified as an innovative immunosuppressive treatment strategy in rodent studies. However, its' clinical potential is still unclear. Therefore, we aimed to assess whether VNS can reduce inflammatory proteins and/or immune cells in humans, through a pre-registered systematic review and meta-analysis according to PRISMA guidelines. The databases Cochrane, Pubmed and World of Knowledge were searched in duplicate up to the 3rd of March 2022 and publications from identified clinical trial registrations were identified until 20th of August 2023. Studies were included if they provided peer-reviewed data for humans who received VNS as short-term (<=1 day) or long-term (>=2 days-365 days) stimulation and reported at least one cytokine or immune cell after treatment.Screening of title, abstract, full text, and data extraction was performed in duplicate by two independent reviewers. Data were pooled using a random-effects model and meta-regression was performed for moderating factors. Reporting bias was assessed. The standardized mean difference (Hedge's g) was used to indicate overall differences of cytokine data (mean and standard deviation or median and interquartile range at the study level) to test our a-priori hypothesis. The systematic review of 36 studies with 1135 participants (355 receiving a control/sham condition and 780 receiving VNS) revealed anti-inflammatory effects of VNS for cytokines in several reports, albeit often in subgroup analyses, but our meta-analyses of 26 studies did not confirm these findings. Although most cytokines were numerically reduced, the reduction did not reach statistical significance after VNS: not in the between-group comparisons (short-term: TNF-α: g = -0.21, p = 0.359; IL-6: g = -0.94, p = 0.112; long-term: TNF-α: g = -0.13, p = 0.196; IL-6: g = -0.67, p = 0.306); nor in the within-study designs (short-term: TNF-α: g = -0.45, p = 0.630; IL-6: g = 0.28, p = 0.840; TNF-α: g = -0.53, p = 0.297; IL-6:g = -0.02, p = 0.954). Only the subgroup analysis of 4 long-term studies with acute inflammation was significant: VNS decreased CRP significantly more than sham stimulation. Additional subgroup analyses including stimulation duration, stimulation method (invasive/non-invasive), immune stimulation, and study quality did not alter results. However, heterogeneity was high, and most studies had poor to fair quality. Given the low number of studies for each disease, a disease-specific analysis was not possible. In conclusion, while numeric effects were reported in individual studies, the current evidence does not substantiate the claim that VNS impacts inflammatory cytokines in humans. However, it may be beneficial during acute inflammatory events. To assess its full potential, high-quality studies and technological advances are required.

Systemic Glucose Regulation by a Hindbrain Inhibitory Circuit in a Mouse Model of Type 1 Diabetes.

INTRODUCTION: Previous work showed that increasing the electrical activity of inhibitory neurons in the dorsal vagal complex (DVC) is sufficient to increase whole-body glucose concentration in normoglycemic mice. Here we tested the hypothesis that deactivating GABAergic neurons in the dorsal hindbrain of hyperglycemic mice decreases synaptic inhibition of parasympathetic motor neurons in the dorsal motor nucleus of the vagus (DMV) and reduces systemic glucose levels. METHODS: Chemogenetic activation or inactivation of GABAergic neurons in the nucleus tractus solitarius (NTS) was used to assess effects of modulating parasympathetic output on blood glucose concentration in normoglycemic and hyperglycemic mice. Patch-clamp electrophysiology in vitro was used to assess cellular effects of chemogenetic manipulation of NTS GABA neurons. RESULTS: Chemogenetic activation of GABAergic NTS neurons in normoglycemic mice increased their action potential firing, resulting in increased inhibitory synaptic input to DMV motor neurons and elevated blood glucose concentration. Deactivation of GABAergic DVC neurons in normoglycemic mice altered their electrical activity but did not alter systemic glucose levels. Conversely, stimulation of GABAergic DVC neurons in mice that were hyperglycemic subsequent to treatment with streptozotocin changed their electrical activity but did not alter whole-body glucose concentration, while deactivation of this inhibitory circuit significantly decreased circulating glucose concentration. Peripheral administration of a brain impermeant muscarinic acetylcholine receptor antagonist abolished these effects. CONCLUSION: Disinhibiting vagal motor neurons decreases hyperglycemia in a mouse model of type 1 diabetes. This inhibitory brainstem circuit emerges as a key parasympathetic regulator of whole-body glucose homeostasis that undergoes functional plasticity in hyperglycemic conditions.

Association of intra-shift nap duration with heart rate variability in medical night shift workers.

Napping during night shifts effectively reduces disease risk and improves work performance, but few studies have investigated the association between napping and physiological changes, particularly in off-duty daily lives. Changes in the autonomic nervous system precede diseases like cardiovascular disease, diabetes, and obesity. Heart rate variability is a good indicator of autonomic nervous system. This study aimed to investigate the link between night shift nap durations and heart rate variability indices in the daily lives of medical workers. As indicators of chronic and long-term alterations, the circadian patterns of heart rate variability indices were evaluated. We recruited 146 medical workers with regular night shifts and divided them into four groups based on their self-reported nap durations. Heart rate variability circadian parameters (midline-estimating statistic of rhythm, amplitude, and acrophase) were obtained by obtaining 24-h electrocardiogram on a day without night shifts, plotting the data of the heart rate variability indices as a function of time, and fitting them into periodic cosine curves. Using clinical scales, depression, anxiety, stress, fatigue, and sleepiness were assessed. Linear regression analysis revealed a positive relationship between 61-120-min naps and 24-h, daytime, and night-time heart rate variability indices, and the parasympathetic activity oscillation amplitude (indexed by high-frequency power, the square root of the mean of the sum of squares of differences between adjacent normal intervals, standard deviation of short-term R-R-interval variability) within one circadian cycle. This study indicated that napping for 61-120 min during night shifts could benefit medical workers' health, providing physiological evidence to promote nap management.