Efferent Nerve Research Articles

Abstract PR013: A vagal sensory-to-sympathetic axis restrains anti-tumor immunity

Abstract Solid tumors are innervated by distinct branches of the peripheral nervous system, and increased tumor innervation has been associated with poor cancer outcomes. However, it remains unexplored whether different types of nerves function together to sense and respond to a tumor, and how neural networks shape cancer immunity. As a major interoceptive system, vagal nerves sense a large variety of body signals and are critical for maintaining physiological homeostasis of visceral organs including the lung. While distinct vagal sensory neuron (VSN) subtypes have been identified to differently regulate pulmonary functions, it is unknown whether these VSNs interact with lung tumors and how they influence cancer progression. Here, we uncover that sensory nerves act through the sympathetic circuit to restrain anti-cancer immunity. Mechanistically, our data suggest that lung tumors hijack the vagal interoceptive system to activate sympathetic efferent nerves in the tumor microenvironment (TME), which in turn drive immune suppression via β2-adrenergic signaling in alveolar macrophages. Our key findings include: By applying anterograde labeling, tissue-clearing and 3D imaging to genetically engineered mouse models, we found that lung adenocarcinoma is richly innervated by vagal sensory nerves. We also showed that neurotrophic factors produced by cancer cells directly promote vagal sensory innervation. Furthermore, scRNA-seq analysis revealed tumor-induced transcriptional reprogramming of lung-innervating VSNs. Using multiple genetic tools to selectively label and deplete different VSN subtypes, we found that Npy2r + /Trpv1 + VSNs but not P2ry1 + VSNs innervate lung tumors and control lung cancer progression by inhibiting anti- cancer immunity. At the organism level, we demonstrated that vagal NPY2R/TRPV1 neurons inhibit anti-cancer immunity via the sympathetic axis. Depletion of vagal NPY2R/TRPV1 neurons resulted in reduced sympathetic nerve activity and a decreased norepinephrine level in the lung TME, whereas pharmacological activation of the sympathetic pathway suppressed the anti-tumor immune responses and restored tumor growth in mice lacking Npy2r + /Trpv1 + VSNs. At the molecular and cellular level, we identified that the vagal-to-sympathetic axis predominantly functions through β2-adrenergic signaling in alveolar macrophages (AMs) to drive immune suppression. AM depletion or selective deletion of β2-adrenergic receptor (ADRB2) in AMs derepressed the anti-tumor immunity and abolished the tumor-inhibiting effect of Npy2r + /Trpv1 + VSN ablation. Taken together, our study establishes an essential role of the sensory-to-sympathetic circuit in controlling cancer immunosurveillance, supporting the notion that the functional integration of sensory and sympathetic nerves systemically regulates anti- cancer immunity. Translationally, our findings from the preclinical model suggest that targeted disruption of the vagal sensory-to-sympathetic axis may provide new treatments for visceral organ cancers by enhancing anti-tumor immunity. Citation Format: Haohan Wei, Chuyue Yu, Bo Hu, Xing Zeng, Hiroshi Ichise, Ronald N. Germain, Rui Chang, Chengcheng Jin. A vagal sensory-to-sympathetic axis restrains anti-tumor immunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR013.

Neuromodulators in Acute and Chronic Cough in Children: An Update From the Literature

Cough is one of the most common reasons leading to pediatric consultations, negatively impacting the quality of life of patients and caregivers. It is defined as a sudden and forceful expulsion of air from the lungs through the mouth, typically triggered by irritation or the stimulation of sensory nerves in the respiratory tract. This reflex is controlled by a neural pathway that includes sensory receptors, afferent nerves, the brainstem’s cough center, efferent nerves, and the muscles involved in coughing. Based on its duration, cough in children may be classified as acute, lasting less than four weeks, and chronic, persisting for more than four weeks. Neuromodulators have shown promise in reducing the frequency and severity of cough by modulating the neural pathways involved in the cough reflex, although they require careful monitoring and patient selection to optimize the outcomes. This review aims to examine the rationale for using neuromodulators in the management of cough in children.

ATP-gated P2x7 receptor is a major channel type at type II auditory nerves and required for hearing sensitivity efferent controlling and noise protection.

Hearing sensitivity and noise protection are mediated and determined by negative feedback of the cochlear efferent system. Type II auditory nerves (ANs) innervate outer hair cells (OHCs) in the cochlea and provide an input to this efferent control. However, little is known about underlying channel information. Here, we report that ATP-gated P2x7 receptor had a predominant expression at type II ANs and the synaptic areas under inner hair cells and OHCs with lateral and medial olivocochlear efferent nerves. Knockout (KO) of P2x7 increased hearing sensitivity with enhanced acoustic startle response (ASR), auditory brainstem response (ABR), and cochlear microphonics (CM) by increasing OHC electromotility, an active cochlear amplifier in mammals. P2x7 KO also increased susceptibility to noise. Middle level noise exposure could impair active cochlear mechanics resulting in permanent hearing loss in P2x7 KO mice. These data demonstrate that P2x7 receptors have a critical role in type II AN function and the cochlear efferent system to control hearing sensitivity; deficiency of P2x7 receptors can impair the cochlear efferent suppression leading to hearing oversensitivity and susceptibility to noise.

Electrophysiological Changes in Median Nerve among Young Male Cigarette Smokers

Background: Cigarette smoking has been associated with numerous cardiovascular and respiratory disorders. Chronic smoking may also disrupt neuronal function and damage neurons in the peripheral nervous system. Median nerve conduction study is an important electrodiagnostic test for the detection of peripheral nerve dysfunction. Objectives: To observe the impact of cigarette smoking on the electrophysiological status of median motor and sensory nerves in apparently healthy male cigarette smokers. Materials and Methods: This case-control study was carried out in the Department of Physiology, Sir Salimullah Medical College, Dhaka, from July 2017 to June 2018 on thirty male cigarette smokers aged 25 to 40 years. For comparison, thirty age and BMI matched non-smoker healthy male subjects were selected as controls. Motor and sensory nerve conduction parameters (latency, amplitude and nerve conduction velocity) of right median nerve were evaluated by standard methods, using standard nerve conduction study and electromyography machines in the Department of Neurology, Dhaka Medical College Hospital. For statistical analysis, unpaired t test was performed. Results: In this study, median sensory nerve latency was significantly prolonged (p ˂ 0.001) and sensory nerve conduction velocity was significantly slower (p ˂ 0.001) in cigarette smokers. The mean amplitude was also slightly reduced in smokers, but statistically, it was insignificant. However, the distal latency of median motor nerve was slightly prolonged whereas, the amplitude and motor nerve conduction velocity were slightly reduced in cigarette smokers in comparison to those of non-smokers. But the differences were not statistically significant. In addition, 10% of cigarette smokers had subclinical impairment in median sensory nerve function. Conclusion: Chronic cigarette smoking induces significant electrophysiological changes in median sensory nerve fibers and causes sensory nerve dysfunction, while it does not markedly affect median motor nerve fibers in young individuals. KYAMC Journal Volume: 15, No: 01, April 2024: 03-07.

Is Our Limited Understanding of the Effects of Nerve Stimulation Resulting in Poor Outcomes and the Need for Better "Rescue Programming" in SNM and PTNS, and Lost Opportunities for New Sites of Stimulation? ICI-RS 2024.

Sacral neuromodulation (SNM) and percutaneous tibial nerve stimulation (PTNS) are strongly recommended by international guidelines bodies for complex lower urinary tract dysfunctions. However, treatment failure and the need for rescue programming still represent a significant need for long-term follow-up. This review aimed to describe current strategies and future directions in patients undergoing such therapies. This is a consensus report of a Think Tank discussed at the Annual Meeting of the International Consultation on Incontinence - Research Society (ICI-RS), June 6-8, 2024 (Bristol, UK): "Is our limited understanding of the effects of nerve stimulation resulting in poor outcomes and the need for better 'rescue programming' in SNM and PTNS, and lost opportunities for new sites of stimulation?" Rescue programming is important from two different perspectives: to improve patient outcomes and to enhance device longevity (for implantable devices). Standard SNM parameters have remained unchanged since its inception for the treatment of OAB, nonobstructive urinary retention, and voiding dysfunction. SNM rescue programming includes intermittent stimulation (cycling on), increased frequency and changes in pulse width (PW). The effect of PW setting on SNM outcomes remains unclear. Monopolar configurations stimulate more motor nerve fibers at lower stimulation voltage; hence, this could be an option in patients who failed bipolar stimulation in the long term. Unfortunately, there is little evidence for rescue programming for PTNS. However, the development of implantable devices for intermittent stimulation of the tibial nerve may increase long-term adherence to therapy and increase interest in alternative programming. There has been recent promising neurostimulation targeting the pudendal nerve (PNS), especially in BPS/IC. More recently, preliminary data addressed the benefits of high-frequency bilateral pudendal nerve block for DESD and adaptive PNS on both urgency and stress UI in women. The exploration of rescue programming and new stimulation sites remains underutilized, and there are opportunities that could potentially expand the therapeutic applications of nerve stimulation. By broadening the range of target sites, clinicians may be able to tailor treatments according to individual patient needs and underlying conditions, thereby improving overall outcomes. However, further studies are still needed to increase the level of evidence, potentially allowing for an individualized treatment both in patients who are candidates for electrostimulation and in those who have already received surgical implants but seek a better outcome.

Renal nerves in physiology, pathophysiology and interoception.

Sympathetic efferent renal nerves have key roles in the regulation of kidney function and blood pressure. Increased renal sympathetic nerve activity is thought to contribute to hypertension by promoting renal sodium retention, renin release and renal vasoconstriction. This hypothesis led to the development of catheter-based renal denervation (RDN) for the treatment of hypertension. Two RDN devices that ablate both efferent and afferent renal nerves received FDA approval for this indication in 2023. However, in animal models, selective ablation of afferent renal nerves resulted in comparable anti-hypertensive effects to ablation of efferent and afferent renal nerves and was associated with a reduction in sympathetic nerve activity. Selective afferent RDN also improved kidney function in a chronic kidney disease model. Notably, the beneficial effects of RDN extend beyond hypertension and chronic kidney disease to other clinical conditions that are associated with elevated sympathetic nerve activity, including heart failure and arrhythmia. These findings suggest that the kidney is an interoceptive organ, as increased renal sensory nerve activity modulates sympathetic activity to other organs. Future studies are needed to translate this knowledge into novel therapies for the treatment of hypertension and other cardiorenal diseases.

Control of nerve-mediated and urothelial ATP release by a protein kinase G-dependent pathway in the mouse bladder

Aim:ATP signalling is involved in urinary bladder motor and sensory pathways, including stimulation-mediated release from parasympathetic varicosities to detrusor muscle and from urothelial cells when mechanically stressed. Both modalities are present in humans and other mammals but are especially prominent in overactive bladder syndromes. There is therefore an unmet need to understand how to regulate such release. This study tested the hypothesis that the nitric oxide (NO•)/ soluble guanylate cyclase (sGC)/ cyclic GMP/ protein kinase-G (PKG) pathway has a central role. Methods:In vitro nerve-mediated contractions and ATP/acetylcholine (ACh) release were measured from bladder wall strips, as was ATP release from urothelial cell suspensions subject to mechanical stresses. Enhanced spontaneous contractile activity was also measured in bladder wall preparations of spinal cord-injured mice. Interventions were designed to increase cellular cGMP levels (a cell-permeable cGMP analogue, a NO•donor, a phosphodiesterase inhibitor (PDEI), a sGC activator), or agents to reduce activity of pathway enzymes (sCG or PKG). Results:ATP-dependent contractions were reduced by the above interventions, as was ATP release; but ACh-dependent contractions and ACh release were unaffected. Spontaneous contractile activity was also reduced by the cGMP analogue and by a PDEI. ATP release from urothelial cell suspensions was also reduced by similar interventions. Conclusions:ATP release from efferent nerves and from urothelial cells were selectively reduced by upregulating the NO•/sGC/cGMP/PKG pathway. Translational aspects are discussed with respect to purinergic pathways and overactive bladder pathologies.

Towards spatially selective efferent neuromodulation: anatomical and functional organization of cardiac fibres in the porcine cervical vagus nerve.

Spatially selective vagus nerve stimulation (sVNS) offers a promising approach for addressing heart disease with enhanced precision. Despite its therapeutic potential, VNS is limited by off-target effects and the need for time-consuming titration. Our research aimed to determine the spatial organization of cardiac afferent and efferent fibres within the vagus nerve of pigs to achieve targeted neuromodulation. Using trial-and-error sVNS in vivo and ex vivo micro-computed tomography fascicle tracing, we found significant spatial separation between cardiac afferent and cardiac efferent fibres at the mid-cervical level and they were localized on average on opposite sides of the nerve cross-section. This was consistent between both in vivo and ex vivo methods. Specifically, cardiac afferent fibres were located near pulmonary fibres, consistent with findings of cardiopulmonary convergent circuits and, notably, cardiac efferent fascicles were exclusive. These cardiac efferent regions were located in close proximity to the recurrent laryngeal regions. This is consistent with the roughly equitable spread across the nerve of the afferent and efferent fibres. Our study demonstrated that targeted neuromodulation via sVNS could achieve scalable heart rate decreases without eliciting cardiac afferent-related reflexes; this is desirable for reducing sympathetic overactivation associated with heart disease. These findings indicate that understanding the spatial organization of cardiac-related fibres within the vagus nerve can lead to more precise and effective VNS therapy, minimizing off-target effects and potentially mitigating the need for titration. KEY POINTS: Spatially selective vagus nerve stimulation (sVNS) presents a promising approach for addressing chronic heart disease with enhanced precision. Our study reveals significant spatial separation between cardiac afferent and efferent fibres in the vagus nerve, particularly at the mid-cervical level. Utilizing trial-and-error sVNS in vivo and micro-computed tomography fascicle tracing, we demonstrate the potential for targeted neuromodulation, achieving therapeutic effects such as scalable heart rate decrease without stimulating cardiac afferent-related reflexes. This spatial understanding opens avenues for more effective VNS therapy, minimizing off-target effects and potentially eliminating the need for titration, thereby expediting therapeutic outcomes in myocardial infarction and related conditions.

Interaction of simultaneous hypoxia and baroreflex loading on control of sympathetic action potential subpopulations.

Efferent muscle sympathetic nerve activity (MSNA) is under tonic baroreflex control. The arterial baroreflex exerts the strongest influence over medium-sized sympathetic action potential (AP) subpopulations in efferent MSNA recordings. Prior work from multiunit MSNA recordings has shown baroreflex loading selectively abolishes the sympathetic response to hypoxia. The purpose of the study was to examine baroreflex control over different-sized AP clusters and characterize the neural recruitment strategies of sympathetic AP subpopulations with baroreflex and combined baroreflex/chemoreflex (i.e., hypoxia) activation. We loaded the arterial baroreceptors [intravenous phenylephrine (PE)] alone and in combination with systemic hypoxia ([Formula: see text] 80%) in nine healthy young men. We extracted sympathetic APs using the wavelet-based methodology and quantified baroreflex gain for individual AP clusters. AP baroreflex threshold gain was measured as the slope of the linear relationship between AP probability versus diastolic blood pressure for 10 normalized clusters. Baroreflex loading with phenylephrine decreased MSNA and AP firing compared with baseline (all P < 0.05). However, the phenylephrine-mediated decrease in AP firing was lost with concurrent hypoxia (P = 0.384). Compared with baseline, baroreflex loading reduced medium-sized AP cluster baroreflex threshold slope (condition P = 0.005) and discharge probability (condition P < 0.0001); these reductions from baseline were maintained during simultaneous hypoxia (both P < 0.05). Present findings indicate a key modulatory role of the baroreceptors on medium-sized APs in blood pressure regulation that withstands competing signals from peripheral chemoreflex activation.NEW & NOTEWORTHY This study provides a novel understanding on baroreflex control of efferent sympathetic nervous system activity during competing stressors: baroreflex loading and peripheral chemoreflex activation. We show chemoreflex activation buffers baroreflex-mediated reductions in sympathetic nervous system activity. More importantly, baroreflex loading reduced baroreflex threshold gain of sympathetic action potential clusters and this reduction withstood chemoreflex activation. These data suggest the arterial baroreflex holds a primary regulatory role over medium-sized sympathetic neurons despite competing chemoreflex signals.

Renal autonomic dynamics in hypertension: how can we evaluate sympathetic activity for renal denervation?

This review explores the various pathophysiological factors influencing antihypertensive effects, involving the regulation of vascular resistance, plasma volume, cardiac function, and the autonomic nervous system, emphasizing the interconnected processes regulating blood pressure (BP). The kidney's pivotal role in BP control and its potential contribution to hypertension is complicated but important to understand the effective mechanisms of renal denervation (RDN), which may be a promising treatment for resistant hypertension. Excessive stimulation of the sympathetic nervous system or the renin-angiotensin-aldosterone system (RAAS) can elevate BP through various physiological changes, contributing to chronic hypertension. Renal sympathetic efferent nerve activation leads to elevated norepinephrine levels and subsequent cascading effects on vasoconstriction, renin release, and sodium reabsorption. RDN reduces BP in resistant hypertension by potentially disrupting sensory afferent nerves, decreasing feedback activation to the central nervous system, and reducing efferent sympathetic nerve activity in the heart and other structures. RDN may also modulate central sympathetic outflow and inhibit renal renin-angiotensin system overactivation. While evidence for RDN efficacy in hypertension is increasing, accurate patient selection becomes crucial, considering complex interactions that vary among patients. This review also discusses methods to evaluate autonomic nerve activity from the golden standard to new potential examination for finding out optimization in stimulation parameters or rigorous patient selection based on appropriate biomarkers.

Prenatal LPS leads to increases in RAS expression within the PVN and overactivation of sympathetic outflow in offspring rats

The renin-angiotensin system (RAS) and the sympathetic nervous system (SNS) are two major blood pressure-regulating systems. The link between the renal and cerebral RAS axes was provided by reflex activation of renal afferents and efferent sympathetic nerves. There is a self-sustaining enhancement of the brain and the intrarenal RAS. In this study, prenatal exposure to lipopolysaccharide (LPS) led to increased RAS activity in the paraventricular nucleus (PVN) and overactivation of sympathetic outflow, accompanied by increased production of reactive oxygen species (ROS) and disturbances between inhibitory and excitatory neurons in PVN. The AT1 receptor blocker losartan and α2 adrenergic receptor agonist clonidine in the PVN significantly decreased renal sympathetic nerve activity (RSNA) and synchronously reduced systolic blood pressure. Prenatal LPS stimulation caused H3 acetylation at H3K9 and H3K14 in the PVN, which suggested that epigenetic changes are involved in transmitting the prenatal adverse stimulative information to the next generation. Additionally, melatonin treatment during pregnancy reduced RAS activity and ROS levels in the PVN; balanced the activity of inhibitory and excitatory neurons in the PVN; increased urine sodium secretion; reduced RSNA and blood pressure. In conclusion, prenatal LPS leads to increased RAS expression within the PVN and overactivation of the sympathetic outflow, thereby contributing to hypertension in offspring rats. Melatonin is expected to be a promising agent for preventing prenatal LPS exposure-induced hypertension.

Renal denervation: a key approach to hypertension and cardiovascular disease.

Sympathetic activation plays a critical role in the development of hypertension and cardiovascular disease, including heart failure and arrhythmias. Renal nerves contribute to the regulation of blood pressure and fluid volume through renal sympathetic efferent nerves, and to the modulation of sympathetic outflow through renal sensory afferent nerves. Previous studies including ours suggest that selective afferent renal denervation with preservation of efferent renal nerves can significantly decrease central sympathetic outflow in animal models of hypertension with renal damage. In Dahl salt-sensitive rats fed high salt diet from an early age, a model of hypertensive heart failure, this central sympathoinhibition by afferent renal denervation may attenuate the development of heart failure without significant blood pressure reduction. Accumulating clinical evidence supports the efficacy of renal denervation as an antihypertensive treatment. However, it remains important to clarify the appropriate indications and predictors of responders to renal denervation in the treatment of hypertension. Several clinical studies suggest beneficial effects of renal denervation in patients with heart disease, with or without hypertension, although most were not sham-controlled. In particular, some clinical studies have demonstrated that renal denervation reduces the incidence of atrial fibrillation or cardiovascular events even without a significant antihypertensive effect. It is essential to accumulate more insightful data in patients undergoing renal denervation, to establish the efficacy of renal denervation in patients with cardiovascular disease in the clinical setting, and to elucidate the therapeutic mechanisms of renal denervation and the renal nerves-linked pathophysiology of cardiovascular disease in basic research. This review outlines the effects of renal denervation on sympathetic activity and organ damage in animal models of hypertension and hypertensive heart failure, including our own data. Beyond the antihypertensive effects, the beneficial effects of renal denervation on cardiovascular disease are also discussed based on clinical studies. Several animal and clinical studies suggest the cardioprotective effects of renal denervation even in the absence of significant blood pressure reduction, probably due to its sympathoinhibitory effects.

What is the Vagal-Adrenal Axis?

Some recent publications have used the term "vagal-adrenal axis" to account for mechanisms involved in the regulation of inflammation by electroacupuncture. This concept proposes that efferent parasympathetic nerve fibers in the vagus directly innervate the adrenal glands to influence catecholamine secretion. Here, we discuss evidence for anatomical and functional links between the vagi and adrenal glands that may be relevant in the context of inflammation and its neural control by factors, including acupuncture. First, we find that evidence for any direct vagal parasympathetic efferent innervation of the adrenal glands is weak and likely artifactual. Second, we find good evidence that vagal afferent fibers directly innervate the adrenal gland, although their function is uncertain. Third, we highlight a wealth of evidence for indirect pathways, whereby vagal afferent signals act via the central nervous system to modify adrenal-dependent anti-inflammatory responses. Vagal afferents, not efferents, are thus the likely key to these phenomena.

The interactive effects of posture and biological sex on the control of muscle sympathetic nerve activity during rhythmic handgrip exercise.

Body posture and biological sex exhibit independent effects on the sympathetic neural responses to dynamic exercise. However, the neural mechanisms (e.g., baroreflex) by which posture impacts sympathetic outflow during rhythmic muscular contractions, and whether biological sex affects posture-mediated changes in efferent sympathetic nerve traffic during exercise, remain unknown. Thus, we tested the hypotheses that increases in muscle sympathetic nerve activity (MSNA) would be greater during upright compared with supine rhythmic handgrip (RHG) exercise, and that females would demonstrate smaller increases in MSNA during upright RHG exercise than males. Twenty young (30 [6] yr; means [SD]) individuals (9 males, 11 females) underwent 6 min of supine and upright (head-up tilt 45°) RHG exercise at 40% maximal voluntary contraction with continuous measurements of MSNA (microneurography), blood pressure (photoplethysmography), and heart rate (electrocardiogram). In the pooled group, absolute MSNA burst frequency (P < 0.001), amplitude (P = 0.009), and total MSNA (P < 0.001) were higher during upright compared with supine RHG exercise. However, body posture did not impact the peak change in MSNA during RHG exercise (range: P = 0.063-0.495). Spontaneous sympathetic baroreflex gain decreased from rest to RHG exercise (P = 0.006) and was not impacted by posture (P = 0.347). During upright RHG exercise, males demonstrated larger increases in MSNA burst amplitude (P = 0.002) and total MSNA (P = 0.001) compared with females, which coincided with greater reductions in sympathetic baroreflex gain among males (P = 0.004). Collectively, these data indicate that acute attenuation of baroreflex-mediated sympathoinhibition permits increases in MSNA during RHG exercise and that males exhibit a greater reserve for efferent sympathetic neural recruitment during orthostasis than females.NEW & NOTEWORTHY The impact of posture and sex on cardiovascular control during rhythmic handgrip (RHG) exercise is unknown. We show that increases in muscle sympathetic nerve activity (MSNA) during RHG are partly mediated by a reduction in sympathetic baroreflex gain. In addition, males demonstrate larger increases in total MSNA during upright RHG than females. These data indicate that the baroreflex partly mediates increases in MSNA during RHG and that males have a greater sympathetic vasoconstrictor reserve than females.

Clinical Neurophysiological Methods Verify Improvement in the Motor Neural Transmission in Patients with Surgically Treated Idiopathic Scoliosis in Long-Term Follow-up

The evaluation of patients after the surgical correction of idiopathic scoliosis in a long-term follow-up with clinical neurophysiological methods has not been presented in detail. This study aimed to compare the results of neurophysiological studies in 45 girls with scoliosis of Lenke types 1–3 performed pre- (T0) and postoperatively, 1 week after surgery (T1) and 6 months after surgery (T2). The parameter values of the surface electromyography while attempting maximal contraction (mcsEMG) and the transcranial motor-evoked potentials (MEPs) recorded in the anterior tibial muscles, as well as the electroneurography (ENG) of the peripheral transmission in the peroneal nerve motor fibers, were compared. The results indicate that efferent neural conduction function both centrally and peripherally, and TA muscle function slightly improved immediately after the surgical correction of scoliosis, and further normalization appeared after six months in the long-term follow-up (at p = 0.03). The sEMG recordings indicate that half a year after surgical treatment in IS patients, the TA muscle motor unit recruitment function, as well as the muscle strength evaluated with Lovett’s scale, was comparable to the normal condition. The ENG recording results indicated a gradual reduction in the motor fiber injury symptoms, mainly of the axonal type, in the peroneal nerves. The surgeries also improved the lumbar ventral roots’ neural transmission to a normal functional status. The MEP amplitude parameter values recorded after the surgical scoliosis corrections in T1 indicated a slight improvement in the efferent transmission of neural impulses within the fibers of the spinal tracts; in the long-term T2 observation period, they reached values comparable to those recorded in healthy volunteers, bilaterally. Preoperatively (T0), the results of all the neurophysiological study parameters in the IS patients were asymmetrical at p = 0.036–0.05 and recorded as worse on the concave side, suggesting the lateralization of neurological motor deficits. One week postoperatively (T1), this asymmetry was recorded as gradually reduced, showing almost no difference between the right and left sides six months later (T2). The presented algorithm for the neurophysiological assessments performed in the pre-, intra-, and long-term postoperative periods using the mcsEMG, MEP, and ENG neurophysiological examinations, together with the clinical studies, may help in the comprehensive functional evaluation of the spinal cord tracts and ventral root neural conduction, which allows the detection of the subclinical neurological changes related to scoliosis itself and the consequences of the corrective surgery. Such an evaluation can also be significant in making final decisions regarding IS surgeries and their personalization after attempting conservative treatments with bracing and kinesiotherapy. Neurophysiological studies, as a sensitive biomarker, allowed us to predict and ascertain the final result of IS treatment in the long-term follow-up, which showed the health status of patients as being comparable to that of healthy volunteers.

Understanding Samaana Vaata in relation to the physiology of digestion

Ayurveda is a way of life governed by the principle that whatever there is in the universe is there in the body also. The concept of Tridosha is one such theory which decides the well-being and the diseased condition of a human being. That is, when in equilibrium leads to health and when vitiated, leads to disease. Vaata being one of the Tridosha leads the other two Dosha, Mala, Dhatus as the wind carries the clouds in the sky. There are five types of Vaata, i.e., Prana, Udana, Samana, Vyana and Apana. Samaana, is situated near Jatharagni and moves all over the Koshta. The function of Samaana Vaata can be corelated with functions such as Grahana, Pachana, Vivechana, Munchana. The myenteric plexus, or plexus of Auerbach, is located between the longitudinal and circular smooth muscle layers of the muscularis in gastrointestinal tract. The motor neurons of these plexus mostly control GI tract motility (movement), particularly the frequency and strength of contraction of the muscularis. This can be co-related to Karma of Samana Vata like Grahana, Munchana. The submucosal plexus, also known as Meissner’s plexus, is a network of autonomic motor nerve fibres located in the submucosa of the gastrointestinal tract. The motor neurons of the submucosal plexus supply the secretory cells of the mucosal epithelium, controlling the secretions and absorption of the organs of the gastrointestinal tract. This can be co-related to Karma of Samana Vaata like Pachana, Vivechana. Hence this article is aimed at further exploration of these anatomical and physiological aspects.

Regulation of Inflammation, Without Impacting Heart Rate, via Electrical Stimulation of the Dorsal Motor Nucleus of the Vagus

The vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. Recently, using optogenetics it has been demonstrated that the brainstem’s dorsal motor nucleus of the vagus (DMN) is a significant source of efferent vagus nerve fibers that control inflammation. In contrast to optogenetics, electrical neuronal stimulation is an approved therapeutic approach. However, the anti-inflammatory effectiveness of electrical stimulation of the DMN (eDMNS) and the possible heart rate (HR) alterations associated with this approach have not been investigated. Here, we examined the effects of eDMNS on the HR and cytokine levels in murine endotoxemia as well as the cecal ligation and puncture (CLP) model of sepsis. C57BL/6 mice (8-10 weeks old), under anesthesia and secured in a stereotaxic frame, received eDMNS via a concentric bipolar electrode in the left or right DMN, or sham treatment. eDMNS (50, 250 or 500 μA and 30 Hz, for 1 min) was performed and HR recorded. In endotoxemia experiments, mice underwent sham or 5-minute eDMNS (250 μA or 50 μA) followed by LPS (0.5 mg/kg) i.p. injection. eDMNS was also studied on mice with cervical unilateral vagotomy or sham surgery. In CLP experiments sham or left eDMNS was performed immediately post CLP. Cytokines and corticosterone were measured 90 mins after LPS administration or 24h after CLP. CLP survival was monitored for 14 days. Both left and right eDMNS at 250 μA and 500 μA significantly reduced HR, compared with pre- and post-stimulation, while 50 μA did not. Left-side eDMNS at 50 μA decreased serum and splenic TNF levels, and increased serum IL-10 during endotoxemia. The anti-inflammatory effect of eDMNS was abrogated in mice with ipsilateral unilateral vagotomy, which was also not associated with serum corticosterone alterations. Right-side eDMNS lowered serum TNF levels and increased IL-10 but had no impact on splenic cytokines. In CLP, left eDMNS decreased serum TNF and IL-6 levels, lowered splenic IL-6 and increased splenic IL-10, and improved survival in mice. For the first time, we demonstrate that an eDMNS regimen, which does not cause bradycardia, mitigates LPS-induced inflammation. These effects are dependent on an intact vagus nerve and are unrelated to corticosteroid alterations. Additionally, eDMNS reduces inflammation and enhances survival in a polymicrobial sepsis model. These findings hold promise for further research into bioelectronic anti-inflammatory strategies aimed at the brainstem DMN. This work was partially funded by NIGMS. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Locally produced nerve growth factor is a novel regulator of (juxta)glomerular and collecting duct functions in the kidney

The dense network of sympathetic efferent and sensory afferent nerves innervating the kidney is well recognized, however the elements and the functional importance of neurotrophin signaling in renal tissues are much less known. Peripherally innervated tissues are known to produce and release nerve growth factor (NGF) which belongs to the neurotrophin family of neuronal signaling proteins and is essential for the growth and survival of peripheral sensory and sympathetic nerves. This study aimed to characterize the expression and role of NGF in the kidney. We hypothesized that NGF is produced by multiple renal tubular and vascular cell types and helps to maintain hemodynamic and tubular transport functions. Local NGF expression was studied using histological sections of kidneys harvested from NGF-GFP reporter mice. To address the functional importance of NGF signaling, a new mouse model was generated by crossing Ren1d-Cre and NGF-floxed mice and Cre/lox-mediated knockout of NGF from cells of the renin lineage co-labeled with the multicolor reporter Confetti (Ren1d-Confetti-NGF KO). WT and NGF KO mice were placed in metabolic cages for urine collections and analysis, and systolic blood pressure (SBP) was measured with tail-cuff pletysmography. Intercalated cells of the collecting duct (CD) showed by far the highest NGF expression among all renal cell types based on the reporter signal in NGF-GFP mice, in addition to select cells in the renal interstitium including juxtaglomerular (JG) renin cells. Since both CD cells and JG cells are part of the renin lineage, the applied genetic strategy using Ren1d-Confetti-NGF KO mice was ideal, and showed diminished NGF expression compared to WT. Urine excretion rate and albuminuria were 3-fold increased in Ren1d-Confetti-NGF KO vs. WT mice, while there was no difference in SBP between WT and KO groups. Immunohistochemistry showed aberrant CD structure with multiple small, undifferentiated cells with apparently lost polarity and reduced AQP2 labeling in CD principal cells in Ren1d-Confetti-NGF KO mice compared to WT. In addition, the characteristic strong apical membrane AQP2 (in principal cells) and H+-ATPase (in intercalated cells) labeling in WT mice was diminished in Ren1d-Confetti-NGF KO mice. JG renin cell number per nephron was significantly reduced in Ren1d-Confetti-NGF KO (2.5±1.0) vs. WT mice (6.2±1.5, n=4 mice each). In summary, our results suggest high level of NGF expression in the adult kidney that plays important physiological functional roles in maintaining collecting duct water and electrolyte reabsorption and acid secretion, and intrarenal renin production. Deficient intrarenal NGF production may cause kidney disease, suggesting the importance of altered renal neurotrophin signaling in pathology development. DK064234, DK123564, DK135290. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Noninvasive focused ultrasound stimulation of the celiac-superior mesenteric ganglion complex regulates inflammation in murine endotoxemia

The nervous system has an important role in the regulation of cytokines and inflammation ( Nature, 2002). The celiac-superior mesenteric ganglion complex (CSMGC) is an important component of the vagus nerve based inflammatory reflex, which controls inflammation ( Nat Neuroscience 2017). In addition to receiving cholinergic innervations from the efferent vagus nerve, the CSMGC is innervated by preganglionic sympathetic splanchnic nerves, which also are involved in the inflammatory regulation. Both neuronal types - vagal and preganglionic sympathetic - interact with catecholaminergic neurons, which reside in this ganglionic complex and innervate the liver, spleen, and other abdominal organs. Despite being a prominent locus of neuronal interactions, the possibilities of directly targeting the CSMGC to regulate cytokine responses and inflammation remains unexplored. To provide insight, we subjected the CSMGC in mice to focused ultrasound stimulation (FUS) - a non-invasive approach, which has been increasingly utilized in neuromodulation. We used ultrasound imaging and doppler to localise the complex in anesthetized 10–14-week-old male C57BL/6J mice. To perform stimulation, the FUS transducer was placed on the abdominal surface over the CSMGC and FUS (1.1MHz and 200mV per pulse, 150 burst cycles, 500μs burst period) or sham stimulation was delivered for 2 mins or 5 mins. Five mins post FUS, mice were injected with lipopolysaccharide (endotoxin, 0.25mg/kg, i.p.) and euthanized after 90 mins. Blood and liver were collected and processed for cytokine analysis. Compared to sham stimulation, FUS of the CSMGC for 5mins (n=11,12/group) significantly decreased serum TNF levels (1,875 ± 750 pg/ml vs 672.9 ± 335 pg/ml, P&lt; 0.0001) and hepatic TNF levels (27.8 ± 8.6 pg/mg vs 16.0 ± 7.1 pg/mg, P= 0.0018) in endotoxemic mice. In contrast, FUS of CSMGC for 2 mins (n=15/group) did not significantly alter serum TNF levels (1,458 ± 599.9 pg/ml vs 1,120 ± 332.5 pg/ml, P=0.1607). These results demonstrate the anti-inflammatory effcacy of noninvasive FUS of the CSMGC. Our findings also identify the CSMGC as an easily targetable new therapeutic site for controlling systemic and hepatic inflammation with a potential for clinical translation. This work was partially supported by NIGMS. R01GM128008. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Electrical stimulation of the dorsal motor nucleus of the vagus in male mice can regulate inflammation without affecting the heart rate

BackgroundThe vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. A major source of efferent vagus nerve fibers that contribute to the regulation of inflammation is the brainstem dorsal motor nucleus of the vagus (DMN), as recently shown using optogenetics. In contrast to optogenetics, electrical neuromodulation has broad therapeutic implications. However, the anti-inflammatory effectiveness of electrical stimulation of the DMN (eDMNS) and the possible heart rate (HR) alterations associated with this approach have not been investigated. Here, we examined the effects of eDMNS on HR and cytokine levels in mice administered with lipopolysaccharide (LPS, endotoxin) and in mice subjected to cecal ligation and puncture (CLP) sepsis. MethodsAnesthetized male 8–10-week-old C57BL/6 mice on a stereotaxic frame were subjected to eDMNS using a concentric bipolar electrode inserted into the left or right DMN or sham stimulation. eDMNS (500, 250 or 50 μA at 30 Hz, for 1 min) was performed and HR recorded. In endotoxemia experiments, sham or eDMNS utilizing 250 μA or 50 μA was performed for 5 mins and was followed by LPS (0.5 mg/kg) i.p. administration. eDMNS was also applied in mice with cervical unilateral vagotomy or sham operation. In CLP experiments sham or left eDMNS was performed immediately post CLP. Cytokines and corticosterone were analyzed 90 mins after LPS administration or 24 h after CLP. CLP survival was monitored for 14 days. ResultsEither left or right eDMNS at 500 μA and 250 μA decreased HR, compared with baseline pre-stimulation. This effect was not observed at 50 μA. Left side eDMNS at 50 μA, compared with sham stimulation, significantly decreased serum and splenic levels of the pro-inflammatory cytokine TNF and increased serum levels of the anti-inflammatory cytokine IL-10 during endotoxemia. The anti-inflammatory effect of eDMNS was abrogated in mice with unilateral vagotomy and was not associated with serum corticosterone alterations. Right side eDMNS in endotoxemic mice suppressed serum TNF and increased serum IL-10 levels but had no effects on splenic cytokines. In mice with CLP, left side eDMNS suppressed serum IL-6, as well as splenic IL-6 and increased splenic IL-10 and significantly improved the survival rate of CLP mice. ConclusionsFor the first time we show that a regimen of eDMNS which does not cause bradycardia alleviates LPS-induced inflammation. These eDMNS anti-inflammatory effects require an intact vagus nerve and are not associated with corticosteroid alterations. eDMNS also decreases inflammation and improves survival in a model of polymicrobial sepsis. These findings are of interest for further studies exploring bioelectronic anti-inflammatory approaches targeting the brainstem DMN.