Sympathetic Signals Research Articles

Sympathetic nerve signals: orchestrators of mammary development and stem cell vitality.

The mammary gland is a dynamic organ that undergoes significant changes at multiple stages of postnatal development. Although the roles of systemic hormones and microenvironmental cues in mammary homeostasis have been extensively studied, the influence of neural signals, particularly those from the sympathetic nervous system, remains poorly understood. Here, using a mouse mammary gland model, we delved into the regulatory role of sympathetic nervous signaling in the context of mammary stem cells and mammary development. Our findings revealed that depletion of sympathetic nerve signals results in defective mammary development during puberty, adulthood, and pregnancy, accompanied by a reduction in mammary stem cell number. Through in vitro three-dimensional culture and in vivo transplantation analyses, we demonstrated that the absence of sympathetic nerve signals hinders mammary stem cell self-renewal and regeneration, while activation of sympathetic nervous signaling promotes these capacities. Mechanistically, sympathetic nerve signals orchestrate mammary stem cell activity and mammary development through the ERK signaling pathway. Collectively, our study unveils the crucial roles of sympathetic nerve signals in sustaining mammary development and regulating mammary stem cell activity, offering a novel perspective on the involvement of the nervous system in modulating adult stem cell function and organ development.

Lateralized response of skull bone marrow via osteopontin signaling in mice after ischemia reperfusion

Skull bone marrow is thought to be an immune tissue closely associated with the central nervous system (CNS). Recent studies have focused on the role of skull bone marrow in central nervous system disorders. In this study, we performed single-cell RNA sequencing on ipsilateral and contralateral skull bone marrow cells after experimental stroke and then performed flow cytometry and analysis of cytokine expression. Skull marrow showed lateralization in response to stroke. Lateralization is demonstrated primarily by the proliferation and differentiation of myeloid and lymphoid lineage cells in the skull bone marrow adjacent to the ischemic region, with an increased proportion of neutrophils compared to monocytes. Analysis of chemokines in the skull revealed marked differences in chemotactic signals between the ipsilateral and contralateral skull, whereas sympathetic signals innervating the skull did not affect cranial bone marrow lateralization. Osteopontin (OPN) is involved in region-specific activation of the skull marrow that promotes inflammation in the meninges, and inhibition of OPN expression improves neurological function.Graphical

Upregulated Mitochondrial Dynamics Is Responsible for the Procatabolic Changes of Chondrocyte Induced by α2-Adrenergic Signal Activation.

Activation of sympathetic tone is important for cartilage degradation in osteoarthritis (OA). Recent studies reported that sympathetic signals can affect the mitochondrial function of target cells. It is unknown whether this effect exits in chondrocytes and affects chondrocyte catabolism. The contribution of mitochondrial dynamics in the activation of α2-adrenergic signal-mediated chondrocyte catabolism was investigated in this study. Primary chondrocytes were stimulated with norepinephrine (NE) alone, or pretreated with an α2-adrenergic receptor (Adra2) antagonist (yohimbine) and followed by stimulation with NE. Changes in chondrocyte metabolism and their mitochondrial dynamics were investigated. We demonstrated that NE stimulation induced increased gene and protein expressions of matrix metalloproteinase-3 and decreased level of aggrecan by chondrocytes. This was accompanied by upregulated mitochondriogenesis and the number of mitochondria, when compared with the vehicle-treated controls. Mitochondrial fusion and fission, and mitophagy also increased significantly in response to NE stimulation. Inhibition of Adra2 attenuated chondrocyte catabolism and mitochondrial dynamics induced by NE. The present findings indicate that upregulation of mitochondrial dynamics through mitochondriogenesis, fusion, fission, and mitophagy is responsible for activation of α2-adrenergic signal-mediated chondrocyte catabolism. The hypothesis that "α2-adrenergic signal activation promotes cartilage degeneration in temporomandibular joint osteoarthritis (TMJ-OA) by upregulating mitochondrial dynamics in chondrocytes" is validated. This represents a new regulatory mechanism in the chondrocytes of TMJ-OA that inhibits abnormal activation of mitochondrial fusion and fission is a potential regulator for improving mitochondrial function and inhibiting chondrocyte injury and contrives a potentially innovative therapeutic direction for the prevention of TMJ-OA.

Increased respiratory modulation of cardiovascular control reflects improved blood pressure regulation in pregnancy.

Hypertensive pregnancy disorders put the maternal-fetal dyad at risk and are one of the leading causes of morbidity and mortality during pregnancy. Multiple efforts have been made to understand the physiological mechanisms behind changes in blood pressure. Still, to date, no study has focused on analyzing the dynamics of the interactions between the systems involved in blood pressure control. In this work, we aim to address this question by evaluating the phase coherence between different signals using wavelet phase coherence. Electrocardiogram, continuous blood pressure, electrocardiogram-derived respiration, and muscle sympathetic nerve activity signals were obtained from ten normotensive pregnant women, ten normotensive non-pregnant women, and ten pregnant women with preeclampsia during rest and cold pressor test. At rest, normotensive pregnant women showed higher phase coherence in the high-frequency band (0.15-0.4Hz) between muscle sympathetic nerve activity and the RR interval, blood pressure, and respiration compared to non-pregnant normotensive women. Although normotensive pregnant women showed no phase coherence differences with respect to hypertensive pregnant women at rest, higher phase coherence between the same pairs of variables was found during the cold pressor test. These results suggest that, in addition to the increased sympathetic tone of normotensive pregnant women widely described in the existing literature, there is an increase in cardiac parasympathetic modulation and respiratory-driven modulation of muscle sympathetic nerve activity and blood pressure that could compensate sympathetic increase and make blood pressure control more efficient to maintain it in normal ranges. Moreover, blunted modulation could prevent its buffer effect and produce an increase in blood pressure levels, as observed in the hypertensive women in this study. This initial exploration of cardiorespiratory coupling in pregnancy opens the opportunity to follow up on more in-depth analyses and determine causal influences.

Autonomic markers of extubation readiness in premature infants.

In premature infants, extubation failure is common and difficult to predict. Heart rate variability (HRV) is a marker of autonomic tone. Our aim is to test the hypothesis that autonomic impairment is associated with extubation readiness. Retrospective study of 89 infants <28 weeks. HRV metrics 24 h prior to extubation were compared for those with and without extubation success within 72 h. Receiver-operating curve analysis was conducted to determine the predictive ability of each metric, and a predictive model was created. Seventy-three percent were successfully extubated. The success group had significantly lower oxygen requirement, higher sympathetic HRV metrics, and a lower parasympathetic HRV metric. α1 (measure of autocorrelation, related to sympathetic tone) was the best predictor of success-area under the curve (AUC) of .73 (p = 0.001), and incorporated into a predictive model had an AUC of 0.81 (p < 0.0001)-sensitivity of 81% and specificity of 78%. Extubation success is associated with HRV. We show an autonomic imbalance with low sympathetic and elevated parasympathetic tone in those who failed. α1, a marker of sympathetic tone, was noted to be the best predictor of extubation success especially when incorporated into a clinical model. This article depicts autonomic markers predictive of extubation success. We depict an autonomic imbalance in those who fail extubation with heightened parasympathetic and blunted sympathetic signal. We describe a predictive model for extubation success with a sensitivity of 81% and specificity of 78%.

Slc12a8 in the lateral hypothalamus maintains energy metabolism and skeletal muscle functions during aging.

Sarcopenia and frailty are urgent socio-economic problems worldwide. Here we demonstrate a functional connection between the lateral hypothalamus (LH) and skeletal muscle through Slc12a8, a recently identified nicotinamide mononucleotide transporter, and its relationship to sarcopenia and frailty. Slc12a8-expressing cells are mainly localized in the LH. LH-specific knockdown of Slc12a8 in young mice decreases activity-dependent energy and carbohydrate expenditure and skeletal muscle functions, including muscle mass, muscle force, intramuscular glycolysis, and protein synthesis. LH-specific Slc12a8 knockdown also decreases sympathetic nerve signals at neuromuscular junctions and β2-adrenergic receptors in skeletal muscle, indicating the importance of the LH-sympathetic nerve-β2-adrenergic receptor axis. LH-specific overexpression of Slc12a8 in aged mice significantly ameliorates age-associated decreases in energy expenditure and skeletal muscle functions. Our results highlight an important role of Slc12a8 in the LH for regulation of whole-body metabolism and skeletal muscle functions and provide insights into the pathogenesis of sarcopenia and frailty during aging.

Loss of the Sympathetic Signal Produces Sterile Inflammation of the Prostate.

Neural innervations exert essential roles in the prostate. However, spatial distribution and regulatory function of such neural inputs are incompletely characterized. Here, we exploited the advanced whole-tissue immunolabeling and optical clearing technique to assess the 3D anatomy of autonomic innervations in the mouse and human prostate for the first time. We observed that sympathetic and parasympathetic inputs in the mouse prostate remained unaffected during castration-induced tissue regression. However, the pharmacologic destruction of sympathetic innervations in the mouse prostate led to sterile inflammation of the tissue, mimicking the disease condition of chronic non-bacterial prostatitis. Also, the genetic ablation of sympathetic inputs produced a similar inflammatory response. Furthermore, we showed that treatment of the specific β2-adrenergic receptor agonists could effectively mitigate the prostate inflammation caused by such sympathetic loss. Together, these results have elucidated the new immunomodulatory function of the sympathetic signal via the β2-adrenergic receptor in prostate inflammatory disease.

Autonomic nervous system receptor-mediated regulation of mast cell degranulation modulates the inflammation after corneal epithelial abrasion

Mast cells (MCs) regulate wound healing and are influenced by the autonomic nervous system (ANS). However, the underlying mechanisms affecting wound healing outcomes remain elusive. Here, we explored the specific role of the ANS by regulating MC degranulation following corneal epithelium abrasion. A mouse model of corneal abrasion was established by mechanically removing a 2-mm central epithelium. Wound closure, neutrophil infiltration, and transcription of injured corneas were investigated using whole-mount immunostaining, flow cytometry, and RNA-sequencing analysis, respectively. Inhibition of MC degranulation by the MC stabilizers cromolyn sodium and lodoxamide tromethamine increased the infiltration of neutrophils and delayed healing of abraded corneas. Moreover, transcriptomic profiling analysis showed that purified MCs from the limbus expressed adrenergic and cholinergic receptors. Pharmacological manipulation and sympathectomy with 6-hydroxydopamine confirmed that sympathetic nervous system signaling inhibited MC degranulation after corneal abrasion, whereas parasympathetic nervous system signaling enhanced MC degranulation. We conclude that normal degranulation of MCs in the corneal limbus and crosstalk between the ANS and MCs are crucial for the appropriate control of inflammation and the repair progress of wounded corneas. This suggests a potential approach for improving defective corneal wound healing by the administration of clinically available autonomic activity-modulating agents.

Untangling Peripheral Sympathetic Neurocircuits

The sympathetic nervous system plays a critical role in regulating many autonomic functions, including cardiac rhythm. The postganglionic neurons in the sympathetic chain ganglia are essential components that relay sympathetic signals to target tissues and disruption of their activity leads to poor health outcomes. Despite this importance, the neurocircuitry within sympathetic ganglia is poorly understood. Canonically, postganglionic sympathetic neurons are thought to simply be activated by monosynaptic inputs from preganglionic cholinergic neurons of the intermediolateral cell columns of the spinal cord. Early electrophysiological studies of sympathetic ganglia where the peripheral nerve trunks were electrically stimulated identified excitatory cholinergic synaptic events in addition to retrograde action potentials, leading some to speculate that excitatory collateral projections are present. However, this seemed unlikely since sympathetic postganglionic neurons were known to synthesize and release norepinephrine and expression of dual neurochemical phenotypes had not been well recognized. In vitro studies clearly established the capacity of cultured sympathetic neurons to express and release acetylcholine and norepinephrine throughout development and even in pathophysiological conditions. Given this insight, we believe that the canonical view of ganglionic transmission needs to be reevaluated and may provide a mechanistic understanding of autonomic imbalance in disease. Further studies likely will require genetic models manipulating neurochemical phenotypes within sympathetic ganglia to resolve the function of cholinergic collateral projections between postganglionic neurons. In this perspective article, we will discuss the evidence for collateral projections in sympathetic ganglia, determine if current laboratory techniques could address these questions, and discuss potential obstacles and caveats.

Eosinophils regulate intra-adipose axonal plasticity.

Sympathetic innervation regulates energy balance, and the nerve density in the adipose tissues changes under various metabolic states, resulting in altered neuronal control and conferring resilience to metabolic challenges. However, the impact of the immune milieu on neuronal innervation is not known. Here, we examined the regulatory role on nerve plasticity by eosinophils and found they increased cell abundance in response to cold and produced nerve growth factor (NGF) in the white adipose tissues (WAT). Deletion of Ngf from eosinophils or depletion of eosinophils impairs cold-induced axonal outgrowth and beiging process. The spatial proximity between sympathetic nerves, IL-33-expressing stromal cells, and eosinophils was visualized in both human and mouse adipose tissues. At the cellular level, the sympathetic adrenergic signal induced calcium flux in the stromal cells and subsequent release of IL-33, which drove the up-regulation of IL-5 from group 2 innate lymphoid cells (ILC2s), leading to eosinophil accretion. We propose a feed-forward loop between sympathetic activity and type 2 immunity that coordinately enhances sympathetic innervation and promotes energy expenditure.

European Society of Hypertension position paper on renal denervation 2021.

This ESH Position Paper 2021 with updated proposed recommendations was deemed necessary after the publication of a set of new pivotal sham-controlled randomized clinical trials (RCTs), which provided important information about the efficacy and safety of endovascular device-based renal denervation (RDN) for hypertension treatment. RDN is effective in reducing or interrupting the sympathetic signals to the kidneys and decreasing whole body sympathetic activity. Five independent, fully completed, sham-controlled RCTs provide conclusive evidence that RDN lowers ambulatory and office blood pressure (BP) to a significantly greater extent than sham treatment. BP-lowering efficacy is evident both in patients with and without concomitant antihypertensive medication. The average decrease of 10 mmHg in office BP is estimated to lower the incidence of cardiovascular events by 25-30%, based on meta-analyses of RCTs using pharmacological treatment. Neither peri-procedural, nor short-term or long-term adverse events or safety signals (available up to 3 years) have been observed. Implementing RDN as an innovative third option in the armamentarium of antihypertensive treatment requires a structured process that ensures the appropriate performance of the endovascular RDN procedure and adequate selection of hypertensive patients. The latter should also incorporate patients' perspective and preference that needs to be respected in a shared decision-making process.

Hypertension due to loss of water

In the current issue of Acta Physiologica, two papers are published investigating the development of arterial hypertension under conditions of pathological loss of free water in two disease models. Kovaric et al 1 studied rats with chronic renal failure, shedding excessive free water via their remnant kidney due to a hypostenuric concentrating defect. Wild et al. 2 investigated a transgenic mouse model for psoriasis, losing free water via the psoriatic skin lesions. In both cases the animals displayed hypertension, cutaneous vasoconstriction, and metabolic adaptations towards enhanced production of urea and organic osmolytes typical for a phylogenetically ancient water conservation response termed aestivation 3 . The international consortia of investigators spearheaded by Titze, Karbach, and Kitada therefore conclude that in both cases the hypertension was due to cutaneous vasoconstriction in an attempt to limit epidermal water loss. Because in either case the hypertension was associated with loss of water, and thus with hypo- rather than hypervolemia, the authors argue, that this concept of pathogenesis of hypertension is antipodal to the classic view that relies on hypervolemia due to sodium retention.

Laparoscopic Ablation System for Complete Circumferential Renal Sympathetic Denervation.

The catheter-based renal denervation (RDN) showed promising results for patients in lowering BP, but there were also many non-responders. One of the possible reasons was the incomplete neural ablation due to the ablation of renal nerves at random sites resulting in asymmetric innervation patterns along the renal artery. We developed a laparoscopic ablation system that is optimized for complete RDN regardless of renal arterial innervation and size. To demonstrate its effectiveness, we evaluated the system using computational simulation and 28-day survival model using pigs. The ablations were focused around the tunica externa, and the ablation patterns could be predicted numerically during RDN treatment. In the animal study, the mean reduction of systolic BP and diastolic BP in the bilateral main renal arteries was 22.8 mmHg and 14.4 mmHg (P<0.001), respectively. The respond to immunostaining targeting tyrosine hydroxylase was significantly reduced at treatment site (108.2 ± 7.5 (control) vs. 63.4 ± 8.7 (treatment), P<0.001), and an increased degree of sympathetic signals interruption to kidneys was associated with the efficacy of RDN. The laparoscopic ablation system achieved complete circumferential RDN at the treatment site and could numerically predict the ablation patterns. These findings clearly suggest that the proposed system can significantly improve the RDN effectiveness by reducing the variation to the percentage of injured nerves and open up a new opportunity to treat uncontrolled hypertension.

Multiscale Deep Neural Network for Obstructive Sleep Apnea Detection Using RR Interval From Single-Lead ECG Signal

The detection of obstructive sleep apnea (OSA) based on single-lead electrocardiogram (ECG) is better suited to the noninvasive needs and hardware conditions of wearable mobile devices. From previous ECG-based OSA detection methods, we can find that deep learning methods have shown great potential and advantages. However, due to the nonstationarity of sympathetic nerve signals and the complex characteristics of heart rate variability (HRV), the neural network under a single scale cannot effectively capture the features of HRV. In this study, an OSA detection method based on a multiscale dilation attention 1-D convolutional neural network (MSDA-1DCNN) and a weighted-loss time-dependent (WLTD) classification model were proposed. The introduction of dilated convolution effectively balanced the relationship between model parameters and performance. Attention mechanism technology modified the multiscale features after fusion and improved the weight of features under important channels. In the final classification part of the network, the combination of weighted cross-entropy loss function and hidden Markov model effectively alleviated the problem of data imbalance and improved the classification accuracy of the classifier. In segment identification, the accuracy, sensitivity, and specificity of the proposed method are 89.4%, 89.8%, and 89.1%, respectively; as for individual identification, the accuracy of that achieved 100%. The results demonstrated that the method proposed in this study can identify sleep apnea accurately.

Role of mTORC2 in biphasic regulation of brown fat metabolism in response to mild and severe cold

Nonshivering thermogenesis is essential for mammals to maintain body temperature. According to the canonical view, temperature is sensed by cutaneous thermoreceptors and nerve impulses transmitted to the hypothalamus, which generates sympathetic signals to ß-adrenergic receptors in brown adipocytes. The energy for heat generation is primarily provided by the oxidation of fatty acids derived from triglyceride hydrolysis and cellular uptake. Fatty acids also activate the uncoupling protein, UCP1, which creates a proton leak that uncouples mitochondrial oxidative phosphorylation from ATP production, resulting in energy dissipation as heat. Recent evidence supports the idea that in response to mild cold, ß-adrenergic signals stimulate not only lipolysis and fatty acid oxidation, but also act through the mTORC2-Akt signaling module to stimulate de novo lipogenesis. This opposing anabolic effect is thought to maintain lipid fuel stores during increased catabolism. We show here, using brown fat-specific Gs-alpha knockout mice and cultured adipocytes that, unlike mild cold, severe cold directly cools brown fat and bypasses ß-adrenergic signaling to inhibit mTORC2. This cell-autonomous effect both inhibits lipogenesis and augments UCP1 expression to enhance thermogenesis. These findings suggest a novel mechanism for overriding ß-adrenergic-stimulated anabolic activities while augmenting catabolic activities to resolve the homeostatic crisis presented by severe cold.

Attenuation of exaggerated blood pressure responses to exercise: a byproduct of improved vascular function with passive heat therapy?

Attenuation of exaggerated blood pressure responses to exercise: a byproduct of improved vascular function with passive heat therapy?

Human adult cardiac autonomic innervation: Controversies in anatomical knowledge and relevance for cardiac neuromodulation.

Cardiac sympathetic blockade is a therapeutic approach for arrhythmias and heart failure and may be a beneficial effect of high thoracic epidural anesthesia. These treatments require detailed knowledge of the spatial location and distribution of cardiac autonomic nerves, however, there are controversies on this subject in humans. To provide a systematic overview of current knowledge on human anatomy of the cardiac autonomic nervous system. In contrast to the often claimed assumption that human preganglionic sympathetic cardiac neurons originate mainly from thoracic spinal segments T1-T4 or T5, there is ample evidence indicating involvement of cervical spinal segment C8 and thoracic spinal segments below T5. Whether cervical ganglia besides the stellate ganglion play a role in transmission of cardiac sympathetic signals is unclear. Similarly, there is debate on the origin of cardiac nerves from different thoracic ganglia. Most human studies report thoracic cardiac nerves emerging from the first to fourth thoracic paravertebral ganglia; others report contributions from the fifth, sixth and even the seventh thoracic ganglia. There is no agreement on the precise composition of nerve plexuses at the cardiac level. After years of debate, it is generally accepted that the vagal nerve contributes to ventricular innervation. Vagal distribution appears higher in atria, whereas adrenergic fibers exceed the number of vagal fibers in the ventricles. Anatomy of the human cardiac autonomic nervous system is highly variable and likely extends beyond generally assumed boundaries. This information is relevant for thoracic epidural anesthesia and procedures targeting neuronal modulation of cardiac sympathetic innervation.

Mild-intensity Exercise Triggers VEGF in the Digestive Tract Via Both Hypoxic and Nonhypoxic Mechanisms

Abstract Hypoxia occurs in the splanchnic region during exercise associated with sympathetic activity. In the elderly, vascular insufficiency and low vascular endothelial growth factor (VEGF) expression are observed. Compared to young people, sympathetic signals of older individuals are blunted and more resistant to splanchnic blood flow alterations during exercise. VEGF induces vasodilation responses and hence may retain blood in the splanchnic vascular bed. We hypothesized that regular mild-intensity exercise triggers weak VEGF expression in the digestive tract of the elderly. The effects of exercise on the levels of VEGF, superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA) and total antioxidant capacity (T-AOC) in the stomach, jejunum, ileum and colon tissues were evaluated. With exercise, the VEGF levels in the stomach and colon increased. Although the SOD, GPx, and MDA levels decreased in the stomach, they increased in the colon. T-AOC increased in the stomach and there was no change in the jejunum, ileum and colon. The hypoperfusion during exercise was not equal in all regions of the gastrointestinal tract in the aged subjects. Hypoxia and other exercise-related mechanisms could have led to this VEGF induction. The stomach, jejunum, and ileum might have developed resistance to ischemia. The induction of VEGF may be beneficial in aging-associated impaired gastrointestinal homeostasis and neovascularization.

Neuromodulation for Ventricular Tachycardia and Atrial Fibrillation: A Clinical Scenario-Based Review.

Autonomic dysregulation in cardiovascular disease plays a major role in the pathogenesis of arrhythmias. Cardiac neural control relies on complex feedback loops consisting of efferent and afferent limbs, which carry sympathetic and parasympathetic signals from the brain to the heart and sensory signals from the heart to the brain. Cardiac disease leads to neural remodeling and sympathovagal imbalances with arrhythmogenic effects. Preclinical studies of modulation at central and peripheral levels of the cardiac autonomic nervous system have yielded promising results, leading to early stage clinical studies of these techniques in atrial fibrillation and refractory ventricular arrhythmias, particularly in patients with inherited primary arrhythmia syndromes and structural heart disease. However, significant knowledge gaps in basic cardiac neurophysiology limit the success of these neuromodulatory therapies. This review discusses the recent advances in neuromodulation for cardiac arrhythmia management, with a clinical scenario-based approach aimed at bringing neurocardiology closer to the realm of the clinical electrophysiologist.

Panicle-Shaped Sympathetic Architecture in the Spleen Parenchyma Modulates Antibacterial Innate Immunity

The nervous system can modulate the body's immunity. However, how efferent neural signals reach out to control the local immunity remains incompletely understood. Here, we report the ImmuView procedure for whole-tissue 3D assessment of neural innervations in the intact immune organs of adult mice. This advanced imaging technique revealed an intricate, panicle-shaped sympathetic architecture in the parenchyma of the spleen but not other immune organs, including the lymph nodes, Peyer's patch, and thymus. In contrast, we observed the minimal presence of parasympathetic innervations in the parenchyma of all of the classic immune organs examined. Specific deletion of the TrkA receptor abolishes the sympathetic architecture in the spleen and such genetic ablation significantly enhanced the spleen antibacterial innate immunity. Moreover, the sympathetic neurotransmitter norepinephrine could inhibit the LPS-elicited innate immunity cell-intrinsically via β2-adrenergic receptor signaling. This study exemplifies the key link that specifically connects the efferent sympathetic signal with the spleen innate immunity.