The sympathetic nervous system plays a vital role in various regulatory mechanisms. These include the well-known fight-or-flight response but also, for example, the processing of external stressors. In addition to many other tissues, the sympathetic nervous system influences bone metabolism. This effect could be highly relevant concerning osseointegration, which is responsible for the long-term success of dental implants. Accordingly, this review aims to summarize the current literature on this topic and to reveal future research perspectives. One in vitro study showed differences in mRNA expression of adrenoceptors cultured on implant surfaces. In vivo, sympathectomy impaired osseointegration in mice, while electrical stimulation of the sympathetic nerves promoted it. As expected, the beta-blocker propranolol improves histological implant parameters and micro-CT measurements. Overall, the present data are considered heterogeneous. However, the available publications reveal the potential for future research and development in dental implantology, which helps to introduce new therapeutic strategies and identify risk factors for dental implant failure.

The sympathetic nervous system is essential for maintaining mammalian homeostasis. How this intricately connected network, composed of preganglionic neurons that reside in the spinal cord and post-ganglionic neurons that comprise a chain of vertebral sympathetic ganglia, arises developmentally is incompletely understood. This problem is especially complex given the vertebral chain of sympathetic ganglia derive secondarily from the dorsal migration of 'primary' sympathetic ganglia that are initially located several hundred microns ventrally from their future pre-synaptic partners. Here we report that the dorsal migration of discrete ganglia is not a simple migration of individual cells but a much more carefully choreographed process that is mediated by extensive interactions of pre-and post-ganglionic neurons. Dorsal migration does not occur in the absence of contact with preganglionic axons, and this is mediated by BDNF/TrkB signalling. Thus BDNF released by preganglionic axons acts chemotactically on TrkB-positive sympathetic neurons, to pattern the developing peripheral nervous system.

In our Dynamic Pathways, account, we hypothesized that childhood stuttering reflects an impairment in speech sensorimotor control that is conditioned by cognitive, linguistic, and emotional factors. The purpose of this study was to investigate potential differences in levels of sympathetic arousal during performance of speech and non-speech tasks between children who do and do not stutter.

We previously showed that leptin inhibits bone formation by an undefined mechanism. Here, we show that hypothalamic leptin-dependent antiosteogenic and anorexigenic networks differ, and that the peripheral mediators of leptin antiosteogenic function appear to be neuronal. Neuropeptides mediating leptin anorexigenic function do not affect bone formation. Leptin deficiency results in low sympathetic tone, and genetic or pharmacological ablation of adrenergic signaling leads to a leptin-resistant high bone mass. beta-adrenergic receptors on osteoblasts regulate their proliferation, and a beta-adrenergic agonist decreases bone mass in leptin-deficient and wild-type mice while a beta-adrenergic antagonist increases bone mass in wild-type and ovariectomized mice. None of these manipulations affects body weight. This study demonstrates a leptin-dependent neuronal regulation of bone formation with potential therapeutic implications for osteoporosis.

Emerging evidence has revealed that noradrenaline (NA), the main neurotransmitter of the sympathetic nervous system (SNS), regulates a variety of immune functions via binding to adrenergic receptors present on immune cells. In this study, we examined the role of NA in the regulation of neutrophil functions. Neutrophils were isolated from the bone marrow of naïve mice and treated with NA at various concentrations to assess the effect on various neutrophil functions. Additionally, we performed cremaster intravital microscopy to examine neutrophil-endothelial cell interactions following NA superfusion in vivo. In a separate group of animals, mice were subjected to an experimental model of stroke and at 4 and 24 h neutrophils were isolated for assessment on their ability to migrate toward various chemokines. Treatment of neutrophils with NA for 4 h significantly impaired neutrophil chemotaxis and induced an N2 neutrophil phenotype with reduced expression of the genes critical for cytoskeleton remodeling and inflammation. Prolonged NA administration promoted neutrophils to release myeloperoxidase and IL-6, but suppressed the production of interferon-γ and IL-10, reduced neutrophil activation and phagocytosis. Superfusion of NA over the cremaster muscle almost completely inhibited fMLP-induced neutrophil adhesion/arrest and transmigration. Furthermore, using a mouse model of stroke, a pathological condition in which SNS activation is evident, neutrophils isolated from poststroke mice showed markedly reduced chemotaxis toward all of the chemokines tested. The findings from our study indicate that neutrophil chemotaxis, activation, and phagocytosis can all be negatively regulated in an NA-dependent manner. A better understanding of the relationship between sympathetic activation and neutrophil function will be important for the development of effective antibacterial interventions.

Upon exposure to external stressors, the body senses them and activates the sympathetic nervous system (SNS) to maintain the homeostasis, which is known as the "fight-or-flight" response. Recent studies have revealed that the SNS also plays pivotal roles in regulating immune responses, such as hematopoiesis, leukocyte mobilization, and inflammation. Indeed, overactivation of the SNS causes many inflammatory diseases, including cardiovascular diseases, metabolic disorders, and autoimmune diseases. However, the molecular basis essential for SNS-mediated immune regulation is not completely understood. In this review, we focus on axon guidance cues, semaphorins, which play multifaceted roles in neural and immune systems. We summarize the functions of semaphorins in the crosstalk between the SNS and the immune system, exploring its pathophysiological roles.

The carotid bodies (CBs) of spontaneously hypertensive (SH) rats exhibit hypertonicity and hyperreflexia contributing to heightened peripheral sympathetic outflow. We hypothesized that CB hyperexcitability is driven by its own sympathetic innervation.

The molecular mechanisms regulating sympathetic innervation of the heart during embryogenesis and its importance for cardiac development and function remain to be fully elucidated. We generated mice in which conditional knockout (CKO) of the Hif1a gene encoding the transcription factor hypoxia-inducible factor 1α (HIF-1α) is mediated by an Islet1-Cre transgene expressed in the cardiac outflow tract, right ventricle and atrium, pharyngeal mesoderm, peripheral neurons, and hindlimbs. These Hif1aCKO mice demonstrate significantly decreased perinatal survival and impaired left ventricular function. The absence of HIF-1α impaired the survival and proliferation of preganglionic and postganglionic neurons of the sympathetic system, respectively. These defects resulted in hypoplasia of the sympathetic ganglion chain and decreased sympathetic innervation of the Hif1aCKO heart, which was associated with decreased cardiac contractility. The number of chromaffin cells in the adrenal medulla was also decreased, indicating a broad dependence on HIF-1α for development of the sympathetic nervous system.

The adipocyte-derived hormone leptin is elevated in obesity and may contribute to vascular risk associated with obesity. The mechanism(s) by which leptin affects vascular disease is unclear, although leptin has been shown to increase sympathetic activity. The aim of this study was to investigate the effect of leptin treatment on endothelial function and the role of the local sympathetic nervous system in mediating these effects.

Interventional techniques such as radiofrequency (RF) treatment can be used to interrupt pain signals transmitted through the sympathetic nervous system (SNS). RF treatments including the pulsed (PRF) and continuous (CRF) modalities show enhanced control over lesion size and enhanced ability to confirm accurate positioning compared to other interventional methods. PRF also acts to reduce the area of the lesion. In this article, we characterize the currently available evidence supporting the use and efficacy of RF treatments in sympathetically mediated pain (SMP) conditions.

Background: The ventromedial hypothalamus (VMH) is an important nuclei in responding to emotional stress, and emotional stress is a risk factor for cardiovascular diseases. However, the role of the VMH in cardiovascular diseases remains unknown. This study aimed to investigate the effects and underlying mechanisms of VMH activation on hypertension related cardiac remodeling in two-kidney-one-clip (2K1C) hypertension (HTN) rats. Methods: Eighteen male Sprague-Dawley rats were injected with AAV-hSyn-hM3D(Gq) into the VMH at 0 weeks and then randomly divided into three groups: (1) sham group (sham 2K1C + saline i.p. injection); (2) HTN group (2K1C + saline i.p. injection); (3) HTN+VMH activation group (2K1C + clozapine-N-oxide i.p. injection). One week later, rats were subjected to a sham or 2K1C operation, and 2 weeks later rats were injected with clozapine-N-oxide or saline for 2 weeks. Results: In the HTN+VMH activation group, FosB expression was significantly increased in VMH sections compared with those of the other two groups. Compared to the HTN group, the HTN+VMH activation group showed significant: (1) increases in systolic blood pressure (SBP); (2) exacerbation of cardiac remodeling; and (3) increases in serum norepinephrine levels and sympathetic indices of heart rate variability. Additionally, myocardial RNA-sequencing analysis showed that VMH activation might regulate the HIF-1 and PPAR signal pathway and fatty acid metabolism. qPCR results confirmed that the relative mRNA expression of HIF-1α was increased and the PPARα and CPT-1 mRNA expression were decreased in the HTN+VMH activation group compared to the HTN group. Conclusions: VMH activation could increase SBP and aggravate cardiac remodeling possibly by sympathetic nerve activation and the HIF-1α/PPARα/CPT-1 signaling pathway might be the underlying mechanism.

Gestational diabetes mellitus (GDM) is associated with vascular dysfunction. Sympathetic nervous system activity (SNA) is an important regulator of vascular function, and is influenced by glucose and insulin. The association between GDM and SNA (re)activity is unknown. We hypothesize that women with GDM would have increased SNA during baseline and during stress.

The pancreatic hormone amylin acts in the central nervous system (CNS) to decrease food intake and body weight. We hypothesized that amylin action in the CNS promotes energy expenditure by increasing the activity of the sympathetic nervous system. In mice, ip administration of amylin significantly increased c-Fos immunoreactivity in hypothalamic and brainstem nuclei. In addition, mice treated with intracerebroventricular (icv) amylin (0.1 and 0.2 nmol) exhibited a dose-related decrease in food intake and body weight, measured 4 and 24 hours after treatment. The icv injection of amylin also increased body temperature in mice. Using direct multifiber sympathetic nerve recording, we found that icv amylin elicited a significant and dose-dependent increase in sympathetic nerve activity (SNA) subserving thermogenic brown adipose tissue (BAT). Of note, icv injection of amylin also evoked a significant and dose-related increase in lumbar and renal SNA. Importantly, icv pretreatment with the amylin receptor antagonist AC187 (20 nmol) abolished the BAT SNA response induced by icv amylin, indicating that the sympathetic effects of amylin are receptor-mediated. Conversely, icv amylin-induced BAT SNA response was enhanced in mice overexpressing the amylin receptor subunit, RAMP1 (receptor-activity modifying protein 1), in the CNS. Our data demonstrate that CNS action of amylin regulates sympathetic nerve outflow to peripheral tissues involved in energy balance and cardiovascular function.

During entrance into torpor heart and respiration rates are greatly reduced in parallel with the reduction of metabolic rate, suggesting an involvement of parasympathetic control. We compared the effect of parasympathetic inhibition with the effect of sympathetic inhibition on spontaneous torpor behaviour in the Djungarian hamster. Hamsters were acclimated to short photoperiod and displayed their standard torpor pattern as observed from T(b) records. Parasympathetic inhibition was achieved by a subcutaneous implant of 21-day release pellets with Atropine and the sympathetic noradrenergic pathway was inhibited with a single injection of 6-Hydroxydopamine. Atropine treatment did not affect the occurrence and quality of spontaneous daily torpor at all. However, the reversible sympathetic inhibition by 6-Hydroxydopamine injection resulted in a complete disappearance of torpor for about 6 days. These results conclude that the onset of daily torpor requires an intact noradrenergic signalling of the sympathetic nervous system. We further observed that parasympathetic as well as sympathetic blockade resulted in an immediate abolishment of ultradian rhythms of body temperature. This suggests that the expression of ultradian oscillations in body temperature require a continued interaction of sympathetic and parasympathetic activity.

Emerging evidence suggests that neural activity contributes to tumor initiation and its acquisition of metastatic properties. More specifically, it has been reported that the sympathetic nervous system regulates tumor angiogenesis, tumor growth, and metastasis. The function of the sympathetic nervous system in primary tumors has been gradually elucidated. However, its functions in pre-metastatic environments and/or the preparation of metastatic environments far from the primary sites are still unknown. To investigate the role of the sympathetic nervous system in pre-metastatic environments, we performed chemical sympathectomy using 6-OHDA in mice and observed a decrease in lung metastasis by attenuating the recruitment of myeloid-derived suppressor cells. Furthermore, we note that neuro-immune cell interactions could be observed in tumor-bearing mouse lungs in conjunction with the decreased expression of Sema3A. These data indicate that the sympathetic nervous system contributes to the preparation of pre-metastatic microenvironments in the lungs, which are mediated by neuro-immune cell interactions.

Enteric viscerofugal neurons provide a pathway by which the enteric nervous system (ENS), otherwise confined to the gut wall, can activate sympathetic neurons in prevertebral ganglia. Firing transmitted through these pathways is currently considered fundamentally mechanosensory. The mouse colon generates a cyclical pattern of neurogenic contractile activity, called the colonic motor complex (CMC). Motor complexes involve a highly coordinated firing pattern in myenteric neurons with a frequency of ∼2 Hz. However, it remains unknown how viscerofugal neurons are activated and communicate with the sympathetic nervous system during this naturally-occurring motor pattern. Here, viscerofugal neurons were recorded extracellularly from rectal nerve trunks in isolated tube and flat-sheet preparations of mouse colon held at fixed circumferential length. In freshly dissected preparations, motor complexes were associated with bursts of viscerofugal firing at 2 Hz that aligned with 2-Hz smooth muscle voltage oscillations. This behavior persisted during muscle paralysis with nicardipine. Identical recordings were made after a 4- to 5-d organotypic culture during which extrinsic nerves degenerated, confirming that recordings were from viscerofugal neurons. Single unit analysis revealed the burst firing pattern emerging from assemblies of viscerofugal neurons differed from individual neurons, which typically made partial contributions, highlighting the importance and extent of ENS-mediated synchronization. Finally, sympathetic neuron firing was recorded from the central nerve trunks emerging from the inferior mesenteric ganglion. Increased sympathetic neuron firing accompanied all motor complexes with a 2-Hz burst pattern similar to viscerofugal neurons. These data provide evidence for a novel mechanism of sympathetic reflex activation derived from synchronized firing output generated by the ENS.

The role of the sympathetic nervous system (SNS) in tumor development, progression and metastasis is studied for more than half a century and is attracting more attention during the last years. In this narrative review, we aim to a chronological and methodological presentation of the most interesting and pioneering studies on the subject.

Long-term reduced hypothalamic estrogen signaling leads to increased food intake and decreased locomotor activity and energy expenditure, and ultimately results in obesity and insulin resistance. In the current study, we aimed to determine the acute obesity-independent effects of hypothalamic estrogen signaling on glucose metabolism. We studied endogenous glucose production (EGP) and insulin sensitivity during selective modulation of systemic or intrahypothalamic estradiol (E2) signaling in rats 1 week after ovariectomy (OVX). OVX caused a 17% decrease in plasma glucose, which was completely restored by systemic E2. Likewise, the administration of E2 by microdialysis, either in the hypothalamic paraventricular nucleus (PVN) or in the ventromedial nucleus (VMH), restored plasma glucose. The infusion of an E2 antagonist via reverse microdialysis into the PVN or VMH attenuated the effect of systemic E2 on plasma glucose. Furthermore, E2 administration in the VMH, but not in the PVN, increased EGP and induced hepatic insulin resistance. E2 administration in both the PVN and the VMH resulted in peripheral insulin resistance. Finally, sympathetic, but not parasympathetic, hepatic denervation blunted the effect of E2 in the VMH on both EGP and hepatic insulin sensitivity. In conclusion, intrahypothalamic estrogen regulates peripheral and hepatic insulin sensitivity via sympathetic signaling to the liver.

Stroke survivors frequently report increased perceived challenge of walking (PCW) in complex environments, restricting their daily ambulation. PCW is conventionally measured through subjective questionnaires or, more recently, through objective quantification of sympathetic nervous system activity during walking tasks. However, how these measurements of PCW reflect daily walking activity post-stroke is unknown. We aimed to compare the subjective and objective assessments of PCW in predicting home and community ambulation. In 29 participants post-stroke, we measured PCW subjectively with the Activities-specific Balance Confidence (ABC) Scale and objectively through electrodermal activity, quantified by change in skin conductance levels (SCL) and skin conductance responses (SCR) between outdoor-complex and indoor-steady-state walking. High-PCW participants were categorized into high-change SCL (ΔSCL ≥ 1.7 μs), high-change SCR (ΔSCR ≥ 0.2 μs) and low ABC (ABC < 72%) groups, while low-PCW participants were categorized into low-change SCL (ΔSCL < 1.7 μs), low-change SCR (ΔSCR < 0.2 μs) and high-ABC (ABC ≥ 72%) groups. Number and location of daily steps were quantified with accelerometry and Global Positioning System devices. Compared to low-change SCL group, the high-change SCL group took fewer steps in home and community (p = 0.04). Neither ABC nor SCR groups differed in home or community steps/day. Objective measurement of PCW via electrodermal sensing more accurately represents home and community ambulation compared to the subjective questionnaire.

Cardiovascular changes occur during mental stress and in certain types of mood disorders. The neural basis for this phenomenon is unknown but it may be dependent on CNS neurons that provide branched projections to affective processing regions of the brain, such as the medial prefrontal cortex, and to the sympathetic outflow system. Because these putative neurons may be connected to these two target sites by chains of neurons, we performed double virus transneuronal tracing experiments and show here that a select subset of neurons in the medial preoptic nucleus (MPN), lateral hypothalamic area (LHA), and nucleus tractus solitarius (NTS) are co-linked to these two sites. Neurotensin MPN, orexin-containing LHA, and catecholamine NTS neurons were the major phenotypes involved in these projections. This novel class of neurons may coordinate cardiovascular changes seen in different emotional states.