Sympathetic Neurons
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2021 ◽  
Aurelia Mapps ◽  
Erica Boehm ◽  
Corinne Beier ◽  
William Thomas Keenan ◽  
Jennifer Langel ◽  

Satellite glia are the major glial cells in sympathetic ganglia, enveloping neuronal cell bodies. Despite this intimate association, how satellite glia contribute to sympathetic functions remain unclear. Here, we show that satellite glia are critical for metabolism, survival, and activity of sympathetic neurons and modulate autonomic behaviors in mice. Adult ablation of satellite glia results in impaired mTOR signaling, soma atrophy, reduced noradrenergic enzymes, and loss of sympathetic neurons. However, persisting neurons have elevated activity, and satellite glia-ablated mice show increased pupil dilation and heart rate, indicative of enhanced sympathetic tone. Satellite glia-specific deletion of Kir4.1, an inward-rectifying potassium channel, largely recapitulates the cellular defects observed in glia-ablated mice, suggesting that satellite glia act in part via extracellular K+ buffering. These findings highlight neuron-satellite glia as functional units in regulating sympathetic output, with implications for disorders linked to sympathetic hyper-activity such as cardiovascular disease and hypertension.

2021 ◽  
pp. 1-12
Robert A. Culibrk ◽  
Ahmad S. Arabiyat ◽  
Carisa A. DeKalb ◽  
Mariah S. Hahn

Background: A significant subset of patients with Alzheimer’s disease (AD) exhibit low bone mineral density and are therefore more fracture-prone, relative to their similarly aged neurotypical counterparts. In addition to chronic immune hyperactivity, behavioral dysregulation of effector peripheral sympathetic neurons—which densely innervate bone and potently modulate bone remodeling—is implicated in this pathological bone reformation. Objective: Thus, there exists a pressing need for a robust in vitro model which allows interrogation of the paracrine interactions between the putative mediators of AD-related osteopenia: sympathetic neurons (SNs) and mesenchymal stem cells (MSCs). Methods: Toward this end, activated SN-like PC12 cells and bone marrow derived MSCs were cultured in poly(ethylene glycol) diacrylate (PEGDA) hydrogels in the presence or absence of the AD-relevant inflammatory cytokine tumor necrosis factor alpha (TNF-α) under mono- and co-culture conditions. Results: PC12s and MSCs exposed separately to TNF-α displayed increased expression of pro-inflammatory mediators and decreased osteopontin (OPN), respectively. These data indicate that TNF-α was capable of inducing a dysregulated state in both cell types consistent with AD. Co-culture of TNF-α-activated PC12s and MSCs further exacerbated pathological behaviors in both cell types. Specifically, PC12s displayed increased secretion of interleukin 6 relative to TNF-α stimulated monoculture controls. Similarly, MSCs demonstrated a further reduction in osteogenic capacity relative to TNF-α stimulated monoculture controls, as illustrated by a significant decrease in OPN and collagen type I alpha I chain. Conclusion: Taken together, these data may indicate that dysregulated sympathetic activity may contribute to AD-related bone loss.

Anna Carolina Zaia Rodrigues ◽  
María Laura Messi ◽  
Zhong‐Min Wang ◽  
Henry Jacob Bonilla ◽  
Willard M. Freeman ◽  

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Peng Shi ◽  
Yunfan Lin ◽  
Qianqian Bi ◽  
Guo Cheng ◽  
Xiao Shen

Hypothalamic paraventricular nucleus (PVN) is a critical integrating region in controlling peripheral sympathetic tonicity. While the vast studies have unraveled the regulatory circuits affecting PVN pre-sympathetic neurons, local factors for maintaining the homeostasis of neuronal excitability are barely understood. In the present study we investigated the role of microglia, the primary resident immune cells of the CNS, in this context. By electrophysiological recording, we found that loss of resident microglia induced an increased firing frequency and attenuated outward potassium currents in the PVN pre-sympathetic neurons, tachycardia and impaired heart rate variability. Combining the transcriptomics analysis of the PVN microglia, we identified a releasable factor, which was dominantly expressed in microglia compared to other brain parenchymal cells. ICV infusion of the recombinant peptide restored potassium currents in the PVN pre-sympathetic neurons and autonomic function in microglia-depleted mice. In summary, our results provided a novel intrinsic regulatory mechanism by which microglia suppress neuronal over excitation in physiological condition.

Annika Winbo ◽  
Suganeya Ramanan ◽  
Emily Eugster ◽  
Annika Rydberg ◽  
Stefan Jovinge ◽  

Sympathetic activation is an established trigger of life-threatening cardiac events in long QT syndrome type 1 (LQT1). KCNQ1 loss-of-function variants, which underlie LQT1, have been associated with both cardiac arrhythmia and neuronal hyperactivity pathologies. However, the LQT1 sympathetic neuronal phenotype is unknown. Here we aimed to study human induced pluripotent stem cell (hiPSC)-derived sympathetic neurons (SNs) to evaluate neuronal functional phenotype in LQT1. We generated hiPSC-SNs from two LQT1 patients with a history of sympathetically triggered arrhythmia and KCNQ1 loss-of-function genotypes (c.781_782delinsTC and p.S349W/p.R518X). Characterisation of hiPSC-SNs was performed using immunohistochemistry, enzyme-linked immunosorbent assay and whole-cell patch clamp electrophysiology, and functional LQT1 hiPSC-SN phenotypes compared to healthy control (WT) hiPSC-SNs. hiPSC-SNs stained positive for tyrosine hydroxylase, peripherin, KCNQ1, and secreted noradrenaline. hiPSC-SNs at 60±2.2 days in vitro had healthy resting membrane potentials (-60±1.3 mV), and fired rapid action potentials with mature kinetics in response to stimulation. Significant hyperactivity in LQT1 hiPSC-SNs was evident via increased noradrenaline release, increased spontaneous action potential frequency, increased total inward current density, and reduced afterhyperpolarisation, compared to age-matched WT hiPSC-SNs. A significantly higher action potential frequency upon current injection and larger synaptic current amplitudes in compound heterozygous p.S349W/p.R518X hiPSC-SNs compared to heterozygous c.781_782delinsTC hiPSC-SNs was also observed, suggesting a potential genotype-phenotype correlation. Together our data reveal increased neurotransmission and excitability in heterozygous and compound heterozygous patient-derived LQT1 sympathetic neurons, suggesting that the cellular arrhythmogenic potential in LQT1 is not restricted to cardiomyocytes.

2021 ◽  
Vol 12 ◽  
Martin Kruse ◽  
Rayne J. Whitten

Phosphoinositides are members of a family of minor phospholipids that make up about 1% of all lipids in most cell types. Despite their low abundance they have been found to be essential regulators of neuronal activities such as action potential firing, release and re-uptake of neurotransmitters, and interaction of cytoskeletal proteins with the plasma membrane. Activation of several different neurotransmitter receptors can deplete phosphoinositide levels by more than 90% in seconds, thereby profoundly altering neuronal behavior; however, despite the physiological importance of this mechanism we still lack a profound quantitative understanding of the connection between phosphoinositide metabolism and neuronal activity. Here, we present a model that describes phosphoinositide metabolism and phosphoinositide-dependent action potential firing in sympathetic neurons. The model allows for a simulation of activation of muscarinic acetylcholine receptors and its effects on phosphoinositide levels and their regulation of action potential firing in these neurons. In this paper, we describe the characteristics of the model, its calibration to experimental data, and use the model to analyze how alterations of surface density of muscarinic acetylcholine receptors or altered activity levels of a key enzyme of phosphoinositide metabolism influence action potential firing of sympathetic neurons. In conclusion, the model provides a comprehensive framework describing the connection between muscarinic acetylcholine signaling, phosphoinositide metabolism, and action potential firing in sympathetic neurons which can be used to study the role of these signaling systems in health and disease.

2021 ◽  
Vol 20 (1) ◽  
Annalise N. vonderEmbse ◽  
Sarah E. Elmore ◽  
Kyle B. Jackson ◽  
Beth A. Habecker ◽  
Katherine E. Manz ◽  

Abstract Background Exposure to the bioaccumulative pesticide dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE) has been associated with increased risk of insulin resistance and obesity in humans and experimental animals. These effects appear to be mediated by reduced brown adipose tissue (BAT) thermogenesis, which is regulated by the sympathetic nervous system. Although the neurotoxicity of DDT is well-established, whether DDT alters sympathetic innervation of BAT is unknown. We hypothesized that perinatal exposure to DDT or DDE promotes thermogenic dysfunction by interfering with sympathetic regulation of BAT thermogenesis. Methods Pregnant C57BL/6 J mice were administered environmentally relevant concentrations of DDTs (p,p’-DDT and o,p’-DDT) or DDE (p,p’-DDE), 1.7 mg/kg and 1.31 mg/kg, respectively, from gestational day 11.5 to postnatal day 5 by oral gavage, and longitudinal body temperature was recorded in male and female offspring. At 4 months of age, metabolic parameters were measured in female offspring via indirect calorimetry with or without the β3 adrenergic receptor agonist, CL 316,243. Immunohistochemical and neurochemical analyses of sympathetic neurons innervating BAT were evaluated. Results We observed persistent thermogenic impairment in adult female, but not male, mice perinatally exposed to DDTs or p,p’-DDE. Perinatal DDTs exposure significantly impaired metabolism in adult female mice, an effect rescued by treatment with CL 316,243 immediately prior to calorimetry experiments. Neither DDTs nor p,p’-DDE significantly altered BAT morphology or the concentrations of norepinephrine and its metabolite DHPG in the BAT of DDTs-exposed mice. However, quantitative immunohistochemistry revealed a 20% decrease in sympathetic axons innervating BAT in adult female mice perinatally exposed to DDTs, but not p,p’-DDE, and 48 and 43% fewer synapses in stellate ganglia of mice exposed to either DDTs or p,p’-DDE, respectively, compared to control. Conclusions These data demonstrate that perinatal exposure to DDTs or p,p’-DDE impairs thermogenesis by interfering with patterns of connectivity in sympathetic circuits that regulate BAT. Graphical abstract

Arthur Lo ◽  
Lucy Norcliffe-Kaufmann ◽  
Ross Vickery ◽  
David Bourdet ◽  
Jitendra Kanodia

Abstract Purpose Ampreloxetine is a novel, selective, long-acting norepinephrine reuptake (NET) inhibitor being investigated as a once-daily oral treatment for symptomatic neurogenic orthostatic hypotension (nOH) in patients with autonomic synucleinopathies. The purpose of this study was to characterize the pharmacokinetic and pharmacodynamic profiles of ampreloxetine in this target population. Methods Patients with nOH were enrolled in a multicenter, phase II clinical trial of ampreloxetine (NCT02705755). They received escalating doses over 5 days in the clinical research unit, followed by 20 weeks of open-label treatment and then a 4-week withdrawal. As neurochemical biomarkers of NET inhibition, we assayed plasma concentrations of norepinephrine (NE) and its main intraneuronal metabolite 3,4-dihydroxyphenylglycol (DHPG) pre- and post-ampreloxetine. Results Thirty-four patients with nOH were enrolled. Plasma ampreloxetine concentrations increased with repeated escalating doses, with peak concentrations observed 6–9 h post-drug administration. The median ampreloxetine dose in the 20-week treatment phase was 10 mg once daily. Plasma ampreloxetine concentrations reached steady state by 2 weeks, with stable plasma levels over 24 h. No influence of age or renal function on ampreloxetine plasma concentrations was observed. On treatment, compared to baseline, plasma NE significantly increased by 71% (p < 0.005), plasma DHPG significantly declined by 22% (p < 0.05), and the NE:DHPG ratio significantly increased (p < 0.001). Conclusions Persistent elevation of plasma NE levels accompanied by reduced DHPG levels after ampreloxetine suggests reduced neuronal reuptake and metabolism of NE in postganglionic efferent sympathetic neurons. The findings are consistent with long-lasting NET inhibition, which may increase vasoconstrictor tone, supporting once-daily ampreloxetine dosing in patients with nOH.

2021 ◽  
Vol 12 ◽  
Tatjana Straka ◽  
Charlotte Schröder ◽  
Andreas Roos ◽  
Laxmikanth Kollipara ◽  
Albert Sickmann ◽  

Recent studies have demonstrated that neuromuscular junctions are co-innervated by sympathetic neurons. This co-innervation has been shown to be crucial for neuromuscular junction morphology and functional maintenance. To improve our understanding of how sympathetic innervation affects nerve–muscle synapse homeostasis, we here used in vivo imaging, proteomic, biochemical, and microscopic approaches to compare normal and sympathectomized mouse hindlimb muscles. Live confocal microscopy revealed reduced fiber diameters, enhanced acetylcholine receptor turnover, and increased amounts of endo/lysosomal acetylcholine-receptor-bearing vesicles. Proteomics analysis of sympathectomized skeletal muscles showed that besides massive changes in mitochondrial, sarcomeric, and ribosomal proteins, the relative abundance of vesicular trafficking markers was affected by sympathectomy. Immunofluorescence and Western blot approaches corroborated these findings and, in addition, suggested local upregulation and enrichment of endo/lysosomal progression and autophagy markers, Rab 7 and p62, at the sarcomeric regions of muscle fibers and neuromuscular junctions. In summary, these data give novel insights into the relevance of sympathetic innervation for the homeostasis of muscle and neuromuscular junctions. They are consistent with an upregulation of endocytic and autophagic trafficking at the whole muscle level and at the neuromuscular junction.

2021 ◽  
Andi Wangzhou ◽  
Candler Paige ◽  
Pradipta R. Ray ◽  
Gregory Dussor ◽  
Theodore J. Price

AbstractBecause somatosensory PNS neurons, in particular nociceptors, are specially tuned to be able to detect a wide variety of both exogenous and endogenous signals, it is widely assumed that these neurons express a greater variety of receptor genes. Because cells detect such signals via cell surface receptors, we sought to formally test the hypothesis that PNS neurons might express a broader array of cell surface receptors than CNS neurons using existing single cell RNA sequencing resources from mouse. We focused our analysis on ion channels, G-protein coupled receptors (GPCRS), receptor tyrosine kinase and cytokine family receptors. In partial support of our hypothesis, we found that mouse PNS somatosensory, sympathetic and enteric neurons and CNS neurons have similar receptor expression diversity in families of receptors examined, with the exception of GPCRs and cytokine receptors which showed greater diversity in the PNS. Surprisingly, these differences were mostly driven by enteric and sympathetic neurons, not by somatosensory neurons or nociceptors. Secondary analysis revealed many receptors that are very specifically expressed in subsets of PNS neurons, including some that are unique among neurons for nociceptors. Finally, we sought to examine specific ligand-receptor interactions between T cells and PNS and CNS neurons. Again, we noted that most interactions between these cells are shared by CNS and PNS neurons despite the fact that T cells only enter the CNS under rare circumstances. Our findings demonstrate that both PNS and CNS neurons express an astonishing array of cell surface receptors and suggest that most neurons are tuned to receive signals from other cells types, in particular immune cells.

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