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Sample records for sympathetic neuronal transport

  1. Retrogradely Transported TrkA Endosomes Signal Locally within Dendrites to Maintain Sympathetic Neuron Synapses

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    Kathryn M. Lehigh

    2017-04-01

    Full Text Available Sympathetic neurons require NGF from their target fields for survival, axonal target innervation, dendritic growth and formation, and maintenance of synaptic inputs from preganglionic neurons. Target-derived NGF signals are propagated retrogradely, from distal axons to somata of sympathetic neurons via TrkA signaling endosomes. We report that a subset of TrkA endosomes that are transported from distal axons to cell bodies translocate into dendrites, where they are signaling competent and move bidirectionally, in close proximity to synaptic protein clusters. Using a strategy for spatially confined inhibition of TrkA kinase activity, we found that distal-axon-derived TrkA signaling endosomes are necessary within sympathetic neuron dendrites for maintenance of synapses. Thus, TrkA signaling endosomes have unique functions in different cellular compartments. Moreover, target-derived NGF mediates circuit formation and synapse maintenance through TrkA endosome signaling within dendrites to promote aggregation of postsynaptic protein complexes.

  2. Metaiodobenzylguanidine [131I] scintigraphy detects impaired myocardial sympathetic neuronal transport function of canine mechanical-overload heart failure

    International Nuclear Information System (INIS)

    Rabinovitch, M.A.; Rose, C.P.; Rouleau, J.L.

    1987-01-01

    In heart failure secondary to chronic mechanical overload, cardiac sympathetic neurons demonstrate depressed catecholamine synthetic and transport function. To assess the potential of sympathetic neuronal imaging for detection of depressed transport function, serial scintigrams were acquired after the intravenous administration of metaiodobenzylguanidine [ 131 I] to 13 normal dogs, 3 autotransplanted (denervated) dogs, 5 dogs with left ventricular failure, and 5 dogs with compensated left ventricular hypertrophy due to a surgical arteriovenous shunt. Nine dogs were killed at 14 hours postinjection for determination of metaiodobenzylguanidine [ 131 I] and endogenous norepinephrine content in left atrium, left ventricle, liver, and spleen. By 4 hours postinjection, autotransplanted dogs had a 39% reduction in mean left ventricular tracer accumulation, reflecting an absent intraneuronal tracer pool. Failure dogs demonstrated an accelerated early mean left ventricular tracer efflux rate (26.0%/hour versus 13.7%/hour in normals), reflecting a disproportionately increased extraneuronal tracer pool. They also showed reduced late left ventricular and left atrial concentrations of tracer, consistent with a reduced intraneuronal tracer pool. By contrast, compensated hypertrophy dogs demonstrated a normal early mean left ventricular tracer efflux rate (16.4%/hour) and essentially normal late left ventricular and left atrial concentrations of tracer. Metaiodobenzylguanidine [ 131 I] scintigraphic findings reflect the integrity of the cardiac sympathetic neuronal transport system in canine mechanical-overload heart failure. Metaiodobenzylguanidine [ 123 I] scintigraphy should be explored as a means of early detection of mechanical-overload heart failure in patients

  3. Glutamate and GABA in vestibulo-sympathetic pathway neurons

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    Gay R Holstein

    2016-02-01

    Full Text Available The vestibulo-sympathetic reflex actively modulates blood pressure during changes in posture. This reflex allows humans to stand up and quadrupeds to rear or climb without a precipitous decline in cerebral perfusion. The vestibulo-sympathetic reflex pathway conveys signals from the vestibular end organs to the caudal vestibular nuclei. These cells, in turn, project to pre-sympathetic neurons in the rostral and caudal ventrolateral medulla (RVLM and CVLM, respectively. The present study assessed glutamate- and GABA-related immunofluorescence associated with central vestibular neurons of the vestibulo-sympathetic reflex pathway in rats. Retrograde FluoroGold tract tracing was used to label vestibular neurons with projections to RVLM or CVLM, and sinusoidal galvanic vestibular stimulation was employed to activate these pathways. Central vestibular neurons of the vestibulo-sympathetic reflex were identified by co-localization of FluoroGold and cFos protein, which accumulates in some vestibular neurons following galvanic stimulation. Triple-label immunofluorescence was used to co-localize glutamate- or GABA- labeling in the identified vestibulo-sympathetic reflex pathway neurons. Most activated projection neurons displayed intense glutamate immunofluorescence, suggestive of glutamatergic neurotransmission. To support this, anterograde tracer was injected into the caudal vestibular nuclei. Vestibular axons and terminals in RVLM and CVLM co-localized the anterograde tracer and vesicular glutamate transporter-2 signals. Other retrogradely-labeled cFos-positive neurons displayed intense GABA immunofluorescence. Vestibulo-sympathetic reflex pathway neurons of both phenotypes were present in the caudal medial and spinal vestibular nuclei, and projected to both RVLM and CVLM. As a group, however, triple-labeled vestibular cells with intense glutamate immunofluorescence were located more rostrally in the vestibular nuclei than the GABAergic neurons. Only the

  4. Effect of nerve activity on transport of nerve growth factor and dopamine β-hydroxylase antibodies in sympathetic neurones

    International Nuclear Information System (INIS)

    Lees, G.; Chubb, I.; Freeman, C.; Geffen, L.; Rush, R.

    1981-01-01

    The effect of nerve activity on the uptake and retrograde transport of nerve growth factor (NGF) and dopamine β-hydroxylase (DBH) antibodies was studied by injecting 125 I-labelled NGF and anti-DBH into the anterior eye chamber of guinea-pigs. Decentralization of the ipsilateral superior cervical ganglion (SCG) had no significant effect on the retrograde transport of either NGF or anti-DBH. Phenoxybenzamine produced a 50% increase in anti-DBH but not NGF accumulation and this effect was prevented by prior decentralization. This demonstrates that NGF is taken up independently of the retrieval of synaptic vesicle components. (Auth.)

  5. A new organellar complex in rat sympathetic neurons.

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    Matt S Ramer

    Full Text Available Membranous compartments of neurons such as axons, dendrites and modified primary cilia are defining features of neuronal phenotype. This is unlike organelles deep to the plasma membrane, which are for the most part generic and not related directly to morphological, neurochemical or functional specializations. However, here we use multi-label immunohistochemistry combined with confocal and electron microscopy to identify a very large (approximately 6 microns in diameter, entirely intracellular neuronal organelle which occurs singly in a ubiquitous but neurochemically distinct and morphologically simple subset of sympathetic ganglion neurons. Although usually toroidal, it also occurs as twists or rods depending on its intracellular position: tori are most often perinuclear whereas rods are often found in axons. These 'loukoumasomes' (doughnut-like bodies bind a monoclonal antibody raised against beta-III-tubulin (SDL.3D10, although their inability to bind other beta-III-tubulin monoclonal antibodies indicate that the responsible antigen is not known. Position-morphology relationships within neurons and their expression of non-muscle heavy chain myosin suggest a dynamic structure. They associate with nematosomes, enigmatic nucleolus-like organelles present in many neural and non-neural tissues, which we now show to be composed of filamentous actin. Loukoumasomes also separately interact with mother centrioles forming the basal body of primary cilia. They express gamma tubulin, a microtubule nucleator which localizes to non-neuronal centrosomes, and cenexin, a mother centriole-associated protein required for ciliogenesis. These data reveal a hitherto undescribed organelle, and depict it as an intracellular transport machine, shuttling material between the primary cilium, the nematosome, and the axon.

  6. Cardiac sympathetic neuronal imaging using PET

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    Lautamaeki, Riikka; Tipre, Dnyanesh; Bengel, Frank M.

    2007-01-01

    Balance of the autonomic nervous system is essential for adequate cardiac performance, and alterations seem to play a key role in the development and progression of various cardiac diseases. PET imaging of the cardiac autonomic nervous system has advanced extensively in recent years, and multiple pre- and postsynaptic tracers have been introduced. The high spatial and temporal resolution of PET enables noninvasive quantification of neurophysiologic processes at the tissue level. Ligands for catecholamine receptors, along with radiolabeled catecholamines and catecholamine analogs, have been applied to determine involvement of sympathetic dysinnervation at different stages of heart diseases such as ischemia, heart failure, and arrhythmia. This review summarizes the recent findings in neurocardiological PET imaging. Experimental studies with several radioligands and clinical findings in cardiac dysautonomias are discussed. (orig.)

  7. Vascular Mural Cells Promote Noradrenergic Differentiation of Embryonic Sympathetic Neurons

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    Vitor Fortuna

    2015-06-01

    Full Text Available The sympathetic nervous system controls smooth muscle tone and heart rate in the cardiovascular system. Postganglionic sympathetic neurons (SNs develop in close proximity to the dorsal aorta (DA and innervate visceral smooth muscle targets. Here, we use the zebrafish embryo to ask whether the DA is required for SN development. We show that noradrenergic (NA differentiation of SN precursors temporally coincides with vascular mural cell (VMC recruitment to the DA and vascular maturation. Blocking vascular maturation inhibits VMC recruitment and blocks NA differentiation of SN precursors. Inhibition of platelet-derived growth factor receptor (PDGFR signaling prevents VMC differentiation and also blocks NA differentiation of SN precursors. NA differentiation is normal in cloche mutants that are devoid of endothelial cells but have VMCs. Thus, PDGFR-mediated mural cell recruitment mediates neurovascular interactions between the aorta and sympathetic precursors and promotes their noradrenergic differentiation.

  8. Vascular Mural Cells Promote Noradrenergic Differentiation of Embryonic Sympathetic Neurons.

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    Fortuna, Vitor; Pardanaud, Luc; Brunet, Isabelle; Ola, Roxana; Ristori, Emma; Santoro, Massimo M; Nicoli, Stefania; Eichmann, Anne

    2015-06-23

    The sympathetic nervous system controls smooth muscle tone and heart rate in the cardiovascular system. Postganglionic sympathetic neurons (SNs) develop in close proximity to the dorsal aorta (DA) and innervate visceral smooth muscle targets. Here, we use the zebrafish embryo to ask whether the DA is required for SN development. We show that noradrenergic (NA) differentiation of SN precursors temporally coincides with vascular mural cell (VMC) recruitment to the DA and vascular maturation. Blocking vascular maturation inhibits VMC recruitment and blocks NA differentiation of SN precursors. Inhibition of platelet-derived growth factor receptor (PDGFR) signaling prevents VMC differentiation and also blocks NA differentiation of SN precursors. NA differentiation is normal in cloche mutants that are devoid of endothelial cells but have VMCs. Thus, PDGFR-mediated mural cell recruitment mediates neurovascular interactions between the aorta and sympathetic precursors and promotes their noradrenergic differentiation. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Egr3 dependent sympathetic target tissue innervation in the absence of neuron death.

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    Lin Li

    Full Text Available Nerve Growth Factor (NGF is a target tissue derived neurotrophin required for normal sympathetic neuron survival and target tissue innervation. NGF signaling regulates gene expression in sympathetic neurons, which in turn mediates critical aspects of neuron survival, axon extension and terminal axon branching during sympathetic nervous system (SNS development. Egr3 is a transcription factor regulated by NGF signaling in sympathetic neurons that is essential for normal SNS development. Germline Egr3-deficient mice have physiologic dysautonomia characterized by apoptotic sympathetic neuron death and abnormal innervation to many target tissues. The extent to which sympathetic innervation abnormalities in the absence of Egr3 is caused by altered innervation or by neuron death during development is unknown. Using Bax-deficient mice to abrogate apoptotic sympathetic neuron death in vivo, we show that Egr3 has an essential role in target tissue innervation in the absence of neuron death. Sympathetic target tissue innervation is abnormal in many target tissues in the absence of neuron death, and like NGF, Egr3 also appears to effect target tissue innervation heterogeneously. In some tissues, such as heart, spleen, bowel, kidney, pineal gland and the eye, Egr3 is essential for normal innervation, whereas in other tissues such as lung, stomach, pancreas and liver, Egr3 appears to have little role in innervation. Moreover, in salivary glands and heart, two tissues where Egr3 has an essential role in sympathetic innervation, NGF and NT-3 are expressed normally in the absence of Egr3 indicating that abnormal target tissue innervation is not due to deregulation of these neurotrophins in target tissues. Taken together, these results clearly demonstrate a role for Egr3 in mediating sympathetic target tissue innervation that is independent of neuron survival or neurotrophin deregulation.

  10. Clinical evaluation of carbon-11-phenylephrine: MAO-sensitive marker of cardiac sympathetic neurons.

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    Raffel, D M; Corbett, J R; del Rosario, R B; Gildersleeve, D L; Chiao, P C; Schwaiger, M; Wieland, D M

    1996-12-01

    The sympathomimetic drug phenylephrine recently has been labeled with 11C for use in PET studies of cardiac sympathetic innervation. Previous reports using isolated perfused rat heart models indicate that phenylephrine is metabolized by intraneuronal monoamine oxidase (MAO). This report compares the imaging characteristics, neuronal selectivity and kinetics of (-)-[11C]phenylephrine (PHEN) to the structurally similar but MAO-resistant analog (-)-[11C]-meta-hydroxyephedrine (HED), an established heart neuronal marker. Fourteen healthy volunteers were studied with PET and PHEN. Ten had paired studies with HED; four of the 10 were scanned a second time with each tracer after oral administration of desipramine, a selective neuronal transport blocker. Hemodynamic and electrocardiographic responses were monitored. Blood levels of intact radiotracer and radiolabeled metabolites were determined from venous blood samples taken during the PET study. Myocardial retention indices for both tracers were calculated. No hemodynamic or electrocardiographic effects were observed with either tracer. PHEN showed reduced myocardial retention at 50 min compared to HED; however, image quality and uniformity of distribution were comparable. PHEN cleared from myocardium with a mean half-time of 59 +/- 5 min, while myocardial levels of HED remained constant. PHEN metabolites appeared in the blood approximately three times faster than HED metabolites. Desipramine pretreatment markedly reduced (> 60%) myocardial retention of both PHEN and HED. PHEN provides PET images of human heart comparable in quality and uniformity to HED. Like HED, PHEN localizes in the sympathetic nerves of the heart. However, the more rapid efflux of PHEN, that is likely mediated by MAO, may provide information on the functional status of cardiac sympathetic neurons unobtainable with HED.

  11. Axon Guidance of Sympathetic Neurons to Cardiomyocytes by Glial Cell Line-Derived Neurotrophic Factor (GDNF)

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    Miwa, Keiko; Lee, Jong-Kook; Takagishi, Yoshiko; Opthof, Tobias; Fu, Xianming; Hirabayashi, Masumi; Watabe, Kazuhiko; Jimbo, Yasuhiko; Kodama, Itsuo; Komuro, Issei

    2013-01-01

    Molecular signaling of cardiac autonomic innervation is an unresolved issue. Here, we show that glial cell line-derived neurotrophic factor (GDNF) promotes cardiac sympathetic innervation in vitro and in vivo. In vitro, ventricular myocytes (VMs) and sympathetic neurons (SNs) isolated from neonatal

  12. Separate neurochemical classes of sympathetic postganglionic neurons project to the left ventricle of the rat heart.

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    Richardson, R J; Grkovic, I; Allen, A M; Anderson, C R

    2006-04-01

    The sympathetic innervation of the rat heart was investigated by retrograde neuronal tracing and multiple label immunohistochemistry. Injections of Fast Blue made into the left ventricular wall labelled sympathetic neurons that were located along the medial border of both the left and right stellate ganglia. Cardiac projecting sympathetic postganglionic neurons could be grouped into one of four neurochemical populations, characterised by their content of calbindin and/or neuropeptide Y (NPY). The subpopulations of neurons contained immunoreactivity to both calbindin and NPY, immunoreactivity to calbindin only, immunoreactivity to NPY only and no immunoreactivity to calbindin or NPY. Sympathetic postganglionic neurons were also labelled in vitro with rhodamine dextran applied to the cut end of a cardiac nerve. The same neurochemical subpopulations of sympathetic neurons were identified by using this technique but in different proportions to those labelled from the left ventricle. Preganglionic terminals that were immunoreactive for another calcium-binding protein, calretinin, preferentially surrounded retrogradely labelled neurons that were immunoreactive for both calbindin and NPY. The separate sympathetic pathways projecting to the rat heart may control different cardiac functions.

  13. Control of sympathetic vasomotor tone by catecholaminergic C1 neurones of the rostral ventrolateral medulla oblongata

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    Marina, Nephtali; Abdala, Ana P.L.; Korsak, Alla; Simms, Annabel E.; Allen, Andrew M.; Paton, Julian F.R.; Gourine, Alexander V.

    2011-01-01

    Aims Increased sympathetic tone in obstructive sleep apnoea results from recurrent episodes of systemic hypoxia and hypercapnia and might be an important contributor to the development of cardiovascular disease. In this study, we re-evaluated the role of a specific population of sympathoexcitatory catecholaminergic C1 neurones of the rostral ventrolateral medulla oblongata in the control of sympathetic vasomotor tone, arterial blood pressure, and hypercapnia-evoked sympathetic and cardiovascular responses. Methods and results In anaesthetized rats in vivo and perfused rat working heart brainstem preparations in situ, C1 neurones were acutely silenced by application of the insect peptide allatostatin following cell-specific targeting with a lentiviral vector to express the inhibitory Drosophila allatostatin receptor. In anaesthetized rats with denervated peripheral chemoreceptors, acute inhibition of 50% of the C1 neuronal population resulted in ∼50% reduction in renal sympathetic nerve activity and a profound fall in arterial blood pressure (by ∼25 mmHg). However, under these conditions systemic hypercapnia still evoked vigorous sympathetic activation and the slopes of the CO2-evoked sympathoexcitatory and cardiovascular responses were not affected by inhibition of C1 neurones. Inhibition of C1 neurones in situ resulted in a reversible fall in perfusion pressure and the amplitude of respiratory-related bursts of thoracic sympathetic nerve activity. Conclusion These data confirm a fundamental physiological role of medullary catecholaminergic C1 neurones in maintaining resting sympathetic vasomotor tone and arterial blood pressure. However, C1 neurones do not appear to mediate sympathoexcitation evoked by central actions of CO2. PMID:21543384

  14. RAGE mediates the inactivation of nAChRs in sympathetic neurons under high glucose conditions.

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    Chandna, Andrew R; Nair, Manoj; Chang, Christine; Pennington, Paul R; Yamamoto, Yasuhiko; Mousseau, Darrell D; Campanucci, Verónica A

    2015-02-01

    Autonomic dysfunction is a serious complication of diabetes and can lead to cardiovascular abnormalities and premature death. It was recently proposed that autonomic dysfunction is triggered by oxidation-mediated inactivation of neuronal nicotinic acetylcholine receptors (nAChRs), impairing synaptic transmission in sympathetic ganglia and resulting in autonomic failure. We investigated whether the receptor for advanced glycation end products (RAGE) and its role in the generation of reactive oxygen species (ROS) could be contributing to the events that initiate sympathetic malfunction under high glucose conditions. Using biochemical, live imaging and electrophysiological tools we demonstrated that exposure of sympathetic neurons to high glucose increases RAGE expression and oxidative markers, and that incubation with RAGE ligands (e.g. AGEs, S100 and HMGB1) mimics both ROS elevation and nAChR inactivation. In contrast, co-treatment with either antioxidants or an anti-RAGE IgG prevented the inactivation of nAChRs. Lastly, a role for RAGE in this context was corroborated by the lack of sensitivity of sympathetic neurons from RAGE knock-out mice to high glucose. These data define a pivotal role for RAGE in initiating the events associated with exposure of sympathetic neurons to high glucose, and strongly support RAGE signaling as a potential therapeutic target in the autonomic complications associated with diabetes. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  15. Sympathetic neurons are a powerful driver of myocyte function in cardiovascular disease.

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    Larsen, Hege E; Lefkimmiatis, Konstantinos; Paterson, David J

    2016-12-14

    Many therapeutic interventions in disease states of heightened cardiac sympathetic activity are targeted to the myocytes. However, emerging clinical data highlights a dominant role in disease progression by the neurons themselves. Here we describe a novel experimental model of the peripheral neuro-cardiac axis to study the neuron's ability to drive a myocyte cAMP phenotype. We employed a co-culture of neonatal ventricular myocytes and sympathetic stellate neurons from normal (WKY) and pro-hypertensive (SHR) rats that are sympathetically hyper-responsive and measured nicotine evoked cAMP responses in the myocytes using a fourth generation FRET cAMP sensor. We demonstrated the dominant role of neurons in driving the myocyte ß-adrenergic phenotype, where SHR cultures elicited heightened myocyte cAMP responses during neural activation. Moreover, cross-culturing healthy neurons onto diseased myocytes rescued the diseased cAMP response of the myocyte. Conversely, healthy myocytes developed a diseased cAMP response if diseased neurons were introduced. Our results provide evidence for a dominant role played by the neuron in driving the adrenergic phenotype seen in cardiovascular disease. We also highlight the potential of using healthy neurons to turn down the gain of neurotransmission, akin to a smart pre-synaptic ß-blocker.

  16. Optogenetic release of norepinephrine from cardiac sympathetic neurons alters mechanical and electrical function.

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    Wengrowski, Anastasia M; Wang, Xin; Tapa, Srinivas; Posnack, Nikki Gillum; Mendelowitz, David; Kay, Matthew W

    2015-02-01

    Release of norepinephrine (NE) from sympathetic neurons enhances heart rate (HR) and developed force through activation of β-adrenergic receptors, and this sympathoexcitation is a key risk for the generation of cardiac arrhythmias. Studies of β-adrenergic modulation of cardiac function typically involve the administration of exogenous β-adrenergic receptor agonists to directly elicit global β-adrenergic receptor activation by bypassing the involvement of sympathetic nerve terminals. In this work, we use a novel method to activate sympathetic fibres within the myocardium of Langendorff-perfused hearts while measuring changes in electrical and mechanical function. The light-activated optogenetic protein channelrhodopsin-2 (ChR2) was expressed in murine catecholaminergic sympathetic neurons. Sympathetic fibres were then photoactivated to examine changes in contractile force, HR, and cardiac electrical activity. Incidence of arrhythmia was measured with and without exposure to photoactivation of sympathetic fibres, and hearts were optically mapped to detect changes in action potential durations and conduction velocities. Results demonstrate facilitation of both developed force and HR after photostimulated release of NE, with increases in contractile force and HR of 34.5 ± 5.5 and 25.0 ± 9.3%, respectively. Photostimulation of sympathetic fibres also made hearts more susceptible to arrhythmia, with greater incidence and severity. In addition, optically mapped action potentials displayed a small but significant shortening of the plateau phase (-5.5 ± 1.0 ms) after photostimulation. This study characterizes a powerful and clinically relevant new model for studies of cardiac arrhythmias generated by increasing the activity of sympathetic nerve terminals and the resulting activation of myocyte β-adrenergic receptors. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

  17. Sympathetic neurons modulate the beat rate of pluripotent cell-derived cardiomyocytes in vitro.

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    Takeuchi, Akimasa; Shimba, Kenta; Mori, Masahide; Takayama, Yuzo; Moriguchi, Hiroyuki; Kotani, Kiyoshi; Lee, Jong-Kook; Noshiro, Makoto; Jimbo, Yasuhiko

    2012-12-01

    Although stem cell-derived cardiomyocytes have great potential for the therapy of heart failure, it is unclear whether their function after grafting can be controlled by the host sympathetic nervous system, a component of the autonomic nervous system (ANS). Here we demonstrate the formation of functional connections between rat sympathetic superior cervical ganglion (SCG) neurons and pluripotent (P19.CL6) cell-derived cardiomyocytes (P19CMs) in compartmentalized co-culture, achieved using photolithographic microfabrication techniques. Formation of synapses between sympathetic neurons and P19CMs was confirmed by immunostaining with antibodies against β-3 tubulin, synapsin I and cardiac troponin-I. Changes in the beat rate of P19CMs were triggered after electrical stimulation of the co-cultured SCG neurons, and were affected by the pulse frequency of the electrical stimulation. Such changes in the beat rate were prevented when propranolol, a β-adrenoreceptor antagonist, was added to the culture medium. These results suggest that the beat rate of differentiated cardiomyocytes can be modulated by electrical stimulation of connected sympathetic neurons.

  18. The Gata3 transcription factor is required for the survival of embryonic and adult sympathetic neurons

    NARCIS (Netherlands)

    K. Tsarovina (Konstantina); T. Reiff (Tobias); J. Stubbusch (Jutta); D. Kurek (Dorota); F.G. Grosveld (Frank); R. Parlato (Rosanna); G. Schütz (Günther); H. Rohrer (Hermann)

    2010-01-01

    textabstractThe transcription factor Gata3 is essential for the development of sympathetic neurons and adrenal chromaffin cells. As Gata3 expression is maintained up to the adult stage, we addressed its function in differentiated sympathoadrenal cells at embryonic and adult stages by conditional

  19. Dysregulation of Neuronal Ca2+ Channel Linked to Heightened Sympathetic Phenotype in Prohypertensive States

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    Larsen, Hege E.; Bardsley, Emma N.; Lefkimmiatis, Konstantinos; Paterson, David J.

    2016-01-01

    Hypertension is associated with impaired nitric oxide (NO)–cyclic nucleotide (CN)-coupled intracellular calcium (Ca2+) homeostasis that enhances cardiac sympathetic neurotransmission. Because neuronal membrane Ca2+ currents are reduced by NO-activated S-nitrosylation, we tested whether CNs affect membrane channel conductance directly in neurons isolated from the stellate ganglia of spontaneously hypertensive rats (SHRs) and their normotensive controls. Using voltage-clamp and cAMP–protein kin...

  20. Highly localized interactions between sensory neurons and sprouting sympathetic fibers observed in a transgenic tyrosine hydroxylase reporter mouse

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    Zhang Jun-Ming

    2011-07-01

    Full Text Available Abstract Background Sprouting of sympathetic fibers into sensory ganglia occurs in many preclinical pain models, providing a possible anatomical substrate for sympathetically enhanced pain. However, the functional consequences of this sprouting have been controversial. We used a transgenic mouse in which sympathetic fibers expressed green fluorescent protein, observable in live tissue. Medium and large diameter lumbar sensory neurons with and without nearby sympathetic fibers were recorded in whole ganglion preparations using microelectrodes. Results After spinal nerve ligation, sympathetic sprouting was extensive by 3 days. Abnormal spontaneous activity increased to 15% and rheobase was reduced. Spontaneously active cells had Aαβ conduction velocities but were clustered near the medium/large cell boundary. Neurons with sympathetic basket formations had a dramatically higher incidence of spontaneous activity (71% and had lower rheobase than cells with no sympathetic fibers nearby. Cells with lower density nearby fibers had intermediate phenotypes. Immunohistochemistry of sectioned ganglia showed that cells surrounded by sympathetic fibers were enriched in nociceptive markers TrkA, substance P, or CGRP. Spontaneous activity began before sympathetic sprouting was observed, but blocking sympathetic sprouting on day 3 by cutting the dorsal ramus in addition to the ventral ramus of the spinal nerve greatly reduced abnormal spontaneous activity. Conclusions The data suggest that early sympathetic sprouting into the sensory ganglia may have highly localized, excitatory effects. Quantitatively, neurons with sympathetic basket formations may account for more than half of the observed spontaneous activity, despite being relatively rare. Spontaneous activity in sensory neurons and sympathetic sprouting may be mutually re-enforcing.

  1. Dynamics of Phosphoinositide-Dependent Signaling in Sympathetic Neurons

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    Kruse, Martin; Vivas, Oscar; Traynor-Kaplan, Alexis; Hille, Bertil

    2016-01-01

    In neurons, loss of plasma membrane phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] leads to a decrease in exocytosis and changes in electrical excitability. Restoration of PI(4,5)P2 levels after phospholipase C activation is therefore essential for a return to basal neuronal activity. However, the dynamics of phosphoinositide metabolism have not been analyzed in neurons. We measured dynamic changes of PI(4,5)P2, phosphatidylinositol 4-phosphate, diacylglycerol, inositol 1,4,5-trisphosphate...

  2. Effects of Electrical Stimulation in Sympathetic Neuron-Cardiomyocyte Co-cultures

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    Takeuchi, Akimasa; Tani, Hiromasa; Mori, Masahide; Moriguchi, Hiroyuki; Kotani, Kiyoshi; Lee, Jong-Kook; Noshiro, Makoto; Jimbo, Yasuhiko

    The sympathetic nervous system is one of the principal sources for regulating cardiovascular functions. Little is known, however, about the network-level interactions between sympathetic neurons and cardiomyocytes. In this study, a semi-separated co-culture system of superior cervical ganglion (SCG) neurons and ventricular myocytes (VMs) was developed by using a polydimethylsyloxane (PDMS) chamber placed on a microelectrode-array (MEA) substrate. Neurites of SCG neurons passed through a conduit of the chamber and reached VMs. Evoked activities of SCG neurons were observed from several electrodes immediately after applying constant-voltage stimulation (1 V, 1 ms, biphasic square pulses) to SCG neurons by using 32 electrodes. Furthermore, this stimulation was applied to SCG neurons at the frequency of 1, 5 and 10 Hz. After applying these three kinds of stimulations, mean minute contraction rate of VMs increased with an increase in the frequency of stimulation. These results suggest that changes in contraction rate of VMs after applying electrical stimulations to SCG neurons depend on frequencies of these stimulations and that the heart-regulating mechanisms as well as that in the body were formed in this co-culture system.

  3. Recruitment pattern of sympathetic muscle neurons during premature ventricular contractions in heart failure patients and controls.

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    Maslov, Petra Zubin; Breskovic, Toni; Brewer, Danielle N; Shoemaker, J Kevin; Dujic, Zeljko

    2012-12-01

    Premature ventricular contractions (PVC) elicit larger bursts of multiunit muscle sympathetic nerve activity (MSNA), reflecting the ability to increase postganglionic axonal recruitment. We tested the hypothesis that chronic heart failure (CHF) limits the ability to recruit postganglionic sympathetic neurons as a response to PVC due to the excessive sympathetic activation in these patients. Sympathetic neurograms of sufficient signal-to-noise ratio were obtained from six CHF patients and from six similarly aged control individuals. Action potentials (APs) were extracted from the multiunit sympathetic neurograms during sinus rhythm bursts and during the post-PVC bursts. These APs were classified on the basis of the frequency per second, the content per burst, and the peak-to-peak amplitude, which formed the basis of binning the APs into active clusters. Compared with controls, CHF had higher APs per burst and higher number of active clusters per sinus rhythm burst (P < 0.05). Compared with sinus rhythm bursts, both groups increased AP frequency and the number of active clusters in the post-PVC burst (P < 0.05). However, compared with controls, the increase in burst integral, AP frequency, and APs per burst during the post-PVC burst was less in CHF patients. Nonetheless, the PVC-induced increase in active clusters per burst was similar between the groups. Thus, these CHF patients retained the ability to recruit larger APs but had a diminished ability to increase overall AP content.

  4. On the number of preganglionic neurones driving human postganglionic sympathetic neurones: a comparison of modelling and empirical data

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    Vaughan G Macefield

    2011-12-01

    Full Text Available Postganglionic sympathetic axons in awake healthy human subjects, regardless of their identity as muscle vasoconstrictor, cutaneous vasoconstrictor or sudomotor neurones, discharge with a low firing probability (~30%, generate low firing rates (~0.5 Hz and typically fire only once per cardiac interval. The purpose of the present study was to use modelling of spike trains in an attempt to define the number of preganglionic neurones that drive an individual postganglionic neurone. Artificial spike trains were generated in 1-3 preganglionic neurones converging onto a single postganglionic neurone. Each preganglionic input fired with a mean interval distribution of either 1000, 1500, 2000, 2500 or 3000 ms and the standard deviation varied between 0.5, 1.0 and 2.0 x the mean interval; the discharge frequency of each preganglionic neurone exhibited positive skewness and kurtosis. Of the 45 patterns examined, the mean discharge properties of the postganglionic neurone could only be explained by it being driven by, on average, two preganglionic neurones firing with a mean interspike interval of 2500 ms and SD of 5000 ms. The mean firing rate resulting from this pattern was 0.22 Hz, comparable to that of spontaneously active muscle vasoconstrictor neurones in healthy subjects (0.40 Hz. Likewise, the distribution of the number of spikes per cardiac interval was similar between the modelled and actual data: 0 spikes (69.5 vs 66.6 %, 1 spike (25.6 vs 21.2 %, 2 spikes (4.3 vs 6.4 %, 3 spikes (0.5 vs 1.7 % and 4 spikes (0.1 vs 0.7 %. Although some features of the firing patterns could be explained by the postganglionic neurone being driven by a single preganglionic neurone, none of the emulated firing patterns generated by the firing of three preganglionic neurones matched the discharge of the real neurones. These modelling data indicate that, on average, human postganglionic sympathetic neurones are driven by two preganglionic inputs.

  5. The localization of primary efferent sympathetic neurons innervating the porcine thymus – a retrograde tracing study

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    Paweł Kulik

    2017-01-01

    Full Text Available The autonomic nervous system is a sophisticated and independent structure composed of two antagonistic (opposing divisions (sympathetic and parasympathetic that control many vital functions including: homeostasis maintenance, heart rate, blood circulation, secretion, etc. Thymus is one of the most important primary lymphoid organs playing a role in the developing of a juvenile’s immune system mainly by maturation, development, and migration of T-cells (T lymphocytes. In the last decades, several studies identifying sources of the thymic autonomic supply have been undertaken in humans and several laboratory rodents but not in higher mammals such as the pig. Therefore, in the present work, retrograde tracing technique of Fast Blue and DiI was used to investigate the sources of sympathetic efferent supply to the porcine thymus. After Fast Blue injection into the right lobe of the thymus, the presence of Fast Blue-positive neurons was found in the unilateral cranial cervical ganglion (82.8 ± 3.0% of total Fast Blue-positive neurons as well as in the middle cervical ganglion (17.2 ± 3.0%. Injection of DiI resulted in the presence of retrograde tracer in neurons of the cranial cervical ganglion (80.4 ± 2.3% of total amount of DiI-labelled neurons, the middle cervical ganglion (18.4 ± 1.9%, and the cervicothoracic ganglion (1.2 ± 0.8%. The present report provides the first data describing in details the localization of primary efferent sympathetic neurons innervating the porcine thymus.

  6. Renal sympathetic nerve, blood flow, and epithelial transport responses to thermal stress.

    Science.gov (United States)

    Wilson, Thad E

    2017-05-01

    Thermal stress is a profound sympathetic stress in humans; kidney responses involve altered renal sympathetic nerve activity (RSNA), renal blood flow, and renal epithelial transport. During mild cold stress, RSNA spectral power but not total activity is altered, renal blood flow is maintained or decreased, and epithelial transport is altered consistent with a sympathetic stress coupled with central volume loaded state. Hypothermia decreases RSNA, renal blood flow, and epithelial transport. During mild heat stress, RSNA is increased, renal blood flow is decreased, and epithelial transport is increased consistent with a sympathetic stress coupled with a central volume unloaded state. Hyperthermia extends these directional changes, until heat illness results. Because kidney responses are very difficult to study in humans in vivo, this review describes and qualitatively evaluates an in vivo human skin model of sympathetically regulated epithelial tissue compared to that of the nephron. This model utilizes skin responses to thermal stress, involving 1) increased skin sympathetic nerve activity (SSNA), decreased skin blood flow, and suppressed eccrine epithelial transport during cold stress; and 2) increased SSNA, skin blood flow, and eccrine epithelial transport during heat stress. This model appears to mimic aspects of the renal responses. Investigations of skin responses, which parallel certain renal responses, may aid understanding of epithelial-sympathetic nervous system interactions during cold and heat stress. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Cardiac sympathetic neuronal damage precedes myocardial fibrosis in patients with Anderson-Fabry disease

    International Nuclear Information System (INIS)

    Imbriaco, Massimo; Piscopo, Valentina; Ponsiglione, Andrea; Nappi, Carmela; Puglia, Marta; Dell'Aversana, Serena; Spinelli, Letizia; Cuocolo, Alberto; Pellegrino, Teresa; Petretta, Mario; Riccio, Eleonora; Pisani, Antonio

    2017-01-01

    Cardiac sympathetic denervation may be detectable in patients with Anderson-Fabry disease (AFD), suggesting its usefulness for early detection of the disease. However, the relationship between sympathetic neuronal damage measured by 123 I-metaiodobenzylguanidine (MIBG) imaging with myocardial fibrosis on cardiac magnetic resonance (CMR) is still unclear. Cardiac sympathetic innervation was assessed by 123 I-MIBG single-photon emission computed tomography (SPECT) in 25 patients with genetically proved AFD. Within one month from MIBG imaging, all patients underwent contrast-enhanced CMR. MIBG defect size and fibrosis size on CMR were measured for the left ventricle (LV) and expressed as %LV. Patients were divided into three groups according to MIBG and CMR findings: (1) matched normal, without MIBG defects and without fibrosis on CMR (n = 10); (2) unmatched, with MIBG defect but without fibrosis (n = 5); and (3) matched abnormal, with MIBG defect and fibrosis (n = 10). The three groups did not differ with respect to age, gender, α-galactosidase, proteinuria, glomerular filtration rate, and troponin I, while New York Heart Association class (p = 0.008), LV hypertrophy (p = 0.05), and enzyme replacement therapy (p = 0.02) were different among groups. Although in patients with matched abnormal findings, there was a significant correlation between MIBG defect size and area of fibrosis at CMR (r 2 = 0.98, p < 0.001), MIBG defect size was larger than fibrosis size (26 ± 23 vs. 18 ± 13%LV, p = 0.02). Sympathetic neuronal damage is frequent in AFD patients, and it may precede myocardial damage, such as fibrosis. Thus, 123 I-MIBG imaging can be considered a challenging technique for early detection of cardiac involvement in AFD. (orig.)

  8. Cardiac sympathetic neuronal damage precedes myocardial fibrosis in patients with Anderson-Fabry disease

    Energy Technology Data Exchange (ETDEWEB)

    Imbriaco, Massimo; Piscopo, Valentina; Ponsiglione, Andrea; Nappi, Carmela; Puglia, Marta; Dell' Aversana, Serena; Spinelli, Letizia; Cuocolo, Alberto [University Federico II, Department of Advanced Biomedical Sciences, Naples (Italy); Pellegrino, Teresa [National Council of Research, Institute of Biostructure and Bioimaging, Naples (Italy); Petretta, Mario [University Federico II, Department of Translational Medical Sciences, Naples (Italy); Riccio, Eleonora; Pisani, Antonio [University of Naples Federico II, Department of Public Health, Naples (Italy)

    2017-12-15

    Cardiac sympathetic denervation may be detectable in patients with Anderson-Fabry disease (AFD), suggesting its usefulness for early detection of the disease. However, the relationship between sympathetic neuronal damage measured by {sup 123}I-metaiodobenzylguanidine (MIBG) imaging with myocardial fibrosis on cardiac magnetic resonance (CMR) is still unclear. Cardiac sympathetic innervation was assessed by {sup 123}I-MIBG single-photon emission computed tomography (SPECT) in 25 patients with genetically proved AFD. Within one month from MIBG imaging, all patients underwent contrast-enhanced CMR. MIBG defect size and fibrosis size on CMR were measured for the left ventricle (LV) and expressed as %LV. Patients were divided into three groups according to MIBG and CMR findings: (1) matched normal, without MIBG defects and without fibrosis on CMR (n = 10); (2) unmatched, with MIBG defect but without fibrosis (n = 5); and (3) matched abnormal, with MIBG defect and fibrosis (n = 10). The three groups did not differ with respect to age, gender, α-galactosidase, proteinuria, glomerular filtration rate, and troponin I, while New York Heart Association class (p = 0.008), LV hypertrophy (p = 0.05), and enzyme replacement therapy (p = 0.02) were different among groups. Although in patients with matched abnormal findings, there was a significant correlation between MIBG defect size and area of fibrosis at CMR (r{sup 2} = 0.98, p < 0.001), MIBG defect size was larger than fibrosis size (26 ± 23 vs. 18 ± 13%LV, p = 0.02). Sympathetic neuronal damage is frequent in AFD patients, and it may precede myocardial damage, such as fibrosis. Thus, {sup 123}I-MIBG imaging can be considered a challenging technique for early detection of cardiac involvement in AFD. (orig.)

  9. Peptidergic modulation of efferent sympathetic neurons in intrathoracic ganglia regulating the canine heart.

    Science.gov (United States)

    Armour, J A

    1989-05-01

    When either substance P or vasoactive intestinal peptide was injected into an acutely decentralized intrathoracic sympathetic ganglion, short-lasting augmentation of cardiac chronotropism and inotropism was induced. These augmentations were induced before the fall in systemic arterial pressure occurred which was a consequence of these peptides leaking into the systemic circulation in enough quantity to alter peripheral vascular resistance directly. When similar volumes of normal saline were injected into an intrathoracic ganglion, no significant cardiac changes were induced. When substance P or vasoactive intestinal peptide was administered into an intrathoracic ganglion, similar cardiac augmentations were induced either before or after the intravenous administration of hexamethonium. In contrast, when these peptides were injected into an intrathoracic ganglion in which the beta-adrenergic blocking agent timolol (0.1 mg/0.1 ml of normal saline) had been administered no cardiac augmentation occurred. These data imply that in the presence of beta-adrenergic blockade intraganglionic administration of substance P or vasoactive intestinal peptide does not modify enough intrathoracic neurons to alter cardiac chronotropism and inotropism detectably. When neuropeptide Y was injected into an intrathoracic ganglion, no cardiac changes occurred. However, when cardiac augmentations were induced by sympathetic preganglionic axon stimulation these were enhanced following the intraganglionic administration of neuropeptide Y. As this effect occurred after timolol was administered into the ipsilateral ganglia, but not after intravenous administration of hexamethonium, it is proposed that the effects of neuropeptide Y are dependent upon functioning intrathoracic ganglionic nicotinic cholinergic synaptic mechanisms. Intravenous administration of either morphine or [D-ala2,D-leu5]enkephalin acetate did not alter the capacity of the preganglionic sympathetic axons to augment the heart

  10. Data in support on the shape of Schwann cells and sympathetic neurons onto microconically structured silicon surfaces

    Directory of Open Access Journals (Sweden)

    C. Simitzi

    2015-09-01

    Full Text Available This article contains data related to the research article entitled “Laser fabricated discontinuous anisotropic microconical substrates as a new model scaffold to control the directionality of neuronal network outgrowth” in the Biomaterials journal [1]. Scanning electron microscopy (SEM analysis is performed to investigate whether Schwann cells and sympathetic neurons alter their morphology according to the underlying topography, comprising arrays of silicon microcones with anisotropic geometrical characteristics [1]. It is observed that although soma of sympathetic neurons always preserves its round shape, this is not the case for Schwann cells that become highly polarized in high roughness microconical substrates.

  11. Activation of hypothalamic RIP-Cre neurons promotes beiging of WAT via sympathetic nervous system.

    Science.gov (United States)

    Wang, Baile; Li, Ang; Li, Xiaomu; Ho, Philip Wl; Wu, Donghai; Wang, Xiaoqi; Liu, Zhuohao; Wu, Kelvin Kl; Yau, Sonata Sy; Xu, Aimin; Cheng, Kenneth Ky

    2018-04-01

    Activation of brown adipose tissue (BAT) and beige fat by cold increases energy expenditure. Although their activation is known to be differentially regulated in part by hypothalamus, the underlying neural pathways and populations remain poorly characterized. Here, we show that activation of rat-insulin-promoter-Cre (RIP-Cre) neurons in ventromedial hypothalamus (VMH) preferentially promotes recruitment of beige fat via a selective control of sympathetic nervous system (SNS) outflow to subcutaneous white adipose tissue (sWAT), but has no effect on BAT Genetic ablation of APPL2 in RIP-Cre neurons diminishes beiging in sWAT without affecting BAT, leading to cold intolerance and obesity in mice. Such defects are reversed by activation of RIP-Cre neurons, inactivation of VMH AMPK, or treatment with a β3-adrenergic receptor agonist. Hypothalamic APPL2 enhances neuronal activation in VMH RIP-Cre neurons and raphe pallidus, thereby eliciting SNS outflow to sWAT and subsequent beiging. These data suggest that beige fat can be selectively activated by VMH RIP-Cre neurons, in which the APPL2-AMPK signaling axis is crucial for this defending mechanism to cold and obesity. © 2018 The Authors.

  12. Double labelling immunohistochemical characterization of autonomic sympathetic neurons innervating the sow retractor clitoridis muscle

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    L Ragionieri

    2009-08-01

    Full Text Available Retrograde neuronal tracing and immunohistochemical methods were used to define the neurochemical content of sympathetic neurons projecting to the sow retractor clitoridis muscle (RCM. Differently from the other smooth muscles of genital organs, the RCM is an isolated muscle that is tonically contracted in the rest phase and relaxed in the active phase. This peculiarity makes it an interesting experimental model. The fluorescent tracer fast blue was injected into the RCM of three 50 kg subjects. After a one-week survival period, the ipsilateral paravertebral ganglion S1, that in a preliminary study showed the greatest number of cells projecting to the muscle, was collected from each animal. The co-existence of tyrosine hydroxylase with choline acetyltransferase, neuronal nitric oxide synthase, calcitonin gene-related peptide, leuenkephalin, neuropeptide Y, substance P and vasoactive intestinal polypeptide was studied under a fluorescent microscope on cryostat sections. Tyrosine hydroxylase was present in about 58% of the neurons projecting to the muscle and was found to be co-localized with each of the other tested substances.Within fast blue-labelled cells negative to the adrenergic marker, small populations of neurons singularly containing each of the other enzymatic markers or peptides were also observed. The present study documents the complexity of the neurochemical interactions that regulate the activity of the smooth myocytes of the RCM and their vascular components.

  13. Voltage-Induced Ca²⁺ Release in Postganglionic Sympathetic Neurons in Adult Mice.

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    Hong-Li Sun

    Full Text Available Recent studies have provided evidence that depolarization in the absence of extracellular Ca2+ can trigger Ca2+ release from internal stores in a variety of neuron subtypes. Here we examine whether postganglionic sympathetic neurons are able to mobilize Ca2+ from intracellular stores in response to depolarization, independent of Ca2+ influx. We measured changes in cytosolic ΔF/F0 in individual fluo-4 -loaded sympathetic ganglion neurons in response to maintained K+ depolarization in the presence (2 mM and absence of extracellular Ca2+ ([Ca2+]e. Progressive elevations in extracellular [K+]e caused increasing membrane depolarizations that were of similar magnitude in 0 and 2 mM [Ca2+]e. Peak amplitude of ΔF/F0 transients in 2 mM [Ca2+]e increased in a linear fashion as the membrane become more depolarized. Peak elevations of ΔF/F0 in 0 mM [Ca2+]e were ~5-10% of those evoked at the same membrane potential in 2 mM [Ca2+]e and exhibited an inverse U-shaped dependence on voltage. Both the rise and decay of ΔF/F0 transients in 0 mM [Ca2+]e were slower than those of ΔF/F0 transients evoked in 2 mM [Ca2+]e. Rises in ΔF/F0 evoked by high [K+]e in the absence of extracellular Ca2+ were blocked by thapsigargin, an inhibitor of endoplasmic reticulum Ca2+ ATPase, or the inositol 1,4,5-triphosphate (IP3 receptor antagonists 2-aminoethoxydiphenyl borate and xestospongin C, but not by extracellular Cd2+, the dihydropyridine antagonist nifedipine, or by ryanodine at concentrations that caused depletion of ryanodine-sensitive Ca2+ stores. These results support the notion that postganglionic sympathetic neurons possess the ability to release Ca2+ from IP3-sensitive internal stores in response to membrane depolarization, independent of Ca2+ influx.

  14. CaMKII Regulates Synaptic NMDA Receptor Activity of Hypothalamic Presympathetic Neurons and Sympathetic Outflow in Hypertension.

    Science.gov (United States)

    Li, De-Pei; Zhou, Jing-Jing; Zhang, Jixiang; Pan, Hui-Lin

    2017-11-01

    NMDAR activity in the hypothalamic paraventricular nucleus (PVN) is increased and critically involved in heightened sympathetic vasomotor tone in hypertension. Calcium/calmodulin-dependent protein kinase II (CaMKII) binds to and modulates NMDAR activity. In this study, we determined the role of CaMKII in regulating NMDAR activity of PVN presympathetic neurons in male spontaneously hypertensive rats (SHRs). NMDAR-mediated EPSCs and puff NMDA-elicited currents were recorded in spinally projecting PVN neurons in SHRs and male Wistar-Kyoto (WKY) rats. The basal amplitude of evoked NMDAR-EPSCs and puff NMDA currents in retrogradely labeled PVN neurons were significantly higher in SHRs than in WKY rats. The CaMKII inhibitor autocamtide-2-related inhibitory peptide (AIP) normalized the increased amplitude of NMDAR-EPSCs and puff NMDA currents in labeled PVN neurons in SHRs but had no effect in WKY rats. Treatment with AIP also normalized the higher frequency of NMDAR-mediated miniature EPSCs of PVN neurons in SHRs. CaMKII-mediated phosphorylation level of GluN2B serine 1303 (S1303) in the PVN, but not in the hippocampus and frontal cortex, was significantly higher in SHRs than in WKY rats. Lowering blood pressure with celiac ganglionectomy in SHRs did not alter the increased level of phosphorylated GluN2B S1303 in the PVN. In addition, microinjection of AIP into the PVN significantly reduced arterial blood pressure and lumbar sympathetic nerve discharges in SHRs. Our findings suggest that CaMKII activity is increased in the PVN and contributes to potentiated presynaptic and postsynaptic NMDAR activity to elevate sympathetic vasomotor tone in hypertension. SIGNIFICANCE STATEMENT Heightened sympathetic vasomotor tone is a major contributor to the development of hypertension. Although glutamate NMDA receptor (NMDAR)-mediated excitatory drive in the hypothalamus plays a critical role in increased sympathetic output in hypertension, the molecular mechanism involved in

  15. Mirror Neurons and Literature: Empathy and the Sympathetic Imagination in the Fiction of J.M. Coetzee

    Directory of Open Access Journals (Sweden)

    Hilmar Heister

    2015-01-01

    Full Text Available In the two essays “The Philosophers and the Animals” and “The Poets and the Animals” (in The Lives of Animals, 1999 J.M. Coetzee lets Elizabeth Costello urge us to use our sympathetic imagination in order to access the experience of others—in particular, animals—and engage with them empathetically. Coetzee’s fiction illustrates how the use of the sympathetic imagination might evoke empathy in the reader. Narrative structure and the character’s mode of introspection engage the reader’s empathy through an ambivalent process of distancing and approximation, as Fritz Breithaupt puts forward in his narrative theory of empathy (Kulturen der Empathie, 2009. The sympathetic imagination and the complementary notion of embodiment feature prominently in Coetzee’s fictional discourse and resonate with neuroscience’s research on mirror neurons and their relation to empathy.

  16. elPBN neurons regulate rVLM activity through elPBN-rVLM projections during activation of cardiac sympathetic afferent nerves

    Science.gov (United States)

    Longhurst, John C.; Tjen-A-Looi, Stephanie C.; Fu, Liang-Wu

    2016-01-01

    The external lateral parabrachial nucleus (elPBN) within the pons and rostral ventrolateral medulla (rVLM) contributes to central processing of excitatory cardiovascular reflexes during stimulation of cardiac sympathetic afferent nerves (CSAN). However, the importance of elPBN cardiovascular neurons in regulation of rVLM activity during CSAN activation remains unclear. We hypothesized that CSAN stimulation excites the elPBN cardiovascular neurons and, in turn, increases rVLM activity through elPBN-rVLM projections. Compared with controls, in rats subjected to microinjection of retrograde tracer into the rVLM, the numbers of elPBN neurons double-labeled with c-Fos (an immediate early gene) and the tracer were increased after CSAN stimulation (P < 0.05). The majority of these elPBN neurons contain vesicular glutamate transporter 3. In cats, epicardial bradykinin and electrical stimulation of CSAN increased the activity of elPBN cardiovascular neurons, which was attenuated (n = 6, P < 0.05) after blockade of glutamate receptors with iontophoresis of kynurenic acid (Kyn, 25 mM). In separate cats, microinjection of Kyn (1.25 nmol/50 nl) into the elPBN reduced rVLM activity evoked by both bradykinin and electrical stimulation (n = 5, P < 0.05). Excitation of the elPBN with microinjection of dl-homocysteic acid (2 nmol/50 nl) significantly increased basal and CSAN-evoked rVLM activity. However, the enhanced rVLM activity induced by dl-homocysteic acid injected into the elPBN was reversed following iontophoresis of Kyn into the rVLM (n = 7, P < 0.05). These data suggest that cardiac sympathetic afferent stimulation activates cardiovascular neurons in the elPBN and rVLM sequentially through a monosynaptic (glutamatergic) excitatory elPBN-rVLM pathway. PMID:27225950

  17. elPBN neurons regulate rVLM activity through elPBN-rVLM projections during activation of cardiac sympathetic afferent nerves.

    Science.gov (United States)

    Guo, Zhi-Ling; Longhurst, John C; Tjen-A-Looi, Stephanie C; Fu, Liang-Wu

    2016-08-01

    The external lateral parabrachial nucleus (elPBN) within the pons and rostral ventrolateral medulla (rVLM) contributes to central processing of excitatory cardiovascular reflexes during stimulation of cardiac sympathetic afferent nerves (CSAN). However, the importance of elPBN cardiovascular neurons in regulation of rVLM activity during CSAN activation remains unclear. We hypothesized that CSAN stimulation excites the elPBN cardiovascular neurons and, in turn, increases rVLM activity through elPBN-rVLM projections. Compared with controls, in rats subjected to microinjection of retrograde tracer into the rVLM, the numbers of elPBN neurons double-labeled with c-Fos (an immediate early gene) and the tracer were increased after CSAN stimulation (P neurons contain vesicular glutamate transporter 3. In cats, epicardial bradykinin and electrical stimulation of CSAN increased the activity of elPBN cardiovascular neurons, which was attenuated (n = 6, P neurons in the elPBN and rVLM sequentially through a monosynaptic (glutamatergic) excitatory elPBN-rVLM pathway. Copyright © 2016 the American Physiological Society.

  18. Individual sympathetic postganglionic neurons coinnervate myenteric ganglia and smooth muscle layers in the gastrointestinal tract of the rat.

    Science.gov (United States)

    Walter, Gary C; Phillips, Robert J; McAdams, Jennifer L; Powley, Terry L

    2016-09-01

    A full description of the terminal architecture of sympathetic axons innervating the gastrointestinal (GI) tract has not been available. To label sympathetic fibers projecting to the gut muscle wall, dextran biotin was injected into the celiac and superior mesenteric ganglia (CSMG) of rats. Nine days postinjection, animals were euthanized and stomachs and small intestines were processed as whole mounts (submucosa and mucosa removed) to examine CSMG efferent terminals. Myenteric neurons were counterstained with Cuprolinic Blue; catecholaminergic axons were stained immunohistochemically for tyrosine hydroxylase. Essentially all dextran-labeled axons (135 of 136 sampled) were tyrosine hydroxylase-positive. Complete postganglionic arbors (n = 154) in the muscle wall were digitized and analyzed morphometrically. Individual sympathetic axons formed complex arbors of varicose neurites within myenteric ganglia/primary plexus and, concomitantly, long rectilinear arrays of neurites within circular muscle/secondary plexus or longitudinal muscle/tertiary plexus. Very few CSMG neurons projected exclusively (i.e., ∼100% of an arbor's varicose branches) to myenteric plexus (∼2%) or smooth muscle (∼14%). With less stringent inclusion criteria (i.e., ≥85% of an axon's varicose branches), larger minorities of neurons projected predominantly to either myenteric plexus (∼13%) or smooth muscle (∼27%). The majority (i.e., ∼60%) of all individual CSMG postganglionics formed mixed, heterotypic arbors that coinnervated extensively (>15% of their varicose branches per target) both myenteric ganglia and smooth muscle. The fact that ∼87% of all sympathetics projected either extensively or even predominantly to smooth muscle, while simultaneously contacting myenteric plexus, is consistent with the view that these neurons control GI muscle directly, if not exclusively. J. Comp. Neurol. 524:2577-2603, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  19. Role of adrenal hormones in the synthesis of noradrenaline in cardiac sympathetic neurones

    Science.gov (United States)

    Bhagat, B.

    1969-01-01

    1. Adrenalectomy or adrenal demedullation affected neither the levels of endogenous catecholamines in the rat heart nor the accumulation of 3H-noradrenaline 1 hr after its intravenous administration. 2. Twenty-four hours after intravenous administration of labelled amine, however, its retention was markedly reduced in the heart of adrenalectomized or demedullated rats. Ganglionic blockade prevented this reduction. 3. Rate calculations from the decline of catecholamine levels after blockade of synthesis with α-methyl-tyrosine showed that cardiac synthesis of noradrenaline increased about four-fold after demedullation and about three-fold after adrenalectomy. This increase in synthesis may compensate for the loss of circulating catecholamines. 4. There was no change in catechol-o-methyl-transferase activity, but monoamine oxidase activity was increased in the homogenates of the heart of adrenalectomized and demedullated rats. The increase in the cardiac monoamine oxidase activity was markedly greater in the adrenalectomized rats than in the demedullated rats. 5. It is suggested that adrenal cortex insufficiency may modulate the rate of synthesis of noradrenaline and monoamine oxidase activity in cardiac sympathetic neurones. PMID:5360339

  20. Modification of sympathetic neuronal function in the rat tail artery by dietary lipid treatment

    International Nuclear Information System (INIS)

    Panek, R.L.; Dixon, W.R.; Rutledge, C.O.

    1985-01-01

    The effect of dietary lipid treatment on sympathetic neuronal function was examined in isolated perfused tail arteries of adult rats. The hypothesis that dietary manipulations alter the lipid environment of receptor proteins which may result in the perturbation of specific membrane-associated processes that regulate peripheral adrenergic neurotransmission in the vasculature was the basis for this investigation. In the present study, rats were fed semisynthetic diets enriched in either 16% coconut oil (saturated fat) or 16% sunflower oil (unsaturated fat). The field stimulation-evoked release of endogenous norepinephrine and total 3 H was decreased significantly in rats receiving the coconut oil diet when compared to either sunflower oil- or standard lab chow-fed rats. Norepinephrine content in artery segments from coconut oil-treated rats was significantly higher compared to either sunflower oil- or standard lab chow-fed rats. Tail arteries from rats receiving the coconut oil diet displayed significantly lower perfusion pressure responses to nerve stimulation at all frequencies tested when compared to the sunflower oil- or standard lab chow-fed rats. Vasoconstrictor responses of perfused tail arteries exposed to exogenous norepinephrine resulted in an EC50 for norepinephrine that was not changed by the dietary treatment, but adult rats receiving the sunflower oil diet displayed a significantly greater maximum response to exogenous norepinephrine (10(-5) M) compared to arteries from either coconut oil- or standard lab chow-fed rats

  1. Hydralazine administration activates sympathetic preganglionic neurons whose activity mobilizes glucose and increases cardiovascular function.

    Science.gov (United States)

    Parker, Lindsay M; Damanhuri, Hanafi A; Fletcher, Sophie P S; Goodchild, Ann K

    2015-04-16

    Hypotensive drugs have been used to identify central neurons that mediate compensatory baroreceptor reflex responses. Such drugs also increase blood glucose. Our aim was to identify the neurochemical phenotypes of sympathetic preganglionic neurons (SPN) and adrenal chromaffin cells activated following hydralazine (HDZ; 10mg/kg) administration in rats, and utilize this and SPN target organ destination to ascribe their function as cardiovascular or glucose regulating. Blood glucose was measured and adrenal chromaffin cell activation was assessed using c-Fos immunoreactivity (-ir) and phosphorylation of tyrosine hydroxylase, respectively. The activation and neurochemical phenotype of SPN innervating the adrenal glands and celiac ganglia were determined using the retrograde tracer cholera toxin B subunit, in combination with in situ hybridization and immunohistochemistry. Blood glucose was elevated at multiple time points following HDZ administration but little evidence of chromaffin cell activation was seen suggesting non-adrenal mechanisms contribute to the sustained hyperglycemia. 16±0.1% of T4-T11 SPN contained c-Fos and of these: 24.3±1.4% projected to adrenal glands and 29±5.5% projected to celiac ganglia with the rest innervating other targets. 62.8±1.4% of SPN innervating adrenal glands were activated and 29.9±3.3% expressed PPE mRNA whereas 53.2±8.6% of SPN innervating celiac ganglia were activated and 31.2±8.8% expressed PPE mRNA. CART-ir SPN innervating each target were also activated and did not co-express PPE mRNA. Neurochemical coding reveals that HDZ administration activates both PPE+SPN, whose activity increase glucose mobilization causing hyperglycemia, as well as CART+SPN whose activity drive vasomotor responses mediated by baroreceptor unloading to raise vascular tone and heart rate. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Innervating sympathetic neurons regulate heart size and the timing of cardiomyocyte cell cycle withdrawal.

    Science.gov (United States)

    Kreipke, R E; Birren, S J

    2015-12-01

    Sympathetic drive to the heart is a key modulator of cardiac function and interactions between heart tissue and innervating sympathetic fibres are established early in development. Significant innervation takes place during postnatal heart development, a period when cardiomyocytes undergo a rapid transition from proliferative to hypertrophic growth. The question of whether these innervating sympathetic fibres play a role in regulating the modes of cardiomyocyte growth was investigated using 6-hydroxydopamine (6-OHDA) to abolish early sympathetic innervation of the heart. Postnatal chemical sympathectomy resulted in rats with smaller hearts, indicating that heart growth is regulated by innervating sympathetic fibres during the postnatal period. In vitro experiments showed that sympathetic interactions resulted in delays in markers of cardiomyocyte maturation, suggesting that changes in the timing of the transition from hyperplastic to hypertrophic growth of cardiomyocytes could underlie changes in heart size in the sympathectomized animals. There was also an increase in the expression of Meis1, which has been linked to cardiomyocyte cell cycle withdrawal, suggesting that sympathetic signalling suppresses cell cycle withdrawal. This signalling involves β-adrenergic activation, which was necessary for sympathetic regulation of cardiomyocyte proliferation and hypertrophy. The effect of β-adrenergic signalling on cardiomyocyte hypertrophy underwent a developmental transition. While young postnatal cardiomyocytes responded to isoproterenol (isoprenaline) with a decrease in cell size, mature cardiomyocytes showed an increase in cell size in response to the drug. Together, these results suggest that early sympathetic effects on proliferation modulate a key transition between proliferative and hypertrophic growth of the heart and contribute to the sympathetic regulation of adult heart size. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

  3. Increased intrinsic excitability of muscle vasoconstrictor preganglionic neurons may contribute to the elevated sympathetic activity in hypertensive rats.

    Science.gov (United States)

    Briant, Linford J B; Stalbovskiy, Alexey O; Nolan, Matthew F; Champneys, Alan R; Pickering, Anthony E

    2014-12-01

    Hypertension is associated with pathologically increased sympathetic drive to the vasculature. This has been attributed to increased excitatory drive to sympathetic preganglionic neurons (SPN) from brainstem cardiovascular control centers. However, there is also evidence supporting increased intrinsic excitability of SPN. To test this hypothesis, we made whole cell recordings of muscle vasoconstrictor-like (MVClike) SPN in the working-heart brainstem preparation of spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WKY) rats. The MVClike SPN have a higher spontaneous firing frequency in the SH rat (3.85 ± 0.4 vs. 2.44 ± 0.4 Hz in WKY; P = 0.011) with greater respiratory modulation of their activity. The action potentials of SH SPN had smaller, shorter afterhyperpolarizations (AHPs) and showed diminished transient rectification indicating suppression of an A-type potassium conductance (IA). We developed mathematical models of the SPN to establish if changes in their intrinsic properties in SH rats could account for their altered firing. Reduction of the maximal conductance density of IA by 15-30% changed the excitability and output of the model from the WKY to a SH profile, with increased firing frequency, amplified respiratory modulation, and smaller AHPs. This change in output is predominantly a consequence of altered synaptic integration. Consistent with these in silico predictions, we found that intrathecal 4-aminopyridine (4-AP) increased sympathetic nerve activity, elevated perfusion pressure, and augmented Traube-Hering waves. Our findings indicate that IA acts as a powerful filter on incoming synaptic drive to SPN and that its diminution in the SH rat is potentially sufficient to account for the increased sympathetic output underlying hypertension. Copyright © 2014 the American Physiological Society.

  4. Efficacy of B-Type Natriuretic Peptide Is Coupled to Phosphodiesterase 2A in Cardiac Sympathetic Neurons.

    Science.gov (United States)

    Li, Dan; Lu, Chieh-Ju; Hao, Guoliang; Wright, Hannah; Woodward, Lavinia; Liu, Kun; Vergari, Elisa; Surdo, Nicoletta C; Herring, Neil; Zaccolo, Manuela; Paterson, David J

    2015-07-01

    Elevated B-type natriuretic peptide (BNP) regulates cGMP-phosphodiesterase activity. Its elevation is regarded as an early compensatory response to cardiac failure where it can facilitate sympathovagal balance and cardiorenal homeostasis. However, recent reports suggest a paradoxical proadrenergic action of BNP. Because phosphodiesterase activity is altered in cardiovascular disease, we tested the hypothesis that BNP might lose its efficacy by minimizing the action of cGMP on downstream pathways coupled to neurotransmission. BNP decreased norepinephrine release from atrial preparations in response to field stimulation and also significantly reduced the heart rate responses to sympathetic nerve stimulation in vitro. Using electrophysiological recording and fluorescence imaging, BNP also reduced the depolarization evoked calcium current and intracellular calcium transient in isolated cardiac sympathetic neurons. Pharmacological manipulations suggested that the reduction in the calcium transient was regulated by a cGMP/protein kinase G pathway. Fluorescence resonance energy transfer measurements for cAMP, and an immunoassay for cGMP, showed that BNP increased cGMP, but not cAMP. In addition, overexpression of phosphodiesterase 2A after adenoviral gene transfer markedly decreased BNP stimulation of cGMP and abrogated the BNP responses to the calcium current, intracellular calcium transient, and neurotransmitter release. These effects were reversed on inhibition of phosphodiesterase 2A. Moreover, phosphodiesterase 2A activity was significantly elevated in stellate neurons from the prohypertensive rat compared with the normotensive control. Our data suggest that abnormally high levels of phosphodiesterase 2A may provide a brake against the inhibitory action of BNP on sympathetic transmission. © 2015 American Heart Association, Inc.

  5. Estimation of regional myocardial sympathetic neuronal function with I-123 metaiodobenzylguanidine (MIBG) myocardial images in patients with cardiomyopathy

    International Nuclear Information System (INIS)

    Tanaka, Takeshi; Aizawa, Tadanori; Kato, Kazuzo; Nakano, Hajime; Igarashi, Masaki; Ueno, Takashi; Hirosawa, Koshichiro; Kusakabe, Kiyoko.

    1989-01-01

    Myocardial SPECT images with I-123 metaiodobenzylguanidine (MIBG) were obtained in 10 patients with cardiomyopathy under stable state. For myocardial imaging, MIBG and Tl-201 (Tl) were simultaneously injected and collected. The ratio of MIBG to Tl (M/T ratio) in ROI was obtained with 50% cut off levels in order to eliminate background activity. The patients were divided into three major groups: (l) those who had the M/T ratio ranging from 0.8 to l.20 at rest and had marked defects in the infero-lateral region on delayed MIBG images, where pathophysiologically accelerated regional sympathetic neuronal function was suspected (n=5), (II) those who had increased M/T ratios (l.6 and l.7) in the basal septal wall (n=3), and (III) those who had decreased M/T ratios (0.7 and 0.75) in the apical septal wall, where depletion of myocardial norepinephrine was suspected (n=2). These findings indicate the potential of myocardial MIBG images to evaluate myocardial distribution of norepinephrine, i.e. myocardial sympathetic neuronal function. Certain shortcomings, such as an increased background due to dual isotopes and an increased pulmonary uptake of MIBG, require further study on quantitative methods. (Namekawa, K)

  6. The Suprachiasmatic nucleus balances sympathetic and parasympathetic output to peripheral organs through separate preautonomic neurons

    NARCIS (Netherlands)

    Buijs, Ruud M.; la Fleur, Susanne E.; Wortel, Joke; van Heyningen, Caroline; Zuiddam, Laura; Mettenleiter, Thomas C.; Kalsbeek, Andries; Nagai, Katsuya; Niijima, Akira

    2003-01-01

    Opposing parasympathetic and sympathetic signals determine the autonomic output of the brain to the body and the change in balance over the sleep-wake cycle. The suprachiasmatic nucleus (SCN) organizes the activity/inactivity cycle and the behaviors that go along with it, but it is unclear how the

  7. Cardiac retention of PET neuronal imaging agent LMI1195 in different species: Impact of norepinephrine uptake-1 and -2 transporters

    International Nuclear Information System (INIS)

    Yu, Ming; Bozek, Jody; Kagan, Mikhail; Guaraldi, Mary; Silva, Paula; Azure, Michael; Onthank, David; Robinson, Simon P.

    2013-01-01

    Introduction: Released sympathetic neurotransmitter norepinephrine (NE) in the heart is cleared by neuronal uptake-1 and extraneuronal uptake-2 transporters. Cardiac uptake-1 and -2 expression varies among species, but the uptake-1 is the primary transporter in humans. LMI1195 is an NE analog labeled with 18 F for PET evaluation of cardiac neuronal function. This study investigated the impact of cardiac neuronal uptake-1 associated with different species on LMI1195 heart uptake. Methods: Cardiac uptake-1 was blocked by desipramine, a selective uptake-1 inhibitor, and sympathetic neuronal denervation was induced by 6-hydroxydopamine, a neurotoxin, in rats, rabbits and nonhuman primates (NHP). Tissue biodistribution and cardiac imaging of LMI1195 and 123 I-metaiodobenzylguanidine (MIBG) were performed. Results: In rats, uptake-1 blockade did not alter LMI1195 heart uptake compared to the control at 60-min post injection [1.41 ± 0.07 vs. 1.47 ± 0.23 % injected dose per gram tissue (%ID/g)]. In contrast, LMI1195 heart uptake was reduced by 80% in uptake-1 blocked rabbits. In sympathetically denervated rats, LMI1195 heart uptake was similar to the control (2.18 ± 0.40 vs. 2.58 ± 0.76 %ID/g). However, the uptake decreased by 79% in denervated rabbits. Similar results were found in MIBG heart uptake in rats and rabbits with uptake-1 blockade. Consistently, LMI1195 cardiac imaging showed comparable myocardial activity in uptake-1 blocked or sympathetically denervated rats to the control, but marked activity reduction in uptake-1 blocked or denervated rabbits and NHPs. Conclusions: LMI1195 is retained in the heart of rabbits and NHPs primarily via the neuronal uptake-1 with high selectivity and can be used for evaluation of cardiac sympathetic denervation. Similar to the human, the neuronal uptake-1 is the dominant transporter for cardiac retention of NE analogs in rabbits and NHPs, but not in rats

  8. Forskolin suppresses delayed-rectifier K+ currents and enhances spike frequency-dependent adaptation of sympathetic neurons.

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    Luis I Angel-Chavez

    Full Text Available In signal transduction research natural or synthetic molecules are commonly used to target a great variety of signaling proteins. For instance, forskolin, a diterpene activator of adenylate cyclase, has been widely used in cellular preparations to increase the intracellular cAMP level. However, it has been shown that forskolin directly inhibits some cloned K+ channels, which in excitable cells set up the resting membrane potential, the shape of action potential and regulate repetitive firing. Despite the growing evidence indicating that K+ channels are blocked by forskolin, there are no studies yet assessing the impact of this mechanism of action on neuron excitability and firing patterns. In sympathetic neurons, we find that forskolin and its derivative 1,9-Dideoxyforskolin, reversibly suppress the delayed rectifier K+ current (IKV. Besides, forskolin reduced the spike afterhyperpolarization and enhanced the spike frequency-dependent adaptation. Given that IKV is mostly generated by Kv2.1 channels, HEK-293 cells were transfected with cDNA encoding for the Kv2.1 α subunit, to characterize the mechanism of forskolin action. Both drugs reversible suppressed the Kv2.1-mediated K+ currents. Forskolin inhibited Kv2.1 currents and IKV with an IC50 of ~32 μM and ~24 µM, respectively. Besides, the drug induced an apparent current inactivation and slowed-down current deactivation. We suggest that forskolin reduces the excitability of sympathetic neurons by enhancing the spike frequency-dependent adaptation, partially through a direct block of their native Kv2.1 channels.

  9. Forskolin suppresses delayed-rectifier K+ currents and enhances spike frequency-dependent adaptation of sympathetic neurons.

    Science.gov (United States)

    Angel-Chavez, Luis I; Acosta-Gómez, Eduardo I; Morales-Avalos, Mario; Castro, Elena; Cruzblanca, Humberto

    2015-01-01

    In signal transduction research natural or synthetic molecules are commonly used to target a great variety of signaling proteins. For instance, forskolin, a diterpene activator of adenylate cyclase, has been widely used in cellular preparations to increase the intracellular cAMP level. However, it has been shown that forskolin directly inhibits some cloned K+ channels, which in excitable cells set up the resting membrane potential, the shape of action potential and regulate repetitive firing. Despite the growing evidence indicating that K+ channels are blocked by forskolin, there are no studies yet assessing the impact of this mechanism of action on neuron excitability and firing patterns. In sympathetic neurons, we find that forskolin and its derivative 1,9-Dideoxyforskolin, reversibly suppress the delayed rectifier K+ current (IKV). Besides, forskolin reduced the spike afterhyperpolarization and enhanced the spike frequency-dependent adaptation. Given that IKV is mostly generated by Kv2.1 channels, HEK-293 cells were transfected with cDNA encoding for the Kv2.1 α subunit, to characterize the mechanism of forskolin action. Both drugs reversible suppressed the Kv2.1-mediated K+ currents. Forskolin inhibited Kv2.1 currents and IKV with an IC50 of ~32 μM and ~24 µM, respectively. Besides, the drug induced an apparent current inactivation and slowed-down current deactivation. We suggest that forskolin reduces the excitability of sympathetic neurons by enhancing the spike frequency-dependent adaptation, partially through a direct block of their native Kv2.1 channels.

  10. Endothelial and Neuronal Nitric Oxide Activate Distinct Pathways on Sympathetic Neurotransmission in Rat Tail and Mesenteric Arteries.

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    Joana Beatriz Sousa

    Full Text Available Nitric oxide (NO seems to contribute to vascular homeostasis regulating neurotransmission. This work aimed at assessing the influence of NO from different sources and respective intracellular pathways on sympathetic neurotransmission, in two vascular beds. Electrically-evoked [3H]-noradrenaline release was assessed in rat mesenteric and tail arteries in the presence of NO donors or endothelial/neuronal nitric oxide synthase (NOS inhibitors. The influence of NO on adenosine-mediated effects was also studied using selective antagonists for adenosine receptors subtypes. Location of neuronal NOS (nNOS was investigated by immunohistochemistry (with specific antibodies for nNOS and for Schwann cells and Confocal Microscopy. Results indicated that: 1 in mesenteric arteries, noradrenaline release was reduced by NO donors and it was increased by nNOS inhibitors; the effect of NO donors was only abolished by the adenosine A1 receptors antagonist; 2 in tail arteries, noradrenaline release was increased by NO donors and it was reduced by eNOS inhibitors; adenosine receptors antagonists were devoid of effect; 3 confocal microscopy showed nNOS staining in adventitial cells, some co-localized with Schwann cells. nNOS staining and its co-localization with Schwann cells were significantly lower in tail compared to mesenteric arteries. In conclusion, in mesenteric arteries, nNOS, mainly located in Schwann cells, seems to be the main source of NO influencing perivascular sympathetic neurotransmission with an inhibitory effect, mediated by adenosine A1 receptors activation. Instead, in tail arteries endothelial NO seems to play a more relevant role and has a facilitatory effect, independent of adenosine receptors activation.

  11. Neuronal uptake and metabolism of 2- and 6-fluorodopamine: false neurotransmitters for positron emission tomographic imaging of sympathetically innervated tissues

    Energy Technology Data Exchange (ETDEWEB)

    Eisenhofer, G.; Hovevey-Sion, D.; Kopin, I.J.; Miletich, R.; Kirk, K.L.; Finn, R.; Goldstein, D.S.

    1989-01-01

    The neuronal uptake and metabolism of 2-fluorodopamine (2F-dopamine), 6-fluorodopamine (6F-dopamine) and tritium-labeled dopamine were compared in heart, submaxillary gland and spleen of rats to assess the utility of 18F-labeled 2F- or 6F-dopamine for positron emission tomographic imaging of sympathetically innervated tissues. Tritiated dopamine with and without 2F- or 6F-dopamine, or tritiated 2F-dopamine alone, were injected i.v. into rats that were or were not pretreated with desipramine to block catecholamine neuronal uptake or with reserpine to block vesicular translocation of catecholamines. Tissue and plasma samples were obtained at intervals up to 1 hr after injections. At 1 hr after injection of tritiated dopamine, tritium-labeled norepinephrine, dopamine, dihydroxyphenylacetic acid and dihydroxyphenylglucol accounted for less than 2% of the tritium in plasma but up to 92% of that in tissues; tritiated norepinephrine accounted for 70% or more of the tritium in tissues. In contrast, at 1 hr after injection of tritiated 2F-dopamine, tritiated 2F-norepinephrine accounted for 30 to 46% of the tritium in tissues. Desipramine and reserpine pretreatment blocked the tissue accumulation of tritiated and fluorinated dopamine as well as their dihydroxy-metabolites, indicating that accumulation of exogenous norepinephrine and dopamine analogs was within sympathetic storage vesicles. Relative to the doses of dopamine precursors, less 2F- and 6F-norepinephrine accumulated in tissues than tritiated norepinephrine, due largely to inefficient beta-hydroxylation of fluorinated dopamine.

  12. Neuronal uptake and metabolism of 2- and 6-fluorodopamine: false neurotransmitters for positron emission tomographic imaging of sympathetically innervated tissues

    International Nuclear Information System (INIS)

    Eisenhofer, G.; Hovevey-Sion, D.; Kopin, I.J.; Miletich, R.; Kirk, K.L.; Finn, R.; Goldstein, D.S.

    1989-01-01

    The neuronal uptake and metabolism of 2-fluorodopamine (2F-dopamine), 6-fluorodopamine (6F-dopamine) and tritium-labeled dopamine were compared in heart, submaxillary gland and spleen of rats to assess the utility of 18F-labeled 2F- or 6F-dopamine for positron emission tomographic imaging of sympathetically innervated tissues. Tritiated dopamine with and without 2F- or 6F-dopamine, or tritiated 2F-dopamine alone, were injected i.v. into rats that were or were not pretreated with desipramine to block catecholamine neuronal uptake or with reserpine to block vesicular translocation of catecholamines. Tissue and plasma samples were obtained at intervals up to 1 hr after injections. At 1 hr after injection of tritiated dopamine, tritium-labeled norepinephrine, dopamine, dihydroxyphenylacetic acid and dihydroxyphenylglucol accounted for less than 2% of the tritium in plasma but up to 92% of that in tissues; tritiated norepinephrine accounted for 70% or more of the tritium in tissues. In contrast, at 1 hr after injection of tritiated 2F-dopamine, tritiated 2F-norepinephrine accounted for 30 to 46% of the tritium in tissues. Desipramine and reserpine pretreatment blocked the tissue accumulation of tritiated and fluorinated dopamine as well as their dihydroxy-metabolites, indicating that accumulation of exogenous norepinephrine and dopamine analogs was within sympathetic storage vesicles. Relative to the doses of dopamine precursors, less 2F- and 6F-norepinephrine accumulated in tissues than tritiated norepinephrine, due largely to inefficient beta-hydroxylation of fluorinated dopamine

  13. Localization and neurochemical characteristics of the extrinsic sympathetic neurons projecting to the pylorus in the domestic pig.

    Science.gov (United States)

    Zalecki, Michal

    2012-01-01

    The pylorus, an important part of the digestive tract controlling the flow of chyme between the stomach and the duodenum, is widely innervated by intrinsic and extrinsic nerves. To determine the locations of postganglionic sympathetic perikarya that innervate the pylorus of the domestic pig, a retrograde tracing method with application of Fast Blue tracer was used. All positive neuronal cell bodies (ca. 1750) were found in the celiac-cranial mesenteric ganglion complex (CSMG), however, the coeliac poles of this complex provided the major input to the pylorus. Afterwards, the immunohistochemical staining procedure was applied to determine biologically active substances expressed in the FB-labeled perikarya. Approximately 77% of the FB-positive cell bodies contained tyrosine hydroxylase (TH), 87% dopamine β-hydroxylase (DβH), 40% neuropeptide Y (NPY), 12% somatostatin (SOM) and 7% galanin (GAL). The presence of all these substances in the ganglion tissue was confirmed by RT-PCR technique. Double immunocytochemistry revealed that all of the TH-positive perikarya contained DβH, about 40% NPY, 12% SOM and 8% GAL. Additionally, all above-cited immunohistochemical markers as well as VIP, PACAP, ChAT, LEU, MET, SP and nNOS were observed within nerve fibers associated with the FB-positive perikarya. Immunocytochemical labeling of the pyloric wall tissue disclosed that TH+, DβH+ and NPY+ nerve fibers innervated ganglia of the myenteric and submucosal plexuses, blood vessels, both muscular layers and the muscularis mucosae; nerve fibers immunoreactive to GAL mostly innervated both muscular layers, while SOM+ nerve fibers were observed within the myenteric plexus. Presented study revealed sources of origin and immunohistochemical characteristics of the sympathetic postganglionic perikarya innervating the porcine pylorus. Copyright © 2011 Elsevier B.V. All rights reserved.

  14. Serotonin and Serotonin Transporters in the Adrenal Medulla: A Potential Hub for Modulation of the Sympathetic Stress Response.

    Science.gov (United States)

    Brindley, Rebecca L; Bauer, Mary Beth; Blakely, Randy D; Currie, Kevin P M

    2017-05-17

    Serotonin (5-HT) is an important neurotransmitter in the central nervous system where it modulates circuits involved in mood, cognition, movement, arousal, and autonomic function. The 5-HT transporter (SERT; SLC6A4) is a key regulator of 5-HT signaling, and genetic variations in SERT are associated with various disorders including depression, anxiety, and autism. This review focuses on the role of SERT in the sympathetic nervous system. Autonomic/sympathetic dysfunction is evident in patients with depression, anxiety, and other diseases linked to serotonergic signaling. Experimentally, loss of SERT function (SERT knockout mice or chronic pharmacological block) has been reported to augment the sympathetic stress response. Alterations to serotonergic signaling in the CNS and thus central drive to the peripheral sympathetic nervous system are presumed to underlie this augmentation. Although less widely recognized, SERT is robustly expressed in chromaffin cells of the adrenal medulla, the neuroendocrine arm of the sympathetic nervous system. Adrenal chromaffin cells do not synthesize 5-HT but accumulate small amounts by SERT-mediated uptake. Recent evidence demonstrated that 5-HT 1A receptors inhibit catecholamine secretion from adrenal chromaffin cells via an atypical mechanism that does not involve modulation of cellular excitability or voltage-gated Ca 2+ channels. This raises the possibility that the adrenal medulla is a previously unrecognized peripheral hub for serotonergic control of the sympathetic stress response. As a framework for future investigation, a model is proposed in which stress-evoked adrenal catecholamine secretion is fine-tuned by SERT-modulated autocrine 5-HT signaling.

  15. Neurotrophin responsiveness of sympathetic neurons is regulated by rapid mobilization of the p75 receptor to the cell surface through TrkA activation of Arf6.

    Science.gov (United States)

    Edward Hickman, F; Stanley, Emily M; Carter, Bruce D

    2018-05-22

    The p75 neurotrophin receptor (p75NTR) plays an integral role in patterning the sympathetic nervous system during development. Initially, p75NTR is expressed at low levels as sympathetic axons project toward their targets, which enables neurotrophin-3 (NT3) to activate TrkA receptors and promote growth. Upon reaching nerve growth factor (NGF) producing tissues, p75NTR is up regulated resulting in formation of TrkA-p75 complexes, which are high affinity binding sites selective for NGF, thereby blunting NT3 signaling. The level of p75NTR expressed on the neuron surface is instrumental in regulating trophic factor response; however, the mechanisms by which p75NTR expression is regulated are poorly understood. Here, we demonstrate a rapid, translation independent increase in surface expression of p75NTR in response to NGF in rat sympathetic neurons. p75NTR was mobilized to the neuron surface from GGA3-postitive vesicles through activation of the GTPase Arf6, which was stimulated by NGF, but not NT3 binding to TrkA. Arf6 activation required PI3 kinase activity and was prevented by an inhibitor of the cytohesin family of Arf6 GEFs. Overexpression of a constitutively active Arf6 mutant (Q67L) was sufficient to significantly increase surface expression of p75NTR even in the absence of NGF. Functionally, expression of active Arf6 markedly attenuated the ability of NT3 to promote neuronal survival and neurite outgrowth while the NGF response was unaltered. These data suggest that NGF activation of Arf6 through TrkA is critical for the increase in p75NTR surface expression that enables the switch in neurotrophin responsiveness during development in the sympathetic nervous system. SIGNIFICANCE STATEMENT p75NTR is instrumental in the regulation of neuronal survival and apoptosis during development and is also implicated as a contributor to aberrant neurodegeneration in numerous conditions. Therefore, a better understanding of the mechanisms that mediate p75NTR surface

  16. Myocardial Infarction Causes Transient Cholinergic Transdifferentiation of Cardiac Sympathetic Nerves via gp130.

    Science.gov (United States)

    Olivas, Antoinette; Gardner, Ryan T; Wang, Lianguo; Ripplinger, Crystal M; Woodward, William R; Habecker, Beth A

    2016-01-13

    Sympathetic and parasympathetic control of the heart is a classic example of norepinephrine (NE) and acetylcholine (ACh) triggering opposing actions. Sympathetic NE increases heart rate and contractility through activation of β receptors, whereas parasympathetic ACh slows the heart through muscarinic receptors. Sympathetic neurons can undergo a developmental transition from production of NE to ACh and we provide evidence that mouse cardiac sympathetic nerves transiently produce ACh after myocardial infarction (MI). ACh levels increased in viable heart tissue 10-14 d after MI, returning to control levels at 21 d, whereas NE levels were stable. At the same time, the genes required for ACh synthesis increased in stellate ganglia, which contain most of the sympathetic neurons projecting to the heart. Immunohistochemistry 14 d after MI revealed choline acetyltransferase (ChAT) in stellate sympathetic neurons and vesicular ACh transporter immunoreactivity in tyrosine hydroxylase-positive cardiac sympathetic fibers. Finally, selective deletion of the ChAT gene from adult sympathetic neurons prevented the infarction-induced increase in cardiac ACh. Deletion of the gp130 cytokine receptor from sympathetic neurons prevented the induction of cholinergic genes after MI, suggesting that inflammatory cytokines induce the transient acquisition of a cholinergic phenotype in cardiac sympathetic neurons. Ex vivo experiments examining the effect of NE and ACh on rabbit cardiac action potential duration revealed that ACh blunted both the NE-stimulated decrease in cardiac action potential duration and increase in myocyte calcium transients. This raises the possibility that sympathetic co-release of ACh and NE may impair adaptation to high heart rates and increase arrhythmia susceptibility. Sympathetic neurons normally make norepinephrine (NE), which increases heart rate and the contractility of cardiac myocytes. We found that, after myocardial infarction, the sympathetic neurons

  17. Influence of the polyol pathway on norepinephrine transporter reduction in diabetic cardiac sympathetic nerves: implications for heterogeneous accumulation of MIBG

    International Nuclear Information System (INIS)

    Kiyono, Yasushi; Kajiyama, Satomi; Fujiwara, Hiromi; Kanegawa, Naoki; Saji, Hideo

    2005-01-01

    Cardiac scintigraphic studies using 123 I-labeled metaiodobenzylguanidine ([ 123 I]MIBG) have demonstrated heterogeneous myocardial accumulation of MIBG in diabetes. The accumulation has been found to correlate with a heterogeneous decrease in the expression of norepinephrine transporter (NET). In diabetic peripheral nerve tissue, polyol pathways are activated and cause nerve dysfunction and degeneration. However, there has been little research on the polyol pathway and cardiac sympathetic nerves. Therefore, to assess the influence of the polyol pathway on cardiac sympathetic nervous function, we investigated the regional accumulation of MIBG and NET protein expression in diabetic model rats treated with aldose reductase inhibitor (ARI) for the blockade of polyol pathways. Rats were given a single intravenous injection of streptozotocin (n=76, STZ-D rats). Starting the day after STZ injection, ARI was administered daily to 42 of the rats for 4 weeks (ARI-D rats). To assess the cardiac sympathetic nervous function, [ 125 I]MIBG autoradiographic experiments were carried out. Finally, NET protein expression was assessed with a saturation binding assay. The myocardial sorbitol concentration was significantly higher in STZ-D rats than in ARI-D rats. There was no heterogeneous accumulation of MIBG in ARI-D rats. There was a heterogeneous decrease of NET expression in STZ-D rats, but not in ARI-D or control rats. The gathered data indicate that the enhanced polyol pathway correlates with the decrease in regional cardiac sympathetic nervous function, and this impairment may lead to the reduction of NET protein in cardiac sympathetic nerves of the diabetic inferior wall. (orig.)

  18. Reduced capacity of cardiac efferent sympathetic neurons to release noradrenaline and modify cardiac function in tachycardia-induced canine heart failure.

    Science.gov (United States)

    Cardinal, R; Nadeau, R; Laurent, C; Boudreau, G; Armour, J A

    1996-09-01

    To investigate the capacity of efferent sympathetic neurons to modulate the failing heart, stellate ganglion stimulation was performed in dogs with biventricular heart failure induced by rapid ventricular pacing (240 beats/min) for 4-6 weeks. Less noradrenaline was released from cardiac myoneural junctions into coronary sinus blood in response to left stellate ganglion stimulation in anesthetized failing heart preparations (582 pg/mL, lower and upper 95% confidence intervals of 288 and 1174 pg/mL, n = 19) compared with healthy heart preparations (6391 pg/mL, 95% confidence intervals of 4180 and 9770 pg/mL, n = 14; p < 0.001). There was substantial adrenaline extraction by failing hearts (49 +/- 6%), although it was slightly lower than in healthy heart preparations (65 +/- 9%, p = 0.055). In contrast with healthy heart preparations, no net release of adrenaline occurred during stellate ganglion stimulation in any of the failing heart preparations, and ventricular tissue levels of adrenaline fell below the sensitivity limit of the HPLC technique. In failing heart preparations, maximal electrical stimulation of right or left stellate ganglia resulted in minimal augmentation of left ventricular intramyocardial (17%) and chamber (12%) systolic pressures. These indices were augmented by 145 and 97%, respectively, following exogenous noradrenaline administration. Thus, the cardiac efferent sympathetic neurons' reduced capacity to release noradrenaline and modify cardiac function can contribute to reduction of sympathetic support to the failing heart.

  19. Evidence that central dopamine receptors modulate sympathetic neuronal activity to the adrenal medulla to alter glucoregulatory mechanisms.

    Science.gov (United States)

    Arnerić, S P; Chow, S A; Bhatnagar, R K; Webb, R L; Fischer, L J; Long, J P

    1984-02-01

    Previous reports suggest that analogs of dopamine (DA) can produce hyperglycemia in rats by interacting with DA receptors. Experiments reported here indicate the site of action and describe the metabolic sequalae associated with the hyperglycemic effect of apomorphine (APO), produced in conscious unrestrained rats. Apomorphine was more potent when administered by intracerebroventricular (i.c.v.) injection than when given subcutaneously (s.c.). Very small doses of the DA receptor antagonist pimozide, given intraventricularly, blocked the hyperglycemic effect of apomorphine administered subcutaneously. Sectioning of the spinal cord at thoracic vertebra T1-2 or sectioning the greater splanchnic nerve blocked apomorphine-induced hyperglycemia; whereas section of the superior colliculus or section at T5-6 had no effect. A dose of apomorphine or epinephrine (EPI) producing a similar degree of hyperglycemia elevated the concentration of EPI in serum to a similar degree, and the increase in EPI in serum preceded the increase in glucose in serum. Fasting animals for 2 or 18 hr had no significant effect on EPI- or apomorphine-induced hyperglycemia despite a reduction (91-93%) of the glycogen content of liver and skeletal muscle during the 18 hr fast. 5-Methoxyindole-2-carboxylic acid (MICA), an inhibitor of gluconeogenesis, blocked EPI- and apomorphine-induced hyperglycemia in rats fasted for 18 hr. However, 5-methoxyindole-2-carboxylic acid was ineffective in blocking hyperglycemia in animals fasted for 2 hr. Changes in insulin or glucagon in serum alone cannot account for the hyperglycemic action of apomorphine. These data demonstrate that apomorphine interacts with central DA receptors located in the hindbrain to activate sympathetic neuronal activity to the adrenal gland which subsequently releases epinephrine to alter homeostasis of glucose. Epinephrine may then, depending on the nutritional status, facilitate glycogenolytic or gluconeogenic processes to produce

  20. The Influence of Prolonged Acetylsalicylic Acid Supplementation-Induced Gastritis on the Neurochemistry of the Sympathetic Neurons Supplying Prepyloric Region of the Porcine Stomach.

    Directory of Open Access Journals (Sweden)

    Katarzyna Palus

    Full Text Available This experiment was designed to establish the localization and neurochemical phenotyping of sympathetic neurons supplying prepyloric area of the porcine stomach in a physiological state and during acetylsalicylic acid (ASA induced gastritis. In order to localize the sympathetic perikarya the stomachs of both control and acetylsalicylic acid treated (ASA group animals were injected with neuronal retrograde tracer Fast Blue (FB. Seven days post FB injection, animals were divided into a control and ASA supplementation group. The ASA group was given 100 mg/kg of b.w. ASA orally for 21 days. On the 28th day all pigs were euthanized with gradual overdose of anesthetic. Then fourteen-micrometer-thick cryostat sections were processed for routine double-labeling immunofluorescence, using primary antisera directed towards tyrosine hydroxylase (TH, dopamine β-hydroxylase (DβH, neuropeptide Y (NPY, galanin (GAL, neuronal nitric oxide synthase (nNOS, leu 5-enkephalin (LENK, cocaine- and amphetamine- regulated transcript peptide (CART, calcitonin gene-related peptide (CGRP, substance P (SP and vasoactive intestinal peptide (VIP. The data obtained in this study indicate that postganglionic sympathetic nerve fibers supplying prepyloric area of the porcine stomach originate from the coeliac-cranial mesenteric ganglion complex (CCMG. In control animals, the FB-labelled neurons expressed TH (94.85 ± 1.01%, DβH (97.10 ± 0.97%, NPY (46.88 ± 2.53% and GAL (8.40 ± 0.53%. In ASA group, TH- and DβH- positive nerve cells were reduced (85.78 ± 2.65% and 88.82 ± 1.63% respectively. Moreover, ASA- induced gastritis resulted in increased expression of NPY (76.59 ± 3.02% and GAL (26.45 ± 2.75% as well as the novo-synthesis of nNOS (6.13 ± 1.11% and LENK (4.77 ± 0.42% in traced CCMG neurons. Additionally, a network of CART-, CGRP-, SP-, VIP-, LENK-, nNOS- immunoreactive (IR nerve fibers encircling the FB-positive perikarya were observed in both intact and ASA

  1. NaCl and osmolarity produce different responses in organum vasculosum of the lamina terminalis neurons, sympathetic nerve activity and blood pressure.

    Science.gov (United States)

    Kinsman, Brian J; Browning, Kirsteen N; Stocker, Sean D

    2017-09-15

    Changes in extracellular osmolarity stimulate thirst and vasopressin secretion through a central osmoreceptor; however, central infusion of hypertonic NaCl produces a greater sympathoexcitatory and pressor response than infusion of hypertonic mannitol/sorbitol. Neurons in the organum vasculosum of the lamina terminalis (OVLT) sense changes in extracellular osmolarity and NaCl. In this study, we discovered that intracerebroventricular infusion or local OVLT injection of hypertonic NaCl increases lumbar sympathetic nerve activity, adrenal sympathetic nerve activity and arterial blood pressure whereas equi-osmotic mannitol/sorbitol did not alter any variable. In vitro whole-cell recordings demonstrate the majority of OVLT neurons are responsive to hypertonic NaCl or mannitol. However, hypertonic NaCl stimulates a greater increase in discharge frequency than equi-osmotic mannitol. Intracarotid or intracerebroventricular infusion of hypertonic NaCl evokes a greater increase in OVLT neuronal discharge frequency than equi-osmotic sorbitol. Collectively, these novel data suggest that subsets of OVLT neurons respond differently to hypertonic NaCl versus osmolarity and subsequently regulate body fluid homeostasis. These responses probably reflect distinct cellular mechanisms underlying NaCl- versus osmo-sensing. Systemic or central infusion of hypertonic NaCl and other osmolytes readily stimulate thirst and vasopressin secretion. In contrast, central infusion of hypertonic NaCl produces a greater increase in arterial blood pressure (ABP) than equi-osmotic mannitol/sorbitol. Although these responses depend on neurons in the organum vasculosum of the lamina terminalis (OVLT), these observations suggest OVLT neurons may sense or respond differently to hypertonic NaCl versus osmolarity. The purpose of this study was to test this hypothesis in Sprague-Dawley rats. First, intracerebroventricular (icv) infusion (5 μl/10 min) of 1.0 m NaCl produced a significantly greater

  2. Neuron-to-neuron transmission of α-synuclein fibrils through axonal transport

    Science.gov (United States)

    Freundt, Eric C.; Maynard, Nate; Clancy, Eileen K.; Roy, Shyamali; Bousset, Luc; Sourigues, Yannick; Covert, Markus; Melki, Ronald; Kirkegaard, Karla; Brahic, Michel

    2012-01-01

    Objective The lesions of Parkinson's disease spread through the brain in a characteristic pattern that corresponds to axonal projections. Previous observations suggest that misfolded α-synuclein could behave as a prion, moving from neuron to neuron and causing endogenous α-synuclein to misfold. Here, we characterized and quantified the axonal transport of α-synuclein fibrils and showed that fibrils could be transferred from axons to second-order neurons following anterograde transport. Methods We grew primary cortical mouse neurons in microfluidic devices to separate soma from axonal projections in fluidically isolated microenvironments. We used live-cell imaging and immunofluorescence to characterize the transport of fluorescent α-synuclein fibrils and their transfer to second-order neurons. Results Fibrillar α-synuclein was internalized by primary neurons and transported in axons with kinetics consistent with slow component-b of axonal transport (fast axonal transport with saltatory movement). Fibrillar α-synuclein was readily observed in the cell bodies of second-order neurons following anterograde axonal transport. Axon-to-soma transfer appeared not to require synaptic contacts. Interpretation These results support the hypothesis that the progression of Parkinson's disease can be caused by neuron-to-neuron spread of α-synuclein aggregates and that the anatomical pattern of progression of lesions between axonally connected areas results from the axonal transport of such aggregates. That the transfer did not appear to be transsynaptic gives hope that α-synuclein fibrils could be intercepted by drugs during the extra-cellular phase of their journey. PMID:23109146

  3. Molecular Mechanisms Underlying β-Adrenergic Receptor-Mediated Cross-Talk between Sympathetic Neurons and Immune Cells

    Directory of Open Access Journals (Sweden)

    Dianne Lorton

    2015-03-01

    Full Text Available Cross-talk between the sympathetic nervous system (SNS and immune system is vital for health and well-being. Infection, tissue injury and inflammation raise firing rates of sympathetic nerves, increasing their release of norepinephrine (NE in lymphoid organs and tissues. NE stimulation of β2-adrenergic receptors (ARs in immune cells activates the cAMP-protein kinase A (PKA intracellular signaling pathway, a pathway that interfaces with other signaling pathways that regulate proliferation, differentiation, maturation and effector functions in immune cells. Immune–SNS cross-talk is required to maintain homeostasis under normal conditions, to develop an immune response of appropriate magnitude after injury or immune challenge, and subsequently restore homeostasis. Typically, β2-AR-induced cAMP is immunosuppressive. However, many studies report actions of β2-AR stimulation in immune cells that are inconsistent with typical cAMP–PKA signal transduction. Research during the last decade in non-immune organs, has unveiled novel alternative signaling mechanisms induced by β2-AR activation, such as a signaling switch from cAMP–PKA to mitogen-activated protein kinase (MAPK pathways. If alternative signaling occurs in immune cells, it may explain inconsistent findings of sympathetic regulation of immune function. Here, we review β2-AR signaling, assess the available evidence for alternative signaling in immune cells, and provide insight into the circumstances necessary for “signal switching” in immune cells.

  4. Neuromodulation and mitochondrial transport: live imaging in hippocampal neurons over long durations.

    Science.gov (United States)

    Edelman, David B; Owens, Geoffrey C; Chen, Sigeng

    2011-06-17

    To understand the relationship between mitochondrial transport and neuronal function, it is critical to observe mitochondrial behavior in live cultured neurons for extended durations(1-3). This is now possible through the use of vital dyes and fluorescent proteins with which cytoskeletal components, organelles, and other structures in living cells can be labeled and then visualized via dynamic fluorescence microscopy. For example, in embryonic chicken sympathetic neurons, mitochondrial movement was characterized using the vital dye rhodamine 123(4). In another study, mitochondria were visualized in rat forebrain neurons by transfection of mitochondrially targeted eYFP(5). However, imaging of primary neurons over minutes, hours, or even days presents a number of issues. Foremost among these are: 1) maintenance of culture conditions such as temperature, humidity, and pH during long imaging sessions; 2) a strong, stable fluorescent signal to assure both the quality of acquired images and accurate measurement of signal intensity during image analysis; and 3) limiting exposure times during image acquisition to minimize photobleaching and avoid phototoxicity. Here, we describe a protocol that permits the observation, visualization, and analysis of mitochondrial movement in cultured hippocampal neurons with high temporal resolution and under optimal life support conditions. We have constructed an affordable stage-top incubator that provides good temperature regulation and atmospheric gas flow, and also limits the degree of media evaporation, assuring stable pH and osmolarity. This incubator is connected, via inlet and outlet hoses, to a standard tissue culture incubator, which provides constant humidity levels and an atmosphere of 5-10% CO(2;)/air. This design offers a cost-effective alternative to significantly more expensive microscope incubators that don't necessarily assure the viability of cells over many hours or even days. To visualize mitochondria, we infect cells

  5. Intraventricular Injection of LKB1 Inhibits the Formation of Diet-Induced Obesity in Rats by Activating the AMPK-POMC Neurons-Sympathetic Nervous System Axis

    Directory of Open Access Journals (Sweden)

    Pengjiao Xi

    2018-05-01

    Full Text Available Background/Aims: Obesity is increasingly becoming a major public health problem worldwide. Peripheral LKB1 inhibits white fat generation, but the effect of central LKB1 on diet-induced obesity (DIO is unknown. Therefore, we examined whether LKB1 over-expression in the hypothalamus can inhibit the development of obesity. Methods: Adult male Sprague-Dawley rats were anesthetized and placed in a stereotaxic apparatus. LKB1-AAV-EGFP (2.0 × 108 or 2.0 × 1010 vector genomes or Control-AAV-EGFP (2.0 × 108 vector genomes was injected into the third ventricle. After administration, the rats were fed a high-fat diet (HFD for 9 weeks to induce obesity. Rats fed a chow fat diet were used as normal controls. Results: LKB1 delivery decreased body weight, energy intake, fat mass, and serum lipid levels. LKB1 also improved HFD-induced hepatic fatty degeneration. Interestingly, LKB1 over-expression in the hypothalamus activated the AMPK-POMC neurons-sympathetic nervous system (SNS axis, which can release epinephrine to promote white fat browning. Conversely, the elevated expression of MC3R/MC4R inhibited food intake. These two factors worked together to inhibit the development of obesity. Conclusions: LKB1 in the hypothalamus may have therapeutic potential for DIO through the activation of the AMPK-POMC neurons-SNS axis.

  6. Intraventricular Injection of LKB1 Inhibits the Formation of Diet-Induced Obesity in Rats by Activating the AMPK-POMC Neurons-Sympathetic Nervous System Axis.

    Science.gov (United States)

    Xi, Pengjiao; Du, Jianying; Liang, Huimin; Han, Jie; Wu, Zhaoxia; Wang, Haomin; He, Lu; Wang, Qiming; Ge, Haize; Li, Yongmei; Xue, Jie; Tian, Derun

    2018-01-01

    Obesity is increasingly becoming a major public health problem worldwide. Peripheral LKB1 inhibits white fat generation, but the effect of central LKB1 on diet-induced obesity (DIO) is unknown. Therefore, we examined whether LKB1 over-expression in the hypothalamus can inhibit the development of obesity. Adult male Sprague-Dawley rats were anesthetized and placed in a stereotaxic apparatus. LKB1-AAV-EGFP (2.0 × 108 or 2.0 × 1010 vector genomes) or Control-AAV-EGFP (2.0 × 108 vector genomes) was injected into the third ventricle. After administration, the rats were fed a high-fat diet (HFD) for 9 weeks to induce obesity. Rats fed a chow fat diet were used as normal controls. LKB1 delivery decreased body weight, energy intake, fat mass, and serum lipid levels. LKB1 also improved HFD-induced hepatic fatty degeneration. Interestingly, LKB1 over-expression in the hypothalamus activated the AMPK-POMC neurons-sympathetic nervous system (SNS) axis, which can release epinephrine to promote white fat browning. Conversely, the elevated expression of MC3R/MC4R inhibited food intake. These two factors worked together to inhibit the development of obesity. LKB1 in the hypothalamus may have therapeutic potential for DIO through the activation of the AMPK-POMC neurons-SNS axis. © 2018 The Author(s). Published by S. Karger AG, Basel.

  7. Sympathetic rhythms and nervous integration.

    Science.gov (United States)

    Gilbey, Michael P

    2007-04-01

    1. The present review focuses on some of the processes producing rhythms in sympathetic nerves influencing cardiovascular functions and considers their potential relevance to nervous integration. 2. Two mechanisms are considered that may account for rhythmic sympathetic discharges. First, neuronal elements of peripheral or central origin produce rhythmic activity by phasically exciting and/or inhibiting neurons within central sympathetic networks. Second, rhythms arise within central sympathetic networks. Evidence is considered that indicates the operation of both mechanisms; the first in muscle and the second in skin sympathetic vasoconstrictor networks. 3. Sympathetic activity to the rat tail, a model for the nervous control of skin circulation, is regulated by central networks involved in thermoregulation and those associated with fear and arousal. In an anaesthetized preparation, activity displays an apparently autonomous rhythm (T-rhythm; 0.4-1.2 Hz) and the level of activity can be manipulated by regulating core body temperature. This model has been used to study rhythm generation in central sympathetic networks and possible functional relevance. 4. A unique insight provided by the T rhythm, into possible physiological function(s) underlying rhythmic sympathetic discharges is that the activity of single sympathetic post-ganglionic neurons within a population innervating the same target can have different rhythm frequencies. Therefore, the graded and dynamic entrainment of the rhythms by inputs, such as central respiratory drive and/or lung inflation-related afferent activity, can produce graded and dynamic synchronization of sympathetic discharges. The degree of synchronization may influence the efficacy of transmission in a target chain of excitable cells. 5. The T-rhythm may be generated within the spinal cord because the intrathecal application of 5-hydroxytryptamine at the L1 level of the spinal cord of a rat spinalized at T10-T11 produces a T-like rhythm

  8. [Nerve growth factor and the physiology of pain: the relationships among interoception, sympathetic neurons and the emotional response indicated by the molecular pathophysiology of congenital insensitivity to pain with anhidrosis].

    Science.gov (United States)

    Indo, Yasuhiro

    2015-05-01

    Nerve growth factor (NGF) is a neurotrophic factor essential for the survival and maintenance of neurons. Congenital insensitivity to pain with anhidrosis (CIPA) is caused by loss-of-function mutations in NTRK1, which encodes a receptor tyrosine kinase, TrkA, for NGF. Mutations in NTRK1 cause the selective loss of NGF-dependent neurons, including both NGF-dependent primary afferents and sympathetic postganglionic neurons, in otherwise intact systems. The NGF-dependent primary afferents are thinly myelinated AΔ or unmyelinated C-fibers that are dependent on the NGF-TrkA system during development. NGF-dependent primary afferents are not only nociceptive neurons that transmit pain and temperature sensation, but also are polymodal receptors that play essential roles for interoception by monitoring various changes in the physiological status of all tissues in the body. In addition, they contribute to various inflammatory processes in acute, chronic and allergic inflammation. Together with sympathetic postganglionic neurons, they maintain the homeostasis of the body and emotional responses via interactions with the brain, immune and endocrine systems. Pain is closely related to emotions that accompany physical responses induced by systemic activation of the sympathetic nervous system. In contrast to a negative image of emotions in daily life, Antonio Damasio proposed the 'Somatic Marker Hypothesis', wherein emotions play critical roles in the decision-making and reasoning processes. According to this hypothesis, reciprocal communication between the brain and the body-proper are essential for emotional responses. Using the pathophysiology of CIPA as a foundation, this article suggests that NGF-dependent neurons constitute a part of the neuronal network required for homeostasis and emotional responses, and indicates that this network plays important roles in mediating the reciprocal communication between the brain and the body-proper.

  9. Automated Measurement of Fast Mitochondrial Transport in Neurons

    Directory of Open Access Journals (Sweden)

    Kyle eMiller

    2015-11-01

    Full Text Available There is a growing recognition that fast mitochondrial transport in neurons is disrupted in multiple neurological diseases and psychiatric disorders. However a major constraint in identifying novel therapeutics based on mitochondrial transport is that the large-scale analysis of fast transport is time consuming. Here we describe methodologies for the automated analysis of fast mitochondrial transport from data acquired using a robotic microscope. We focused on addressing questions of measurement precision, speed, reliably, workflow ease, statistical processing and presentation. We used optical flow and particle tracking algorithms, implemented in ImageJ, to measure mitochondrial movement in primary cultured cortical and hippocampal neurons. With it, we are able to generate complete descriptions of movement profiles in an automated fashion of hundred of thousands of mitochondria with a processing time of approximately one hour. We describe the calibration of the parameters of the tracking algorithms and demonstrate that they are capable of measuring the fast transport of a single mitochondrion. We then show that the methods are capable of reliably measuring the inhibition of fast mitochondria transport induced by the disruption of microtubules with the drug nocodazole in both hippocampal and cortical neurons. This work lays the foundation for future large-scale screens designed to identify compounds that modulate mitochondrial motility.

  10. Effects of the angiotensin-converting enzyme inhibitor enalapril on sympathetic neuronal function and {beta}-adrenergic desensitization in heart failure after myocardial infarction in rats

    Energy Technology Data Exchange (ETDEWEB)

    Igawa, Akihiko; Nozawa, Takashi; Yoshida, Naohiro [Toyama Medical and Pharmaceutical Univ. (Japan)] [and others

    2002-11-01

    One of the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in the treatment of heart failure may derive from sympathoinhibition and the prevention of {beta}-adrenergic desensitization. However, the roles of these properties in the overall effects of ACE inhibitor are not clear. We studied the effects of chronic enalapril treatment (20 mg/L in drinking water for 12 weeks) on left ventricular (LV) function, cardiac norepinephrine (NE), sympathetic neuronal function assessed by {sup 131}I-metaiodobenzylguanidine (MIBG), {beta}-receptors, and isometric contraction of papillary muscle in rats with myocardial infarction (MI) induced by coronary artery ligation. Decreased LV function in the MI rats was associated with reduced cardiac NE content and MIBG uptake, and severely blunted responses of non-infarcted papillary muscle to isoproterenol, forskolin, and calcium. Enalapril attenuated LV remodeling in association with a reduction of the ventricular loading condition and restored baseline developed tension of non-infarcted papillary muscle to the level of sham-operated rats. However, enalapril did not improve cardiac NE content, MIBG uptake, or inotropic responsiveness to {beta}-agonists. These results suggest that the major effect of the ACE inhibitor enalapril in the treatment of heart failure is not due to sympathoinhibition or restoration of {beta}-adrenergic pathway in this model of heart failure. (author)

  11. Effects of the angiotensin-converting enzyme inhibitor enalapril on sympathetic neuronal function and β-adrenergic desensitization in heart failure after myocardial infarction in rats

    International Nuclear Information System (INIS)

    Igawa, Akihiko; Nozawa, Takashi; Yoshida, Naohiro

    2002-01-01

    One of the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in the treatment of heart failure may derive from sympathoinhibition and the prevention of β-adrenergic desensitization. However, the roles of these properties in the overall effects of ACE inhibitor are not clear. We studied the effects of chronic enalapril treatment (20 mg/L in drinking water for 12 weeks) on left ventricular (LV) function, cardiac norepinephrine (NE), sympathetic neuronal function assessed by 131 I-metaiodobenzylguanidine (MIBG), β-receptors, and isometric contraction of papillary muscle in rats with myocardial infarction (MI) induced by coronary artery ligation. Decreased LV function in the MI rats was associated with reduced cardiac NE content and MIBG uptake, and severely blunted responses of non-infarcted papillary muscle to isoproterenol, forskolin, and calcium. Enalapril attenuated LV remodeling in association with a reduction of the ventricular loading condition and restored baseline developed tension of non-infarcted papillary muscle to the level of sham-operated rats. However, enalapril did not improve cardiac NE content, MIBG uptake, or inotropic responsiveness to β-agonists. These results suggest that the major effect of the ACE inhibitor enalapril in the treatment of heart failure is not due to sympathoinhibition or restoration of β-adrenergic pathway in this model of heart failure. (author)

  12. Expression, transport, and axonal sorting of neuronal CCL21 in large dense-core vesicles

    NARCIS (Netherlands)

    de Jong, Eiko K.; Vinet, Jonathan; Stanulovic, Vesna S.; Meijer, Michel; Wesseling, Evelyn; Sjollema, Klaas; Boddeke, Hendrikus W. G. M.; Biber, Knut

    2008-01-01

    Neurons are highly polarized cells, and neuron-neuron communication is based on directed transport and release of neurotransmitters, neuropeptides, and neurotrophins. Directed communication may also be attributed to neuron-microglia signaling, since neuronal damage can induce a microglia reaction at

  13. Expression, transport, and axonal sorting of neuronal CCL21 in large dense-core vesicles.

    NARCIS (Netherlands)

    Jong, E.K. de; Vinet, J.; Stanulovic, V.S.; Meijer, M.; Wesseling, E.; Sjollema, K.; Boddeke, H.W.; Biber, K.

    2008-01-01

    Neurons are highly polarized cells, and neuron-neuron communication is based on directed transport and release of neurotransmitters, neuropeptides, and neurotrophins. Directed communication may also be attributed to neuron-microglia signaling, since neuronal damage can induce a microglia reaction at

  14. The neurite growth inhibitory effects of soluble TNFα on developing sympathetic neurons are dependent on developmental age.

    Science.gov (United States)

    Nolan, Aoife M; Collins, Louise M; Wyatt, Sean L; Gutierrez, Humberto; O'Keeffe, Gerard W

    2014-01-01

    During development, the growth of neural processes is regulated by an array of cellular and molecular mechanisms which influence growth rate, direction and branching. Recently, many members of the TNF superfamily have been shown to be key regulators of neurite growth during development. The founder member of this family, TNFα can both promote and inhibit neurite growth depending on the cellular context. Specifically, transmembrane TNFα promotes neurite growth, while soluble TNFα inhibits it. While the growth promoting effects of TNFα are restricted to a defined developmental window of early postnatal development, whether the growth inhibitory effects of soluble TNFα occur throughout development is unknown. In this study we used the extensively studied, well characterised neurons of the superior cervical ganglion to show that the growth inhibitory effects of soluble TNFα are restricted to a specific period of late embryonic and early postnatal development. Furthermore, we show that this growth inhibitory effect of soluble TNFα requires NF-κB signalling at all developmental stages at which soluble TNFα inhibits neurite growth. These findings raise the possibility that increases in the amount of soluble TNFα in vivo, for example as a result of maternal inflammation, could negatively affect neurite growth in developing neurons at specific stages of development. Copyright © 2015 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

  15. Sodium transport through the cerebral sodium-glucose transporter exacerbates neuron damage during cerebral ischaemia.

    Science.gov (United States)

    Yamazaki, Yui; Harada, Shinichi; Wada, Tetsuyuki; Yoshida, Shigeru; Tokuyama, Shogo

    2016-07-01

    We recently demonstrated that the cerebral sodium-glucose transporter (SGLT) is involved in postischaemic hyperglycaemia-induced exacerbation of cerebral ischaemia. However, the associated SGLT-mediated mechanisms remain unclear. Thus, we examined the involvement of cerebral SGLT-induced excessive sodium ion influx in the development of cerebral ischaemic neuronal damage. [Na+]i was estimated according to sodium-binding benzofuran isophthalate fluorescence. In the in vitro study, primary cortical neurons were prepared from fetuses of ddY mice. Primary cortical neurons were cultured for 5 days before each treatment with reagents, and these survival rates were assessed using biochemical assays. In in vivo study, a mouse model of focal ischaemia was generated using middle cerebral artery occlusion (MCAO). In these experiments, treatment with high concentrations of glucose induced increment in [Na+]i, and this phenomenon was suppressed by the SGLT-specific inhibitor phlorizin. SGLT-specific sodium ion influx was induced using a-methyl-D-glucopyranoside (a-MG) treatments, which led to significant concentration-dependent declines in neuronal survival rates and exacerbated hydrogen peroxide-induced neuronal cell death. Moreover, phlorizin ameliorated these effects. Finally, intracerebroventricular administration of a-MG exacerbated the development of neuronal damage induced by MCAO, and these effects were ameliorated by the administration of phlorizin. Hence, excessive influx of sodium ions into neuronal cells through cerebral SGLT may exacerbate the development of cerebral ischaemic neuronal damage. © 2016 Royal Pharmaceutical Society.

  16. Netrin-1 controls sympathetic arterial innervation.

    Science.gov (United States)

    Brunet, Isabelle; Gordon, Emma; Han, Jinah; Cristofaro, Brunella; Broqueres-You, Dong; Liu, Chun; Bouvrée, Karine; Zhang, Jiasheng; del Toro, Raquel; Mathivet, Thomas; Larrivée, Bruno; Jagu, Julia; Pibouin-Fragner, Laurence; Pardanaud, Luc; Machado, Maria J C; Kennedy, Timothy E; Zhuang, Zhen; Simons, Michael; Levy, Bernard I; Tessier-Lavigne, Marc; Grenz, Almut; Eltzschig, Holger; Eichmann, Anne

    2014-07-01

    Autonomic sympathetic nerves innervate peripheral resistance arteries, thereby regulating vascular tone and controlling blood supply to organs. Despite the fundamental importance of blood flow control, how sympathetic arterial innervation develops remains largely unknown. Here, we identified the axon guidance cue netrin-1 as an essential factor required for development of arterial innervation in mice. Netrin-1 was produced by arterial smooth muscle cells (SMCs) at the onset of innervation, and arterial innervation required the interaction of netrin-1 with its receptor, deleted in colorectal cancer (DCC), on sympathetic growth cones. Function-blocking approaches, including cell type-specific deletion of the genes encoding Ntn1 in SMCs and Dcc in sympathetic neurons, led to severe and selective reduction of sympathetic innervation and to defective vasoconstriction in resistance arteries. These findings indicate that netrin-1 and DCC are critical for the control of arterial innervation and blood flow regulation in peripheral organs.

  17. The sympathetic and sensory innervation of rat airways: origin and neurochemical characterisation

    OpenAIRE

    Radtke, Anne

    2010-01-01

    Sensory and sympathetic innervation of Brown Norway rat airways were investigated using retrograde neuronal tracing with fluorescent dyes and double labelling immunofluorescence. Sensory neurons projecting to the lung are located in nodose and jugular vagal ganglia. Sympathetic neuronal supply of the lung originates in the stellate ganglia and superior cervical ganglia. Concerning immuno-reactivity for the SP and NOS in sensory and NPY and TH in sympathetic neurons were investigated. IR for S...

  18. Origins of the sympathetic innervation to the nasal-associated lymphoid tissue (NALT): an anatomical substrate for a neuroimmune connection.

    Science.gov (United States)

    Marafetti, Lucas E; Romeo, Horacio E

    2014-11-15

    The participation of sympathetic nerve fibers in the innervation of the nasal-associated lymphoid tissues (NALT) was investigated in hamsters. Vesicular monoamine transporter 2 (VMAT2), an established sympathetic marker, is expressed in all neurons of superior cervical ganglia (SCG). In addition, VMAT2 -immunoreactive nerve fibers were localized in the NALT as well as in adjacent anatomical structures of the upper respiratory tract. Unilateral surgical ablation of the SCG abolished VMAT2 innervation patterns ipsilaterally while the contra lateral side is unaffected. These results provide the anatomical substrate for a neuroimmune connection in the NALT. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Assessment of cardiac sympathetic nerve integrity with positron emission tomography

    International Nuclear Information System (INIS)

    Raffel, David M.; Wieland, Donald M.

    2001-01-01

    The autonomic nervous system plays a critical role in the regulation of cardiac function. Abnormalities of cardiac innervation have been implicated in the pathophysiology of many heart diseases, including sudden cardiac death and congestive heart failure. In an effort to provide clinicians with the ability to regionally map cardiac innervation, several radiotracers for imaging cardiac sympathetic neurons have been developed. This paper reviews the development of neuronal imaging agents and discusses their emerging role in the noninvasive assessment of cardiac sympathetic innervation

  20. Sympathetic Innervation during Development Is Necessary for Pancreatic Islet Architecture and Functional Maturation

    Directory of Open Access Journals (Sweden)

    Philip Borden

    2013-07-01

    Full Text Available Sympathetic neurons depend on target-derived neurotrophic cues to control their survival and growth. However, whether sympathetic innervation contributes reciprocally to the development of target tissues is less clear. Here, we report that sympathetic innervation is necessary for the formation of the pancreatic islets of Langerhans and for their functional maturation. Genetic or pharmacological ablation of sympathetic innervation during development resulted in altered islet architecture, reduced insulin secretion, and impaired glucose tolerance in mice. Similar defects were observed with pharmacological blockade of β-adrenergic signaling. Conversely, the administration of a β-adrenergic agonist restored islet morphology and glucose tolerance in deinnervated animals. Furthermore, in neuron-islet cocultures, sympathetic neurons promoted islet cell migration in a β-adrenergic-dependent manner. This study reveals that islet architecture requires extrinsic inductive cues from neighboring tissues such as sympathetic nerves and suggests that early perturbations in sympathetic innervation might underlie metabolic disorders.

  1. Infection and Transport of Herpes Simplex Virus Type 1 in Neurons: Role of the Cytoskeleton

    Science.gov (United States)

    2018-01-01

    Herpes simplex virus type 1 (HSV-1) is a neuroinvasive human pathogen that has the ability to infect and replicate within epithelial cells and neurons and establish a life-long latent infection in sensory neurons. HSV-1 depends on the host cellular cytoskeleton for entry, replication, and exit. Therefore, HSV-1 has adapted mechanisms to promote its survival by exploiting the microtubule and actin cytoskeletons to direct its active transport, infection, and spread between neurons and epithelial cells during primary and recurrent infections. This review will focus on the currently known mechanisms utilized by HSV-1 to harness the neuronal cytoskeleton, molecular motors, and the secretory and exocytic pathways for efficient virus entry, axonal transport, replication, assembly, and exit from the distinct functional compartments (cell body and axon) of the highly polarized sensory neurons. PMID:29473915

  2. Intracellular ascorbic acid inhibits transport of glucose by neurons, but not by astrocytes.

    Science.gov (United States)

    Castro, Maite A; Pozo, Miguel; Cortés, Christian; García, María de Los Angeles; Concha, Ilona I; Nualart, Francisco

    2007-08-01

    It has been demonstrated that glutamatergic activity induces ascorbic acid (AA) depletion in astrocytes. Additionally, different data indicate that AA may inhibit glucose accumulation in primary cultures of rat hippocampal neurons. Thus, our hypothesis postulates that AA released from the astrocytes during glutamatergic synaptic activity may inhibit glucose uptake by neurons. We observed that cultured neurons express the sodium-vitamin C cotransporter 2 and the facilitative glucose transporters (GLUT) 1 and 3, however, in hippocampal brain slices GLUT3 was the main transporter detected. Functional activity of GLUTs was confirmed by means of kinetic analysis using 2-deoxy-d-glucose. Therefore, we showed that AA, once accumulated inside the cell, inhibits glucose transport in both cortical and hippocampal neurons in culture. Additionally, we showed that astrocytes are not affected by AA. Using hippocampal slices, we observed that upon blockade of monocarboxylate utilization by alpha-cyano-4-hydroxycinnamate and after glucose deprivation, glucose could rescue neuronal response to electrical stimulation only if AA uptake is prevented. Finally, using a transwell system of separated neuronal and astrocytic cultures, we observed that glutamate can reduce glucose transport in neurons only in presence of AA-loaded astrocytes, suggesting the essential role of astrocyte-released AA in this effect.

  3. Quantitative analysis of intraneuronal transport in human iPS neurons

    Directory of Open Access Journals (Sweden)

    Haruko Nakamura

    2015-08-01

    Full Text Available Induced pluripotent stem (iPS cells are promising tools to investigate disease mechanism and develop new drugs. Intraneuronal transport, which is fundamental for neuronal survival and function, is vulnerable to various pharmacological and chemical agents and is disrupted in some neurodegenerative disorders. We applied a quantification method for axonal transport by counting CM-DiI–labeled particles traveling along the neurite, which allowed us to monitor and quantitate, for the first time, intraneuronal transport in human neurons differentiated from iPS cells (iCell neurons. We evaluated the acute effects of several anti-neoplastic agents that have been previously shown to affect intraneuronal transport. Vincristine, paclitaxel and oxaliplatin decreased the number of moving particle along neurites. Cisplatin, however, produced no effect on intraneuronal transport, which is in contrast to our previous report indicating that it inhibits transport in chick dorsal root ganglion neurons. Our system may be a useful method for assessing intraneuronal transport and neurotoxicity in human iPS neurons.

  4. Dync1h1 Mutation Causes Proprioceptive Sensory Neuron Loss and Impaired Retrograde Axonal Transport of Dorsal Root Ganglion Neurons.

    Science.gov (United States)

    Zhao, Jing; Wang, Yi; Xu, Huan; Fu, Yuan; Qian, Ting; Bo, Deng; Lu, Yan-Xin; Xiong, Yi; Wan, Jun; Zhang, Xiang; Dong, Qiang; Chen, Xiang-Jun

    2016-07-01

    Sprawling (Swl) is a radiation-induced mutation which has been identified to have a nine base pair deletion in dynein heavy chain 1 (DYNC1H1: encoded by a single gene Dync1h1). This study is to investigate the phenotype and the underlying mechanism of the Dync1h1 mutant. To display the phenotype of Swl mutant mice, we examined the embryos of homozygous (Swl/Swl) and heterozygous (Swl/+) mice and their postnatal dorsal root ganglion (DRG) of surviving Swl/+ mice. The Swl/+ mice could survive for a normal life span, while Swl/Swl could only survive till embryonic (E) 8.5 days. Excessive apoptosis of Swl/+ DRG neurons was revealed during E11.5-E15.5 days, and the peak rate was at E13.5 days. In vitro study of mutated DRG neurons showed impaired retrograde transport of dynein-driven nerve growth factor (NGF). Mitochondria, another dynein-driven cargo, demonstrated much slower retrograde transport velocity in Swl/+ neurons than in wild-type (WT) neurons. Nevertheless, the Swl, Loa, and Cra mutations did not affect homodimerization of DYNC1H1. The Swl/Swl mutation of Dync1h1 gene led to embryonic mal-development and lethality, whereas the Swl/+ DRG neurons demonstrated deficient retrograde transport in dynein-driven cargos and excessive apoptosis during mid- to late-developmental stages. The underlying mechanism of the mutation may not be due to impaired homodimerization of DYNC1H1. © 2016 John Wiley & Sons Ltd.

  5. Augmented Endothelial-Specific L-Arginine Transport Blunts the Contribution of the Sympathetic Nervous System to Obesity Induced Hypertension in Mice.

    Directory of Open Access Journals (Sweden)

    Niwanthi W Rajapakse

    Full Text Available Augmenting endothelial specific transport of the nitric oxide precursor L-arginine via cationic amino acid transporter-1 (CAT1 can prevent obesity related hypertension. We tested the hypotheses that CAT1 overexpression prevents obesity-induced hypertension by buffering the influence of the sympathetic nervous system (SNS on the maintenance of arterial pressure and by buffering pressor responses to stress. Wild type (WT; n=13 and CAT1 overexpressing mice (CAT+; n=13 were fed a normal or a high fat diet for 20 weeks. Mice fed a high fat diet were returned to the control diet before experiments commenced. Baseline mean arterial pressure (MAP and effects of restraint-, shaker- and almond feeding-stress and ganglionic blockade (pentolinium; 5 mg/kg; i.p. on MAP were determined in conscious mice. Fat feeding increased body weight to a similar extent in WT and CAT+ but MAP was greater only in WT compared to appropriate controls (by 29%. The depressor response to pentolinium was 65% greater in obese WT than lean WT (P < 0.001, but was similar in obese and lean CAT+ (P = 0.65. In lean WT and CAT+, pressor responses to shaker and feeding stress, but not restraint stress, were less in the latter genotype compared to the former (P ≤ 0.001. Pressor responses to shaker and feeding stress were less in obese WT than lean WT (P ≤ 0.001, but similar in obese and lean CAT+. The increase in MAP in response to restraint stress was less in obese WT (22 ± 2%, but greater in obese CAT+ (37 ± 2%, when compared to respective lean WT (31 ± 3% and lean CAT+ controls (27 ± 2%; P ≤ 0.02. We conclude that CAT1 overexpression prevents obesity-induced hypertension by reducing the influence of the SNS on the maintenance of arterial pressure but not by buffering pressor responses to stress.

  6. Augmented Endothelial-Specific L-Arginine Transport Blunts the Contribution of the Sympathetic Nervous System to Obesity Induced Hypertension in Mice.

    Science.gov (United States)

    Rajapakse, Niwanthi W; Karim, Florian; Evans, Roger G; Kaye, David M; Head, Geoffrey A

    2015-01-01

    Augmenting endothelial specific transport of the nitric oxide precursor L-arginine via cationic amino acid transporter-1 (CAT1) can prevent obesity related hypertension. We tested the hypotheses that CAT1 overexpression prevents obesity-induced hypertension by buffering the influence of the sympathetic nervous system (SNS) on the maintenance of arterial pressure and by buffering pressor responses to stress. Wild type (WT; n=13) and CAT1 overexpressing mice (CAT+; n=13) were fed a normal or a high fat diet for 20 weeks. Mice fed a high fat diet were returned to the control diet before experiments commenced. Baseline mean arterial pressure (MAP) and effects of restraint-, shaker- and almond feeding-stress and ganglionic blockade (pentolinium; 5 mg/kg; i.p.) on MAP were determined in conscious mice. Fat feeding increased body weight to a similar extent in WT and CAT+ but MAP was greater only in WT compared to appropriate controls (by 29%). The depressor response to pentolinium was 65% greater in obese WT than lean WT (P lean CAT+ (P = 0.65). In lean WT and CAT+, pressor responses to shaker and feeding stress, but not restraint stress, were less in the latter genotype compared to the former (P ≤ 0.001). Pressor responses to shaker and feeding stress were less in obese WT than lean WT (P ≤ 0.001), but similar in obese and lean CAT+. The increase in MAP in response to restraint stress was less in obese WT (22 ± 2%), but greater in obese CAT+ (37 ± 2%), when compared to respective lean WT (31 ± 3%) and lean CAT+ controls (27 ± 2%; P ≤ 0.02). We conclude that CAT1 overexpression prevents obesity-induced hypertension by reducing the influence of the SNS on the maintenance of arterial pressure but not by buffering pressor responses to stress.

  7. A high mitochondrial transport rate characterizes CNS neurons with high axonal regeneration capacity.

    Directory of Open Access Journals (Sweden)

    Romain Cartoni

    Full Text Available Improving axonal transport in the injured and diseased central nervous system has been proposed as a promising strategy to improve neuronal repair. However, the contribution of each cargo to the repair mechanism is unknown. DRG neurons globally increase axonal transport during regeneration. Because the transport of specific cargos after axonal insult has not been examined systematically in a model of enhanced regenerative capacity, it is unknown whether the transport of all cargos would be modulated equally in injured central nervous system neurons. Here, using a microfluidic culture system we compared neurons co-deleted for PTEN and SOCS3, an established model of high axonal regeneration capacity, to control neurons. We measured the axonal transport of three cargos (mitochondria, synaptic vesicles and late endosomes in regenerating axons and found that the transport of mitochondria, but not the other cargos, was increased in PTEN/SOCS3 co-deleted axons relative to controls. The results reported here suggest a pivotal role for this organelle during axonal regeneration.

  8. Live-cell imaging of post-golgi transport vesicles in cultured hippocampal neurons

    DEFF Research Database (Denmark)

    Jensen, Camilla Stampe; Misonou, Hiroaki

    2015-01-01

    compartments of neurons. In the past two decades, the establishment and advancement of fluorescent protein technology have provided us with opportunities to study how proteins are trafficked in living cells. However, live imaging of trafficking processes in neurons necessitate imaging tools to distinguish...... the several different routes that neurons use for protein trafficking. Here we provide a novel protocol to selectively visualize post-Golgi transport vesicles carrying fluorescent-labeled ion channel proteins in living neurons. Further, we provide a number of analytical tools we developed to quantify...... mechanisms by which post-Golgi vesicles are trafficked in neurons. Our protocol uniquely combines the classic temperature-block with close monitoring of the transient expression of transfected protein tagged with fluorescent proteins, and provides a quick and easy way to study protein trafficking in living...

  9. Super-resolution microscopy reveals functional organization of dopamine transporters into cholesterol and neuronal activity-dependent nanodomains

    DEFF Research Database (Denmark)

    Rahbek-Clemmensen, Troels; Lycas, Matthew D.; Erlendsson, Simon

    2017-01-01

    is dynamically sequestrated into cholesterol-dependent nanodomains in the plasma membrane of presynaptic varicosities and neuronal projections of dopaminergic neurons. Stochastic optical reconstruction microscopy reveals irregular dopamine transporter nanodomains (∼70 nm mean diameter) that were highly sensitive...... to cholesterol depletion. Live photoactivated localization microscopy shows a similar dopamine transporter membrane organization in live heterologous cells. In neurons, dual-color dSTORM shows that tyrosine hydroxylase and vesicular monoamine transporter-2 are distinctively localized adjacent to...

  10. Neuronal and non-neuronal GABA transporters as targets for antiepileptic drugs

    DEFF Research Database (Denmark)

    Madsen, Karsten K; White, H Steve; Schousboe, Arne

    2010-01-01

    of transmembrane transport and enzymatic degradation. The development of tiagabine selectively inhibiting the GABA transporter GAT1 constitutes a proof of concept that the GABA transporters are interesting drug targets in the context of antiepileptic drugs. The review provides a detailed analysis of the role......,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol) has been shown to possess a novel anticonvulsant profile in animal models of epilepsy, involving the ability to inhibit GABA transport mediated by GAT1 and BGT1 at the same time....

  11. Snapin-regulated late endosomal transport is critical for efficient autophagy-lysosomal function in neurons.

    Science.gov (United States)

    Cai, Qian; Lu, Li; Tian, Jin-Hua; Zhu, Yi-Bing; Qiao, Haifa; Sheng, Zu-Hang

    2010-10-06

    Neuron maintenance and survival require late endocytic transport from distal processes to the soma where lysosomes are predominantly localized. Here, we report a role for Snapin in attaching dynein to late endosomes through its intermediate chain (DIC). snapin(-/-) neurons exhibit aberrant accumulation of immature lysosomes, clustering and impaired retrograde transport of late endosomes along processes, reduced lysosomal proteolysis due to impaired delivery of internalized proteins and hydrolase precursors from late endosomes to lysosomes, and impaired clearance of autolysosomes, combined with reduced neuron viability and neurodegeneration. The phenotypes are rescued by expressing the snapin transgene, but not the DIC-binding-defective Snapin-L99K mutant. Snapin overexpression in wild-type neurons enhances late endocytic transport and lysosomal function, whereas expressing the mutant defective in Snapin-DIC coupling shows a dominant-negative effect. Altogether, our study highlights new mechanistic insights into how Snapin-DIC coordinates retrograde transport and late endosomal-lysosomal trafficking critical for autophagy-lysosomal function, and thus neuronal homeostasis. Copyright © 2010 Elsevier Inc. All rights reserved.

  12. Immobilization of Caenorhabditis elegans to Analyze Intracellular Transport in Neurons.

    Science.gov (United States)

    Niwa, Shinsuke

    2017-10-18

    Axonal transport and intraflagellar transport (IFT) are essential for axon and cilia morphogenesis and function. Kinesin superfamily proteins and dynein are molecular motors that regulate anterograde and retrograde transport, respectively. These motors use microtubule networks as rails. Caenorhabditis elegans (C. elegans) is a powerful model organism to study axonal transport and IFT in vivo. Here, I describe a protocol to observe axonal transport and IFT in living C. elegans. Transported cargo can be visualized by tagging cargo proteins using fluorescent proteins such as green fluorescent protein (GFP). C. elegans is transparent and GFP-tagged cargo proteins can be expressed in specific cells under cell-specific promoters. Living worms can be fixed by microbeads on 10% agarose gel without killing or anesthetizing the worms. Under these conditions, cargo movement can be directly observed in the axons and cilia of living C. elegans without dissection. This method can be applied to the observation of any cargo molecule in any cells by modifying the target proteins and/or the cells they are expressed in. Most basic proteins such as molecular motors and adaptor proteins that are involved in axonal transport and IFT are conserved in C. elegans. Compared to other model organisms, mutants can be obtained and maintained more easily in C. elegans. Combining this method with various C. elegans mutants can clarify the molecular mechanisms of axonal transport and IFT.

  13. A possible role of the non-GAT1 GABA transporters in transfer of GABA from GABAergic to glutamatergic neurons in mouse cerebellar neuronal cultures

    DEFF Research Database (Denmark)

    Suñol, C; Babot, Z; Cristòfol, R

    2010-01-01

    Cultures of dissociated cerebellum from 7-day-old mice were used to investigate the mechanism involved in synthesis and cellular redistribution of GABA in these cultures consisting primarily of glutamatergic granule neurons and a smaller population of GABAergic Golgi and stellate neurons......3 transporters. Only a small population of cells were immuno-stained for GAD while many cells exhibited VGlut-1 like immuno-reactivity which, however, never co-localized with GAD positive neurons. This likely reflects the small number of GABAergic neurons compared to the glutamatergic granule......M concentrations (95%). Essentially all neurons showed GABA like immunostaining albeit with differences in intensity. The results indicate that GABA which is synthesized in a small population of GAD-positive neurons is redistributed to essentially all neurons including the glutamatergic granule cells. GAT1...

  14. Neuronal glucose transporter isoform 3 deficient mice demonstrate features of autism spectrum disorders.

    Science.gov (United States)

    Zhao, Y; Fung, C; Shin, D; Shin, B-C; Thamotharan, S; Sankar, R; Ehninger, D; Silva, A; Devaskar, S U

    2010-03-01

    Neuronal glucose transporter (GLUT) isoform 3 deficiency in null heterozygous mice led to abnormal spatial learning and working memory but normal acquisition and retrieval during contextual conditioning, abnormal cognitive flexibility with intact gross motor ability, electroencephalographic seizures, perturbed social behavior with reduced vocalization and stereotypies at low frequency. This phenotypic expression is unique as it combines the neurobehavioral with the epileptiform characteristics of autism spectrum disorders. This clinical presentation occurred despite metabolic adaptations consisting of an increase in microvascular/glial GLUT1, neuronal GLUT8 and monocarboxylate transporter isoform 2 concentrations, with minimal to no change in brain glucose uptake but an increase in lactate uptake. Neuron-specific glucose deficiency has a negative impact on neurodevelopment interfering with functional competence. This is the first description of GLUT3 deficiency that forms a possible novel genetic mechanism for pervasive developmental disorders, such as the neuropsychiatric autism spectrum disorders, requiring further investigation in humans.

  15. Neuronal Glucose Transporter Isoform 3 Deficient Mice Demonstrate Features of Autism Spectrum Disorders

    OpenAIRE

    Zhao, Yuanzi; Fung, Camille; Shin, Don; Shin, Bo-Chul; Thamotharan, Shanthie; Sankar, Raman; Ehninger, Dan; Silva, Alcino; Devaskar, Sherin U.

    2009-01-01

    Neuronal glucose transporter (GLUT) isoform 3 deficiency in null heterozygous mice led to abnormal spatial learning and working memory but normal acquisition and retrieval during contextual conditioning, abnormal cognitive flexibility with intact gross motor ability, electroencephalographic seizures, perturbed social behavior with reduced vocalization and stereotypies at low frequency. This phenotypic expression is unique as it combines the neurobehavioral with the epileptiform characteristic...

  16. Clonidine, an α2 receptor agonist, diminishes GABAergic neurotransmission to cardiac vagal neurons in the nucleus ambiguus

    OpenAIRE

    Philbin, Kerry E.; Bateman, Ryan J.; Mendelowitz, David

    2010-01-01

    In hypertension there is an autonomic imbalance in which sympathetic activity dominates over parasympathetic control. Parasympathetic activity to the heart originates from cardiac vagal neurons located in the nucleus ambiguus. Pre-sympathetic neurons that project to sympathetic neurons in the spinal cord are located in the ventral brainstem in close proximity to cardiac vagal neurons, and many of these pre-sympathetic neurons are catecholaminergic. In addition to their projection to the spina...

  17. Wallerian degeneration slow mouse neurons are protected against cell death caused by mechanisms involving mitochondrial electron transport dysfunction.

    Science.gov (United States)

    Tokunaga, Shinji; Araki, Toshiyuki

    2012-03-01

    Ischemia elicits a variety of stress responses in neuronal cells, which result in cell death. wld(S) Mice bear a mutation that significantly delays Wallerian degeneration. This mutation also protects all neuronal cells against other types of stresses resulting in cell death, including ischemia. To clarify the types of stresses that neuronal cell bodies derived from wld(S) mice are protected from, we exposed primary cultured neurons derived from wld(S) mice to various components of hypoxic stress. We found that wld(S) mouse neurons are protected against cellular injury induced by reoxygenation following hypoxic stress. Furthermore, we found that wld(S) mouse neurons are protected against functional impairment of the mitochondrial electron transport chain. These data suggest that Wld(S) protein expression may provide protection against neuronal cell death caused by mechanisms involving mitochondrial electron transport dysfunction. Copyright © 2011 Wiley Periodicals, Inc.

  18. Oscillations, complex spatiotemporal behavior, and information transport in networks of excitatory and inhibitory neurons

    International Nuclear Information System (INIS)

    Destexhe, A.

    1994-01-01

    Various types of spatiotemporal behavior are described for two-dimensional networks of excitatory and inhibitory neurons with time delayed interactions. It is described how the network behaves as several structural parameters are varied, such as the number of neurons, the connectivity, and the values of synaptic weights. A transition from spatially uniform oscillations to spatiotemporal chaos via intermittentlike behavior is observed. The properties of spatiotemporally chaotic solutions are investigated by evaluating the largest positive Lyapunov exponent and the loss of correlation with distance. Finally, properties of information transport are evaluated during uniform oscillations and spatiotemporal chaos. It is shown that the diffusion coefficient increases significantly in the spatiotemporal phase similar to the increase of transport coefficients at the onset of fluid turbulence. It is proposed that such a property should be seen in other media, such as chemical turbulence or networks of oscillators. The possibility of measuring information transport from appropriate experiments is also discussed

  19. Glutamate transporter activity promotes enhanced Na+/K+-ATPase -mediated extracellular K+ management during neuronal activity

    DEFF Research Database (Denmark)

    Larsen, Brian R; Holm, Rikke; Vilsen, Bente

    2016-01-01

    , in addition, Na+ /K+ -ATPase-mediated K+ clearance could be governed by astrocytic [Na+ ]i . During most neuronal activity, glutamate is released in the synaptic cleft and is re-absorbed by astrocytic Na+ -coupled glutamate transporters, thereby elevating [Na+ ]i . It thus remains unresolved whether...... the different Na+ /K+ -ATPase isoforms are controlled by [K+ ]o or [Na+ ]i during neuronal activity. Hippocampal slice recordings of stimulus-induced [K+ ]o transients with ion-sensitive microelectrodes revealed reduced Na+ /K+ -ATPase-mediated K+ management upon parallel inhibition of the glutamate transporter......+ affinity to the α1 and α2 isoforms than the β2 isoform. In summary, enhanced astrocytic Na+ /K+ -ATPase-dependent K+ clearance was obtained with parallel glutamate transport activity. The astrocytic Na+ /K+ -ATPase isoform constellation α2β1 appeared to be specifically geared to respond to the [Na+ ]i...

  20. Concentration of membrane antigens by forward transport and trapping in neuronal growth cones.

    Science.gov (United States)

    Sheetz, M P; Baumrind, N L; Wayne, D B; Pearlman, A L

    1990-04-20

    Formation of the nervous system requires that neuronal growth cones follow specific paths and then stop at recognition signals, sensed at the growth cone's leading edge. We used antibody-coated gold particles viewed by video-enhanced differential interference contrast microscopy to observe the distribution and movement of two cell surface molecules, N-CAM and the 2A1 antigen, on growth cones of cultured cortical neurons. Gold particles are occasionally transported forward at 1-2 microns/s to the leading edge where they are trapped but continue to move. Concentration at the edge persists after cytochalasin D treatment or ATP depletion, but active movements to and along edges cease. We also observed a novel outward movement of small cytoplasmic aggregates at 1.8 microns/s in filopodia. We suggest that active forward transport and trapping involve reversible attachment of antigens to and transport along cytoskeletal elements localized to edges of growth cones.

  1. Intracellular pH regulation by acid-base transporters in mammalian neurons

    Science.gov (United States)

    Ruffin, Vernon A.; Salameh, Ahlam I.; Boron, Walter F.; Parker, Mark D.

    2014-01-01

    Intracellular pH (pHi) regulation in the brain is important in both physiological and physiopathological conditions because changes in pHi generally result in altered neuronal excitability. In this review, we will cover 4 major areas: (1) The effect of pHi on cellular processes in the brain, including channel activity and neuronal excitability. (2) pHi homeostasis and how it is determined by the balance between rates of acid loading (JL) and extrusion (JE). The balance between JE and JL determine steady-state pHi, as well as the ability of the cell to defend pHi in the face of extracellular acid-base disturbances (e.g., metabolic acidosis). (3) The properties and importance of members of the SLC4 and SLC9 families of acid-base transporters expressed in the brain that contribute to JL (namely the Cl-HCO3 exchanger AE3) and JE (the Na-H exchangers NHE1, NHE3, and NHE5 as well as the Na+- coupled HCO3− transporters NBCe1, NBCn1, NDCBE, and NBCn2). (4) The effect of acid-base disturbances on neuronal function and the roles of acid-base transporters in defending neuronal pHi under physiopathologic conditions. PMID:24592239

  2. Herpes simplex virus vectors overexpressing the glucose transporter gene protect against seizure-induced neuron loss.

    OpenAIRE

    Lawrence, M S; Ho, D Y; Dash, R; Sapolsky, R M

    1995-01-01

    We have generated herpes simplex virus (HSV) vectors vIE1GT and v alpha 4GT bearing the GLUT-1 isoform of the rat brain glucose transporter (GT) under the control of the human cytomegalovirus ie1 and HSV alpha 4 promoters, respectively. We previously reported that such vectors enhance glucose uptake in hippocampal cultures and the hippocampus. In this study we demonstrate that such vectors can maintain neuronal metabolism and reduce the extent of neuron loss in cultures after a period of hypo...

  3. Amyloid-Beta Induced Changes in Vesicular Transport of BDNF in Hippocampal Neurons

    Directory of Open Access Journals (Sweden)

    Bianca Seifert

    2016-01-01

    Full Text Available The neurotrophin brain derived neurotrophic factor (BDNF is an important growth factor in the CNS. Deficits in transport of this secretory protein could underlie neurodegenerative diseases. Investigation of disease-related changes in BDNF transport might provide insights into the cellular mechanism underlying, for example, Alzheimer’s disease (AD. To analyze the role of BDNF transport in AD, live cell imaging of fluorescently labeled BDNF was performed in hippocampal neurons of different AD model systems. BDNF and APP colocalized with low incidence in vesicular structures. Anterograde as well as retrograde transport of BDNF vesicles was reduced and these effects were mediated by factors released from hippocampal neurons into the extracellular medium. Transport of BDNF was altered at a very early time point after onset of human APP expression or after acute amyloid-beta(1-42 treatment, while the activity-dependent release of BDNF remained unaffected. Taken together, extracellular cleavage products of APP induced rapid changes in anterograde and retrograde transport of BDNF-containing vesicles while release of BDNF was unaffected by transgenic expression of mutated APP. These early transport deficits might lead to permanently impaired brain functions in the adult brain.

  4. One-dimensional deterministic transport in neurons measured by dispersion-relation phase spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Wang Ru [Quantitative Light Imaging Laboratory, Department of Mechanical Science and Engineering, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801 (United States); Wang Zhuo; Leigh, Joe; Popescu, Gabriel [Quantitative Light Imaging Laboratory, Department of Electrical and Computer Engineering, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801 (United States); Sobh, Nahil [Beckman Institute for Advanced Science and Technology, Department of Civil and Environmental Engineering, and Department of Mechanical Engineering and Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801 (United States); Millet, Larry; Gillette, Martha U [Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801 (United States); Levine, Alex J, E-mail: alevine@chem.ucla.edu, E-mail: gpopescu@illinois.edu [Department of Chemistry and Biochemistry and Department of Physics and Astronomy, University of California at Los Angeles, Los Angeles, CA 90095 (United States)

    2011-09-21

    We studied the active transport of intracellular components along neuron processes using a new method developed in our laboratory: dispersion-relation phase spectroscopy. This method is able to quantitatively map spatially the heterogeneous dynamics of the concentration field of the cargos at submicron resolution without the need for tracking individual components. The results in terms of density correlation function reveal that the decay rate is linear in wavenumber, which is consistent with a narrow Lorentzian distribution of cargo velocity. (paper)

  5. Enhanced neuronal glucose transporter expression reveals metabolic choice in a HD Drosophila model.

    Science.gov (United States)

    Besson, Marie Thérèse; Alegría, Karin; Garrido-Gerter, Pamela; Barros, Luis Felipe; Liévens, Jean-Charles

    2015-01-01

    Huntington's disease is a neurodegenerative disorder caused by toxic insertions of polyglutamine residues in the Huntingtin protein and characterized by progressive deterioration of cognitive and motor functions. Altered brain glucose metabolism has long been suggested and a possible link has been proposed in HD. However, the precise function of glucose transporters was not yet determined. Here, we report the effects of the specifically-neuronal human glucose transporter expression in neurons of a Drosophila model carrying the exon 1 of the human huntingtin gene with 93 glutamine repeats (HQ93). We demonstrated that overexpression of the human glucose transporter in neurons ameliorated significantly the status of HD flies by increasing their lifespan, reducing their locomotor deficits and rescuing eye neurodegeneration. Then, we investigated whether increasing the major pathways of glucose catabolism, glycolysis and pentose-phosphate pathway (PPP) impacts HD. To mimic increased glycolytic flux, we overexpressed phosphofructokinase (PFK) which catalyzes an irreversible step in glycolysis. Overexpression of PFK did not affect HQ93 fly survival, but protected from photoreceptor loss. Overexpression of glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of the PPP, extended significantly the lifespan of HD flies and rescued eye neurodegeneration. Since G6PD is able to synthesize NADPH involved in cell survival by maintenance of the redox state, we showed that tolerance to experimental oxidative stress was enhanced in flies co-expressing HQ93 and G6PD. Additionally overexpressions of hGluT3, G6PD or PFK were able to circumvent mitochondrial deficits induced by specific silencing of genes necessary for mitochondrial homeostasis. Our study confirms the involvement of bioenergetic deficits in HD course; they can be rescued by specific expression of a glucose transporter in neurons. Finally, the PPP and, to a lesser extent, the glycolysis seem to mediate the hGluT3

  6. Enhanced neuronal glucose transporter expression reveals metabolic choice in a HD Drosophila model.

    Directory of Open Access Journals (Sweden)

    Marie Thérèse Besson

    Full Text Available Huntington's disease is a neurodegenerative disorder caused by toxic insertions of polyglutamine residues in the Huntingtin protein and characterized by progressive deterioration of cognitive and motor functions. Altered brain glucose metabolism has long been suggested and a possible link has been proposed in HD. However, the precise function of glucose transporters was not yet determined. Here, we report the effects of the specifically-neuronal human glucose transporter expression in neurons of a Drosophila model carrying the exon 1 of the human huntingtin gene with 93 glutamine repeats (HQ93. We demonstrated that overexpression of the human glucose transporter in neurons ameliorated significantly the status of HD flies by increasing their lifespan, reducing their locomotor deficits and rescuing eye neurodegeneration. Then, we investigated whether increasing the major pathways of glucose catabolism, glycolysis and pentose-phosphate pathway (PPP impacts HD. To mimic increased glycolytic flux, we overexpressed phosphofructokinase (PFK which catalyzes an irreversible step in glycolysis. Overexpression of PFK did not affect HQ93 fly survival, but protected from photoreceptor loss. Overexpression of glucose-6-phosphate dehydrogenase (G6PD, the key enzyme of the PPP, extended significantly the lifespan of HD flies and rescued eye neurodegeneration. Since G6PD is able to synthesize NADPH involved in cell survival by maintenance of the redox state, we showed that tolerance to experimental oxidative stress was enhanced in flies co-expressing HQ93 and G6PD. Additionally overexpressions of hGluT3, G6PD or PFK were able to circumvent mitochondrial deficits induced by specific silencing of genes necessary for mitochondrial homeostasis. Our study confirms the involvement of bioenergetic deficits in HD course; they can be rescued by specific expression of a glucose transporter in neurons. Finally, the PPP and, to a lesser extent, the glycolysis seem to

  7. Streptozotocin alters glucose transport, connexin expression and endoplasmic reticulum functions in neurons and astrocytes.

    Science.gov (United States)

    Biswas, Joyshree; Gupta, Sonam; Verma, Dinesh Kumar; Singh, Sarika

    2017-07-25

    The study was undertaken to explore the cell-specific streptozotocin (STZ)-induced mechanistic alterations. STZ-induced rodent model is a well-established experimental model of Alzheimer's disease (AD) and in our previous studies we have established it as an in vitro screening model of AD by employing N2A neuronal cells. Therefore, STZ was selected in the present study to understand the STZ-induced cell-specific alterations by utilizing neuronal N2A and astrocytes C6 cells. Both neuronal and astrocyte cells were treated with STZ at 10, 50, 100 and 1000μM concentrations for 48h. STZ exposure caused significant decline in cellular viability and augmented cytotoxicity of cells involving astrocytes activation. STZ treatment also disrupted the energy metabolism by altered glucose uptake and its transport in both cells as reflected with decreased expression of glucose transporters (GLUT) 1/3. The consequent decrease in ATP level and decreased mitochondrial membrane potential was also observed in both the cells. STZ caused increased intracellular calcium which could cause the initiation of endoplasmic reticulum (ER) stress. Significant upregulation of ER stress-related markers were observed in both cells after STZ treatment. The cellular communication of astrocytes and neurons was altered as reflected by increased expression of connexin 43 along with DNA fragmentation. STZ-induced apoptotic death was evaluated by elevated expression of caspase-3 and PI/Hoechst staining of cells. In conclusion, study showed that STZ exert alike biochemical alterations, ER stress and cellular apoptosis in both neuronal and astrocyte cells. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  8. Sympathetic chain Schwannoma

    International Nuclear Information System (INIS)

    Al-Mashat, Faisal M.

    2009-01-01

    Schwannomas are rare, benign, slowly growing tumors arising from Schwann cells that line nerve sheaths. Schwannomas arising from the cervical sympathetic chain are extremely rare. Here, we report a case of a 70-year-old man who presented with only an asymptomatic neck mass. Physical examination revealed a left sided Horner syndrome and a neck mass with transmitted pulsation and anterior displacement of the carotid artery. Computed tomography (CT) showed a well-defined non-enhancing mass with vascular displacement. The nerve of origin of this encapsulated tumor was the sympathetic chain. The tumor was excised completely intact. The pathologic diagnosis was Schwannoma (Antoni type A and Antoni type B). The patient has been well and free of tumor recurrence for 14 months with persistence of asymptomatic left sided Horner syndrome. The clinical, radiological and pathological evaluations, therapy and postoperative complications of this tumor are discussed. (author)

  9. A cAMP/PKA/Kinesin-1 Axis Promotes the Axonal Transport of Mitochondria in Aging Drosophila Neurons.

    Science.gov (United States)

    Vagnoni, Alessio; Bullock, Simon L

    2018-04-23

    Mitochondria play fundamental roles within cells, including energy provision, calcium homeostasis, and the regulation of apoptosis. The transport of mitochondria by microtubule-based motors is critical for neuronal structure and function. This process allows local requirements for mitochondrial functions to be met and also facilitates recycling of these organelles [1, 2]. An age-related reduction in mitochondrial transport has been observed in neurons of mammalian and non-mammalian organisms [3-6], and has been proposed to contribute to the broader decline in neuronal function that occurs during aging [3, 5-7]. However, the factors that influence mitochondrial transport in aging neurons are poorly understood. Here we provide evidence using the tractable Drosophila wing nerve system that the cyclic AMP/protein kinase A (cAMP/PKA) pathway promotes the axonal transport of mitochondria in adult neurons. The level of the catalytic subunit of PKA decreases during aging, and acute activation of the cAMP/PKA pathway in aged flies strongly stimulates mitochondrial motility. Thus, the age-related impairment of transport is reversible. The expression of many genes is increased by PKA activation in aged flies. However, our results indicate that elevated mitochondrial transport is due in part to upregulation of the heavy chain of the kinesin-1 motor, the level of which declines during aging. Our study identifies evolutionarily conserved factors that can strongly influence mitochondrial motility in aging neurons. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  10. Transcriptional dysregulation of γ-aminobutyric acid transporter in parvalbumin-containing inhibitory neurons in the prefrontal cortex in schizophrenia.

    Science.gov (United States)

    Bitanihirwe, Byron K Y; Woo, Tsung-Ung W

    2014-12-30

    Parvalbumin (PV)-containing neurons are functionally compromised in schizophrenia. Using double in situ hybridization in postmortem human prefrontal cortex, we found that the messenger RNA (mRNA) for the γ-aminobutyric acid (GABA) transporter GAT-1 was undetectable in 22-41% of PV neurons in layers 3-4 in schizophrenia. In the remaining PV neurons with detectable GAT-1 mRNA, transcript expression was decreased by 26% in layer 3. Hence, the dysfunction of PV neurons involves the molecular dysregulation of presynaptic GABA reuptake. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  11. Olfactory marker protein: turnover and transport in normal and regenerating neurons

    International Nuclear Information System (INIS)

    Kream, R.M.; Margolis, F.L.

    1984-01-01

    A 19,000-dalton acidic protein designated olfactory marker protein (OMP) is a cell-specific marker of mature olfactory chemosensory neurons. Intranasal irrigation of mouse olfactory epithelium with [ 35 S]methionine labeled OMP to high specific activity. Turnover and transport characteristics of 35 S-labeled OMP were compared to those of 35 S-labeled global cytosol protein in groups of young, adult, and Triton-treated adult mice. The latter contained primarily large numbers of regenerating olfactory neurons. In olfactory epithelium of young and Triton-treated mice, the specific activity of OMP was three times that of global cytosol protein, whereas in adults the two measures were equal. In all three groups, however, the rate of degradation of OMP was roughly equal to that of cytosol protein (T1/2 . 5 to 6 days). By contrast, differences in T1/2 for OMP decline in the bulb of adult, young, and Triton-treated adult mice were highly significant (T1/2's of 9.3, 6.1, and 4 to 5 days, respectively; p . 0.001). The specific activity of [35S]methionine incorporated in OMP exceeded that of the free amino acid 5-fold, indicating minimal precursor reutilization during the course of our experiments. Turnover data indicate that increased isotope incorporation into OMP in the epithelium is matched by an accelerated rate of degradation in the bulb. This may be correlated with the physiological state or developmental age of the primary neurons since in young and Triton-treated adult mice, rapidly maturing ''young'' olfactory neurons represent a larger proportion of the total population than in adults. Thus, OMP behaves as a typical, relatively slowly transported soluble protein (v . 2 to 4 mm/day, slow component b)

  12. Protective actions of the vesicular monoamine transporter 2 (VMAT2) in monoaminergic neurons.

    Science.gov (United States)

    Guillot, Thomas S; Miller, Gary W

    2009-04-01

    Vesicular monoamine transporters (VMATs) are responsible for the packaging of neurotransmitters such as dopamine, serotonin, norepinephrine, and epinephrine into synaptic vesicles. These proteins evolved from precursors in the major facilitator superfamily of transporters and are among the members of the toxin extruding antiporter family. While the primary function of VMATs is to sequester neurotransmitters within vesicles, they can also translocate toxicants away from cytosolic sites of action. In the case of dopamine, this dual role of VMAT2 is combined-dopamine is more readily oxidized in the cytosol where it can cause oxidative stress so packaging into vesicles serves two purposes: neurotransmission and neuroprotection. Furthermore, the deleterious effects of exogenous toxicants on dopamine neurons, such as MPTP, can be attenuated by VMAT2 activity. The active metabolite of MPTP can be kept within vesicles and prevented from disrupting mitochondrial function thereby sparing the dopamine neuron. The highly addictive drug methamphetamine is also neurotoxic to dopamine neurons by using dopamine itself to destroy the axon terminals. Methamphetamine interferes with vesicular sequestration and increases the production of dopamine, escalating the amount in the cytosol and leading to oxidative damage of terminal components. Vesicular transport seems to resist this process by sequestering much of the excess dopamine, which is illustrated by the enhanced methamphetamine neurotoxicity in VMAT2-deficient mice. It is increasingly evident that VMAT2 provides neuroprotection from both endogenous and exogenous toxicants and that while VMAT2 has been adapted by eukaryotes for synaptic transmission, it is derived from phylogenetically ancient proteins that originally evolved for the purpose of cellular protection.

  13. Imbalance between sympathetic and sensory innervation in peritoneal endometriosis.

    Science.gov (United States)

    Arnold, Julia; Barcena de Arellano, Maria L; Rüster, Carola; Vercellino, Giuseppe F; Chiantera, Vito; Schneider, Achim; Mechsner, Sylvia

    2012-01-01

    To investigate possible mechanisms of pain pathophysiology in patients with peritoneal endometriosis, a clinical study on sensory and sympathetic nerve fibre sprouting in endometriosis was performed. Peritoneal lesions (n=40) and healthy peritoneum (n=12) were immunostained and analysed with anti-protein gene product 9.5 (PGP 9.5), anti-substance P (SP) and anti-tyrosine hydroxylase (TH), specific markers for intact nerve fibres, sensory nerve fibres and sympathetic nerve fibres, respectively, to identify the ratio of sympathetic and sensory nerve fibres. In addition, immune cell infiltrates in peritoneal endometriotic lesions were analysed and the nerve growth factor (NGF) and interleukin (IL)-1β expression was correlate with the nerve fibre density. Peritoneal fluids from patients with endometriosis (n=40) and without endometriosis (n=20) were used for the in vitro neuronal growth assay. Cultured chicken dorsal root ganglia (DRG) and sympathetic ganglia were stained with anti-growth associated protein 43 (anti-GAP 43), anti-SP and anti-TH. We could detect an increased sensory and decreased sympathetic nerve fibres density in peritoneal lesions compared to healthy peritoneum. Peritoneal fluids of patients with endometriosis compared to patients without endometriosis induced an increased sprouting of sensory neurites from DRG and decreased neurite outgrowth from sympathetic ganglia. In conclusion, this study demonstrates an imbalance between sympathetic and sensory nerve fibres in peritoneal endometriosis, as well as an altered modulation of peritoneal fluids from patients with endometriosis on sympathetic and sensory innervation which might directly be involved in the maintenance of inflammation and pain. Copyright © 2011 Elsevier Inc. All rights reserved.

  14. A biophysical analysis of mitochondrial movement: differences between transport in neuronal cell bodies versus processes.

    Science.gov (United States)

    Narayanareddy, Babu Reddy Janakaloti; Vartiainen, Suvi; Hariri, Neema; O'Dowd, Diane K; Gross, Steven P

    2014-07-01

    There is an increasing interest in factors that can impede cargo transport by molecular motors inside the cell. Although potentially relevant (Yi JY, Ori-McKenney KM, McKenney RJ, Vershinin M, Gross SP, Vallee RB. High-resolution imaging reveals indirect coordination of opposite motors and a role for LIS1 in high-load axonal transport. J Cell Biol 2011;195:193-201), the importance of cargo size and subcellular location has received relatively little attention. Here we address these questions taking advantage of the fact that mitochondria - a common cargo - in Drosophila neurons exhibit a wide distribution of sizes. In addition, the mitochondria can be genetically marked with green fluorescent protein (GFP) making it possible to visualize and compare their movement in the cell bodies and in the processes of living cells. Using total internal reflection microscopy coupled with particle tracking and analysis, we quantified the transport properties of GFP-positive mitochondria as a function of their size and location. In neuronal cell bodies, we find little evidence for significant opposition to motion, consistent with a previous study on lipid droplets (Shubeita GT, Tran SL, Xu J, Vershinin M, Cermelli S, Cotton SL, Welte MA, Gross SP. Consequences of motor copy number on the intracellular transport of kinesin-1-driven lipid droplets. Cell 2008;135:1098-1107). However, in the processes, we observe an inverse relationship between the mitochondrial size and velocity and the run distances. This can be ameliorated via hypotonic treatment to increase process size, suggesting that motor-mediated movement is impeded in this more-confined environment. Interestingly, we also observe local mitochondrial accumulations in processes but not in cell bodies. Such accumulations do not completely block the transport but do increase the probability of mitochondria-mitochondria interactions. They are thus particularly interesting in relation to mitochondrial exchange of elements.

  15. Tissue Specific Expression of Cre in Rat Tyrosine Hydroxylase and Dopamine Active Transporter-Positive Neurons.

    Science.gov (United States)

    Liu, Zhenyi; Brown, Andrew; Fisher, Dan; Wu, Yumei; Warren, Joe; Cui, Xiaoxia

    2016-01-01

    The rat is a preferred model system over the mouse for neurological studies, and cell type-specific Cre expression in the rat enables precise ablation of gene function in neurons of interest, which is especially valuable for neurodegenerative disease modeling and optogenetics. Yet, few such Cre rats are available. Here we report the characterization of two Cre rats, tyrosine hydroxylase (TH)-Cre and dopamine active transporter (DAT or Slc6a3)-Cre, by using a combination of immunohistochemistry (IHC) and mRNA fluorescence in situ hybridization (FISH) as well as a fluorescent reporter for Cre activity. We detected Cre expression in expected neurons in both Cre lines. Interestingly, we also found that in Th-Cre rats, but not DAT-Cre rats, Cre is expressed in female germ cells, allowing germline excision of the floxed allele and hence the generation of whole-body knockout rats. In summary, our data demonstrate that targeted integration of Cre cassette lead to faithful recapitulation of expression pattern of the endogenous promoter, and mRNA FISH, in addition to IHC, is an effective method for the analysis of the spatiotemporal gene expression patterns in the rat brain, alleviating the dependence on high quality antibodies that are often not available against rat proteins. The Th-Cre and the DAT-Cre rat lines express Cre in selective subsets of dopaminergic neurons and should be particularly useful for researches on Parkinson's disease.

  16. Decreased adrenoceptor stimulation in heart failure rats reduces NGF expression by cardiac parasympathetic neurons.

    Science.gov (United States)

    Hasan, Wohaib; Smith, Peter G

    2014-04-01

    Postganglionic cardiac parasympathetic and sympathetic nerves are physically proximate in atrial cardiac tissue allowing reciprocal inhibition of neurotransmitter release, depending on demands from central cardiovascular centers or reflex pathways. Parasympathetic cardiac ganglion (CG) neurons synthesize and release the sympathetic neurotrophin nerve growth factor (NGF), which may serve to maintain these close connections. In this study we investigated whether NGF synthesis by CG neurons is altered in heart failure, and whether norepinephrine from sympathetic neurons promotes NGF synthesis. NGF and proNGF immunoreactivity in CG neurons in heart failure rats following chronic coronary artery ligation was investigated. NGF immunoreactivity was decreased significantly in heart failure rats compared to sham-operated animals, whereas proNGF expression was unchanged. Changes in neurochemistry of CG neurons included attenuated expression of the cholinergic marker vesicular acetylcholine transporter, and increased expression of the neuropeptide vasoactive intestinal polypeptide. To further investigate norepinephrine's role in promoting NGF synthesis, we cultured CG neurons treated with adrenergic receptor (AR) agonists. An 82% increase in NGF mRNA levels was detected after 1h of isoproterenol (β-AR agonist) treatment, which increased an additional 22% at 24h. Antagonist treatment blocked isoproterenol-induced increases in NGF transcripts. In contrast, the α-AR agonist phenylephrine did not alter NGF mRNA expression. These results are consistent with β-AR mediated maintenance of NGF synthesis in CG neurons. In heart failure, a decrease in NGF synthesis by CG neurons may potentially contribute to reduced connections with adjacent sympathetic nerves. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. AMPUTATION AND REFLEX SYMPATHETIC DYSTROPHY

    NARCIS (Netherlands)

    GEERTZEN, JHB; EISMA, WH

    Reflex sympathetic dystrophy is a chronic pain syndrome characterized by chronic burning pain, restricted range of motion, oedema and vasolability. Patients are difficult to treat and the prognosis is very often poor. This report emphasizes that an amputation in case of a reflex sympathetic

  18. Orexins control intestinal glucose transport by distinct neuronal, endocrine, and direct epithelial pathways.

    Science.gov (United States)

    Ducroc, Robert; Voisin, Thierry; El Firar, Aadil; Laburthe, Marc

    2007-10-01

    Orexins are neuropeptides involved in energy homeostasis. We investigated the effect of orexin A (OxA) and orexin B (OxB) on intestinal glucose transport in the rat. Injection of orexins led to a decrease in the blood glucose level in oral glucose tolerance tests (OGTTs). Effects of orexins on glucose entry were analyzed in Ussing chambers using the Na(+)-dependent increase in short-circuit current (Isc) to quantify jejunal glucose transport. The rapid and marked increase in Isc induced by luminal glucose was inhibited by 10 nmol/l OxA or OxB (53 and 59%, respectively). Response curves to OxA and OxB were not significantly different with half-maximal inhibitory concentrations at 0.9 and 0.4 nmol/l, respectively. On the one hand, OxA-induced inhibition of Isc was reduced by the neuronal blocker tetrodotoxin (TTX) and by a cholecystokinin (CCK) 2R antagonist, indicating involvement of neuronal and endocrine CCK-releasing cells. The OX(1)R antagonist SB334867 had no effect on OxA-induced inhibition, which is likely to occur via a neuronal and/or endocrine OX(2)R. On the other hand, SB334867 induced a significant right shift of the concentration-effect curve for OxB. This OxB-preferring OX(1)R pathway was not sensitive to TTX or to CCKR antagonists, suggesting that OxB may act directly on enterocytic OX(1)R. These distinct effects of OxA and OxB are consistent with the expression of OX(1)R and OX(2)R mRNA in the epithelial and nonepithelial tissues, respectively. Our data delineate a new function for orexins as inhibitors of intestinal glucose absorption and provide a new basis for orexin-induced short-term control of energy homeostasis.

  19. A novel dopamine transporter transgenic mouse line for identification and purification of midbrain dopaminergic neurons reveals midbrain heterogeneity

    DEFF Research Database (Denmark)

    Christiansen, Mia Apuschkin; Stilling, Sara; Rahbek-Clemmensen, Troels

    2015-01-01

    Midbrain dopaminergic (DAergic) neurons are a heterogeneous cell group, composed of functionally distinct cell populations projecting to the basal ganglia, prefrontal cortex and limbic system. Despite their functional significance, the midbrain population of DAergic neurons is sparse, constituting...... of the dopamine transporter (DAT) promoter was characterized. Confocal microscopy analysis of brain sections showed strong eGFP signal reporter in midbrain regions and striatal terminals that co-localized with the DAergic markers DAT and tyrosine hydroxylase (TH). Thorough quantification of co...

  20. Botulinum neurotoxins A and E undergo retrograde axonal transport in primary motor neurons.

    Directory of Open Access Journals (Sweden)

    Laura Restani

    2012-12-01

    Full Text Available The striking differences between the clinical symptoms of tetanus and botulism have been ascribed to the different fate of the parental neurotoxins once internalised in motor neurons. Tetanus toxin (TeNT is known to undergo transcytosis into inhibitory interneurons and block the release of inhibitory neurotransmitters in the spinal cord, causing a spastic paralysis. In contrast, botulinum neurotoxins (BoNTs block acetylcholine release at the neuromuscular junction, therefore inducing a flaccid paralysis. Whilst overt experimental evidence supports the sorting of TeNT to the axonal retrograde transport pathway, recent findings challenge the established view that BoNT trafficking is restricted to the neuromuscular junction by highlighting central effects caused by these neurotoxins. These results suggest a more complex scenario whereby BoNTs also engage long-range trafficking mechanisms. However, the intracellular pathways underlying this process remain unclear. We sought to fill this gap by using primary motor neurons either in mass culture or differentiated in microfluidic devices to directly monitor the endocytosis and axonal transport of full length BoNT/A and BoNT/E and their recombinant binding fragments. We show that BoNT/A and BoNT/E are internalised by spinal cord motor neurons and undergo fast axonal retrograde transport. BoNT/A and BoNT/E are internalised in non-acidic axonal carriers that partially overlap with those containing TeNT, following a process that is largely independent of stimulated synaptic vesicle endo-exocytosis. Following intramuscular injection in vivo, BoNT/A and TeNT displayed central effects with a similar time course. Central actions paralleled the peripheral spastic paralysis for TeNT, but lagged behind the onset of flaccid paralysis for BoNT/A. These results suggest that the fast axonal retrograde transport compartment is composed of multifunctional trafficking organelles orchestrating the simultaneous transfer

  1. Dynein-dependent transport of nanos RNA in Drosophila sensory neurons requires Rumpelstiltskin and the germ plasm organizer Oskar.

    Science.gov (United States)

    Xu, Xin; Brechbiel, Jillian L; Gavis, Elizabeth R

    2013-09-11

    Intracellular mRNA localization is a conserved mechanism for spatially regulating protein production in polarized cells, such as neurons. The mRNA encoding the translational repressor Nanos (Nos) forms ribonucleoprotein (RNP) particles that are dendritically localized in Drosophila larval class IV dendritic arborization (da) neurons. In nos mutants, class IV da neurons exhibit reduced dendritic branching complexity, which is rescued by transgenic expression of wild-type nos mRNA but not by a localization-compromised nos derivative. While localization is essential for nos function in dendrite morphogenesis, the mechanism underlying the transport of nos RNP particles was unknown. We investigated the mechanism of dendritic nos mRNA localization by analyzing requirements for nos RNP particle motility in class IV da neuron dendrites through live imaging of fluorescently labeled nos mRNA. We show that dynein motor machinery components mediate transport of nos mRNA in proximal dendrites. Two factors, the RNA-binding protein Rumpelstiltskin and the germ plasm protein Oskar, which are required for diffusion/entrapment-mediated localization of nos during oogenesis, also function in da neurons for formation and transport of nos RNP particles. Additionally, we show that nos regulates neuronal function, most likely independent of its dendritic localization and function in morphogenesis. Our results reveal adaptability of localization factors for regulation of a target transcript in different cellular contexts.

  2. Higher transport and metabolism of glucose in astrocytes compared with neurons: a multiphoton study of hippocampal and cerebellar tissue slices.

    Science.gov (United States)

    Jakoby, Patrick; Schmidt, Elke; Ruminot, Iván; Gutiérrez, Robin; Barros, L Felipe; Deitmer, Joachim W

    2014-01-01

    Glucose is the most important energy substrate for the brain, and its cellular distribution is a subject of great current interest. We have employed fluorescent glucose probes, the 2-deoxy-D-glucose derivates 6- and 2-([N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose) (2-NBDG), to measure transport and metabolism of glucose in acute slices of mouse hippocampus and cerebellum. In the hippocampus, 6-NBDG, which is not metabolized and hence indicates glucose transport, was taken up faster in astrocyte-rich layers (Stratum radiatum [S.r.], Stratum oriens [S.o.]) than in pyramidal cells. Metabolizable 2-NBDG showed larger signals in S.r. and S.o. than in Stratum pyramidale, suggesting faster glucose utilization rate in the astrocyte versus the neuronal compartment. Similarly, we found higher uptake and temperature-sensitive metabolism of 2-NBDG in Bergmann glia when compared with adjacent Purkinje neurons of cerebellar slices. A comparison between 6-NBDG transport and glucose transport in cultured cells using a fluorescence resonance energy transfer nanosensor showed that relative to glucose, 6-NBDG is transported better by neurons than by astrocytes. These results indicate that the preferential transport and metabolism of glucose by glial cells versus neurons proposed for the hippocampus and cerebellum by ourselves (in vitro) and for the barrel cortex by Chuquet et al. (in vivo) is more pronounced than anticipated.

  3. In vivo neuronal synthesis and axonal transport of Kunitz protease inhibitor (KPI)-containing forms of the amyloid precursor protein.

    Science.gov (United States)

    Moya, K L; Confaloni, A M; Allinquant, B

    1994-11-01

    We have shown previously that the amyloid precursor protein (APP) is synthesized in retinal ganglion cells and is rapidly transported down the axons, and that different molecular weight forms of the precursor have different developmental time courses. Some APP isoforms contain a Kunitz protease inhibitor (KPI) domain, and APP that lacks the KPI domain is considered the predominant isoform in neurons. We now show that, among the various rapidly transported APPs, a 140-kDa isoform contains the KPI domain. This APP isoform is highly expressed in rapidly growing retinal axons, and it is also prominent in adult axon endings. This 140-kDa KPI-containing APP is highly sulfated compared with other axonally transported isoforms. These results show that APP with the KPI domain is a prominent isoform synthesized in neurons in vivo, and they suggest that the regulation of protease activity may be an important factor during the establishment of neuronal connections.

  4. BDNF regulates the expression and distribution of vesicular glutamate transporters in cultured hippocampal neurons.

    Directory of Open Access Journals (Sweden)

    Carlos V Melo

    Full Text Available BDNF is a pro-survival protein involved in neuronal development and synaptic plasticity. BDNF strengthens excitatory synapses and contributes to LTP, presynaptically, through enhancement of glutamate release, and postsynaptically, via phosphorylation of neurotransmitter receptors, modulation of receptor traffic and activation of the translation machinery. We examined whether BDNF upregulated vesicular glutamate receptor (VGLUT 1 and 2 expression, which would partly account for the increased glutamate release in LTP. Cultured rat hippocampal neurons were incubated with 100 ng/ml BDNF, for different periods of time, and VGLUT gene and protein expression were assessed by real-time PCR and immunoblotting, respectively. At DIV7, exogenous application of BDNF rapidly increased VGLUT2 mRNA and protein levels, in a dose-dependent manner. VGLUT1 expression also increased but only transiently. However, at DIV14, BDNF stably increased VGLUT1 expression, whilst VGLUT2 levels remained low. Transcription inhibition with actinomycin-D or α-amanitine, and translation inhibition with emetine or anisomycin, fully blocked BDNF-induced VGLUT upregulation. Fluorescence microscopy imaging showed that BDNF stimulation upregulates the number, integrated density and intensity of VGLUT1 and VGLUT2 puncta in neurites of cultured hippocampal neurons (DIV7, indicating that the neurotrophin also affects the subcellular distribution of the transporter in developing neurons. Increased VGLUT1 somatic signals were also found 3 h after stimulation with BDNF, further suggesting an increased de novo transcription and translation. BDNF regulation of VGLUT expression was specifically mediated by BDNF, as no effect was found upon application of IGF-1 or bFGF, which activate other receptor tyrosine kinases. Moreover, inhibition of TrkB receptors with K252a and PLCγ signaling with U-73122 precluded BDNF-induced VGLUT upregulation. Hippocampal neurons express both isoforms during

  5. α-Tubulin Tyrosination and CLIP-170 Phosphorylation Regulate the Initiation of Dynein-Driven Transport in Neurons

    Directory of Open Access Journals (Sweden)

    Jeffrey J. Nirschl

    2016-03-01

    Full Text Available Motor-cargo recruitment to microtubules is often the rate-limiting step of intracellular transport, and defects in this recruitment can cause neurodegenerative disease. Here, we use in vitro reconstitution assays with single-molecule resolution, live-cell transport assays in primary neurons, computational image analysis, and computer simulations to investigate the factors regulating retrograde transport initiation in the distal axon. We find that phosphorylation of the cytoskeletal-organelle linker protein CLIP-170 and post-translational modifications of the microtubule track combine to precisely control the initiation of retrograde transport. Computer simulations of organelle dynamics in the distal axon indicate that while CLIP-170 primarily regulates the time to microtubule encounter, the tyrosination state of the microtubule lattice regulates the likelihood of binding. These mechanisms interact to control transport initiation in the axon in a manner sensitive to the specialized cytoskeletal architecture of the neuron.

  6. A synthetic peptide shows retro- and anterograde neuronal transport before disrupting the chemosensation of plant-pathogenic nematodes.

    Directory of Open Access Journals (Sweden)

    Dong Wang

    2011-03-01

    Full Text Available Cyst nematodes are a group of plant pathogens each with a defined host range that cause major losses to crops including potato, soybean and sugar beet. The infective mobile stage hatches from dormant eggs and moves a short distance through the soil to plant roots, which it then invades. A novel strategy for control has recently been proposed in which the plant is able to secrete a peptide which disorientates the infective stage and prevents invasion of the pathogen. This study provides indirect evidence to support the mechanism by which one such peptide disrupts chemosensory function in nematodes. The peptide is a disulphide-constrained 7-mer with the amino acid sequence CTTMHPRLC that binds to nicotinic acetylcholine receptors. A fluorescently tagged version of this peptide with both epifluorescent and confocal microscopy was used to demonstrate that retrograde transport occurs from an aqueous environment along bare-ending primary cilia of chemoreceptive sensilla. The peptide is transported to the cell bodies of these neurons and on to a limited number of other neurons to which they connect. It appears to be localised in both neuronal processes and organelles adjacent to nuclei of some neurons suggesting it could be transported through the Golgi apparatus. The peptide takes 2.5 h to reach the neuronal cell bodies. Comparative studies established that similar but less abundant uptake occurs for Caenorhabditis elegans along its well studied dye-filling chemoreceptive neurons. Incubation in peptide solution or root-exudate from transgenic plants that secrete the peptide disrupted normal orientation of infective cyst nematodes to host root diffusate. The peptide probably undergoes transport along the dye-filling non-cholinergic chemoreceptive neurons to their synapses where it is taken up by the interneurons to which they connect. Coordinated responses to chemoreception are disrupted when the sub-set of cholinergic interneurons secrete the peptide

  7. A synthetic peptide shows retro- and anterograde neuronal transport before disrupting the chemosensation of plant-pathogenic nematodes.

    Science.gov (United States)

    Wang, Dong; Jones, Laura M; Urwin, Peter E; Atkinson, Howard J

    2011-03-07

    Cyst nematodes are a group of plant pathogens each with a defined host range that cause major losses to crops including potato, soybean and sugar beet. The infective mobile stage hatches from dormant eggs and moves a short distance through the soil to plant roots, which it then invades. A novel strategy for control has recently been proposed in which the plant is able to secrete a peptide which disorientates the infective stage and prevents invasion of the pathogen. This study provides indirect evidence to support the mechanism by which one such peptide disrupts chemosensory function in nematodes. The peptide is a disulphide-constrained 7-mer with the amino acid sequence CTTMHPRLC that binds to nicotinic acetylcholine receptors. A fluorescently tagged version of this peptide with both epifluorescent and confocal microscopy was used to demonstrate that retrograde transport occurs from an aqueous environment along bare-ending primary cilia of chemoreceptive sensilla. The peptide is transported to the cell bodies of these neurons and on to a limited number of other neurons to which they connect. It appears to be localised in both neuronal processes and organelles adjacent to nuclei of some neurons suggesting it could be transported through the Golgi apparatus. The peptide takes 2.5 h to reach the neuronal cell bodies. Comparative studies established that similar but less abundant uptake occurs for Caenorhabditis elegans along its well studied dye-filling chemoreceptive neurons. Incubation in peptide solution or root-exudate from transgenic plants that secrete the peptide disrupted normal orientation of infective cyst nematodes to host root diffusate. The peptide probably undergoes transport along the dye-filling non-cholinergic chemoreceptive neurons to their synapses where it is taken up by the interneurons to which they connect. Coordinated responses to chemoreception are disrupted when the sub-set of cholinergic interneurons secrete the peptide at synapses that

  8. Pet measurements of presynaptic sympathetic nerve terminals in the heart

    International Nuclear Information System (INIS)

    Schwaiger, M.; Hutchins, G.D.; Wieland, D.M.

    1991-01-01

    [ 18 F]Metaraminol (FMR) and [ 11 C]hydroxyephedrine (HED) are catecholamine analogues that have been developed at the University of Michigan for the noninvasive characterization of the sympathetic nervous system of the heart using positron emission tomography (PET). Pharmacological studies employing neurotoxins and uptake inhibitors have demonstrated that both FMR and HED specifically trace the uptake and storage of catecholamines in sympathetic nerve terminals with little nonspecific tracer accumulation. These compounds exhibit excellent qualitative imaging characteristics with heart-to-blood ratios exceeding 6:1 as early as 15 min after intravenous injection in both animals (HED and FMR) and humans (HED). Tracer kinetic modeling techniques have been employed for the quantitative assessment of neuronal catecholamine uptake and storage. Indices of neuronal function, such as the volume of tracer distribution derived from the kinetic models, have been employed in preliminary human studies. Comparison of the tissue distribution volume of HED between normal (control subjects) and denervated (recent transplant patients) cardiac tissue demonstrates a dynamic range of approximately 5:1. This distribution volume is reduced by 60% from normal in patients with dilated cardiomyopathy, indicating dysfunction of the sympathetic system. These results show that HED used in combination with PET provides a sophisticated quantitative approach for studying the sympathetic nervous system of the normal and diseased human heart

  9. Positron emission tomographic imaging of cardiac sympathetic innervation and function

    International Nuclear Information System (INIS)

    Goldstein, D.S.; Chang, P.C.; Eisenhofer, G.; Miletich, R.; Finn, R.; Bacher, J.; Kirk, K.L.; Bacharach, S.; Kopin, I.J.

    1990-01-01

    Sites of uptake, storage, and metabolism of [ 18 F]fluorodopamine and excretion of [ 18 F]fluorodopamine and its metabolites were visualized using positron emission tomographic (PET) scanning after intravenous injection of the tracer into anesthetized dogs. Radioactivity was concentrated in the renal pelvis, heart, liver, spleen, salivary glands, and gall bladder. Uptake of 18F by the heart resulted in striking delineation of the left ventricular myocardium. Pretreatment with desipramine markedly decreased cardiac positron emission, consistent with dependence of the heart on neuronal uptake (uptake-1) for removal of circulating catecholamines. In reserpinized animals, cardiac positron emission was absent within 30 minutes after injection of [ 18 F]-6-fluorodopamine, demonstrating that the emission in untreated animals was from radioactive labeling of the sympathetic storage vesicles. Decreased positron emission from denervated salivary glands confirmed that the tracer was concentrated in sympathetic neurons. Radioactivity in the gall bladder and urinary system depicted the hepatic and renal excretion of the tracer and its metabolites. Administration of tyramine or nitroprusside increased and ganglionic blockade with trimethaphan decreased the rate of loss of myocardial radioactivity. The results show that PET scanning after administration of [ 18 F]fluorodopamine can be used to visualize sites of sympathetic innervation, follow the metabolism and renal and hepatic excretion of catecholamines, and examine cardiac sympathetic function

  10. The sympathetic innervation of the heart: Important new insights.

    Science.gov (United States)

    Coote, J H; Chauhan, R A

    2016-08-01

    Autonomic control of the heart has a significant influence over development of life threatening arrhythmias that can lead to sudden cardiac death. Sympathetic activity is known to be upregulated during these conditions and hence the sympathetic nerves present a target for treatment. However, a better understanding of the anatomy and physiology of cardiac sympathetic nerves is required for the progression of clinical interventions. This review explores the organization of the cardiac sympathetic nerves, from the preganglionic origin to the postganglionic innervations, and provides an overview of literature surrounding anti-arrhythmic therapies including thoracic sympathectomy and dorsal spinal cord stimulation. Several features of the innervation are clear. The cardiac nerves differentially supply the nodal and myocardial tissue of the heart and are dependent on activity generated in spinal neurones in the upper thoracic cord which project to synapse with ganglion cells in the stellate complex on each side. Networks of spinal interneurones determine the pattern of activity. Groups of spinal neurones selectively target specific regions of the heart but whether they exhibit a functional selectivity has still to be elucidated. Electrical or ischemic signals can lead to remodeling of nerves in the heart or ganglia. Surgical and electrical methods are proving to be clinically beneficial in reducing atrial and ventricular arrhythmias, heart failure and severe cardiac pain. This is a rapidly developing area and we need more basic understanding of how these methods work to ensure safety and reduction of side effects. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Uptake and transport of manganese in primary and secondary olfactory neurones in pike.

    Science.gov (United States)

    Tjälve, H; Mejàre, C; Borg-Neczak, K

    1995-07-01

    gamma-spectrometry and autoradiography were used to examine the axoplasmic flow of manganese in the olfactory nerves and to study the uptake of the metal in the brain after application of 54Mn2+ in the olfactory chambers of pikes. The results show that the 54Mn2+ is taken up in the olfactory receptor cells and is transported at a constant rate along the primary olfactory neurones into the brain. The maximal velocity for the transported 54Mn2+ was 2.90 +/- 0.21 mm/hr (mean +/- S.E.) at 10 degrees, which was the temperature used in the experiments. The 54Mn2+ accumulated in the entire olfactory bulbs, although most marked in central and caudal parts. The metal was also seen to migrate into large areas of the telencephalon, apparently mainly via the secondary olfactory axons present in the medial olfactory tract. A transfer along fibres of the medial olfactory tract probably also explains the labelling which was seen in the diencephalon down to the hypothalamus. The results also showed that there is a pathway connecting the two olfactory bulbs of the pike and that this can carry the metal. Our data further showed a marked accumulation of 54Mn2+ in the meningeal epithelium and in the contents of the meningeal sacs surrounding the olfactory bulbs. It appears from our study that manganese has the ability to pass the synaptic junctions between the primary and the secondary olfactory neurones in the olfactory bulbs and to migrate along secondary olfactory pathways into the telencephalon and the diencephalon.(ABSTRACT TRUNCATED AT 250 WORDS)

  12. SYMPATHETIC SOLAR FILAMENT ERUPTIONS

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Rui; Liu, Ying D.; Zimovets, Ivan; Hu, Huidong; Yang, Zhongwei [State Key Laboratory of Space Weather, National Space Science Center, Chinese Academy of Sciences, Beijing 100190 (China); Dai, Xinghua, E-mail: liuxying@spaceweather.ac.cn [Key Laboratory of Solar Activity, National Astronomical Observatories, Chinese Academy of Sciences, Beijing 100012 (China)

    2016-08-10

    The 2015 March 15 coronal mass ejection as one of the two that together drove the largest geomagnetic storm of solar cycle 24 so far was associated with sympathetic filament eruptions. We investigate the relations between the different filaments involved in the eruption. A surge-like small-scale filament motion is confirmed as the trigger that initiated the erupting filament with multi-wavelength observations and using a forced magnetic field extrapolation method. When the erupting filament moved to an open magnetic field region, it experienced an obvious acceleration process and was accompanied by a C-class flare and the rise of another larger filament that eventually failed to erupt. We measure the decay index of the background magnetic field, which presents a critical height of 118 Mm. Combining with a potential field source surface extrapolation method, we analyze the distributions of the large-scale magnetic field, which indicates that the open magnetic field region may provide a favorable condition for F2 rapid acceleration and have some relation with the largest solar storm. The comparison between the successful and failed filament eruptions suggests that the confining magnetic field plays an important role in the preconditions for an eruption.

  13. Prefrontal changes in the glutamate-glutamine cycle and neuronal/glial glutamate transporters in depression with and without suicide

    NARCIS (Netherlands)

    Zhao, J.; Verwer, R.W.H.; van Wamelen, D.J.; Qi, X.R.; Gao, S.F.; Lucassen, P.J.; Swaab, D.F.

    2016-01-01

    There are indications for changes in glutamate metabolism in relation to depression or suicide. The glutamate-glutamine cycle and neuronal/glial glutamate transporters mediate the uptake of the glutamate and glutamine. The expression of various components of the glutamate-glutamine cycle and the

  14. The projection and synaptic organisation of NTS afferent connections with presympathetic neurons, GABA and nNOS neurons in the paraventricular nucleus of the hypothalamus

    Science.gov (United States)

    Affleck, V.S.; Coote, J.H.; Pyner, S.

    2012-01-01

    Elevated sympathetic nerve activity, strongly associated with cardiovascular disease, is partly generated from the presympathetic neurons of the paraventricular nucleus of the hypothalamus (PVN). The PVN-presympathetic neurons regulating cardiac and vasomotor sympathetic activity receive information about cardiovascular status from receptors in the heart and circulation. These receptors signal changes via afferent neurons terminating in the nucleus tractus solitarius (NTS), some of which may result in excitation or inhibition of PVN-presympathetic neurons. Understanding the anatomy and neurochemistry of NTS afferent connections within the PVN could provide important clues to the impairment in homeostasis cardiovascular control associated with disease. Transynaptic labelling has shown the presence of neuronal nitric oxide synthase (nNOS)-containing neurons and GABA interneurons that terminate on presympathetic PVN neurons any of which may be the target for NTS afferents. So far NTS connections to these diverse neuronal pools have not been demonstrated and were investigated in this study. Anterograde (biotin dextran amine – BDA) labelling of the ascending projection from the NTS and retrograde (fluorogold – FG or cholera toxin B subunit – CTB) labelling of PVN presympathetic neurons combined with immunohistochemistry for GABA and nNOS was used to identify the terminal neuronal targets of the ascending projection from the NTS. It was shown that NTS afferent terminals are apposed to either PVN-GABA interneurons or to nitric oxide producing neurons or even directly to presympathetic neurons. Furthermore, there was evidence that some NTS axons were positive for vesicular glutamate transporter 2 (vGLUT2). The data provide an anatomical basis for the different functions of cardiovascular receptors that mediate their actions via the NTS–PVN pathways. PMID:22698695

  15. Organic cation transporter 2 (SLC22A2), a low-affinity and high-capacity choline transporter, is preferentially enriched on synaptic vesicles in cholinergic neurons.

    Science.gov (United States)

    Nakata, T; Matsui, T; Kobayashi, K; Kobayashi, Y; Anzai, N

    2013-11-12

    Organic cation transporters (OCTs) are expressed mainly in the kidney and liver. OCTs transport intrinsic organic cations, including monoamine, dopamine, serotonine and choline, across the plasma membrane. Here, we demonstrate that OCT2 (SLC22A2) is expressed in cholinergic neurons, motoneurons in the anterior horn of the spinal cord, and is implicated in acetylcholine (Ach) recycling in presynaptic terminals. Application of rabbit anti-peptide antibody revealed that OCT2 was expressed in the anterior horn of the spinal cord. Double immunostaining of muscle sections with anti-OCT2 and alpha-bungarotoxin (BTX) revealed that OCT2 was localized in the neuromuscular junctions (NMJs). Immunoelectron microscopy revealed that OCT2 was localized both in synaptic vesicles (SVs) in presynaptic terminals around the motoneurons (C-terminals) and in SVs in nerve terminals in NMJs. The similarity in the distribution of OCT2 in cholinergic neurons and that of vesicular acetyl choline transporter (VAchT), and the fact that OCT2 can transport choline suggest that OCT2 could work as a low-affinity and high-capacity choline transporter at presynaptic terminals in cholinergic neurons in a firing-dependent manner. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  16. Expression profile of vesicular nucleotide transporter (VNUT, SLC17A9) in subpopulations of rat dorsal root ganglion neurons.

    Science.gov (United States)

    Nishida, Kentaro; Nomura, Yuka; Kawamori, Kanako; Moriyama, Yoshinori; Nagasawa, Kazuki

    2014-09-05

    ATP plays an important role in the signal transduction between sensory neurons and satellite cells in dorsal root ganglia (DRGs). In primary cultured DRG neurons, ATP is known to be stored in lysosomes via a vesicular nucleotide transporter (VNUT), and to be released into the intercellular space through exocytosis. DRGs consist of large-, medium- and small-sized neurons, which play different roles in sensory transmission, but there is no information on the expression profiles of VNUT in DRG subpopulations. Here, we obtained detailed expression profiles of VNUT in isolated rat DRG tissues. On immunohistochemical analysis, VNUT was found in DRG neurons, and was predominantly expressed by the small- and medium-sized DRG ones, as judged upon visual inspection, and this was compatible with the finding that the number of VNUT-positive DRG neurons in IB4-positive cells was greater than that in NF200-positive ones. These results suggest that VNUT play a role in ATP accumulation in DRG neurons, especially in small- and medium-sized ones, and might be involved in ATP-mediated nociceptive signaling in DRGs. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  17. Constitutively internalized dopamine transporter is targeted to late endosomes and lysosomal degradation in heterologous cell lines and dopaminergic neurons

    DEFF Research Database (Denmark)

    Eriksen, Jacob; Madsen, Kenneth; Vægter, Christian Bjerggaard

    and amphetamine, a substrate of the DAT. In antibody feeding experiments we observed that Tac-DAT was constitutively internalized faster than Tac alone and using an ELISA based assay we could quantify time-dependent intracellular accumulation of the transporter. Incubation with inhibitors of lysosomal degradation...... (leupeptin, chloroquine, or ammonium chloride) increased the amount of transporter accumulated intracellularly over time, suggesting that constitutively endocytosed transporter was targeted to lysosomal degradation. This was further supported by expression of Tac-DAT in the immortalized dopaminergic cell...... dopaminergic neurons and visualized the DAT directly in the neurons using the fluorescent cocaine analog JHC 1-064. These data showed pronounced colocalization upon constitutive internalization with Lysotracker, a late endosomal/lysosomal marker; however only little co-lolization was observed with Alexa488...

  18. Neuronal 3',3,5-triiodothyronine (T3) uptake and behavioral phenotype of mice deficient in Mct8, the neuronal T3 transporter mutated in Allan-Herndon-Dudley syndrome.

    Science.gov (United States)

    Wirth, Eva K; Roth, Stephan; Blechschmidt, Cristiane; Hölter, Sabine M; Becker, Lore; Racz, Ildiko; Zimmer, Andreas; Klopstock, Thomas; Gailus-Durner, Valerie; Fuchs, Helmut; Wurst, Wolfgang; Naumann, Thomas; Bräuer, Anja; de Angelis, Martin Hrabé; Köhrle, Josef; Grüters, Annette; Schweizer, Ulrich

    2009-07-29

    Thyroid hormone transport into cells requires plasma membrane transport proteins. Mutations in one of these, monocarboxylate transporter 8 (MCT8), have been identified as underlying cause for the Allan-Herndon-Dudley syndrome, an X-linked mental retardation in which the patients also present with abnormally high 3',3,5-triiodothyronine (T(3)) plasma levels. Mice deficient in Mct8 replicate the thyroid hormone abnormalities observed in the human condition. However, no neurological deficits have been described in mice lacking Mct8. Therefore, we subjected Mct8-deficient mice to a comprehensive immunohistochemical, neurological, and behavioral screen. Several behavioral abnormalities were found in the mutants. Interestingly, some of these behavioral changes are compatible with hypothyroidism, whereas others rather indicate hyperthyroidism. We thus hypothesized that neurons exclusively dependent on Mct8 are in a hypothyroid state, whereas neurons expressing other T(3) transporters become hyperthyroid, if they are exposed directly to the high plasma T(3). The majority of T(3) uptake in primary cortical neurons is mediated by Mct8, but pharmacological inhibition suggested functional expression of additional T(3) transporter classes. mRNAs encoding six T(3) transporters, including L-type amino acid transporters (LATs), were coexpressed with Mct8 in isolated neurons. We then demonstrated Lat2 expression in cultured neurons and throughout murine brain development. In contrast, LAT2 is expressed in microglia in the developing human brain during gestation, but not in neurons. We suggest that lack of functional complementation by alternative thyroid hormone transporters in developing human neurons precipitates the devastating neurodevelopmental phenotype in MCT8-deficient patients, whereas Mct8-deficient mouse neurons are functionally complemented by other transporters, for possibly Lat2.

  19. Investigating the Slow Axonal Transport of Neurofilaments: A Precursor for Optimal Neuronal Signaling

    Science.gov (United States)

    Johnson, Christopher M.

    Neurofilaments are the intermediate filaments of neurons and are the most abundant structure of the neuronal cytoskeleton. Once synthesized within the cell body they are then transported throughout the axon along microtubule tracks, driven by the molecular motors kinesin and dynein. This movement is characterized by long pauses with no movement interrupted by infrequent bouts of rapid movement, resulting in an aggregate dense cytoskeletal structure, which serves to regulate an axon's shape and size. Curiously, the modulated kinetics of these polymers produces a very regular, yet non-uniform, morphology in myelinated axons which are composed of discretely spaced myelin-ensheathed segments that are separated by short constricted regions called "nodes of Ranvier". This unique design optimizes the conduction velocity of myelinated axons at minimal fiber size. Hence, neurofilaments regulate the axon caliber to optimize neuron function. The goal of this dissertation is to investigate the motile mechanism of neurofilament transport as well as the resulting electrophysiological effects that follow. We start by examining highly time-resolved kymograph images generated from recorded neurofilament movement via epifluorescence microscopy. Using kymograph analysis, edge detection algorithms, and pixel smoothing tactics, neurofilament trajectories are extracted and used to obtain statistical distributions for the characteristics of how these filaments move within cells. The results suggest that the observed intermittent and bidirectional motions of these filaments might be explained by a model in which dynein and kinesin motors attach to a single neurofilament cargo and interact through mechanical forces only (i.e. a "tug-of-war" model). We test this hypothesis by developing two discrete-state stochastic models for the kinetic cycles of kinesin and dynein, which are then incorporated into a separate stochastic model that represents the posed tug-of-war scenario. We then

  20. Effect of sympathetic activity on capsaicin-evoked pain, hyperalgesia, and vasodilatation.

    Science.gov (United States)

    Baron, R; Wasner, G; Borgstedt, R; Hastedt, E; Schulte, H; Binder, A; Kopper, F; Rowbotham, M; Levine, J D; Fields, H L

    1999-03-23

    Painful nerve and tissue injuries can be exacerbated by activity in sympathetic neurons. The mechanisms of sympathetically maintained pain (SMP) are unclear. To determine the effect of cutaneous sympathetic activity on pain induced by primary afferent C-nociceptor sensitization with capsaicin in humans. In healthy volunteers capsaicin was applied topically (n = 12) or injected into the forearm skin (n = 10) to induce spontaneous pain, dynamic and punctate mechanical hyperalgesia, and antidromic (axon reflex) vasodilatation (flare). Intensity of pain and hyperalgesia, axon reflex vasodilatation (laser Doppler), and flare size and area of hyperalgesia (planimetry) were assessed. The local skin temperature at the application and measurement sites was kept constant at 35 degrees C. In each individual the analyses were performed during the presence of high and low sympathetic skin activity induced by whole-body cooling and warming with a thermal suit. By this method sympathetic vasoconstrictor activity is modulated in the widest range that can be achieved physiologically. The degree of vasoconstrictor discharge was monitored by measuring skin blood flow (laser Doppler) and temperature (infrared thermometry) at the index finger. The intensity and spatial distribution of capsaicin-evoked spontaneous pain and dynamic and punctate mechanical hyperalgesia were identical during the presence of high and low sympathetic discharge. Antidromic vasodilatation and flare size were significantly diminished when sympathetic vasoconstrictor neurons were excited. Cutaneous sympathetic vasoconstrictor activity does not influence spontaneous pain and mechanical hyperalgesia after capsaicin-induced C-nociceptor sensitization. When using physiologic stimulation of sympathetic activity, the capsaicin model is not useful for elucidating mechanisms of SMP. In neuropathic pain states with SMP, different mechanisms may be present.

  1. Glial and Neuronal Glutamate Transporters Differ in the Na+ Requirements for Activation of the Substrate-Independent Anion Conductance

    Directory of Open Access Journals (Sweden)

    Christopher B. Divito

    2017-05-01

    Full Text Available Excitatory amino acid transporters (EAATs are secondary active transporters of L-glutamate and L- or D-aspartate. These carriers also mediate a thermodynamically uncoupled anion conductance that is gated by Na+ and substrate binding. The activation of the anion channel by binding of Na+ alone, however, has only been demonstrated for mammalian EAAC1 (EAAT3 and EAAT4. To date, no difference has been observed for the substrate dependence of anion channel gating between the glial, EAAT1 and EAAT2, and the neuronal isoforms EAAT3, EAAT4 and EAAT5. Here we describe a difference in the Na+-dependence of anion channel gating between glial and neuronal isoforms. Chloride flux through transporters without glutamate binding has previously been described as substrate-independent or “leak” channel activity. Choline or N-methyl-D-glucamine replacement of external Na+ ions significantly reduced or abolished substrate-independent EAAT channel activity in EAAT3 and EAAT4 yet has no effect on EAAT1 or EAAT2. The interaction of Na+ with the neuronal carrier isoforms was concentration dependent, consistent with previous data. The presence of substrate and Na+-independent open states in the glial EAAT isoforms is a novel finding in the field of EAAT function. Our results reveal an important divergence in anion channel function between glial and neuronal glutamate transporters and highlight new potential roles for the EAAT-associated anion channel activity based on transporter expression and localization in the central nervous system.

  2. Neurochemical and behavioral characterization of neuronal glutamate transporter EAAT3 heterozygous mice

    Directory of Open Access Journals (Sweden)

    Luis F. González

    2017-10-01

    Full Text Available Abstract Background Obsessive–compulsive disorder (OCD is a severe neuropsychiatric condition affecting 1–3% of the worldwide population. OCD has a strong genetic component, and the SLC1A1 gene that encodes neuronal glutamate transporter EAAT3 is a strong candidate for this disorder. To evaluate the impact of reduced EAAT3 expression in vivo, we studied male EAAT3 heterozygous and wild-type littermate mice using a battery of behavioral paradigms relevant to anxiety (open field test, elevated plus maze and compulsivity (marble burying, as well as locomotor activity induced by amphetamine. Using high-performance liquid chromatography, we also determined tissue neurotransmitter levels in cortex, striatum and thalamus—brain areas that are relevant to OCD. Results Compared to wild-type littermates, EAAT3 heterozygous male mice have unaltered baseline anxiety-like, compulsive-like behavior and locomotor activity. Administration of acute amphetamine (5 mg/kg intraperitoneally increased locomotion with no differences across genotypes. Tissue levels of glutamate, GABA, dopamine and serotonin did not vary between EAAT3 heterozygous and wild-type mice. Conclusions Our results indicate that reduced EAAT3 expression does not impact neurotransmitter content in the corticostriatal circuit nor alter anxiety or compulsive-like behaviors.

  3. Sympathetic ingrowth: A result of cholinergic nerve injury in the adult mammalian brain

    International Nuclear Information System (INIS)

    Davis, J.N.

    1986-01-01

    This paper describes sympathetic ingrowth, its regulation and function. The study leads to a better understanding of the molecular mechanisms that probably underlie the regulation of other neuronal rearrangements. The authors examine tritium-2-deoxyglucose uptake in the hippocampal formation after septal leasions. Preliminary experiments suggest that the septo-hippocampal fibers do influence tritium-2-deoxyglucose uptake throughout the hippocampal formation in normal animals. If sympathetic ingrowth also can influence this uptake, this could provide further evidence for an adaptive role of this noradrenergic replacement of cholinergic neurons

  4. Adrenergic innervation of the developing chick heart: neural crest ablations to produce sympathetically aneural hearts

    International Nuclear Information System (INIS)

    Kirby, M.; Stewart, D.

    1984-01-01

    Ablation of various regions of premigratory trunk neural crest which gives rise to the sympathetic trunks was used to remove sympathetic cardiac innervation. Neuronal uptake of [ 3 H]-norepinephrine was used as an index of neuronal development in the chick atrium. Following ablation of neural crest over somites 10-15 or 15-20, uptake was significantly decreased in the atrium at 16 and 17 days of development. Ablation of neural crest over somites 5-10 and 20-25 caused no decrease in [ 3 H]-norepinephrine uptake. Removal of neural crest over somites 5-25 or 10-20 caused approximately equal depletions of [ 3 H]-norepinephrine uptake in the atrium. Cardiac norepinephrine concentration was significantly depressed following ablation of neural crest over somites 5-25 but not over somites 10-20. Light-microscopic and histofluorescent preparations confirmed the absence of sympathetic trunks in the region of the normal origin of the sympathetic cardiac nerves following neural crest ablation over somites 10-20. The neural tube and dorsal root ganglia were damaged in the area of the neural-crest ablation; however, all of these structures were normal cranial and caudal to the lesioned area. Development of most of the embryos as well as the morphology of all of the hearts was normal following the lesion. These results indicate that it is possible to produce sympathetically aneural hearts by neural-crest ablation; however, sympathetic cardiac nerves account for an insignificant amount of cardiac norepinephrine

  5. Monocarboxylate transporter-dependent mechanism confers resistance to oxygen- and glucose-deprivation injury in astrocyte-neuron co-cultures.

    Science.gov (United States)

    Gao, Chen; Zhou, Liya; Zhu, Wenxia; Wang, Hongyun; Wang, Ruijuan; He, Yunfei; Li, Zhiyun

    2015-05-06

    Hypoxic and low-glucose stressors contribute to neuronal death in many brain diseases. Astrocytes are anatomically well-positioned to shield neurons from hypoxic injury. During hypoxia/ischemia, lactate released from astrocytes is taken up by neurons and stored for energy. This process is mediated by monocarboxylate transporters (MCTs) in the central nervous system. In the present study, we investigated the ability of astrocytes to protect neurons from oxygen- and glucose-deprivation (OGD) injury via an MCT-dependent mechanism in vitro. Primary cultures of neurons, astrocytes, and astrocytes-neurons derived from rat hippocampus were subjected to OGD, MCT inhibition with small interfering (si)RNA. Cell survival and expression of MCT4, MCT2, glial fibrillary acidic protein, and neuronal nuclear antigen were evaluated. OGD significantly increased cell death in neuronal cultures and up-regulated MCT4 expression in astrocyte cultures, but no increased cell death was observed in neuron-astrocyte co-cultures or astrocyte cultures. However, neuronal cell death in co-cultures was increased by exposure to MCT4- or MCT2-specific siRNA, and this effect was attenuated by the addition of lactate into the extracellular medium of neuronal cultures prior to OGD. These findings demonstrate that resistance to OGD injury in astrocyte-neuron co-cultures occurs via an MCT-dependent mechanism. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  6. High specific radioactivity (1R,2S)-4-[18F]fluorometaraminol: a PET radiotracer for mapping sympathetic nerves of the heart

    International Nuclear Information System (INIS)

    Langer, Oliver; Valette, Heric; Dolle, Frederic; Halldin, Christer; Loc'h, Christian; Fuseau, Chantal; Coulon, Christine; Ottaviani, Michele; Bottlaender, Michel; Maziere, Bernard; Crouzel, Christian

    2000-01-01

    The radiolabeled catecholamine analogue (1R,2S)-6-[ 18 F]fluorometaraminol (6-[ 18 F]FMR) is a substrate for the neuronal norepinephrine transporter. It has been used as a positron emission tomography (PET) ligand to map sympathetic nerves in dog heart. 6-[ 18 F]FMR could be only synthesized with low specific radioactivity, which precluded its use in human subjects. We have recently prepared (1R,2S)-4-[ 18 F]fluorometaraminol (4-[ 18 F]FMR), a new fluoro-analogue of metaraminol, with high specific radioactivity (56-106 GBq/μmol). In the present study, we demonstrate in rats that 4-[ 18 F]FMR possesses similar affinity toward myocardial norepinephrine transport mechanisms as 6-[ 18 F]FMR. When compared with control animals, an 80% and 76% reduction in myocardial uptake was observed in animals pretreated with desipramine (an inhibitor of the neuronal norepinephrine transporter) and with reserpine (a blocker of the vesicular storage of monoamines), respectively. The entire radioactivity in rat myocardium represented unmetabolized parent tracer as determined by high performance liquid chromatography analysis of tissue extracts. In dogs, myocardial kinetics of 4-[ 18 F]FMR were assessed using PET. A rapid and high uptake was observed, followed by prolonged cardiac retention. A heart-to-lung ratio of 15 was reached 10 min after injection of the radiotracer. Pretreatment with desipramine reduced the heart half-life of 4-[ 18 F]FMR by 90% compared with control. Moreover, an infusion of tyramine caused a rapid decline of radioactivity in the heart. This demonstrates that 4-[ 18 F]FMR specifically visualizes sympathetic neurons in dog heart. High specific radioactivity 4-[ 18 F]FMR is a promising alternative to 6-[ 18 F]FMR for myocardial neuronal mapping with PET in humans

  7. High specific radioactivity (1R,2S)-4-[{sup 18}F]fluorometaraminol: a PET radiotracer for mapping sympathetic nerves of the heart

    Energy Technology Data Exchange (ETDEWEB)

    Langer, Oliver; Valette, Heric; Dolle, Frederic E-mail: dolle@dsvidf.cea.fr; Halldin, Christer; Loc' h, Christian; Fuseau, Chantal; Coulon, Christine; Ottaviani, Michele; Bottlaender, Michel; Maziere, Bernard; Crouzel, Christian

    2000-04-01

    The radiolabeled catecholamine analogue (1R,2S)-6-[{sup 18}F]fluorometaraminol (6-[{sup 18}F]FMR) is a substrate for the neuronal norepinephrine transporter. It has been used as a positron emission tomography (PET) ligand to map sympathetic nerves in dog heart. 6-[{sup 18}F]FMR could be only synthesized with low specific radioactivity, which precluded its use in human subjects. We have recently prepared (1R,2S)-4-[{sup 18}F]fluorometaraminol (4-[{sup 18}F]FMR), a new fluoro-analogue of metaraminol, with high specific radioactivity (56-106 GBq/{mu}mol). In the present study, we demonstrate in rats that 4-[{sup 18}F]FMR possesses similar affinity toward myocardial norepinephrine transport mechanisms as 6-[{sup 18}F]FMR. When compared with control animals, an 80% and 76% reduction in myocardial uptake was observed in animals pretreated with desipramine (an inhibitor of the neuronal norepinephrine transporter) and with reserpine (a blocker of the vesicular storage of monoamines), respectively. The entire radioactivity in rat myocardium represented unmetabolized parent tracer as determined by high performance liquid chromatography analysis of tissue extracts. In dogs, myocardial kinetics of 4-[{sup 18}F]FMR were assessed using PET. A rapid and high uptake was observed, followed by prolonged cardiac retention. A heart-to-lung ratio of 15 was reached 10 min after injection of the radiotracer. Pretreatment with desipramine reduced the heart half-life of 4-[{sup 18}F]FMR by 90% compared with control. Moreover, an infusion of tyramine caused a rapid decline of radioactivity in the heart. This demonstrates that 4-[{sup 18}F]FMR specifically visualizes sympathetic neurons in dog heart. High specific radioactivity 4-[{sup 18}F]FMR is a promising alternative to 6-[{sup 18}F]FMR for myocardial neuronal mapping with PET in humans.

  8. Biophysics of active vesicle transport, an intermediate step that couples excitation and exocytosis of serotonin in the neuronal soma.

    Directory of Open Access Journals (Sweden)

    Francisco F De-Miguel

    Full Text Available Transmitter exocytosis from the neuronal soma is evoked by brief trains of high frequency electrical activity and continues for several minutes. Here we studied how active vesicle transport towards the plasma membrane contributes to this slow phenomenon in serotonergic leech Retzius neurons, by combining electron microscopy, the kinetics of exocytosis obtained from FM1-43 dye fluorescence as vesicles fuse with the plasma membrane, and a diffusion equation incorporating the forces of local confinement and molecular motors. Electron micrographs of neurons at rest or after stimulation with 1 Hz trains showed cytoplasmic clusters of dense core vesicles at 1.5±0.2 and 3.7±0.3 µm distances from the plasma membrane, to which they were bound through microtubule bundles. By contrast, after 20 Hz stimulation vesicle clusters were apposed to the plasma membrane, suggesting that transport was induced by electrical stimulation. Consistently, 20 Hz stimulation of cultured neurons induced spotted FM1-43 fluorescence increases with one or two slow sigmoidal kinetics, suggesting exocytosis from an equal number of vesicle clusters. These fluorescence increases were prevented by colchicine, which suggested microtubule-dependent vesicle transport. Model fitting to the fluorescence kinetics predicted that 52-951 vesicles/cluster were transported along 0.60-6.18 µm distances at average 11-95 nms(-1 velocities. The ATP cost per vesicle fused (0.4-72.0, calculated from the ratio of the ΔG(process/ΔG(ATP, depended on the ratio of the traveling velocity and the number of vesicles in the cluster. Interestingly, the distance-dependence of the ATP cost per vesicle was bistable, with low energy values at 1.4 and 3.3 µm, similar to the average resting distances of the vesicle clusters, and a high energy barrier at 1.6-2.0 µm. Our study confirms that active vesicle transport is an intermediate step for somatic serotonin exocytosis by Retzius neurons and provides a

  9. Axonal collateral-collateral transport of tract tracers in brain neurons: false anterograde labelling and useful tool.

    Science.gov (United States)

    Chen, S; Aston-Jones, G

    1998-02-01

    It is well established that some neuroanatomical tracers may be taken up by local axonal terminals and transported to distant axonal collaterals (e.g., transganglionic transport in dorsal root ganglion cells). However, such collateral-collateral transport of tracers has not been systematically examined in the central nervous system. We addressed this issue with four neuronal tracers--biocytin, biotinylated dextran amine, cholera toxin B subunit, and Phaseolus vulgaris-leucoagglutinin--in the cerebellar cortex. Labelling of distant axonal collaterals in the cerebellar cortex (indication of collateral-collateral transport) was seen after focal iontophoretic microinjections of each of the four tracers. However, collateral-collateral transport properties differed among these tracers. Injection of biocytin or Phaseolus vulgaris-leucoagglutinin in the cerebellar cortex yielded distant collateral labelling only in parallel fibres. In contrast, injection of biotinylated dextran amine or cholera toxin B subunit produced distant collateral labelling of climbing fibres and mossy fibres, as well as parallel fibres. The present study is the first systematic examination of collateral-collateral transport following injection of anterograde tracers in brain. Such collateral-collateral transport may produce false-positive conclusions regarding neural connections when using these tracers for anterograde transport. However, this property may also be used as a tool to determine areas that are innervated by common distant afferents. In addition, these results may indicate a novel mode of chemical communication in the nervous system.

  10. Retrograde transport of [3H]-D-aspartate label by cochlear and vestibular efferent neurons

    International Nuclear Information System (INIS)

    Schwarz, D.W.; Schwarz, I.E.

    1988-01-01

    [ 3 H]-D-aspartic acid was injected into the inner ear of rats. After a six hour survival time, labeled cells were found at all locations known to contain efferent cochlear or vestibular neurons. Most labeled neurons were found in the ipsilateral lateral superior olivary nucleus (LSO), although both ventral nuclei of the trapezoid body (VTB), group E, and the caudal pontine reticular nucleus (CPR) just adjacent to the ascending limb of the facial nerve also contained labeled cells. Because not all efferent neurons in the rat could be previously shown to be cholinergic, aspartate and glutamate are efferent transmitter candidates

  11. Axonal transport of TDP-43 mRNA granules in neurons is impaired by ALS-causing mutations

    Science.gov (United States)

    Carrasco, Monica A.; Williams, Luis A.; Winborn, Christina S.; Han, Steve S. W.; Kiskinis, Evangelos; Winborn, Brett; Freibaum, Brian D.; Kanagaraj, Anderson; Clare, Alison J.; Badders, Nisha M.; Bilican, Bilada; Chaum, Edward; Chandran, Siddharthan; Shaw, Christopher E.; Eggan, Kevin C.; Maniatis, Tom; Taylor, J. Paul

    2014-01-01

    Summary The RNA binding protein TDP-43 regulates RNA metabolism at multiple levels, including transcription, RNA splicing, and mRNA stability. TDP-43 is a major component of the cytoplasmic inclusions characteristic of amyotrophic lateral sclerosis and some types of frontotemporal lobar degeneration. The importance of TDP-43 in disease is underscored by the fact that dominant missense mutations are sufficient to cause disease, although the role of TDP-43 in pathogenesis is unknown. Here we show that TDP-43 forms cytoplasmic mRNP granules that undergo bidirectional, microtubule-dependent transport in neurons in vitro and in vivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function in vivo and in vitro, including in stem cell-derived motor neurons from ALS patients bearing any one of three different TDP-43 ALS-causing mutations. Thus, TDP43 mutations that cause ALS lead to partial loss of a novel cytoplasmic function of TDP-43. PMID:24507191

  12. Divalent metal transporter 1 (DMT1) in the brain: implications for a role in iron transport at the blood-brain barrier, and neuronal and glial pathology.

    Science.gov (United States)

    Skjørringe, Tina; Burkhart, Annette; Johnsen, Kasper Bendix; Moos, Torben

    2015-01-01

    Iron is required in a variety of essential processes in the body. In this review, we focus on iron transport in the brain and the role of the divalent metal transporter 1 (DMT1) vital for iron uptake in most cells. DMT1 locates to cellular membranes and endosomal membranes, where it is a key player in non-transferrin bound iron uptake and transferrin-bound iron uptake, respectively. Four isoforms of DMT1 exist, and their respective characteristics involve a complex cell-specific regulatory machinery all controlling iron transport across these membranes. This complexity reflects the fine balance required in iron homeostasis, as this metal is indispensable in many cell functions but highly toxic when appearing in excess. DMT1 expression in the brain is prominent in neurons. Of serious dispute is the expression of DMT1 in non-neuronal cells. Recent studies imply that DMT1 does exist in endosomes of brain capillary endothelial cells denoting the blood-brain barrier. This supports existing evidence that iron uptake at the BBB occurs by means of transferrin-receptor mediated endocytosis followed by detachment of iron from transferrin inside the acidic compartment of the endosome and DMT1-mediated pumping iron into the cytosol. The subsequent iron transport across the abluminal membrane into the brain likely occurs by ferroportin. The virtual absent expression of transferrin receptors and DMT1 in glial cells, i.e., astrocytes, microglia and oligodendrocytes, suggest that the steady state uptake of iron in glia is much lower than in neurons and/or other mechanisms for iron uptake in these cell types prevail.

  13. Renal sympathetic denervation in hypertension.

    Science.gov (United States)

    Doumas, Michael; Faselis, Charles; Papademetriou, Vasilios

    2011-11-01

    Despite the abundance of antihypertensive drugs, resistant hypertension remains a major clinical problem. Recent technological advances render interventional management of resistant hypertension one of the hottest topics in the hypertension field. The aim of this review is to present the pathophysiologic background and the mechanisms mediating blood pressure reduction after renal sympathetic denervation, to analyze recent findings with this fascinating approach and to critically suggest future research directions. Catheter-based, ablation-induced renal sympathetic denervation was initially studied in 45 patients with resistant hypertension in a proof-of-concept study. Impressive blood pressure reductions of about 30/15  mmHg were achieved at 6 months, without serious complications. A second, controlled, randomized (but not blinded) study confirmed the results, verifying the efficacy and safety of the procedure. A recent report revealed the 2-year durability of blood pressure reduction. Data published so far indicate that ablation-induced renal denervation is a feasible, effective, and well tolerated interventional approach for the management of resistant hypertension. The groundbreaking studies of renal denervation in drug-resistant hypertension pave the way for further research in other disease conditions in which sympathetic overactivity seems to play a critical role. This initial wave of enthusiasm needs to be followed by rigorous investigation, for the proper identification of the potential and the limitations, indications, and contraindications of this approach.

  14. Clinical evaluation of 123I-MIBG for assessment of sympathetic nervous system in the heart

    International Nuclear Information System (INIS)

    Hirosawa, Koushitiro; Tanaka, Takeshi; Hisada, Kin-ichi; Bunko, Hisashi.

    1991-01-01

    Multi-center clinical trial of 123 I-metaiodobenzylguanidine ( 123 I-MIBG) was carried out to assess its utility as a scintigraphic imaging agent reflecting sympathetic neuronal function in cardiovascular field. Studies were performed on patients with heart diseases of three categories, myocardial infarction, angina pectoris and cardiomyopathy. Scintigraphic images, reflecting sympathetic neuronal function, were obtained with 123 I-MIBG from all of those categories of patients and the efficacy of the imaging was revealed in 781 (95.0%) out of 822 patients. In some patients abnormality was suggested in sympathetic neuronal function with 123 I-MIBG imaging, in spite of normal findings with myocardial perfusion scintigraphy by 201 TlCl. In all 981 patients studied with 123 I-MIBG, there have been no severe adverse reactions, except complaints of burning on injection site of the agent or nausea, ect. from 4 patients. We conclude that 123 I-MIBG imaging is one of the effective tools for diagnostic use reflecting topical sympathetic neuronal function in the heart, judging from its safety and efficacy. (author)

  15. Electroacupuncture Improved the Function of Myocardial Ischemia Involved in the Hippocampus-Paraventricular Nucleus-Sympathetic Nerve Pathway

    Directory of Open Access Journals (Sweden)

    Shuai Cui

    2018-01-01

    Full Text Available We investigated the hippocampus-paraventricular nucleus- (PVN- sympathetic nerve pathway in electroacupuncture (EA at the heart meridian for the treatment of myocardial ischemia by observing PVN neuronal discharge, sympathetic nerve discharge, and hemodynamics parameters. Sprague Dawley (SD rats were equally divided into four groups: Sham, Model, Model + EA, and Model + EA + Lesion. The model rat was established by ligating the left anterior descending branch of the coronary artery. Changes in the sympathetic nerve discharge and hemodynamic parameters were observed. The Model + EA exhibited a significantly lower discharge frequency of PVN neurons compared with the Model. The Model + EA + Lesion had a significantly higher discharge frequency compared with the Model + EA. The total discharge frequency of PVN neurons and interneurons were positively correlated with the sympathetic nerve discharge. The total discharge frequency of PVN neurons was positively correlated with heart rate (HR and negatively correlated with mean arterial pressure (MAP and rate pressure product (RPP. The discharge frequency of interneurons was positively correlated with HR and negatively correlated with MAP and RPP. The hippocampus-PVN-sympathetic nerve pathway is involved in electroacupuncture at the heart meridian and interneurons are the key neurons in PVNs.

  16. Agmatine suppresses peripheral sympathetic tone by inhibiting N-type Ca(2+) channel activity via imidazoline I2 receptor activation.

    Science.gov (United States)

    Kim, Young-Hwan; Jeong, Ji-Hyun; Ahn, Duck-Sun; Chung, Seungsoo

    2016-08-26

    Agmatine, a putative endogenous ligand of imidazoline receptors, suppresses cardiovascular function by inhibiting peripheral sympathetic tone. However, the molecular identity of imidazoline receptor subtypes and its cellular mechanism underlying the agmatine-induced sympathetic suppression remains unknown. Meanwhile, N-type Ca(2+) channels are important for the regulation of NA release in the peripheral sympathetic nervous system. Therefore, it is possible that agmatine suppresses NA release in peripheral sympathetic nerve terminals by inhibiting Ca(2+) influx through N-type Ca(2+) channels. We tested this hypothesis by investigating agmatine effect on electrical field stimulation (EFS)-evoked contraction and NA release in endothelium-denuded rat superior mesenteric arterial strips. We also investigated the effect of agmatine on the N-type Ca(2+) current in superior cervical ganglion (SCG) neurons in rats. Our study demonstrates that agmatine suppresses peripheral sympathetic outflow via the imidazoline I2 receptor in rat mesenteric arteries. In addition, the agmatine-induced suppression of peripheral vascular sympathetic tone is mediated by modulating voltage-dependent N-type Ca(2+) channels in sympathetic nerve terminals. These results suggest a potential cellular mechanism for the agmatine-induced suppression of peripheral sympathetic tone. Furthermore, they provide basic and theoretical information regarding the development of new agents to treat hypertension. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Pituitary adenylate cyclase-activating polypeptide stimulates glucose production via the hepatic sympathetic innervation in rats.

    Science.gov (United States)

    Yi, Chun-Xia; Sun, Ning; Ackermans, Mariette T; Alkemade, Anneke; Foppen, Ewout; Shi, Jing; Serlie, Mireille J; Buijs, Ruud M; Fliers, Eric; Kalsbeek, Andries

    2010-07-01

    The unraveling of the elaborate brain networks that control glucose metabolism presents one of the current challenges in diabetes research. Within the central nervous system, the hypothalamus is regarded as the key brain area to regulate energy homeostasis. The aim of the present study was to investigate the hypothalamic mechanism involved in the hyperglycemic effects of the neuropeptide pituitary adenylyl cyclase-activating polypeptide (PACAP). Endogenous glucose production (EGP) was determined during intracerebroventricular infusions of PACAP-38, vasoactive intestinal peptide (VIP), or their receptor agonists. The specificity of their receptors was examined by coinfusions of receptor antagonists. The possible neuronal pathway involved was investigated by 1) local injections in hypothalamic nuclei, 2) retrograde neuronal tracing from the thoracic spinal cord to hypothalamic preautonomic neurons together with Fos immunoreactivity, and 3) specific hepatic sympathetic or parasympathetic denervation to block the autonomic neuronal input to liver. Intracerebroventricular infusion of PACAP-38 increased EGP to a similar extent as a VIP/PACAP-2 (VPAC2) receptor agonist, and intracerebroventricular administration of VIP had significantly less influence on EGP. The PACAP-38 induced increase of EGP was significantly suppressed by preinfusion of a VPAC2 but not a PAC1 receptor antagonist, as well as by hepatic sympathetic but not parasympathetic denervation. In the hypothalamus, Fos immunoreactivity induced by PACAP-38 was colocalized within autonomic neurons in paraventricular nuclei projecting to preganglionic sympathetic neurons in the spinal cord. Local infusion of PACAP-38 directly into the PVN induced a significant increase of EGP. This study demonstrates that PACAP-38 signaling via sympathetic preautonomic neurons located in the paraventricular nucleus is an important component in the hypothalamic control of hepatic glucose production.

  18. Selective retrograde transport of D-aspartate in spinal interneurons anc cortical neurons of rats

    International Nuclear Information System (INIS)

    Rustioni, A.; Cuenod, M.

    1982-01-01

    Retrograde labeling of neuronal elements in the brain and spinal cord has been investigated by autoradiographic techniques following injections of D-[ 3 H]aspartate (asp), [ 3 H]γ-aminobutyric acid (GABA) or horseradish peroxidase (HRP) in the medulla and spinal cord of rats. Twenty-four hours after D-[ 3 H]asp injections focused upon the cuneate nucleus, autoradiographic labeling is present over fibers in the pyramidal tract, internal capsule and over layer V pyramids in the forelimb representation of the sensorimotor cortex. After [ 3 H]GABA injections in the same nucleus no labeling attributable to retrograde translocation can be detected in spinal segments, brain stem or cortex. Conversely, injections of 30% HRP in the cuneate nucleus label neurons in several brain stem nuclei, in spinal gray and in layer V of the sensorimotor cortex. D-[ 3 H]Asp injections focused on the dorsal horn at cervical segments label a fraction of perikarya of the substantia gelatinosa and a sparser population of larger neurons in laminae IV to VI for a distance of 3-5 segments above and below the injection point. No brain stem neuronal perikarya appear labeled following spinal injections of D-[ 3 H]asp although autoradiographic grains overlie pyramidal tract fibers on the side contralateral to the injection. (Auth.)

  19. Leptin regulates bone formation via the sympathetic nervous system

    Science.gov (United States)

    Takeda, Shu; Elefteriou, Florent; Levasseur, Regis; Liu, Xiuyun; Zhao, Liping; Parker, Keith L.; Armstrong, Dawna; Ducy, Patricia; Karsenty, Gerard

    2002-01-01

    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.

  20. The Molecular Motor KIF1A Transports the TrkA Neurotrophin Receptor and Is Essential for Sensory Neuron Survival and Function.

    Science.gov (United States)

    Tanaka, Yosuke; Niwa, Shinsuke; Dong, Ming; Farkhondeh, Atena; Wang, Li; Zhou, Ruyun; Hirokawa, Nobutaka

    2016-06-15

    KIF1A is a major axonal transport motor protein, but its functional significance remains elusive. Here we show that KIF1A-haploinsufficient mice developed sensory neuropathy. We found progressive loss of TrkA(+) sensory neurons in Kif1a(+/-) dorsal root ganglia (DRGs). Moreover, axonal transport of TrkA was significantly disrupted in Kif1a(+/-) neurons. Live imaging and immunoprecipitation assays revealed that KIF1A bound to TrkA-containing vesicles through the adaptor GTP-Rab3, suggesting that TrkA is a cargo of the KIF1A motor. Physiological measurements revealed a weaker capsaicin response in Kif1a(+/-) DRG neurons. Moreover, these neurons were hyposensitive to nerve growth factor, which could explain the reduced neuronal survival and the functional deficiency of the pain receptor TRPV1. Because phosphatidylinositol 3-kinase (PI3K) signaling significantly rescued these phenotypes and also increased Kif1a mRNA, we propose that KIF1A is essential for the survival and function of sensory neurons because of the TrkA transport and its synergistic support of the NGF/TrkA/PI3K signaling pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. DIRECT VISUALIZATION OF THE DOPAMINE TRANSPORTER IN CULTURED NEWBORN RAT MIDBRAIN NEURONS USING THE FLUORESCENT COCAINE ANALOGUE JHC 1-64

    DEFF Research Database (Denmark)

    Rasmussen, Søren; Vægter, Christian Bjerggaard; Cha, J

    In this study we have established methods for visualization and tracking of the dopamine transporter (DAT) in cultured dopaminergic neurons in real time using a fluorescent cocaine analogue JHC 1-64 and confocal fluorescence microscopy. The initial binding experiments in HEK 293 cells stably...... 1-64 was prevented by excess concentrations of dopamine, cocaine, mazindol, or RTI-55, whereas the norepinephrine and/or serotonin transporter specific inhibitors desmethylimipramine and citalopram did not affect fluorescent labeling of the neurons. This strongly supports that JHC 1-64 specifically...

  2. Postendocytic sorting of constitutively internalized dopamine transporter in cell lines and dopaminergic neurons

    DEFF Research Database (Denmark)

    Eriksen, Jacob; Bjørn-Yoshimoto, Walden Emil; Jørgensen, Trine Nygaard

    2010-01-01

    The dopamine transporter (DAT) mediates reuptake of released dopamine and is the target for psychostimulants, such as cocaine and amphetamine. DAT undergoes marked constitutive endocytosis, but little is known about the fate and sorting of the endocytosed transporter. To study DAT sorting in cells...... lines, we fused the one-transmembrane segment protein Tac to DAT, thereby generating a transporter (TacDAT) with an extracellular antibody epitope suited for trafficking studies. TacDAT was functional and endocytosed constitutively in HEK293 cells. According to an ELISA-based assay, TacDAT intracellular...

  3. Riluzole increases the rate of glucose transport in L6 myotubes and NSC-34 motor neuron-like cells via AMPK pathway activation.

    Science.gov (United States)

    Daniel, Bareket; Green, Omer; Viskind, Olga; Gruzman, Arie

    2013-09-01

    Riluzole is the only approved ALS drug. Riluzole influences several cellular pathways, but its exact mechanism of action remains unclear. Our goal was to study the drug's influence on the glucose transport rate in two ALS relevant cell types, neurons and myotubes. Stably transfected wild-type or mutant G93A human SOD1 NSC-34 motor neuron-like cells and rat L6 myotubes were exposed to riluzole. The rate of glucose uptake, translocation of glucose transporters to the cell's plasma membrane and the main glucose transport regulatory proteins' phosphorylation levels were measured. We found that riluzole increases the glucose transport rate and up-regulates the translocation of glucose transporters to plasma membrane in both types of cells. Riluzole leads to AMPK phosphorylation and to the phosphorylation of its downstream target, AS-160. In conclusion, increasing the glucose transport rate in ALS affected cells might be one of the mechanisms of riluzole's therapeutic effect. These findings can be used to rationally design and synthesize novel anti-ALS drugs that modulate glucose transport in neurons and skeletal muscles.

  4. Dynamic interaction between the heart and its sympathetic innervation following T5 spinal cord transection.

    Science.gov (United States)

    Lujan, Heidi L; Janbaih, Hussein; DiCarlo, Stephen E

    2012-10-15

    Midthoracic spinal cord injury (SCI) is associated with enhanced sympathetic support of heart rate as well as myocardial damage related to calcium overload. The myocardial damage may elicit an enhanced sympathetic support of contractility to maintain ventricular function. In contrast, the level of inotropic drive may be reduced to match the lower afterload that results from the injury-induced reduction in arterial pressure. Accordingly, the inotropic response to midthoracic SCI may be increased or decreased but has not been investigated and therefore remains unknown. Furthermore, the altered ventricular function may be associated with anatomical changes in cardiac sympathetic innervation. To determine the inotropic drive following midthoracic SCI, a telemetry device was used for repeated measurements of left ventricular (LV) function, with and without beta-adrenergic receptor blockade, in rats before and after midthoracic SCI or sham SCI. In addition, NGF content (ELISA) and dendritic arborization (cholera toxin B immunohistochemistry and Sholl analysis) of cardiac-projecting sympathetic postganglionic neurons in the stellate ganglia were determined. Midthoracic SCI was associated with an enhanced sympathetic support of heart rate, dP/dt(+), and dP/dt(-). Importantly, cardiac function was lower following blockade of the sympathetic nervous system in rats with midthoracic SCI compared with sham-operated rats. Finally, these functional neuroplastic changes were associated with an increased NGF content and structural neuroplasticity within the stellate ganglia. Results document impaired LV function with codirectional changes in chronotropic and inotropic responses following midthoracic SCI. These functional changes were associated with a dynamic interaction between the heart and its sympathetic innervation.

  5. Fishy Business: Effect of Omega-3 Fatty Acids on Zinc Transporters and Free Zinc Availability in Human Neuronal Cells

    Directory of Open Access Journals (Sweden)

    Damitha De Mel

    2014-08-01

    Full Text Available Omega-3 (ω-3 fatty acids are one of the two main families of long chain polyunsaturated fatty acids (PUFA. The main omega-3 fatty acids in the mammalian body are α-linolenic acid (ALA, docosahexaenoic acid (DHA and eicosapentaenoic acid (EPA. Central nervous tissues of vertebrates are characterized by a high concentration of omega-3 fatty acids. Moreover, in the human brain, DHA is considered as the main structural omega-3 fatty acid, which comprises about 40% of the PUFAs in total. DHA deficiency may be the cause of many disorders such as depression, inability to concentrate, excessive mood swings, anxiety, cardiovascular disease, type 2 diabetes, dry skin and so on. On the other hand, zinc is the most abundant trace metal in the human brain. There are many scientific studies linking zinc, especially excess amounts of free zinc, to cellular death. Neurodegenerative diseases, such as Alzheimer’s disease, are characterized by altered zinc metabolism. Both animal model studies and human cell culture studies have shown a possible link between omega-3 fatty acids, zinc transporter levels and free zinc availability at cellular levels. Many other studies have also suggested a possible omega-3 and zinc effect on neurodegeneration and cellular death. Therefore, in this review, we will examine the effect of omega-3 fatty acids on zinc transporters and the importance of free zinc for human neuronal cells. Moreover, we will evaluate the collective understanding of mechanism(s for the interaction of these elements in neuronal research and their significance for the diagnosis and treatment of neurodegeneration.

  6. Fishy business: effect of omega-3 fatty acids on zinc transporters and free zinc availability in human neuronal cells.

    Science.gov (United States)

    De Mel, Damitha; Suphioglu, Cenk

    2014-08-15

    Omega-3 (ω-3) fatty acids are one of the two main families of long chain polyunsaturated fatty acids (PUFA). The main omega-3 fatty acids in the mammalian body are α-linolenic acid (ALA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Central nervous tissues of vertebrates are characterized by a high concentration of omega-3 fatty acids. Moreover, in the human brain, DHA is considered as the main structural omega-3 fatty acid, which comprises about 40% of the PUFAs in total. DHA deficiency may be the cause of many disorders such as depression, inability to concentrate, excessive mood swings, anxiety, cardiovascular disease, type 2 diabetes, dry skin and so on. On the other hand, zinc is the most abundant trace metal in the human brain. There are many scientific studies linking zinc, especially excess amounts of free zinc, to cellular death. Neurodegenerative diseases, such as Alzheimer's disease, are characterized by altered zinc metabolism. Both animal model studies and human cell culture studies have shown a possible link between omega-3 fatty acids, zinc transporter levels and free zinc availability at cellular levels. Many other studies have also suggested a possible omega-3 and zinc effect on neurodegeneration and cellular death. Therefore, in this review, we will examine the effect of omega-3 fatty acids on zinc transporters and the importance of free zinc for human neuronal cells. Moreover, we will evaluate the collective understanding of mechanism(s) for the interaction of these elements in neuronal research and their significance for the diagnosis and treatment of neurodegeneration.

  7. Sympathetic vasoconstrictor nerve function in alcoholic neuropathy

    DEFF Research Database (Denmark)

    Jensen, K; Andersen, K; Smith, T

    1984-01-01

    (18% and 48% decrease respectively). However, in three patients with moderate neuropathy, and in one patient with no signs of neuropathy, this veno-arteriolar reflex was absent, indicating dysfunction of the peripheral sympathetic adrenergic nerve fibres. The three patients also showed a lesser degree......The peripheral sympathetic vasomotor nerve function was investigated in 18 male chronic alcoholics admitted for intellectual impairment or polyneuropathy. By means of the local 133Xenon washout technique, the sympathetic veno-arteriolar axon-reflex was studied. This normally is responsible for a 50...... comprise not only the peripheral sensory and motor nerve fibres, but also the thin pseudomotor and vasomotor nerves....

  8. Impairment of retrograde neuronal transport in oxaliplatin-induced neuropathy demonstrated by molecular imaging.

    Directory of Open Access Journals (Sweden)

    Dawid Schellingerhout

    Full Text Available BACKGROUND AND PURPOSE: The purpose of our study was to utilize a molecular imaging technology based on the retrograde axonal transport mechanism (neurography, to determine if oxaliplatin-induced neurotoxicity affects retrograde axonal transport in an animal model. MATERIALS AND METHODS: Mice (n = 8/group were injected with a cumulative dose of 30 mg/kg oxaliplatin (sufficient to induce neurotoxicity or dextrose control injections. Intramuscular injections of Tetanus Toxin C-fragment (TTc labeled with Alexa 790 fluorescent dye were done (15 ug/20 uL in the left calf muscles, and in vivo fluorescent imaging performed (0-60 min at baseline, and then weekly for 5 weeks, followed by 2-weekly imaging out to 9 weeks. Tissues were harvested for immunohistochemical analysis. RESULTS: With sham treatment, TTc transport causes fluorescent signal intensity over the thoracic spine to increase from 0 to 60 minutes after injection. On average, fluorescence signal increased 722%+/-117% (Mean+/-SD from 0 to 60 minutes. Oxaliplatin treated animals had comparable transport at baseline (787%+/-140%, but transport rapidly decreased through the course of the study, falling to 363%+/-88%, 269%+/-96%, 191%+/-58%, 121%+/-39%, 75%+/-21% with each successive week and stabilizing around 57% (+/-15% at 7 weeks. Statistically significant divergence occurred at approximately 3 weeks (p≤0.05, linear mixed-effects regression model. Quantitative immuno-fluorescence histology with a constant cutoff threshold showed reduced TTc in the spinal cord at 7 weeks for treated animals versus controls (5.2 Arbitrary Units +/-0.52 vs 7.1 AU +/-1.38, p0.56, T-test. CONCLUSION: We show-for the first time to our knowledge-that neurographic in vivo molecular imaging can demonstrate imaging changes in a model of oxaliplatin-induced neuropathy. Impaired retrograde neural transport is suggested to be an important part of the pathophysiology of oxaliplatin-induced neuropathy.

  9. Local synaptic signaling enhances the stochastic transport of motor-driven cargo in neurons

    KAUST Repository

    Newby, Jay; Bressloff, Paul C

    2010-01-01

    The tug-of-war model of motor-driven cargo transport is formulated as an intermittent trapping process. An immobile trap, representing the cellular machinery that sequesters a motor-driven cargo for eventual use, is located somewhere within a

  10. Mechanosensing in hypothalamic osmosensory neurons.

    Science.gov (United States)

    Prager-Khoutorsky, Masha

    2017-11-01

    Osmosensory neurons are specialized cells activated by increases in blood osmolality to trigger thirst, secretion of the antidiuretic hormone vasopressin, and elevated sympathetic tone during dehydration. In addition to multiple extrinsic factors modulating their activity, osmosensory neurons are intrinsically osmosensitive, as they are activated by increased osmolality in the absence of neighboring cells or synaptic contacts. This intrinsic osmosensitivity is a mechanical process associated with osmolality-induced changes in cell volume. This review summarises recent findings revealing molecular mechanisms underlying the mechanical activation of osmosensory neurons and highlighting important roles of microtubules, actin, and mechanosensitive ion channels in this process. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Sympathetic stimulation alters left ventricular relaxation and chamber size.

    Science.gov (United States)

    Burwash, I G; Morgan, D E; Koilpillai, C J; Blackmore, G L; Johnstone, D E; Armour, J A

    1993-01-01

    Alterations in left ventricular (LV) contractility, relaxation, and chamber dimensions induced by efferent sympathetic nerve stimulation were investigated in nine anesthetized open-chest dogs in sinus rhythm. Supramaximal stimulation of acutely decentralized left stellate ganglia augmented heart rate, LV systolic pressure, and rate of LV pressure rise (maximum +dP/dt, 1,809 +/- 191 to 6,304 +/- 725 mmHg/s) and fall (maximum -dP/dt, -2,392 +/- 230 to -4,458 +/- 482 mmHg/s). It also reduced the time constant of isovolumic relaxation, tau (36.5 +/- 4.8 to 14.9 +/- 1.1 ms). Simultaneous two-dimensional echocardiography recorded reductions in end-diastolic and end-systolic LV cross-sectional chamber areas (23 and 31%, respectively), an increase in area ejection fraction (32%), and increases in end-diastolic and end-systolic wall thicknesses (14 and 13%, respectively). End-systolic and end-diastolic wall stresses were unchanged by stellate ganglion stimulation (98 +/- 12 to 95 +/- 9 dyn x 10(3)/cm2; 6.4 +/- 2.4 to 2.4 +/- 0.3 dyn x 10(3)/cm2, respectively). Atrial pacing to similar heart rates did not alter monitored indexes of contractility. Dobutamine and isoproterenol induced changes similar to those resulting from sympathetic neuronal stimulation. These data indicate that when the efferent sympathetic nervous system increases left ventricular contractility and relaxation, concomitant reductions in systolic and diastolic dimensions of that chamber occur that are associated with increasing wall thickness such that LV wall stress changes are minimized.

  12. Altered astrocyte glutamate transporter regulation of hypothalamic neurosecretory neurons in heart failure rats.

    Science.gov (United States)

    Potapenko, Evgeniy S; Biancardi, Vinicia C; Zhou, Yiqiang; Stern, Javier E

    2012-08-01

    Neurohumoral activation, which includes augmented plasma levels of the neurohormone vasopressin (VP), is a common finding in heart failure (HF) that contributes to morbidity and mortality in this disease. While an increased activation of magnocellular neurosecretory cells (MNCs) and enhanced glutamate function in HF is well documented, the precise underlying mechanisms remain to be elucidated. Here, we combined electrophysiology and protein measurements to determine whether altered glial glutamate transporter function and/or expression occurs in the hypothalamic supraoptic nucleus (SON) during HF. Patch-clamp recordings obtained from MNCs in brain slices show that pharmacological blockade of astrocyte glutamate transporter 1 (GLT1) function [500 μM dihydrokainate (DHK)], resulted in a persistent N-methyl-D-aspartate receptor (NMDAR)-mediated inward current (tonic I(NMDA)) in sham rats, an effect that was significantly smaller in MNCs from HF rats. In addition, we found a diminished GLT1 protein content in plasma membrane (but not cytosolic) fractions of SON punches in HF rats. Conversely, astrocyte GLAST expression was significantly higher in the SON of HF rats, while nonselective blockade of glutamate transport activity (100 μM TBOA) evoked an enhanced tonic I(NMDA) activation in HF rats. Steady-state activation of NMDARs by extracellular glutamate levels was diminished during HF. Taken together, these results support a shift in the relative expression and function of two major glial glutamate transporters (from GLT1 to GLAST predominance) during HF. This shift may act as a compensatory mechanism to preserve an adequate basal glutamate uptake level in the face of an enhanced glutamatergic afferent activity in HF rats.

  13. Spinal Cord Injury-Induced Dysautonomia via Plasticity in Paravertebral Sympathetic Postganglionic

    Science.gov (United States)

    2016-10-01

    resting membrane potential (-57 ± 9 mV ) [Fig. 4A], membrane resistance (985 ± 501 MΩ), and τm (99 ± 49 ms) [Fig. 4B]. Threshold voltage was...typically 10 mV higher than resting membrane potential, action potentials displayed after-hyperpolarization and some cells displayed post-inhibitory...firing in rat sympathetic neurons and thereby contribute to ganglionic amplification. Frontiers in neurology 1:130. Springer MG, Kullmann PH, Horn JP

  14. Constitutive endocytosis and turnover of the neuronal glycine transporter GlyT2 is dependent on ubiquitination of a C-terminal lysine cluster.

    Directory of Open Access Journals (Sweden)

    Jaime de Juan-Sanz

    Full Text Available Inhibitory glycinergic neurotransmission is terminated by sodium and chloride-dependent plasma membrane glycine transporters (GlyTs. The mainly glial glycine transporter GlyT1 is primarily responsible for the completion of inhibitory neurotransmission and the neuronal glycine transporter GlyT2 mediates the reuptake of the neurotransmitter that is used to refill synaptic vesicles in the terminal, a fundamental role in the physiology and pathology of glycinergic neurotransmission. Indeed, inhibitory glycinergic neurotransmission is modulated by the exocytosis and endocytosis of GlyT2. We previously reported that constitutive and Protein Kinase C (PKC-regulated endocytosis of GlyT2 is mediated by clathrin and that PKC accelerates GlyT2 endocytosis by increasing its ubiquitination. However, the role of ubiquitination in the constitutive endocytosis and turnover of this protein remains unexplored. Here, we show that ubiquitination of a C-terminus four lysine cluster of GlyT2 is required for constitutive endocytosis, sorting into the slow recycling pathway and turnover of the transporter. Ubiquitination negatively modulates the turnover of GlyT2, such that increased ubiquitination driven by PKC activation accelerates transporter degradation rate shortening its half-life while decreased ubiquitination increases transporter stability. Finally, ubiquitination of GlyT2 in neurons is highly responsive to the free pool of ubiquitin, suggesting that the deubiquitinating enzyme (DUB ubiquitin C-terminal hydrolase-L1 (UCHL1, as the major regulator of neuronal ubiquitin homeostasis, indirectly modulates the turnover of GlyT2. Our results contribute to the elucidation of the mechanisms underlying the dynamic trafficking of this important neuronal protein which has pathological relevance since mutations in the GlyT2 gene (SLC6A5 are the second most common cause of human hyperekplexia.

  15. Drosophila divalent metal ion transporter Malvolio is required in dopaminergic neurons for feeding decisions.

    Science.gov (United States)

    Søvik, E; LaMora, A; Seehra, G; Barron, A B; Duncan, J G; Ben-Shahar, Y

    2017-06-01

    Members of the natural resistance-associated macrophage protein (NRAMP) family are evolutionarily conserved metal ion transporters that play an essential role in regulating intracellular divalent cation homeostasis in both prokaryotes and eukaryotes. Malvolio (Mvl), the sole NRAMP family member in insects, plays a role in food choice behaviors in Drosophila and other species. However, the specific physiological and cellular processes that require the action of Mvl for appropriate feeding decisions remain elusive. Here, we show that normal food choice requires Mvl function specifically in the dopaminergic system, and can be rescued by supplementing food with manganese. Collectively, our data indicate that the action of the Mvl transporter affects food choice behavior via the regulation of dopaminergic innervation of the mushroom bodies, a principle brain region associated with decision-making in insects. Our studies suggest that the homeostatic regulation of the intraneuronal levels of divalent cations plays an important role in the development and function of the dopaminergic system and associated behaviors. © 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  16. Direct effects of glucose, insulin, GLP-1, and GIP on bulbospinal neurons in the rostral ventrolateral medulla in neonatal wistar rats.

    Science.gov (United States)

    Oshima, Naoki; Onimaru, Hiroshi; Matsubara, Hidehito; Uchida, Takahiro; Watanabe, Atsushi; Imakiire, Toshihiko; Nishida, Yasuhiro; Kumagai, Hiroo

    2017-03-06

    Although patients with diabetes mellitus (DM) often exhibit hypertension, the mechanisms responsible for this correlation are not well known. We hypothesized that the bulbospinal neurons in the rostral ventrolateral medulla (RVLM) are affected by the levels of glucose, insulin, or incretins (glucagon like peptide-1 [GLP-1] or glucose-dependent insulinotropic peptide [GIP]) in patients with DM. To investigate whether RVLM neurons are activated by glucose, insulin, GLP-1, or GIP, we examined changes in the membrane potentials of bulbospinal RVLM neurons using whole-cell patch-clamp technique during superfusion with various levels of glucose or these hormones in neonatal Wistar rats. A brainstem-spinal cord preparation was used for the experiments. A low level of glucose stimulated bulbospinal RVLM neurons. During insulin superfusion, almost all the RVLM neurons were depolarized, while during GLP-1 or GIP superfusion, almost all the RVLM neurons were hyperpolarized. Next, histological examinations were performed to examine transporters for glucose and receptors for insulin, GLP-1, and GIP on RVLM neurons. Low-level glucose-depolarized RVLM neurons exhibited the presence of glucose transporter 3 (GLUT3). Meanwhile, insulin-depolarized, GLP-1-hyperpolarized, and GIP-hyperpolarized RVLM neurons showed each of the respective specific receptor. These results indicate that a low level of glucose stimulates bulbospinal RVLM neurons via specific transporters on these neurons, inducing hypertension. Furthermore, an increase in insulin or a reduction in incretins may also activate the sympathetic nervous system and induce hypertension by activating RVLM neurons via their own receptors. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  17. Plasma dihydroxyphenylalanine (DOPA) is independent of sympathetic activity in humans

    DEFF Research Database (Denmark)

    Eldrup, E; Christensen, N J; Andreasen, J

    1989-01-01

    in diabetic patients with autonomic neuropathy compared to diabetics without neuropathy, whereas baseline plasma DOPA concentrations were similar in the three groups investigated: 6.55 (5.03-7.26, median [interquartile range], n = 8) nmol l-1 in diabetics with neuropathy, 7.41 (5.79-7.97, n = 8) nmol l-1...... in diabetics without neuropathy, and 6.85 (5.58-7.36, n = 8) nmol l-1 in controls. No relationship was obtained between baseline values of plasma NE and plasma DOPA. Plasma DOPA did not change in the upright position, whereas plasma NE increased significantly. Our results indicate that plasma DOPA...... is not related to sympathetic activity and may be of non-neuronal origin....

  18. Organic cation transporter-mediated ergothioneine uptake in mouse neural progenitor cells suppresses proliferation and promotes differentiation into neurons.

    Directory of Open Access Journals (Sweden)

    Takahiro Ishimoto

    Full Text Available The aim of the present study is to clarify the functional expression and physiological role in neural progenitor cells (NPCs of carnitine/organic cation transporter OCTN1/SLC22A4, which accepts the naturally occurring food-derived antioxidant ergothioneine (ERGO as a substrate in vivo. Real-time PCR analysis revealed that mRNA expression of OCTN1 was much higher than that of other organic cation transporters in mouse cultured cortical NPCs. Immunocytochemical analysis showed colocalization of OCTN1 with the NPC marker nestin in cultured NPCs and mouse embryonic carcinoma P19 cells differentiated into neural progenitor-like cells (P19-NPCs. These cells exhibited time-dependent [(3H]ERGO uptake. These results demonstrate that OCTN1 is functionally expressed in murine NPCs. Cultured NPCs and P19-NPCs formed neurospheres from clusters of proliferating cells in a culture time-dependent manner. Exposure of cultured NPCs to ERGO or other antioxidants (edaravone and ascorbic acid led to a significant decrease in the area of neurospheres with concomitant elimination of intracellular reactive oxygen species. Transfection of P19-NPCs with small interfering RNA for OCTN1 markedly promoted formation of neurospheres with a concomitant decrease of [(3H]ERGO uptake. On the other hand, exposure of cultured NPCs to ERGO markedly increased the number of cells immunoreactive for the neuronal marker βIII-tubulin, but decreased the number immunoreactive for the astroglial marker glial fibrillary acidic protein (GFAP, with concomitant up-regulation of neuronal differentiation activator gene Math1. Interestingly, edaravone and ascorbic acid did not affect such differentiation of NPCs, in contrast to the case of proliferation. Knockdown of OCTN1 increased the number of cells immunoreactive for GFAP, but decreased the number immunoreactive for βIII-tubulin, with concomitant down-regulation of Math1 in P19-NPCs. Thus, OCTN1-mediated uptake of ERGO in NPCs inhibits

  19. Local synaptic signaling enhances the stochastic transport of motor-driven cargo in neurons

    KAUST Repository

    Newby, Jay

    2010-08-23

    The tug-of-war model of motor-driven cargo transport is formulated as an intermittent trapping process. An immobile trap, representing the cellular machinery that sequesters a motor-driven cargo for eventual use, is located somewhere within a microtubule track. A particle representing a motor-driven cargo that moves randomly with a forward bias is introduced at the beginning of the track. The particle switches randomly between a fast moving phase and a slow moving phase. When in the slow moving phase, the particle can be captured by the trap. To account for the possibility that the particle avoids the trap, an absorbing boundary is placed at the end of the track. Two local signaling mechanisms-intended to improve the chances of capturing the target-are considered by allowing the trap to affect the tug-of-war parameters within a small region around itself. The first is based on a localized adenosine triphosphate (ATP) concentration gradient surrounding a synapse, and the second is based on a concentration of tau-a microtubule-associated protein involved in Alzheimer\\'s disease-coating the microtubule near the synapse. It is shown that both mechanisms can lead to dramatic improvements in the capture probability, with a minimal increase in the mean capture time. The analysis also shows that tau can cause a cargo to undergo random oscillations, which could explain some experimental observations. © 2010 IOP Publishing Ltd.

  20. Difference in transient ischemia-induced neuronal damage and glucose transporter-1 immunoreactivity in the hippocampus between adult and young gerbils

    Directory of Open Access Journals (Sweden)

    Seung Min Park

    2016-05-01

    Full Text Available Objective(s: The alteration of glucose transporters is closely related with the pathogenesis of brain edema. We compared neuronal damage/death in the hippocampus between adult and young gerbils following transient cerebral ischemia/reperfusion and changes of glucose transporter-1(GLUT-1-immunoreactive microvessels in their ischemic hippocampal CA1 region. Materials and Methods: Transient cerebral ischemia was developed by 5-min occlusion of both common carotid arteries. Neuronal damage was examined by cresyl violet staining, NeuN immunohistochemistry and Fluoro-Jade B histofluorescence staining and changes in GLUT-1 expression was carried out by immunohistochemistry. Results: About 90% of pyramidal neurons only in the adult CA1 region were damaged after ischemia/reperfusion; in the young, about 53 % of pyramidal neurons were damaged from 7 days after ischemia/reperfusion. The density of GLUT-1-immunoreactive microvessels was significantly higher in the young sham-group than that in the adult sham-group. In the ischemia-operated-groups, the density of GLUT-1-immunoreactive microvessels was significantly decreased in the adult and young at 1 and 4 days post-ischemia, respectively, thereafter, the density of GLUT-1-immunoreactive microvessels was gradually increased in both groups after ischemia/reperfusion. Conclusion: CA1 pyramidal neurons of the young gerbil were damaged much later than that in the adult and that GLUT-1-immunoreactive microvessels were significantly decreased later in the young. These data indicate that GLUT-1 might differently contribute to neuronal damage according to age after ischemic insults.

  1. Testicular regulation of neuronal glucose and monocarboxylate transporter gene expression profiles in CNS metabolic sensing sites during acute and recurrent insulin-induced hypoglycemia.

    Science.gov (United States)

    Vavaiya, Kamlesh V; Paranjape, Sachin A; Briski, Karen P

    2007-01-01

    Recurrent insulin-induced hypoglycemia (RIIH) impairs glucose counter-regulatory function in male humans and rodents and, in the latter, diminishes neuronal activation in CNS structures that monitor metabolic homeostasis, including the lateral hypothalamic area (LHA) and dorsal vagal complex (DVC). We investigated whether habituated neuronal reactivity in CNS sensing sites to hypoglycemia is correlated with modified monocarboxylate and/or glucose uptake by using quantitative real-time RT-PCR to analyze neuronal monocarboxylate transporter (MCT2) and glucose transporter variant (GLUT and GLUT4) gene expression profiles in the microdissected LHA, ventromedial nucleus hypothalamus (VMH), and DVC after one or multiple insulin injections. Because orchidectomy (ORDX) maintains uniform glycemic responses to RIIH in male rats, we also examined whether regional gene response patterns are testes dependent. In the intact male rat DVC, MCT2, GLUT3, and GLUT4 gene expression was not altered by acute hypoglycemia but was enhanced by RIIH. MCT2 and GLUT3 mRNA levels in the ORDX rat DVC did not differ among groups, but GLUT4 transcripts were progressively increased by acute and recurrent hypoglycemia. Precedent hypoglycemia decreased or increased basal MCT2 and GLUT4 gene expression, respectively, in the intact rat LHA; LHA GLUT3 transcription was augmented by RIIH in intact rats only. Acute hypoglycemia suppressed MCT2, GLUT3, and GLUT4 gene expression in the intact rat VMH, a response that was abolished by RIIH. In ORDX rats, VMH gene transcript levels were unchanged in response to one dose of insulin but were selectively diminished during RIIH. These data demonstrate site-specific, testes-dependent effects of acute and recurrent hypoglycemia on neuronal metabolic substrate transporter gene expression in characterized rat brain metabolic sensing loci and emphasize the need to assess the impact of potential alterations in glucose and lactate uptake during RIIH on general and

  2. Sympathetic vasoconstriction takes an unexpected pannexin detour

    DEFF Research Database (Denmark)

    Schak Nielsen, Morten

    2015-01-01

    Sympathetic vasoconstriction plays an important role in the control of blood pressure and the distribution of blood flow. In this issue of Science Signaling, Billaud et al. show that sympathetic vasoconstriction occurs through a complex scheme involving the activation of large-pore pannexin 1...... channels and the subsequent release of adenosine triphosphate that promotes contraction in an autocrine and paracrine manner. This elaborate mechanism may function as a point of intercept for other signaling pathways-for example, in relation to the phenomenon "functional sympatholysis," in which exercise...... abrogates sympathetic vasoconstriction in skeletal muscle. Because pannexin 1 channels are inhibited by nitric oxide, they may function as a switch to turn off adrenergic signaling in skeletal muscle during exercise....

  3. Polyphenols, Antioxidants and the Sympathetic Nervous System.

    Science.gov (United States)

    Bruno, Rosa Maria; Ghiadoni, Lorenzo

    2018-01-01

    A high dietary intake of polyphenols has been associated with a reduced cardiovascular mortality, due to their antioxidant properties. However, growing evidence suggests that counteracting oxidative stress in cardiovascular disease might also reduce sympathetic nervous system overactivity. This article reviews the most commonly used techniques to measure sympathetic activity in humans; the role of sympathetic activation in the pathophysiology of cardiovascular diseases; current evidence demonstrating that oxidative stress is involved in the regulation of sympathetic activity and how antioxidants and polyphenols might counteract sympathetic overactivity, particularly focusing on preliminary data from human studies. The main mechanisms by which polyphenols are cardioprotective are related to the improvement of vascular function and their anti-atherogenic effect. Furthermore, a blood pressure-lowering effect was consistently demonstrated in randomized controlled trials in humans, when the effect of flavonoid-rich foods, such as tea and chocolate, was tested. More recent studies suggest that inhibition of sympathetic overactivity might be one of the mechanisms by which these substances exert their cardioprotective effects. Indeed, an increased adrenergic traffic to the vasculature is a major mechanism of disease in a number of cardiovascular and extra-cardiac diseases, including hypertension, obesity, metabolic syndrome and heart failure. A considerable body of evidence, mostly from experimental studies, support the hypothesis that reactive oxygen species might exert sympathoexcitatory effects both at the central and at the peripheral level. Accordingly, supplementation with antioxidants might reduce adrenergic overdrive to the vasculature and blunt cardiovascular reactivity to stress. While supplementation with "classical" antioxidants such as ROS-scavengers has many limitations, increasing the intake of polyphenol-rich foods seems to be a promising novel therapeutic

  4. Chloroquine causes similar electroretinogram modifications, neuronal phospholipidosis and marked impairment of synaptic vesicle transport in Albino and Pigmented Rats

    International Nuclear Information System (INIS)

    Lezmi, Stéphane; Rokh, Najla; Saint-Macary, Gérard; Pino, Michael; Sallez, Valérie; Thevenard, Françoise; Roome, Nigel; Rosolen, Serge

    2013-01-01

    Retinal toxicity of chloroquine has been known for several years, but the mechanism(s) of toxicity remain controversial; some author support the idea that the binding of chloroquine to melanin pigments in the retinal pigmented epithelium (RPE) play a major toxic role by concentrating the drug in the eye. In our study, 12 albinos Sprague-Dawley (SD) and 12 pigmented Brown Norway (BN) rats were treated orally for 3 months with chloroquine to compare functional and pathological findings. On Flash electroretinograms (ERG) performed in scotopic conditions, similar and progressive (time-dependent) delayed onset and decreased amplitudes of oscillatory potentials (from Day 71) and b-waves (on Day 92) were identified in both BN and SD rats. In both strains, identical morphological changes consisted of neuronal phospholipidosis associated with UV auto-fluorescence without evidence of retinal degeneration and gliosis; the RPE did not show any morphological lesions or autofluorescence. IHC analyses demonstrated a decrease in GABA expression in the inner nuclear layer. In addition, a marked accumulation of synaptic vesicles coupled with a marked disruption of neurofilaments in the optic nerve fibers was identified. In conclusion, ERG observations were very similar to those described in humans. Comparable ERG modifications, histopathology and immunohistochemistry findings were observed in the retina of both rat strains suggesting that melanin pigment is unlikely involved. chloroquine-induced impairment of synaptic vesicle transport, likely related to disruption of neurofilaments was identified and non-previously reported. This new mechanism of toxicity may also be responsible for the burry vision described in humans chronically treated with chloroquine

  5. Chloroquine causes similar electroretinogram modifications, neuronal phospholipidosis and marked impairment of synaptic vesicle transport in albino and pigmented rats.

    Science.gov (United States)

    Lezmi, Stéphane; Rokh, Najla; Saint-Macary, Gérard; Pino, Michael; Sallez, Valérie; Thevenard, Françoise; Roome, Nigel; Rosolen, Serge

    2013-06-07

    Retinal toxicity of chloroquine has been known for several years, but the mechanism(s) of toxicity remain controversial; some author support the idea that the binding of chloroquine to melanin pigments in the retinal pigmented epithelium (RPE) play a major toxic role by concentrating the drug in the eye. In our study, 12 albinos Sprague-Dawley (SD) and 12 pigmented Brown Norway (BN) rats were treated orally for 3 months with chloroquine to compare functional and pathological findings. On Flash electroretinograms (ERG) performed in scotopic conditions, similar and progressive (time-dependent) delayed onset and decreased amplitudes of oscillatory potentials (from Day 71) and b-waves (on Day 92) were identified in both BN and SD rats. In both strains, identical morphological changes consisted of neuronal phospholipidosis associated with UV auto-fluorescence without evidence of retinal degeneration and gliosis; the RPE did not show any morphological lesions or autofluorescence. IHC analyses demonstrated a decrease in GABA expression in the inner nuclear layer. In addition, a marked accumulation of synaptic vesicles coupled with a marked disruption of neurofilaments in the optic nerve fibers was identified. In conclusion, ERG observations were very similar to those described in humans. Comparable ERG modifications, histopathology and immunohistochemistry findings were observed in the retina of both rat strains suggesting that melanin pigment is unlikely involved. chloroquine-induced impairment of synaptic vesicle transport, likely related to disruption of neurofilaments was identified and non-previously reported. This new mechanism of toxicity may also be responsible for the burry vision described in humans chronically treated with chloroquine. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  6. Cholinergic neurons in the dorsomedial hypothalamus regulate mouse brown adipose tissue metabolism

    Directory of Open Access Journals (Sweden)

    Jae Hoon Jeong

    2015-06-01

    Conclusion: DMH cholinergic neurons directly send efferent signals to sympathetic premotor neurons in the Rpa. Elevated cholinergic input to this area reduces BAT activity through activation of M2 mAChRs on serotonergic neurons. Therefore, the direct DMHACh–Rpa5-HT pathway may mediate physiological heat-defense responses to elevated environmental temperature.

  7. Altered differential control of sympathetic outflow following sedentary conditions: Role of subregional neuroplasticity in the RVLM

    Directory of Open Access Journals (Sweden)

    Madhan Subramanian

    2016-07-01

    Full Text Available Despite the classically held belief of an all-or-none activation of the sympathetic nervous system, differential responses in sympathetic nerve activity (SNA can occur acutely at varying magnitudes and in opposing directions. Sympathetic nerves also appear to contribute differentially to various disease states including hypertension and heart failure. Previously we have reported that sedentary conditions enhanced responses of splanchnic SNA (SSNA but not lumbar SNA (LSNA to activation of the rostral ventrolateral medulla (RVLM in rats. Bulbospinal RVLM neurons from sedentary rats also exhibit increased dendritic branching in rostral regions of the RVLM. We hypothesized that regionally specific structural neuroplasticity would manifest as enhanced SSNA but not LSNA following activation of the rostral RVLM. To test this hypothesis, groups of physically active (10-12 weeks on running wheels or sedentary, male Sprague-Dawley rats were instrumented to record mean arterial pressure, LSNA and SSNA under Inactin anesthesia and during microinjections of glutamate (30 nl, 10 mM into multiple sites within the RVLM. Sedentary conditions enhanced SSNA but not LSNA responses and SSNA responses were enhanced at more central and rostral sites. Results suggest that enhanced SSNA responses in rostral RVLM coincide with enhanced dendritic branching in rostral RVLM observed previously. Identifying structural and functional neuroplasticity in specific populations of RVLM neurons may help identify new treatments for cardiovascular diseases, known to be more prevalent in sedentary individuals.

  8. Sympathetic Nerve Injury in Thyroid Cancer

    Directory of Open Access Journals (Sweden)

    Evangelos Diamantis

    2018-04-01

    Full Text Available The double innervation of the thyroid comes from the sympathetic and parasympathetic nervous system. Injury rates during surgery are at 30% but can be minimized by upwardly preparing the thyroid vessels at the level of thyroid capsule. Several factors have been accused of increasing the risk of injury including age and tumor size. Our aim was to investigate of there is indeed any possible correlations between these factors and a possible increase in injury rates following thyroidectomy. Seven studies were included in the meta-analysis. Statistical correlation was observed for a positive relationship between injury of the sympathetic nerve and thyroid malignancy surgery (p < 0.001; I2 = 74% No statistical correlations were observed for a negative or positive relationship between injury of the sympathetic nerve and tumor size. There was also no statistically significant value observed for the correlation of the patients’ age with the risk of sympathetic nerve injury (p = 0.388. Lack of significant correlation reported could be due to the small number of studies and great heterogeneity between them.

  9. Literary ethnographic writing as sympathetic experiment

    DEFF Research Database (Denmark)

    Dalsgaard, Anne Line

    perhaps only implicitly) of research. But we have no direct access to the subjective world of others and can only inhabit their point of view by way of imagination. Writing literary ethnographic text is one way, I will argue, of experimenting with such sympathetic imagination. By putting together observed...

  10. Renal Sympathetic Denervation: Hibernation or Resurrection?

    Science.gov (United States)

    Papademetriou, Vasilios; Doumas, Michael; Tsioufis, Costas

    The most current versions of renal sympathetic denervation have been invented as minimally invasive approaches for the management of drug-resistant hypertension. The anatomy, physiology and pathophysiology of renal sympathetic innervation provide a strong background supporting an important role of the renal nerves in the regulation of blood pressure (BP) and volume. In addition, historical data with surgical sympathectomy and experimental data with surgical renal denervation indicate a beneficial effect on BP levels. Early clinical studies with transcatheter radiofrequency ablation demonstrated impressive BP reduction, accompanied by beneficial effects in target organ damage and other disease conditions characterized by sympathetic overactivity. However, the failure of the SYMPLICITY 3 trial to meet its primary efficacy end point raised a lot of concerns and put the field of renal denervation into hibernation. This review aims to translate basic research into clinical practice by presenting the anatomical and physiological basis for renal sympathetic denervation, critically discussing the past and present knowledge in this field, where we stand now, and also speculating about the future of the intervention and potential directions for research. © 2016 S. Karger AG, Basel.

  11. Insulin growth factors regulate the mitotic cycle in cultured rat sympathetic neuroblasts

    International Nuclear Information System (INIS)

    DiCicco-Bloom, E.; Black, I.B.

    1988-01-01

    While neuronal mitosis is uniquely restricted to early development, the underlying regulation remains to be defined. The authors have now developed a dissociated, embryonic sympathetic neuron culture system that uses fully defined medium in which cells enter the mitotic cycle. The cultured cells expressed two neuronal traits, tyrosine hydroxylase and the neuron-specific 160-kDa neurofilament subunit protein, but were devoid of glial fibrillary acidic protein, a marker for non-myelin-forming Schwann cells in ganglia. Approximately one-third of the tyrosine hydroxylase-positive cells synthesized DNA in culture, specifically incorporating [ 3 H]thymidine into their nuclei. They used this system to define factors regulating the mitotic cycle in sympathetic neuroblasts. Members of the insulin family of growth factors, including insulin and insulin-like growth factors I and II, regulated DNA synthesis in the presumptive neuroblasts. Insulin more than doubled the proportion of tyrosine hydroxylase-positive cells entering the mitotic cycle, as indicated by autoradiography of [ 3 H]thymidine incorporation into nuclei. Scintillation spectrometry was an even more sensitive index of DNA synthesis. In contrast, the trophic protein nerve growth factor exhibited no mitogenic effect, suggesting that the mitogenic action of insulin growth factors is highly specific. The observations are discussed in the context of the detection of insulin growth factors and receptors in the developing brain

  12. Increase of transcription factor EB (TFEB) and lysosomes in rat DRG neurons and their transportation to the central nerve terminal in dorsal horn after nerve injury.

    Science.gov (United States)

    Jung, J; Uesugi, N; Jeong, N Y; Park, B S; Konishi, H; Kiyama, H

    2016-01-28

    In the spinal dorsal horn (DH), nerve injury activates microglia and induces neuropathic pain. Several studies clarified an involvement of adenosine triphosphate (ATP) in the microglial activation. However, the origin of ATP together with the release mechanism is unclear. Recent in vitro study revealed that an ATP marker, quinacrine, in lysosomes was released from neurite terminal of dorsal root ganglion (DRG) neurons to extracellular space via lysosomal exocytosis. Here, we demonstrate a possibility that the lysosomal ingredient including ATP released from DRG neurons by lysosomal-exocytosis is an additional source of the glial activation in DH after nerve injury. After rat L5 spinal nerve ligation (SNL), mRNA for transcription factor EB (TFEB), a transcription factor controlling lysosomal activation and exocytosis, was induced in the DRG. Simultaneously both lysosomal protein, LAMP1- and vesicular nuclear transporter (VNUT)-positive vesicles were increased in L5 DRG neurons and ipsilateral DH. The quinacrine staining in DH was increased and co-localized with LAMP1 immunoreactivity after nerve injury. In DH, LAMP1-positive vesicles were also co-localized with a peripheral nerve marker, Isolectin B4 (IB4) lectin. Injection of the adenovirus encoding mCherry-LAMP1 into DRG showed that mCherry-positive lysosomes are transported to the central nerve terminal in DH. These findings suggest that activation of lysosome synthesis including ATP packaging in DRG, the central transportation of the lysosome, and subsequent its exocytosis from the central nerve terminal of DRG neurons in response to nerve injury could be a partial mechanism for activation of microglia in DH. This lysosome-mediated microglia activation mechanism may provide another clue to control nociception and pain. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  13. Sympathetic activation during early pregnancy in humans

    Science.gov (United States)

    Jarvis, Sara S; Shibata, Shigeki; Bivens, Tiffany B; Okada, Yoshiyuki; Casey, Brian M; Levine, Benjamin D; Fu, Qi

    2012-01-01

    Sympathetic activity has been reported to increase in normotensive pregnant women, and to be even greater in women with gestational hypertension and preeclampsia at term. Whether sympathetic overactivity develops early during pregnancy, remaining high throughout gestation, or whether it only occurs at term providing the substrate for hypertensive disorders is unknown. We tested the hypothesis that sympathetic activation occurs early during pregnancy in humans. Eleven healthy women (29 ± 3 (SD) years) without prior hypertensive pregnancies were tested during the mid-luteal phase (PRE) and early pregnancy (EARLY; 6.2 ± 1.2 weeks of gestation). Muscle sympathetic nerve activity (MSNA) and haemodynamics were measured supine, at 30 deg and 60 deg upright tilt for 5 min each. Blood samples were drawn for catecholamines, direct renin, and aldosterone. MSNA was significantly greater during EARLY than PRE (supine: 25 ± 8 vs. 14 ± 8 bursts min−1, 60 deg tilt: 49 ± 14 vs. 40 ± 10 bursts min−1; main effect, P < 0.05). Resting diastolic pressure trended lower (P = 0.09), heart rate was similar, total peripheral resistance decreased (2172 ± 364 vs. 2543 ± 352 dyne s cm−5; P < 0.05), sympathetic vascular transduction was blunted (0.10 ± 0.05 vs. 0.36 ± 0.47 units a.u.−1 min−1; P < 0.01), and both renin (supine: 27.9 ± 6.2 vs. 14.2 ± 8.7 pg ml−1, P < 0.01) and aldosterone (supine: 16.7 ± 14.1 vs. 7.7 ± 6.8 ng ml−1, P = 0.05) were higher during EARLY than PRE. These results suggest that sympathetic activation is a common characteristic of early pregnancy in humans despite reduced diastolic pressure and total peripheral resistance. These observations challenge conventional thinking about blood pressure regulation during pregnancy, showing marked sympathetic activation occurring within the first few weeks of conception, and may provide the substrate for pregnancy induced cardiovascular complications. PMID:22687610

  14. Decreased adrenoceptor stimulation in heart failure rats reduces NGF expression by cardiac parasympathetic neurons

    OpenAIRE

    Hasan, Wohaib; Smith, Peter G

    2013-01-01

    Postganglionic cardiac parasympathetic and sympathetic nerves are physically proximate in atrial cardiac tissue allowing reciprocal inhibition of neurotransmitter release, depending on demands from central cardiovascular centers or reflex pathways. Parasympathetic cardiac ganglion (CG) neurons synthesize and release the sympathetic neurotrophin nerve growth factor (NGF), which may serve to maintain these close connections. In this study we investigated whether NGF synthesis by CG neurons is a...

  15. Decreased expression of vesicular glutamate transporter 1 and complexin II mRNAs in schizophrenia: further evidence for a synaptic pathology affecting glutamate neurons.

    Science.gov (United States)

    Eastwood, S L; Harrison, P J

    2005-03-01

    Synaptic protein gene expression is altered in schizophrenia. In the hippocampal formation there may be particular involvement of glutamatergic neurons and their synapses, but overall the profile remains unclear. In this in situ hybridization histochemistry (ISHH) study, we examined four informative synaptic protein transcripts: vesicular glutamate transporter (VGLUT) 1, VGLUT2, complexin I, and complexin II, in dorsolateral prefrontal cortex (DPFC), superior temporal cortex (STC), and hippocampal formation, in 13 subjects with schizophrenia and 18 controls. In these areas, VGLUT1 and complexin II are expressed primarily by excitatory neurons, whereas complexin I is mainly expressed by inhibitory neurons. In schizophrenia, VGLUT1 mRNA was decreased in hippocampal formation and DPFC, complexin II mRNA was reduced in DPFC and STC, and complexin I mRNA decreased in STC. Hippocampal VGLUT1 mRNA declined with age selectively in the schizophrenia group. VGLUT2 mRNA was not quantifiable due to its low level. The data provide additional evidence for a synaptic pathology in schizophrenia, in terms of a reduced expression of three synaptic protein genes. In the hippocampus, the loss of VGLUT1 mRNA supports data indicating that glutamatergic presynaptic deficits are prominent, whereas the pattern of results in temporal and frontal cortex suggests broadly similar changes may affect inhibitory and excitatory neurons. The impairment of synaptic transmission implied by the synaptic protein reductions may contribute to the dysfunction of cortical neural circuits that characterises the disorder.

  16. Effects of renal sympathetic denervation on cardiac sympathetic activity and function in patients with therapy resistant hypertension

    NARCIS (Netherlands)

    van Brussel, Peter M.; Eeftinck Schattenkerk, Daan W.; Dobrowolski, Linn C.; de Winter, Robbert J.; Reekers, Jim A.; Verberne, Hein J.; Vogt, Liffert; van den Born, Bert-Jan H.

    2016-01-01

    Renal sympathetic denervation (RSD) is currently being investigated in multiple studies of sympathetically driven cardiovascular diseases such as heart failure and arrhythmias. Our aim was to assess systemic and cardiac sympatholytic effects of RSD by the measurement of cardiac sympathetic activity

  17. Chronic Hyperinsulinaemic Hypoglycaemia in Rats Is Accompanied by Increased Body Weight, Hyperleptinaemia, and Decreased Neuronal Glucose Transporter Levels in the Brain

    Directory of Open Access Journals (Sweden)

    Vivi F. H. Jensen

    2017-01-01

    Full Text Available The brain is vulnerable to hypoglycaemia due to a continuous need of energy substrates to meet its high metabolic demands. Studies have shown that severe acute insulin-induced hypoglycaemia results in oxidative stress in the rat brain, when neuroglycopenia cannot be evaded despite increased levels of cerebral glucose transporters. Compensatory measures in the brain during chronic insulin-induced hypoglycaemia are less well understood. The present study investigated how the brain of nondiabetic rats copes with chronic insulin-induced hypoglycaemia for up to eight weeks. Brain level of different substrate transporters and redox homeostasis was evaluated. Hyperinsulinaemia for 8 weeks consistently lowered blood glucose levels by 30–50% (4–6 mM versus 7–9 mM in controls. The animals had increased food consumption, body weights, and hyperleptinaemia. During infusion, protein levels of the brain neuronal glucose transporter were decreased, whereas levels of lipid peroxidation products were unchanged. Discontinued infusion was followed by transient systemic hyperglycaemia and decreased food consumption and body weight. After 4 weeks, plasma levels of lipid peroxidation products were increased, possibly as a consequence of hyperglycaemia-induced oxidative stress. The present data suggests that chronic moderate hyperinsulinaemic hypoglycaemia causes increased body weight and hyperleptinaemia. This is accompanied by decreased neuronal glucose transporter levels, which may be leptin-induced.

  18. Chronic Hyperinsulinaemic Hypoglycaemia in Rats Is Accompanied by Increased Body Weight, Hyperleptinaemia, and Decreased Neuronal Glucose Transporter Levels in the Brain.

    Science.gov (United States)

    Jensen, Vivi F H; Mølck, Anne-Marie; Chapman, Melissa; Alifrangis, Lene; Andersen, Lene; Lykkesfeldt, Jens; Bøgh, Ingrid B

    2017-01-01

    The brain is vulnerable to hypoglycaemia due to a continuous need of energy substrates to meet its high metabolic demands. Studies have shown that severe acute insulin-induced hypoglycaemia results in oxidative stress in the rat brain, when neuroglycopenia cannot be evaded despite increased levels of cerebral glucose transporters. Compensatory measures in the brain during chronic insulin-induced hypoglycaemia are less well understood. The present study investigated how the brain of nondiabetic rats copes with chronic insulin-induced hypoglycaemia for up to eight weeks. Brain level of different substrate transporters and redox homeostasis was evaluated. Hyperinsulinaemia for 8 weeks consistently lowered blood glucose levels by 30-50% (4-6 mM versus 7-9 mM in controls). The animals had increased food consumption, body weights, and hyperleptinaemia. During infusion, protein levels of the brain neuronal glucose transporter were decreased, whereas levels of lipid peroxidation products were unchanged. Discontinued infusion was followed by transient systemic hyperglycaemia and decreased food consumption and body weight. After 4 weeks, plasma levels of lipid peroxidation products were increased, possibly as a consequence of hyperglycaemia-induced oxidative stress. The present data suggests that chronic moderate hyperinsulinaemic hypoglycaemia causes increased body weight and hyperleptinaemia. This is accompanied by decreased neuronal glucose transporter levels, which may be leptin-induced.

  19. Neurochemistry of bulbospinal presympathetic neurons of the medulla oblongata.

    Science.gov (United States)

    Stornetta, Ruth L

    2009-11-01

    This review focuses on presympathetic neurons in the medulla oblongata including the adrenergic cell groups C1-C3 in the rostral ventrolateral medulla and the serotonergic, GABAergic and glycinergic neurons in the ventromedial medulla. The phenotypes of these neurons including colocalized neuropeptides (e.g., neuropeptide Y, enkephalin, thyrotropin-releasing hormone, substance P) as well as their relative anatomical location are considered in relation to predicting their function in control of sympathetic outflow, in particular the sympathetic outflows controlling blood pressure and thermoregulation. Several explanations are considered for how the neuroeffectors coexisting in these neurons might be functioning, although their exact purpose remains unknown. Although there is abundant data on potential neurotransmitters and neuropeptides contained in the presympathetic neurons, we are still unable to predict function and physiology based solely on the phenotype of these neurons.

  20. Postirradiation changes in the systems of active ion transport. Na,K-ATPase of neurons in neuroglia

    International Nuclear Information System (INIS)

    Shainskaya, A.M.; Dvoretskij, A.I.; Valetova, Yu.O.

    1989-01-01

    A study was made of the effect of X-radiation (0.31 C/kg and 3.875 C/kg) on Na,K-ATPase in fractions enriched with neurons and neuroglia. The results show the impairment of the neuronal-glial relationship in Na,K-ATPase activity. The most important differences in the pattern of changes in Na,K-ATPase system of brain cells were followed up after irradiaion with lethal and sublethal doses

  1. Resting sympathetic activity is associated with the sympathetically mediated component of energy expenditure following a meal.

    Science.gov (United States)

    Limberg, Jacqueline K; Malterer, Katherine R; Matzek, Luke J; Levine, James A; Charkoudian, Nisha; Miles, John M; Joyner, Michael J; Curry, Timothy B

    2017-08-01

    Individuals with high plasma norepinephrine (NE) levels at rest have a smaller reduction in resting energy expenditure (REE) following β -adrenergic blockade. If this finding extends to the response to a meal, it could have important implications for the role of the sympathetic nervous system in energy balance and weight gain. We hypothesized high muscle sympathetic nerve activity (MSNA) would be associated with a low sympathetically mediated component of energy expenditure following a meal. Fourteen young, healthy adults completed two visits randomized to continuous saline (control) or intravenous propranolol to achieve systemic β -adrenergic blockade. Muscle sympathetic nerve activity and REE were measured (indirect calorimetry) followed by a liquid mixed meal (Ensure). Measures of energy expenditure continued every 30 min for 5 h after the meal and are reported as an area under the curve (AUC). Sympathetic support of energy expenditure was calculated as the difference between the AUC during saline and β -blockade (AUC P ropranolol -AUC S aline , β -REE) and as a percent (%) of control (AUC P ropranolol ÷AUC S aline  × 100). β -REE was associated with baseline sympathetic activity, such that individuals with high resting MSNA (bursts/100 heart beats) and plasma NE had the greatest sympathetically mediated component of energy expenditure following a meal (MSNA: β -REE R  =   -0.58, P =  0.03; %REE R  = -0.56, P =  0.04; NE: β -REE R  = -0.55, P  = 0.0535; %REE R  = -0.54, P  = 0.0552). Contrary to our hypothesis, high resting sympathetic activity is associated with a greater sympathetically mediated component of energy expenditure following a liquid meal. These findings may have implications for weight maintenance in individuals with varying resting sympathetic activity. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  2. Sympathetic reflex control of blood flow in human peripheral tissues

    DEFF Research Database (Denmark)

    Henriksen, O

    1991-01-01

    Sympathetic vasoconstrictor reflexes are essential for the maintenance of arterial blood pressure in upright position. It has been generally believed that supraspinal sympathetic vasoconstrictor reflexes elicited by changes in baroreceptor activity play an important role. Recent studies on human...... sympathetic vasoconstrictor reflexes are blocked. Blood flow has been measure by the local 133Xe-technique. The results indicate the presence of spinal as well as supraspinal sympathetic vasoconstrictor reflexes to human peripheral tissues. Especially is emphasized the presence of a local sympathetic veno...... skeletal muscle, cutaneous and subcutaneous tissues of the limbs indicate that the situation is more complex. Measurements have been carried out during acute as well as chronic sympathetic denervation. Spinal sympathetic reflex mechanisms have been evaluated in tetraplegic patients, where supraspinal...

  3. Identification of the endogenous key substrates of the human organic cation transporter OCT2 and their implication in function of dopaminergic neurons.

    Directory of Open Access Journals (Sweden)

    Dirk Taubert

    Full Text Available BACKGROUND: The etiology of neurodegenerative disorders, such as the accelerated loss of dopaminergic neurons in Parkinson's disease, is unclear. Current hypotheses suggest an abnormal function of the neuronal sodium-dependent dopamine transporter DAT to contribute to cell death in the dopaminergic system, but it has not been investigated whether sodium-independent amine transporters are implicated in the pathogenesis of Parkinson's disease. METHODOLOGY/PRINCIPAL FINDINGS: By the use of a novel tandem-mass spectrometry-based substrate search technique, we have shown that the dopaminergic neuromodulators histidyl-proline diketopiperazine (cyclo(his-pro and salsolinol were the endogenous key substrates of the sodium-independent organic cation transporter OCT2. Quantitative real-time mRNA expression analysis revealed that OCT2 in contrast to its related transporters was preferentially expressed in the dopaminergic regions of the substantia nigra where it colocalized with DAT and tyrosine hydroxylase. By assessing cell viability with the MTT reduction assay, we found that salsolinol exhibited a selective toxicity toward OCT2-expressing cells that was prevented by cyclo(his-pro. A frequent genetic variant of OCT2 with the amino acid substitution R400C reduced the transport efficiency for the cytoprotective cyclo(his-pro and thereby increased the susceptibility to salsolinol-induced cell death. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that the OCT2-regulated interplay between cyclo(his-pro and salsolinol is crucial for nigral cell integrity and that a shift in transport efficiency may impact the risk of Parkinson's disease.

  4. Foxo1 regulates Dbh expression and the activity of the sympathetic nervous system in vivo

    Directory of Open Access Journals (Sweden)

    Daisuke Kajimura

    2014-10-01

    Full Text Available The transcription factor FoxO1 regulates multiple physiological processes. Here, we show that FoxO1 is highly expressed in neurons of the locus coeruleus and of various sympathetic ganglions, but not in the adrenal medulla. Consistent with this pattern of expression, mice lacking FoxO1 only in sympathetic neurons (FoxO1Dbh−/− display a low sympathetic tone without modification of the catecholamine content in the adrenal medulla. As a result, FoxO1Dbh−/− mice demonstrate an increased insulin secretion, improved glucose tolerance, low energy expenditure, and high bone mass. FoxO1 favors catecholamine synthesis because it is a potent regulator of the expression of Dbh that encodes the initial and rate-limiting enzyme in the synthesis of these neurotransmitters. By identifying FoxO1 as a transcriptional regulator of the sympathetic tone, these results advance our understanding of the control of some aspects of metabolism and of bone mass accrual.

  5. N-Methyl-D aspartate receptor-mediated effect on glucose transporter-3 levels of high glucose exposed-SH-SY5Y dopaminergic neurons.

    Science.gov (United States)

    Engin, Ayse Basak; Engin, Evren Doruk; Karakus, Resul; Aral, Arzu; Gulbahar, Ozlem; Engin, Atilla

    2017-11-01

    High glucose and insulin lead to neuronal insulin resistance. Glucose transport into the neurons is achieved by regulatory induction of surface glucose transporter-3 (GLUT3) instead of the insulin. N-methyl-D aspartate (NMDA) receptor activity increases GLUT3 expression. This study explored whether an endogenous NMDA receptor antagonist, kynurenic acid (KynA) affects the neuronal cell viability at high glucose concentrations. SH-SY5Y neuroblastoma cells were exposed to 150-250 mg/dL glucose and 40 μU/mL insulin. In KynA and N-nitro-l-arginine methyl ester (L-NAME) supplemented cultures, oxidative stress, mitochondrial metabolic activity (MTT), nitric oxide as nitrite+nitrate (NOx) and GLUT3 were determined at the end of 24 and 48-h incubation periods. Viable cells were counted by trypan blue dye. High glucose-exposed SH-SY5Y cells showed two-times more GLUT3 expression at second 24-h period. While GLUT3-stimulated glucose transport and oxidative stress was increased, total mitochondrial metabolic activity was significantly reduced. Insulin supplementation to high glucose decreased NOx synthesis and GLUT3 levels, in contrast oxidative stress increased three-fold. KynA significantly reduced oxidative stress, and increased MTT by regulating NOx production and GLUT3 expression. KynA is a noteworthy compound, as an endogenous, specific NMDA receptor antagonist; it significantly reduces oxidative stress, while increasing cell viability at high glucose and insulin concentrations. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Diabetic cardiac autonomic dysfunction. Parasympathetic versus sympathetic

    International Nuclear Information System (INIS)

    Uehara, Akihiko; Kurata, Chinori; Sugi, Toshihiko; Mikami, Tadashi; Shouda, Sakae

    1999-01-01

    Diabetic cardiac autonomic dysfunction often causes lethal arrhythmia and sudden cardiac death. 123 I-Metaiodobenzylguanidine (MIBG) can evaluate cardiac sympathetic dysfunction, and analysis of heart rate variability (HRV) can reflect cardiac parasympathetic activity. We examined whether cardiac parasympathetic dysfunction assessed by HRV may correlate with sympathetic dysfunction assessed by MIBG in diabetic patients. In 24-hour electrocardiography, we analyzed 4 HRV parameters: high-frequency power (HF), HF in the early morning (EMHF), rMSSD and pNN50. MIBG planar images and SPECT were obtained 15 minutes (early) and 150 minutes (late) after injection and the heart washout rate was calculated. The defect score in 9 left ventricular regions was scored on a 4 point scale (0=normal - 3=severe defect). In 20 selected diabetic patients without congestive heart failure, coronary artery disease and renal failure, parasympathetic HRV parameters had a negative correlation with the sum of defect scores (DS) in the late images (R=-0.47 to -0.59, p<0.05) and some parameters had a negative correlation with the washout rate (R=-0.50 to -0.55, p<0.05). In a total of 64 diabetic patients also, these parameters had a negative correlation with late DS (R=-0.28 to -0.35, p<0.05) and early DS (R=-0.27 to -0.32, p<0.05). The progress of diabetic cardiac parasympathetic dysfunction may parallel the sympathetic one. (author)

  7. Depolarization-induced release of [(3)H]D-aspartate from GABAergic neurons caused by reversal of glutamate transporters

    DEFF Research Database (Denmark)

    Jensen, J B; Pickering, D S; Schousboe, A

    2000-01-01

    if glutamate in addition to gamma-aminobutyric acid (GABA) could be released from these cultures. The neurons were preloaded with [(3)H]D-aspartate and subsequently its release was followed during depolarization induced by a high potassium concentration or the alpha-amino-3-hydroxy-5-methyl-4......-isoxazolepropionic acid (AMPA) receptor agonists, AMPA and kainate. Depolarization of the neurons with 55 mM potassium increased the release of [(3)H]D-aspartate by more than 10-fold. When the non-specific calcium-channel blockers cobalt or lanthanum were included in the stimulation buffer with potassium......, the release of [(3)H]D-aspartate was decreased by about 40%. These results indicated that some of the released [(3)H]D-aspartate might originate from a vesicular pool. When AMPA was applied to the neurons, the release of [(3)H]D-aspartate was increased 2-fold and could not be prevented or decreased...

  8. Reactive oxygen species in the paraventricular nucleus of the hypothalamus alter sympathetic activity during metabolic syndrome.

    Directory of Open Access Journals (Sweden)

    JOSIANE CAMPOS CRUZ

    2015-12-01

    Full Text Available The paraventricular nucleus of the hypothalamus (PVN contains heterogeneous populations of neurons involved in autonomic and neuroendocrine regulation. The PVN plays an important role in the sympathoexcitatory response to increasing circulating levels of angiotensin II (Ang-II, which activates AT1 receptors in the circumventricular organs (OCVs, mainly in the subfornical organ (SFO. Circulating Ang-II induces a de novo synthesis of Ang-II in SFO neurons projecting to pre-autonomic PVN neurons. Activation of AT1 receptors induces intracellular increases in reactive oxygen species (ROS, leading to increases in sympathetic nerve activity (SNA. Chronic sympathetic nerve activation promotes a series of metabolic disorders that characterizes the metabolic syndrome (MetS: dyslipidemia, hyperinsulinemia, glucose intolerance, hyperleptinemia and elevated plasma hormone levels, such as noradrenaline, glucocorticoids, leptin, insulin and Ang-II. This review will discuss the contribution of our laboratory and others regarding the sympathoexcitation caused by peripheral Ang-II-induced reactive oxygen species along the subfornical organ and paraventricular nucleus of the hypothalamus. We hypothesize that this mechanism could be involved in metabolic disorders underlying MetS.

  9. Study of nerve fibers nature reinforcing duodenal contractions by electrical stimulation of sympathetic nerve

    Directory of Open Access Journals (Sweden)

    Sveshnikov D.S.

    2011-09-01

    Full Text Available The subject of the article is to investigate the mechanism of increased reactions by electrical stimulation of the sympathetic nerve. Materials and methods: Experiments on dogs have shown that stimulant reactions during blockade of a-adrenergic by phentolamine and (3-adrenergic receptors with propranolol were completely eliminated by lizer-gol —the blocker of 5-HT12-receptors. Results: Infusion of lizergol did not influence on duodenal motor activity and the function of the vagus nerve. Conclusion: Effector neuron is found out to be serotonergic and its action is provided by 5-HT1 2 receptors

  10. Sympathetic influence on cerebral blood flow and metabolism during exercise in humans

    DEFF Research Database (Denmark)

    Seifert, Thomas; Secher, Niels H

    2011-01-01

    This review focuses on the possibility that autonomic activity influences cerebral blood flow (CBF) and metabolism during exercise in humans. Apart from cerebral autoregulation, the arterial carbon dioxide tension, and neuronal activation, it may be that the autonomic nervous system influences CBF...... perfusion and reduces the near-infrared determined cerebral oxygenation at rest, but not during exercise associated with an increased cerebral metabolic rate for oxygen (CMRO(2)), suggesting competition between CMRO(2) and sympathetic control of CBF. CMRO(2) does not change during even intense handgrip...

  11. Fibromyalgia: When Distress Becomes (Un)sympathetic Pain

    OpenAIRE

    Martinez-Lavin, Manuel

    2012-01-01

    Fibromyalgia is a painful stress-related disorder. A key issue in fibromyalgia research is to investigate how distress could be converted into pain. The sympathetic nervous system is the main element of the stress response system. In animal models, physical trauma, infection, or distressing noise can induce abnormal connections between the sympathetic nervous system and the nociceptive system. Dorsal root ganglia sodium channels facilitate this type of sympathetic pain. Similar mechanisms may...

  12. Quantitation of cardiac sympathetic innervation in rabbits using 11C-hydroxyephedrine PET: relation to 123I-MIBG uptake

    International Nuclear Information System (INIS)

    Nomura, Yusuke; Kajinami, Kouji; Matsunari, Ichiro; Takamatsu, Hiroyuki; Murakami, Yoshihiro; Matsuya, Takahiro; Chen, Wei-Ping; Taki, Junichi; Nakajima, Kenichi; Nekolla, Stephan G.

    2006-01-01

    Although 11 C-hydroxyephedrine ( 11 C-HED) PET is used to map cardiac sympathetic innervation, no studies have shown the feasibility of quantitation of 11 C-HED PET in small- to medium-sized animals. Furthermore, its relation to 123 I-MIBG uptake, the most widely used sympathetic nervous tracer, is unknown. The aims of this study were to establish in vivo sympathetic nerve imaging in rabbits using 11 C-HED PET, and to compare the retention of 11 C-HED with that of 123 I-MIBG. Twelve rabbits were assigned to three groups; control (n=4), chemical denervation by 6-hydroxydopamine (6-OHDA) (n=4) and reserpine treated to inhibit vesicular uptake (n=4). After simultaneous injection of 11 C-HED and 123 I-MIBG, all animals underwent dynamic 11 C-HED PET for 40 min with arterial blood sampling. The 11 C-HED retention fraction and normalised 11 C-HED activity measured by tissue sampling were compared with those measured by PET. Both the 11 C-HED retention fraction and the normalised 11 C-HED activity measured by PET correlated closely with those measured by tissue sampling (R=0.96027, p 11 C-HED and 123 I-MIBG. Reserpine pretreatment reduced 11 C-HED retention by 50%, but did not reduce 123 I-MIBG retention at 40 min after injection. Non-invasive quantitation of cardiac sympathetic innervation using 11 C-HED PET is feasible and gives reliable estimates of cardiac sympathetic innervation in rabbits. Additionally, although both 11 C-HED and 123 I-MIBG are specific for sympathetic neurons, 11 C-HED may be more specific for intravesicular uptake than 123 I-MIBG in some situations, such as that seen in reserpine pretreatment. (orig.)

  13. Renal sympathetic denervation for resistant hypertension.

    Science.gov (United States)

    Froeschl, Michael; Hadziomerovic, Adnan; Ruzicka, Marcel

    2013-05-01

    Resistant hypertension is an increasingly prevalent health problem associated with important adverse cardiovascular outcomes. The pathophysiology that underlies this condition involves increased function of both the sympathetic nervous system and the renin-angiotensin II-aldosterone system. A crucial link between these 2 systems is the web of sympathetic fibres that course within the adventitia of the renal arteries. These nerves can be targeted by applying radiofrequency energy from the lumen of the renal arteries to renal artery walls (percutaneous renal sympathetic denervation [RSD]), an approach that has attracted great interest. This paper critically reviews the evidence supporting the use of RSD. Small studies suggest that RSD can produce dramatic blood pressure reductions: In the randomized Symplicity HTN-2 trial of 106 patients, the mean fall in blood pressure at 6 months in patients who received the treatment was 32/12 mm Hg. However, there are limitations to the evidence for RSD in the treatment of resistant hypertension. These include the small number of patients studied; the lack of any placebo-controlled evidence; the fact that blood pressure outcomes were based on office assessments, as opposed to 24-hour ambulatory monitoring; the lack of longer-term efficacy data; and the lack of long-term safety data. Some of these concerns are being addressed in the ongoing Renal Denervation in Patients With Uncontrolled Hypertension (Symplicity HTN-3) trial. The first percutaneous RSD system was approved by Health Canada in the spring of 2012. But until more and better-quality data are available, this procedure should generally be reserved for those patients whose resistant hypertension is truly uncontrolled. Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  14. Sympathetic skin responses in patients with hyperthyroidism.

    Science.gov (United States)

    Gozke, E; Ozyurt, Z; Dortcan, N; Ore, O; Kocer, A; Ozer, E

    2007-01-01

    The aim of this study was to investigate the disorders of sympathetic nervous system in patients with hyperthyroidism using sympathetic skin response (SSR). Twenty-two newly diagnosed cases with hyperthyroidism were included in the study. The results were compared with those of 20 healthy controls. SSR was recorded with the contralateral electrical stimulation of the median nerve (of the upper extremities) and tibial nerve (of the lower extremities) with active electrodes placed on palms and soles and reference electrodes attached on the dorsal aspects of hands and feet. Ages of the cases with hyperthyroidism and controls ranged between 15-65 years (mean: 46.7 +/- 15.0 years) and 24-62 years (mean: 39.6 +/- 9.8 years) respectively (p > 0.05). In all the control subjects SSR could be obtained, while from the lower extremities of 4 cases with hyperthyroidism (18.0%) SSR could not be elicited. Mean SSR latencies of lower extremities were found significantly longer than control group (p nervous system involvement in cases with hyperthyroidism.

  15. Sympathetic nervous dysregulation in the absence of systolic left ventricular dysfunction in a rat model of insulin resistance with hyperglycemia

    Directory of Open Access Journals (Sweden)

    Suuronen Erik J

    2011-08-01

    Full Text Available Abstract Background Diabetes mellitus is strongly associated with cardiovascular dysfunction, derived in part from impairment of sympathetic nervous system signaling. Glucose, insulin, and non-esterified fatty acids are potent stimulants of sympathetic activity and norepinephrine (NE release. We hypothesized that sustained hyperglycemia in the high fat diet-fed streptozotocin (STZ rat model of sustained hyperglycemia with insulin resistance would exhibit progressive sympathetic nervous dysfunction in parallel with deteriorating myocardial systolic and/or diastolic function. Methods Cardiac sympathetic nervous integrity was investigated in vivo via biodistribution of the positron emission tomography radiotracer and NE analogue [11C]meta-hydroxyephedrine ([11C]HED. Cardiac systolic and diastolic function was evaluated by echocardiography. Plasma and cardiac NE levels and NE reuptake transporter (NET expression were evaluated as correlative measurements. Results The animal model displays insulin resistance, sustained hyperglycemia, and progressive hypoinsulinemia. After 8 weeks of persistent hyperglycemia, there was a significant 13-25% reduction in [11C]HED retention in myocardium of STZ-treated hyperglycemic but not euglycemic rats as compared to controls. There was a parallel 17% reduction in immunoblot density for NE reuptake transporter, a 1.2 fold and 2.5 fold elevation of cardiac and plasma NE respectively, and no change in sympathetic nerve density. No change in ejection fraction or fractional area change was detected by echocardiography. Reduced heart rate, prolonged mitral valve deceleration time, and elevated transmitral early to atrial flow velocity ratio measured by pulse-wave Doppler in hyperglycemic rats suggest diastolic impairment of the left ventricle. Conclusions Taken together, these data suggest that sustained hyperglycemia is associated with elevated myocardial NE content and dysregulation of sympathetic nervous system

  16. Delineating neurotrophin-3 dependent signaling pathways underlying sympathetic axon growth along intermediate targets.

    Science.gov (United States)

    Keeler, Austin B; Suo, Dong; Park, Juyeon; Deppmann, Christopher D

    2017-07-01

    Postganglionic sympathetic neurons detect vascular derived neurotrophin 3 (NT3) via the axonally expressed receptor tyrosine kinase, TrkA, to promote chemo-attraction along intermediate targets. Once axons arrive to their final target, a structurally related neurotrophic factor, nerve growth factor (NGF), also acts through TrkA to promote final target innervation. Does TrkA signal differently at these different locales? We previously found that Coronin-1 is upregulated in sympathetic neurons upon exposure to NGF, thereby endowing the NGF-TrkA complex with new signaling capabilities (i.e. calcium signaling), which dampens axon growth and branching. Based on the notion that axons do not express functional levels of Coronin-1 prior to final target innervation, we developed an in vitro model for axon growth and branching along intermediate targets using Coro1a -/- neurons grown in NT3. We found that, similar to NGF-TrkA, NT3-TrkA is capable of inducing MAPK and PI3K in the presence or absence of Coronin-1. However, unlike NGF, NT3 does not induce calcium release from intracellular stores. Using a combination of pharmacology, knockout neurons and in vitro functional assays, we suggest that the NT3-TrkA complex uses Ras/MAPK and/or PI3K-AKT signaling to induce axon growth and inhibit axon branching along intermediate targets. However, in the presence of Coronin-1, these signaling pathways lose their ability to impact NT3 dependent axon growth or branching. This is consistent with a role for Coronin-1 as a molecular switch for axon behavior and suggests that Coronin-1 suppresses NT3 dependent axon behavior. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Renal sympathetic denervation: MDCT evaluation of the renal arteries.

    LENUS (Irish Health Repository)

    Hutchinson, Barry D

    2013-08-01

    Percutaneous transluminal renal sympathetic denervation is a new treatment of refractory systemic hypertension. The purpose of this study was to assess the clinical utility of MDCT to evaluate the anatomic configuration of the renal arteries in the context of renal sympathetic denervation.

  18. The Effect of Sympathetic Antagonists on the Antidepressant Action ...

    African Journals Online (AJOL)

    Alprazolam is an anti-anxiety drug shown to be effective in the treatment of depression. In this study, the effect of sympathetic receptor antagonists on alprazolam–induced antidepressant action was studied using a mouse model of forced swimming behavioral despair. The interaction of three sympathetic receptor ...

  19. Elevated mRNA-levels of distinct mitochondrial and plasma membrane Ca2+ transporters in individual hypoglossal motor neurons of endstage SOD1 transgenic mice.

    Directory of Open Access Journals (Sweden)

    Tobias eMühling

    2014-11-01

    Full Text Available Disturbances in Ca2+ homeostasis and mitochondrial dysfunction have emerged as major pathogenic features in familial and sporadic forms of Amyotrophic Lateral Sclerosis (ALS, a fatal degenerative motor neuron disease. However, the distinct molecular ALS-pathology remains unclear. Recently, an activity-dependent Ca2+ homeostasis deficit, selectively in highly vulnerable cholinergic motor neurons in the hypoglossal nucleus (hMNs from a common ALS mouse model, endstage superoxide dismutase SOD1G93A transgenic mice, was described. This functional deficit was defined by a reduced hMN mitochondrial Ca2+ uptake capacity and elevated Ca2+ extrusion across the plasma membrane. To address the underlying molecular mechanisms, here we quantified mRNA-levels of respective potential mitochondrial and plasma membrane Ca2+ transporters in individual, choline-acetyltransferase (ChAT positive hMNs from wildtype (WT and endstage SOD1G93A mice, by combining UV laser microdissection with RT-qPCR techniques, and specific data normalization. As ChAT cDNA levels as well as cDNA and genomic DNA levels of the mitochondrially encoded NADH dehydrogenase ND1 were not different between hMNs from WT and endstage SOD1G93A mice, these genes were used to normalize hMN-specific mRNA-levels of plasma membrane and mitochondrial Ca2+ transporters, respectively. We detected about 2-fold higher levels of the mitochondrial Ca2+ transporters MCU/MICU1, Letm1 and UCP2 in remaining hMNs from endstage SOD1G93A mice. These higher expression-levels of mitochondrial Ca2+ transporters in individual hMNs were not associated with a respective increase in number of mitochondrial genomes, as evident from hMN specific ND1 DNA quantification. Normalized mRNA-levels for the plasma membrane Na2+/Ca2+exchanger NCX1 was also about 2-fold higher in hMNs from SOD1G93A mice. Thus, pharmacological stimulation of Ca2+ transporters in highly vulnerable hMNs might offer a novel neuroprotective strategy for ALS.

  20. Dopamine-induced apoptosis in human neuronal cells: inhibition by nucleic acides antisense to the dopamine transporter

    International Nuclear Information System (INIS)

    Porat, S.; Gabbay, M.; Tauber, M.; Ratovitski, T.; Blinder, E.; Simantov, R.

    1996-01-01

    Human neuroblastoma NMB cells take up [ 3 H]dopamine in a selective manner indicating that dopamine transporters are responsible for this uptake. These cells were therefore used as a model to study dopamine neurotoxicity, and to elucidate the role of dopamine transporters in controlling cell death. Treatment with 0.05-0.4 mM dopamine changed cells' morphology within 4 h, accompanied by retraction of processes, shrinkage, apoptosis-like atrophy, accumulation of apoptotic particles, DNA fragmentation and cell death. Cycloheximide inhibited dopamine's effect, suggesting that induction of apoptosis by dopamine was dependent upon protein synthesis. Dopamine cytotoxicity, monitored morphologically by flow cytometric analysis, and by lactate dehydrogenase released, was blocked by cocaine but not by the noradrenaline and serotonin uptake blockers desimipramine and imipramine, respectively. Attempting to inhibit dopamine transport and toxicity in a drug-free and highly selective way, three 18-mer dopamine transporter antisense phosphorothioate oligonucleotides (numbers 1, 2 and 3) and a new plasmid vector expressing the entire rat dopamine transporter complementary DNA in the antisense orientation were prepared and tested. Antisense phosphorothioate oligonucleotide 3 inhibited [ 3 H]dopamine uptake in a time- and dose-dependent manner. Likewise, transient transfection of NMB cells with the plasmid expressing dopamine transporter complementary DNA in the antisense orientation partially blocked [ 3 H]dopamine uptake. Antisense phosphorothioate oligonucleotide 3 also decreased, dose-dependently, the toxic effect of dopamine and 6-hydroxydopamine. Western blot analysis with newly prepared anti-human dopamine transporter antibodies showed that antisense phosphorothioate oligonucleotide 3 decreased the transporter protein level. These studies contribute to better understand the mechanism of dopamine-induced apoptosis and neurotoxicity. (Copyright (c) 1996 Elsevier Science B

  1. Orexins control intestinal glucose transport by distinct neuronal, endocrine and direct epithelial pathways. : Orexins regulate intestinal glucose absorption

    OpenAIRE

    Ducroc, Robert; Voisin, Thierry; El Firar, Aadil; Laburthe, Marc

    2007-01-01

    International audience; Objective : Orexins are neuropeptides involved in energy homeostasis. We investigated the effect of orexin A (OxA) and OxB on intestinal glucose transport in the rat. Research Design and Methods : Injection of orexins led to a decrease in the blood glucose level in OGTT. Effects of orexins on glucose entry were analysed in Ussing chamber using the Na+-dependent increase in short-circuit current to quantify jejunal glucose transport. Results & Conclusions : The rapid an...

  2. Sympathetic block by metal clips may be a reversible operation

    DEFF Research Database (Denmark)

    Thomsen, Lars L; Mikkelsen, Rasmus T; Derejko, Miroslawa

    2014-01-01

    , but the question of reversibility remains controversial. Two recent experimental studies found severe histological signs of nerve damage 4-6 weeks after clip removal, but they only used conventional histopathological staining methods. METHODS: Thoracoscopic clipping of the sympathetic trunk was performed in adult...... the sympathetic chain vary tremendously. Most surgeons transect or resect the sympathetic chain, but application of a metal clip that blocks transmission of nerve impulses in the sympathetic chain is used increasingly worldwide. This approach offers potential reversibility if patients regret surgery...... suggests in theory that application of metal clips to the sympathetic chain is a reversible procedure if only the observation period is prolonged. Further studies with longer periods between application and removal as well as investigations of nerve conduction should be encouraged, because we do not know...

  3. Differential Toxicities of Intraneurally Injected Mercuric Chloride for Sympathetic and Somatic Motor Fibers: An Ultrastructural Study

    Directory of Open Access Journals (Sweden)

    Shih-Jung Cheng

    2011-02-01

    Conclusion: This study demonstrated an undue susceptibility of sympathetic fibers to mercury intoxication. The mechanisms that underlie the selective reaction of sympathetic fibers to mercury warrant further investigation.

  4. Mature neurons dynamically restrict apoptosis via redundant premitochondrial brakes.

    Science.gov (United States)

    Annis, Ryan P; Swahari, Vijay; Nakamura, Ayumi; Xie, Alison X; Hammond, Scott M; Deshmukh, Mohanish

    2016-12-01

    Apoptotic cell death is critical for the early development of the nervous system, but once the nervous system is established, the apoptotic pathway becomes highly restricted in mature neurons. However, the mechanisms underlying this increased resistance to apoptosis in these mature neurons are not completely understood. We have previously found that members of the miR-29 family of microRNAs (miRNAs) are induced with neuronal maturation and that overexpression of miR-29 was sufficient to restrict apoptosis in neurons. To determine whether endogenous miR-29 alone was responsible for the inhibition of cytochrome c release in mature neurons, we examined the status of the apoptotic pathway in sympathetic neurons deficient for all three miR-29 family members. Unexpectedly, we found that the apoptotic pathway remained largely restricted in miR-29-deficient mature neurons. We therefore probed for additional mechanisms by which mature neurons resist apoptosis. We identify miR-24 as another miRNA that is upregulated in the maturing cerebellum and sympathetic neurons that can act redundantly with miR-29 by targeting a similar repertoire of prodeath BH3-only genes. Overall, our results reveal that mature neurons engage multiple redundant brakes to restrict the apoptotic pathway and ensure their long-term survival. © 2016 Federation of European Biochemical Societies.

  5. Identification of neurons that express ghrelin receptors in autonomic pathways originating from the spinal cord.

    Science.gov (United States)

    Furness, John B; Cho, Hyun-Jung; Hunne, Billie; Hirayama, Haruko; Callaghan, Brid P; Lomax, Alan E; Brock, James A

    2012-06-01

    Functional studies have shown that subsets of autonomic preganglionic neurons respond to ghrelin and ghrelin mimetics and in situ hybridisation has revealed receptor gene expression in the cell bodies of some preganglionic neurons. Our present goal has been to determine which preganglionic neurons express ghrelin receptors by using mice expressing enhanced green fluorescent protein (EGFP) under the control of the promoter for the ghrelin receptor (also called growth hormone secretagogue receptor). The retrograde tracer Fast Blue was injected into target organs of reporter mice under anaesthesia to identify specific functional subsets of postganglionic sympathetic neurons. Cryo-sections were immunohistochemically stained by using anti-EGFP and antibodies to neuronal markers. EGFP was detected in nerve terminal varicosities in all sympathetic chain, prevertebral and pelvic ganglia and in the adrenal medulla. Non-varicose fibres associated with the ganglia were also immunoreactive. No postganglionic cell bodies contained EGFP. In sympathetic chain ganglia, most neurons were surrounded by EGFP-positive terminals. In the stellate ganglion, neurons with choline acetyltransferase immunoreactivity, some being sudomotor neurons, lacked surrounding ghrelin-receptor-expressing terminals, although these terminals were found around other neurons. In the superior cervical ganglion, the ghrelin receptor terminals innervated subgroups of neurons including neuropeptide Y (NPY)-immunoreactive neurons that projected to the anterior chamber of the eye. However, large NPY-negative neurons projecting to the acini of the submaxillary gland were not innervated by EGFP-positive varicosities. In the celiaco-superior mesenteric ganglion, almost all neurons were surrounded by positive terminals but the VIP-immunoreactive terminals of intestinofugal neurons were EGFP-negative. The pelvic ganglia contained groups of neurons without ghrelin receptor terminal innervation and other groups with

  6. Reflex sympathetic dystrophy syndrome: MR imaging study

    International Nuclear Information System (INIS)

    Masciocchi, C.; Fascetti, E.; Bonanni, G.; Calvisi, V.; Buoni, C.; Passariello, R.

    1987-01-01

    Reflex sympathetic dystrophy syndrome (RSDS) is characterized by pain, swelling, and limitation of motion. The etiology and pathophysiology mechanism have not yet been identified. We considered eight patients with clinical signs of RSDS, in five cases located at the knee joint and in three cases in the hip. In all cases conventional radiography and radionuclide bone scanning were performed before MR imaging. Conventional radiography was negative in three cases while scintigraphy demonstrated the lesion in all patients. MR imaging showed an area of low intensity signal on T1-weighted scans and an increased signal intensity on T2-weighted images. This area is located at the bone marrow and its regular and homogeneous. This specific finding on MR images is due to reflect edema by hyperemia of the bone marrow. The MR imaging diagnosis was confirmed on clinical and radiological follow-up. MR imaging can have a role in the differential diagnosis when other studies are nondiagnostic or nonspecific for RSDS

  7. Sympathetic cooling of nanospheres with cold atoms

    Science.gov (United States)

    Montoya, Cris; Witherspoon, Apryl; Ranjit, Gambhir; Casey, Kirsten; Kitching, John; Geraci, Andrew

    2016-05-01

    Ground state cooling of mesoscopic mechanical structures could enable new hybrid quantum systems where mechanical oscillators act as transducers. Such systems could provide coupling between photons, spins and charges via phonons. It has recently been shown theoretically that optically trapped dielectric nanospheres could reach the ground state via sympathetic cooling with trapped cold atoms. This technique can be beneficial in cases where cryogenic operation of the oscillator is not practical. We describe experimental advances towards coupling an optically levitated dielectric nanosphere to a gas of cold Rubidium atoms. The sphere and the cold atoms are in separate vacuum chambers and are coupled using a one-dimensional optical lattice. This work is partially supported by NSF, Grant Nos. PHY-1205994,PHY-1506431.

  8. Loss of Sympathetic Nerves in Spleens from Patients with End Stage Sepsis

    Directory of Open Access Journals (Sweden)

    Donald B. Hoover

    2017-12-01

    Full Text Available The spleen is an important site for central regulation of immune function by noradrenergic sympathetic nerves, but little is known about this major region of neuroimmune communication in humans. Experimental studies using animal models have established that sympathetic innervation of the spleen is essential for cholinergic anti-inflammatory responses evoked by vagal nerve stimulation, and clinical studies are evaluating this approach for treating inflammatory diseases. Most data on sympathetic nerves in spleen derive from rodent studies, and this work has established that remodeling of sympathetic innervation can occur during inflammation. However, little is known about the effects of sepsis on spleen innervation. Our primary goals were to (i localize noradrenergic nerves in human spleen by immunohistochemistry for tyrosine hydroxylase (TH, a specific noradrenergic marker, (ii determine if nerves occur in close apposition to leukocytes, and (iii determine if splenic sympathetic innervation is altered in patients who died from end stage sepsis. Staining for vesicular acetylcholine transporter (VAChT was done to screen for cholinergic nerves. Archived paraffin tissue blocks were used. Control samples were obtained from trauma patients or patients who died after hemorrhagic stroke. TH + nerves were associated with arteries and arterioles in all control spleens, occurring in bundles or as nerve fibers. Individual TH + nerve fibers entered the perivascular region where some appeared in close apposition to leukocytes. In marked contrast, spleens from half of the septic patients lacked TH + nerves fibers and the average abundance of TH + nerves for the septic group was only 16% of that for the control group (control: 0.272 ± 0.060% area, n = 6; sepsis: 0.043 ± 0.026% area, n = 8; P < 0.005. All spleens lacked cholinergic innervation. Our results provide definitive evidence for the distribution of noradrenergic

  9. Neuronal degeneration in autonomic nervous system of Dystonia musculorum mice

    Directory of Open Access Journals (Sweden)

    Liu Kang-Jen

    2011-01-01

    Full Text Available Abstract Background Dystonia musculorum (dt is an autosomal recessive hereditary neuropathy with a characteristic uncoordinated movement and is caused by a defect in the bullous pemphigoid antigen 1 (BPAG1 gene. The neural isoform of BPAG1 is expressed in various neurons, including those in the central and peripheral nerve systems of mice. However, most previous studies on neuronal degeneration in BPAG1-deficient mice focused on peripheral sensory neurons and only limited investigation of the autonomic system has been conducted. Methods In this study, patterns of nerve innervation in cutaneous and iridial tissues were examined using general neuronal marker protein gene product 9.5 via immunohistochemistry. To perform quantitative analysis of the autonomic neuronal number, neurons within the lumbar sympathetic and parasympathetic ciliary ganglia were calculated. In addition, autonomic neurons were cultured from embryonic dt/dt mutants to elucidate degenerative patterns in vitro. Distribution patterns of neuronal intermediate filaments in cultured autonomic neurons were thoroughly studied under immunocytochemistry and conventional electron microscopy. Results Our immunohistochemistry results indicate that peripheral sensory nerves and autonomic innervation of sweat glands and irises dominated degeneration in dt/dt mice. Quantitative results confirmed that the number of neurons was significantly decreased in the lumbar sympathetic ganglia as well as in the parasympathetic ciliary ganglia of dt/dt mice compared with those of wild-type mice. We also observed that the neuronal intermediate filaments were aggregated abnormally in cultured autonomic neurons from dt/dt embryos. Conclusions These results suggest that a deficiency in the cytoskeletal linker BPAG1 is responsible for dominant sensory nerve degeneration and severe autonomic degeneration in dt/dt mice. Additionally, abnormally aggregated neuronal intermediate filaments may participate in

  10. Renal sympathetic nerve ablation for treatment-resistant hypertension

    Science.gov (United States)

    Krum, Henry; Schlaich, Markus; Sobotka, Paul

    2013-01-01

    Hypertension is a major risk factor for increased cardiovascular events with accelerated sympathetic nerve activity implicated in the pathogenesis and progression of disease. Blood pressure is not adequately controlled in many patients, despite the availability of effective pharmacotherapy. Novel procedure- as well as device-based strategies, such as percutaneous renal sympathetic nerve denervation, have been developed to improve blood pressure in these refractory patients. Renal sympathetic denervation not only reduces blood pressure but also renal as well as systemic sympathetic nerve activity in such patients. The reduction in blood pressure appears to be sustained over 3 years after the procedure, which suggests absence of re-innervation of renal sympathetic nerves. Safety appears to be adequate. This approach may also have potential in other disorders associated with enhanced sympathetic nerve activity such as congestive heart failure, chronic kidney disease and metabolic syndrome. This review will focus on the current status of percutaneous renal sympathetic nerve denervation, clinical efficacy and safety outcomes and prospects beyond refractory hypertension. PMID:23819768

  11. HIF2A and IGF2 Expression Correlates in Human Neuroblastoma Cells and Normal Immature Sympathetic Neuroblasts

    Directory of Open Access Journals (Sweden)

    Sofie Mohlin

    2013-03-01

    Full Text Available During normal sympathetic nervous system (SNS development, cells of the ganglionic lineage can malignantly transform and develop into the childhood tumor neuroblastoma. Hypoxia-inducible transcription factors (HIFs mediate cellular responses during normal development and are central in the adaptation to oxygen shortage. HIFs are also implicated in the progression of several cancer forms, and high HIF-2α expression correlates with disseminated disease and poor outcome in neuroblastoma. During normal SNS development, HIF2A is transiently expressed in neuroblasts and chromaffin cells. SNS cells can, during development, be distinguished by distinct gene expression patterns, and insulin-like growth factor 2 (IGF2 is a marker of sympathetic chromaffin cells, whereas sympathetic neuroblasts lack IGF2 expression. Despite the neuronal derivation of neuroblastomas, we show that neuroblastoma cell lines and specimens express IGF2 and that expression of HIF2A and IGF2 correlates, with the strongest correlation in high-stage tumors. In neuroblastoma, both IGF2 and HIF2A are hypoxia-driven and knocking down IGF2 at hypoxia resulted in downregulated HIF2A levels. HIF-2α and IGF2 were strongly expressed in subsets of immature neuroblastoma cells, suggesting that these two genes could be co-expressed also at early stages of SNS development. We show that IGF2 is indeed expressed in sympathetic chain ganglia at embryonic week 6.5, a developmental stage when HIF-2α is present. These findings provide a rationale for the unexpected IGF2 expression in neuroblastomas and might suggest that IGF2 and HIF2A positive neuroblastoma cells are arrested at an embryonic differentiation stage corresponding to the stage when sympathetic chain ganglia begins to coalesce.

  12. Role of the rostral ventrolateral medulla (RVLM) in the patterning of vestibular system influences on sympathetic nervous system outflow to the upper and lower body.

    Science.gov (United States)

    Sugiyama, Yoichiro; Suzuki, Takeshi; Yates, Bill J

    2011-05-01

    Research on animal models as well as human subjects has demonstrated that the vestibular system contributes to regulating the distribution of blood in the body through effects on the sympathetic nervous system. Elimination of vestibular inputs results in increased blood flow to the hindlimbs during vestibular stimulation, because it attenuates the increase in vascular resistance that ordinarily occurs in the lower body during head-up tilts. Additionally, the changes in vascular resistance produced by vestibular stimulation differ between body regions. Electrical stimulation of vestibular afferents produces an inhibition of most hindlimb vasoconstrictor fibers and a decrease in hindlimb vascular resistance, but an initial excitation of most upper body vasoconstrictor fibers accompanied by an increase in upper body vascular resistance. The present study tested the hypothesis that neurons in the principal vasomotor region of the brainstem, the rostral ventrolateral medulla (RVLM), whose projections extended past the T10 segment, to spinal levels containing sympathetic preganglionic neurons regulating lower body blood flow, respond differently to electrical stimulation of the vestibular nerve than RVLM neurons whose axons terminate rostral to T10. Contrary to our hypothesis, the majority of RVLM neurons were excited by vestibular stimulation, despite their level of projection in the spinal cord. These findings indicate that the RVLM is not solely responsible for establishing the patterning of vestibular-sympathetic responses. This patterning apparently requires the integration by spinal circuitry of labyrinthine signals transmitted from the brainstem, likely from regions in addition to the RVLM.

  13. Exposure to a high-fat diet during development alters leptin and ghrelin sensitivity and elevates renal sympathetic nerve activity and arterial pressure in rabbits.

    Science.gov (United States)

    Prior, Larissa J; Davern, Pamela J; Burke, Sandra L; Lim, Kyungjoon; Armitage, James A; Head, Geoffrey A

    2014-02-01

    Exposure to maternal obesity or a maternal diet rich in fat during development may have adverse outcomes in offspring, such as the development of obesity and hypertension. The present study examined the effect of a maternal high-fat diet (m-HFD) on offspring blood pressure and renal sympathetic nerve activity, responses to stress, and sensitivity to central administration of leptin and ghrelin. Offspring of New Zealand white rabbits fed a 13% HFD were slightly heavier than offspring from mothers fed a 4% maternal normal fat diet (Pfat pad mass (P=0.015). Mean arterial pressure, heart rate, and renal sympathetic nerve activity at 4 months of age were 7%, 7%, and 24% greater, respectively (Pfat diet rabbits, and the renal sympathetic nerve activity response to airjet stress was enhanced in the m-HFD group. m-HFD offspring had markedly elevated pressor and renal sympathetic nerve activity responses to intracerebroventricular leptin (5-100 µg) and enhanced sympathetic responses to intracerebroventricular ghrelin (1-5 nmol). In contrast, there was resistance to the anorexic effects of intracerebroventricular leptin and less neuronal activation as detected by Fos immunohistochemistry in the arcuate (-57%; Pfat diet rabbits. We conclude that offspring from mothers consuming an HFD exhibit an adverse cardiovascular profile in adulthood because of altered central hypothalamic sensitivity to leptin and ghrelin.

  14. Sympathetic arousal as a marker of chronicity in childhood stuttering.

    Science.gov (United States)

    Zengin-Bolatkale, Hatun; Conture, Edward G; Walden, Tedra A; Jones, Robin M

    2018-01-01

    This study investigated whether sympathetic activity during a stressful speaking task was an early marker for stuttering chronicity. Participants were 9 children with persisting stuttering, 23 children who recovered, and 17 children who do not stutter. Participants performed a stress-inducing picture-naming task and skin conductance was measured across three time points. Findings indicated that at the initial time point, children with persisting stuttering exhibited higher sympathetic arousal during the stressful speaking task than children whose stuttering recovered. Findings are taken to suggest that sympathetic activity may be an early marker of heightened risk for chronic stuttering.

  15. Intracranial Pressure Is a Determinant of Sympathetic Activity

    Directory of Open Access Journals (Sweden)

    Eric A. Schmidt

    2018-02-01

    Full Text Available Intracranial pressure (ICP is the pressure within the cranium. ICP rise compresses brain vessels and reduces cerebral blood delivery. Massive ICP rise leads to cerebral ischemia, but it is also known to produce hypertension, bradycardia and respiratory irregularities due to a sympatho-adrenal mechanism termed Cushing response. One still unresolved question is whether the Cushing response is a non-synaptic acute brainstem ischemic mechanism or part of a larger physiological reflex for arterial blood pressure control and homeostasis regulation. We hypothesize that changes in ICP modulates sympathetic activity. Thus, modest ICP increase and decrease were achieved in mice and patients with respectively intra-ventricular and lumbar fluid infusion. Sympathetic activity was gauged directly by microneurography, recording renal sympathetic nerve activity in mice and muscle sympathetic nerve activity in patients, and gauged indirectly in both species by heart-rate variability analysis. In mice (n = 15, renal sympathetic activity increased from 29.9 ± 4.0 bursts.s−1 (baseline ICP 6.6 ± 0.7 mmHg to 45.7 ± 6.4 bursts.s−1 (plateau ICP 38.6 ± 1.0 mmHg and decreased to 34.8 ± 5.6 bursts.s−1 (post-infusion ICP 9.1 ± 0.8 mmHg. In patients (n = 10, muscle sympathetic activity increased from 51.2 ± 2.5 bursts.min−1 (baseline ICP 8.3 ± 1.0 mmHg to 66.7 ± 2.9 bursts.min−1 (plateau ICP 25 ± 0.3 mmHg and decreased to 58.8 ± 2.6 bursts.min−1 (post-infusion ICP 14.8 ± 0.9 mmHg. In patients 7 mmHg ICP rise significantly increases sympathetic activity by 17%. Heart-rate variability analysis demonstrated a significant vagal withdrawal during the ICP rise, in accordance with the microneurography findings. Mice and human results are alike. We demonstrate in animal and human that ICP is a reversible determinant of efferent sympathetic outflow, even at relatively low ICP levels. ICP is a biophysical stress related to the forces within the brain. But ICP

  16. Influence of acute treatment with sibutramine on the sympathetic neurotransmission of the young rat vas deferens.

    Science.gov (United States)

    de Souza, Bruno Palmieri; da Silva, Edilson Dantas; Jurkiewicz, Aron; Jurkiewicz, Neide Hyppolito

    2014-09-05

    The effects of acute treatment with sibutramine on the peripheral sympathetic neurotransmission in vas deferens of young rats were still not evaluated. Therefore, we carried out this study in order to verify the effects of acute sibutramine treatment on the neuronal- and exogenous agonist-induced contractions of the young rat vas deferens. Young 45-day-old male Wistar rats were pretreated with sibutramine 6 mg/kg and after 4h the vas deferens was used for experiment. The acute treatment with sibutramine was able to increase the potency (pD2) of noradrenaline and phenylephrine. Moreover, the efficacy (Emax) of noradrenaline was increased while the efficacy of serotonin and nicotine were decreased. The maximum effect induced by a single concentration of tyramine was diminished in the vas deferens from treated group. Moreover, the leftward shift of the noradrenaline curves promoted by uptake blockers (cocaine and corticosterone) and β-adrenoceptor antagonist (propranolol) was reduced in the vas deferens of treated group. The initial phasic and secondary tonic components of the neuronal-evoked contractions of vas deferens from treated group at the frequencies of 2 Hz were decreased. Moreover, only the initial phasic component at 5 Hz was diminished by the acute treatment with sibutramine. In conclusion, we showed that the acute treatment with sibutramine in young rats was able to affect the peripheral sympathetic nervous system by inhibition of noradrenaline uptake and reduction of the neuronal content of this neurotransmitter, leading to an enhancement of vas deferens sensitivity to noradrenaline. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. Atypical dopamine transporter inhibitors R-modafinil and JHW 007 differentially affect D2 autoreceptor neurotransmission and the firing rate of midbrain dopamine neurons.

    Science.gov (United States)

    Avelar, Alicia J; Cao, Jianjing; Newman, Amy Hauck; Beckstead, Michael J

    2017-09-01

    Abuse of psychostimulants like cocaine that inhibit dopamine (DA) reuptake through the dopamine transporter (DAT) represents a major public health issue, however FDA-approved pharmacotherapies have yet to be developed. Recently a class of ligands termed "atypical DAT inhibitors" has gained attention due to their range of effectiveness in increasing extracellular DA levels without demonstrating significant abuse liability. These compounds not only hold promise as therapeutic agents to treat stimulant use disorders but also as experimental tools to improve our understanding of DAT function. Here we used patch clamp electrophysiology in mouse brain slices to explore the effects of two atypical DAT inhibitors (R-modafinil and JHW 007) on the physiology of single DA neurons in the substantia nigra and ventral tegmental area. Despite their commonalities of being DAT inhibitors that lack cocaine-like behavioral profiles, these compounds exhibited surprisingly divergent cellular effects. Similar to cocaine, R-modafinil slowed DA neuron firing in a D2 receptor-dependent manner and rapidly enhanced the amplitude and duration of D2 receptor-mediated currents in the midbrain. In contrast, JHW 007 exhibited little effect on firing, slow DAT blockade, and an unexpected inhibition of D2 receptor-mediated currents that may be due to direct D2 receptor antagonism. Furthermore, pretreatment with JHW 007 blunted the cellular effects of cocaine, suggesting that it may be valuable to investigate similar DAT inhibitors as potential therapeutic agents. Further exploration of these and other atypical DAT inhibitors may reveal important cellular effects of compounds that will have potential as pharmacotherapies for treating cocaine use disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Evidence that BDNF regulates heart rate by a mechanism involving increased brainstem parasympathetic neuron excitability

    OpenAIRE

    Wan, Ruiqian; Weigand, Letitia A.; Bateman, Ryan; Griffioen, Kathleen; Mendelowitz, David; Mattson, Mark P.

    2014-01-01

    Autonomic control of heart rate is mediated by cardioinhibitory parasympathetic cholinergic neurons located in the brainstem and stimulatory sympathetic noradrenergic neurons. During embryonic development the survival and cholinergic phenotype of brainstem autonomic neurons is promoted by brain-derived neurotrophic factor (BDNF). We now provide evidence that BDNF regulates heart rate by a mechanism involving increased brainstem cardioinhibitory parasympathetic activity. Mice with a BDNF haplo...

  19. Autonomic nervous system dysfunction in children with severe tetanus: dissociation of cardiac and vascular sympathetic control

    Directory of Open Access Journals (Sweden)

    Mazzei de Davila C.A.

    2003-01-01

    Full Text Available The medical records of ten pediatric patients with a clinical diagnosis of tetanus were reviewed retrospectively. The heart rate and blood pressure of all tetanus patients were measured noninvasively every hour during the first two weeks of hospitalization. Six of ten tetanus patients presented clinical evidence of sympathetic hyperactivity (group A and were compared with a control group consisting of four children who required mechanical ventilation for diseases other than tetanus (group B. Heart rate and blood pressure simultaneously and progressively increased to a maximum by day 7. The increase over baseline was 43.70 ± 11.77 bpm (mean ± SD for heart rate (P<0.01 and 38.60 ± 26.40 mmHg for blood pressure (P<0.01. These values were higher and significantly different from those of the control group (group B at day 6, which had an average heart rate increase over baseline of 19.35 ± 12.26 bpm (P<0.05 and blood pressure of 10.24 ± 13.30 mmHg (P<0.05. By the end of the second week of hospitalization, in group A the increase of systolic blood pressure over baseline had diminished to 9.60 ± 15.37 mmHg (P<0.05, but the heart rate continued to be elevated (27.80 ± 33.92 bpm, P = NS, when compared to day 7 maximal values. The dissociation of these two cardiovascular variables at the end of the second week of hospitalization suggests the presence of asymmetric cardiac and vascular sympathetic control. One possible explanation for these observations is a selective and delayed action of tetanus toxin on the inhibitory neurons which control sympathetic outflow to the heart.

  20. Muscle afferent receptors engaged in augmented sympathetic responsiveness in peripheral artery disease

    Directory of Open Access Journals (Sweden)

    Jianhua eLi

    2012-07-01

    Full Text Available The exercise pressor reflex (EPR is a neural control mechanism responsible for the cardiovascular responses to exercise. As exercise is initiated, thin fiber muscle afferent nerves are activated by mechanical and metabolic stimuli arising in the contracting muscles. This leads to reflex increases in arterial blood pressure and heart rate primarily through activation of sympathetic nerve activity (SNA. Studies of humans and animals have indicated that the EPR is exaggerated in a number of cardiovascular diseases. For the last several years, studies have specifically employed a rodent model to examine the mechanisms at receptor and cellular levels by which responses of SNA and blood pressure to static exercise are heightened in peripheral artery disease (PAD, one of the most common cardiovascular disorders. A rat model of this disease has well been established. Specifically, femoral artery occlusion is used to study intermittent claudication that is observed in human PAD. The receptors on thin fiber muscle afferents that are engaged in this disease include transient receptor potential vanilloid type 1 (TRPV1, purinergic P2X and acid sensing ion channel (ASIC. The role played by nerve growth factor (NGF in regulating those sensory receptors in the processing of amplified EPR was also investigated. The purpose of this review is to focus on a theme namely that PAD accentuates autonomic reflex responses to exercise and further address regulatory mechanisms leading to abnormal sympathetic responsiveness. This review will present some of recent results in regard with several receptors in muscle sensory neurons in contribution to augmented autonomic reflex responses in PAD. Review of the findings from recent studies would lead to a better understanding in integrated processing of sympathetic nervous system in PAD.

  1. Schwanomma From Cervical Sympathetic Chain Ganglion – A Rare Presentation

    Science.gov (United States)

    Asma, A. Affee

    2015-01-01

    Schwanommas arising from cervical sympathetic chain are tumours that are rare in occurrence. These lesions are usually difficult to differentiate from a vagal schwanomma and a carotid body tumour during the initial workup. In this report, a rarely seen huge cervical sympathetic chain schwanomma case with partial Horner’s syndrome is being presented in detail, which to our known knowledge, is one of the few cases reported in literature. PMID:26557566

  2. Sympathetic skin response evoked by laser skin stimulation

    OpenAIRE

    Rossi, P.; Truini, A.; Serrao, M.; Iannetti, G. D.; Parisi, L.; Pozzessere, G.; Cruccu, G.

    2002-01-01

    The objective of this study was to evoke sympathetic skin responses (SSRs) in healthy subjects using laser stimulation and to compare these responses with those induced by conventional electrical stimuli. Twenty healthy subjects were investigated. SSRs were obtained using electrical and laser stimuli delivered to the wrist controlateral to the recording site. The sympathetic sudomotor conduction velocity (SSFCV) was measured in 8 subjects by simultaneously recording the SSR from the hand and ...

  3. Sympathetic Responses to Central Hypovolemia: New Insights from Microneurographic Recordings

    Science.gov (United States)

    2012-04-26

    Surgical Research, Fort Sam Houston, TX, USA 2 Department of Health and Kinesiology , The University of Texas at San Antonio, San Antonio, TX, USA Edited...suggested that this phenomenon may represent sympathetic baroreflex deafferentation (Cooke et al., 2009), as the fused bursts observed during intense ...Convertino, V. A. (2009). Muscle sympathetic nerve activity during intense lower body negative pressure to presyn- cope in humans. J. Physiol. (Lond

  4. Schwanomma From Cervical Sympathetic Chain Ganglion - A Rare Presentation.

    Science.gov (United States)

    Asma, A Affee; Kannah, E

    2015-10-01

    Schwanommas arising from cervical sympathetic chain are tumours that are rare in occurrence. These lesions are usually difficult to differentiate from a vagal schwanomma and a carotid body tumour during the initial workup. In this report, a rarely seen huge cervical sympathetic chain schwanomma case with partial Horner's syndrome is being presented in detail, which to our known knowledge, is one of the few cases reported in literature.

  5. Vestibular control of sympathetic activity. An otolith-sympathetic reflex in humans.

    Science.gov (United States)

    Kaufmann, H; Biaggioni, I; Voustianiouk, A; Diedrich, A; Costa, F; Clarke, R; Gizzi, M; Raphan, T; Cohen, B

    2002-04-01

    It has been proposed that a vestibular reflex originating in the otolith organs and other body graviceptors modulates sympathetic activity during changes in posture with regard to gravity. To test this hypothesis, we selectively stimulated otolith and body graviceptors sinusoidally along different head axes in the coronal plane with off-vertical axis rotation (OVAR) and recorded sympathetic efferent activity in the peroneal nerve (muscle sympathetic nerve activity, MSNA), blood pressure, heart rate, and respiratory rate. All parameters were entrained during OVAR at the frequency of rotation, with MSNA increasing in nose-up positions during forward linear acceleration and decreasing when nose-down. MSNA was correlated closely with blood pressure when subjects were within +/-90 degrees of nose-down positions with a delay of 1.4 s, the normal latency of baroreflex-driven changes in MSNA. Thus, in the nose-down position, MSNA was probably driven by baroreflex afferents. In contrast, when subjects were within +/-45 degrees of the nose-up position, i.e., when positive linear acceleration was maximal along the naso-ocipital axis, MSNA was closely related to gravitational acceleration at a latency of 0.4 s. This delay is too short for MSNA changes to be mediated by the baroreflex, but it is compatible with the delay of a response originating in the vestibular system. We postulate that a vestibulosympathetic reflex, probably originating mainly in the otolith organs, contributes to blood pressure maintenance during forward linear acceleration. Because of its short latency, this reflex may be one of the earliest mechanisms to sustain blood pressure upon standing.

  6. Sympathetic neural modulation of the immune system

    International Nuclear Information System (INIS)

    Madden, K.S.

    1989-01-01

    One route by which the central nervous system communicates with lymphoid organs in the periphery is through the sympathetic nervous system (SNS). To study SNS regulation of immune activity in vivo, selective removal of peripheral noradrenergic nerve fibers was achieved by administration of the neurotoxic drug, 6-hydroxydopamine (6-OHDA), to adult mice. To assess SNS influence on lymphocyte proliferation in vitro, uptake of 125 iododeoxyuridine ( 125 IUdR), a DNA precursor, was measured following 6-OHDA treatment. Sympathectomy prior to epicutaneous immunization with TNCB did not alter draining lymph nodes (LN) cell proliferation, whereas 6-OHDA treatment before footpad immunization with KLH reduced DNA synthesis in popliteal LN by 50%. In mice which were not deliberately immunized, sympathectomy stimulated 125 IUdR uptake inguinal and axillary LN, spleen, and bone marrow. In vitro, these LN and spleen cells exhibited decreased proliferation responses to the T cell mitogen, concanavalin A (Con A), whereas lipopolysaccharide (LPS)-stimulated IgG secretion was enhanced. Studies examining 51 Cr-labeled lymphocyte trafficking to LN suggested that altered cell migration may play a part in sympathectomy-induced changes in LN cell function

  7. Bone mineral density in reflex sympathetic dystrophy

    International Nuclear Information System (INIS)

    Saghaphi, M.; Azarian, A.

    2002-01-01

    Objectives: Reflex Sympathetic Dystrophy (RSD) is a complex of symptoms that produce pain burning sensation, swelling, tenderness, autonomic and physical dysfunction in joint areas, particularly distal of a limb. Osteopenia or osteoporosis is an important finding that is produced gradually in involved limb. Three phase bone can scan help to diagnosis of RSD. The disease may be bilateral but is mostly unilateral. As it is believed that bone densitometry will show osteopenia more accurate than plain comparative radiographs of the involved limbs, we investigated in patients with RSD. Methods: During last three years, 8 patients with RSD were admitted. Bone mineral density was measured for 5 patients by DEXA method. The patients were 3 males and 2 females with age range of 20 to 48 years (mean 32 years). The involved areas were ankle and foot in 4, and wrist and hand in one patient. Results: Mean Bone Mineral Content (BMC) of 4 involved lower limbs were 475 +-73 grams comparing with 516+-72 grams of uninvolved limbs (p t h patient was not significant. conclusion: comparative bone mineral density in patients with RSD of the lower limbs contributes to more accurate diagnosis than plain radiographs

  8. Release of NPY in pig pancreas: Dual parasympathetic and sympathetic regulation

    International Nuclear Information System (INIS)

    Sheikh, S.P.; Holst, J.J.; Skak-Nielsen, T.; Knigge, U.; Warberg, J.; Theodorsson-Norheim, E.; Hoekfelt, T.; Lundberg, J.M.; Schwartz, T.W.

    1988-01-01

    Several lines of evidence have connected neuropeptide Y (NPY), a 36-residue polypeptide, to the sympathetic division of the autonomic nervous system. The authors studied the localization, the molecular characteristics, and the release of NPY and norepinephrine (NE) in the porcine pancreas. Immunohistochemical investigations revealed that NPY nerves around blood vessels were likely to be of adrenergic nature, whereas NPY-immunoreactive fibers close to exocrine and endocrine cells may originate from local ganglia also containing VIP (vasoactive intestinal peptide) and PHI (peptide histidine isoleucine). Electrical stimulation of the splanchnic nerve supply to the isolated perfused pig pancreas resulted in a corelease of NPY and NE into the venous effluent. Stimulation of the vagal nerves caused a sevenfold larger release of NPY without affecting the NE secretion. Characterization of the NPY immunoreactivity in the pancreatic tissue and in the venous effluent by gel filtration, high-performance liquid chromatography, and isoelectric focusing shoed that the immunoreactive NPY was indistinguishable from synthetic porcine NPY. It is concluded that, although NPY is associated with sympathetic perivascular neurons, the majority of the pancreatic NPY-containing nerve fibers are likely to belong to the parasympathetic division of the autonomic nervous system

  9. Sympathetic Neurotransmitters Modulate Osteoclastogenesis and Osteoclast Activity in the Context of Collagen-Induced Arthritis

    Science.gov (United States)

    Muschter, Dominique; Schäfer, Nicole; Stangl, Hubert; Straub, Rainer H.; Grässel, Susanne

    2015-01-01

    Excessive synovial osteoclastogenesis is a hallmark of rheumatoid arthritis (RA). Concomitantly, local synovial changes comprise neuronal components of the peripheral sympathetic nervous system. Here, we wanted to analyze if collagen-induced arthritis (CIA) alters bone marrow-derived macrophage (BMM) osteoclastogenesis and osteoclast activity, and how sympathetic neurotransmitters participate in this process. Therefore, BMMs from Dark Agouti rats at different CIA stages were differentiated into osteoclasts in vitro and osteoclast number, cathepsin K activity, matrix resorption and apoptosis were analyzed in the presence of acetylcholine (ACh), noradrenaline (NA) vasoactive intestinal peptide (VIP) and assay-dependent, adenylyl cyclase activator NKH477. We observed modulation of neurotransmitter receptor mRNA expression in CIA osteoclasts without affecting protein level. CIA stage-dependently altered marker gene expression associated with osteoclast differentiation and activity without affecting osteoclast number or activity. Neurotransmitter stimulation modulated osteoclast differentiation, apoptosis and activity. VIP, NA and adenylyl cyclase activator NKH477 inhibited cathepsin K activity and osteoclastogenesis (NKH477, 10-6M NA) whereas ACh mostly acted pro-osteoclastogenic. We conclude that CIA alone does not affect metabolism of in vitro generated osteoclasts whereas stimulation with NA, VIP plus specific activation of adenylyl cyclase induced anti-resorptive effects probably mediated via cAMP signaling. Contrary, we suggest pro-osteoclastogenic and pro-resorptive properties of ACh mediated via muscarinic receptors. PMID:26431344

  10. Sympathetic network drive during water deprivation does not increase respiratory or cardiac rhythmic sympathetic nerve activity.

    Science.gov (United States)

    Holbein, Walter W; Toney, Glenn M

    2013-06-15

    Effects of water deprivation on rhythmic bursting of sympathetic nerve activity (SNA) were investigated in anesthetized, bilaterally vagotomized, euhydrated (control) and 48-h water-deprived (WD) rats (n = 8/group). Control and WD rats had similar baseline values of mean arterial pressure, heart rate, end-tidal CO2, and central respiratory drive. Although integrated splanchnic SNA (sSNA) was greater in WD rats than controls (P analysis of respiratory rhythmic bursting of sSNA revealed that inspiratory rhythmic burst amplitude was actually smaller (P analysis revealed that water deprivation had no effect on either the amplitude or periodicity of the cardiac rhythmic oscillation of sSNA. Collectively, these data indicate that the increase of sSNA produced by water deprivation is not attributable to either increased respiratory or cardiac rhythmic burst discharge. Thus the sympathetic network response to acute water deprivation appears to differ from that of chronic sympathoexcitation in neurogenic forms of arterial hypertension, where increased respiratory rhythmic bursting of SNA and baroreflex adaptations have been reported.

  11. C1 neurons: the body's EMTs.

    Science.gov (United States)

    Guyenet, Patrice G; Stornetta, Ruth L; Bochorishvili, Genrieta; Depuy, Seth D; Burke, Peter G R; Abbott, Stephen B G

    2013-08-01

    The C1 neurons reside in the rostral and intermediate portions of the ventrolateral medulla (RVLM, IVLM). They use glutamate as a fast transmitter and synthesize catecholamines plus various neuropeptides. These neurons regulate the hypothalamic pituitary axis via direct projections to the paraventricular nucleus and regulate the autonomic nervous system via projections to sympathetic and parasympathetic preganglionic neurons. The presympathetic C1 cells, located in the RVLM, are probably organized in a roughly viscerotopic manner and most of them regulate the circulation. C1 cells are variously activated by hypoglycemia, infection or inflammation, hypoxia, nociception, and hypotension and contribute to most glucoprivic responses. C1 cells also stimulate breathing and activate brain stem noradrenergic neurons including the locus coeruleus. Based on the various effects attributed to the C1 cells, their axonal projections and what is currently known of their synaptic inputs, subsets of C1 cells appear to be differentially recruited by pain, hypoxia, infection/inflammation, hemorrhage, and hypoglycemia to produce a repertoire of stereotyped autonomic, metabolic, and neuroendocrine responses that help the organism survive physical injury and its associated cohort of acute infection, hypoxia, hypotension, and blood loss. C1 cells may also contribute to glucose and cardiovascular homeostasis in the absence of such physical stresses, and C1 cell hyperactivity may contribute to the increase in sympathetic nerve activity associated with diseases such as hypertension.

  12. C1 neurons: the body's EMTs

    Science.gov (United States)

    Stornetta, Ruth L.; Bochorishvili, Genrieta; DePuy, Seth D.; Burke, Peter G. R.; Abbott, Stephen B. G.

    2013-01-01

    The C1 neurons reside in the rostral and intermediate portions of the ventrolateral medulla (RVLM, IVLM). They use glutamate as a fast transmitter and synthesize catecholamines plus various neuropeptides. These neurons regulate the hypothalamic pituitary axis via direct projections to the paraventricular nucleus and regulate the autonomic nervous system via projections to sympathetic and parasympathetic preganglionic neurons. The presympathetic C1 cells, located in the RVLM, are probably organized in a roughly viscerotopic manner and most of them regulate the circulation. C1 cells are variously activated by hypoglycemia, infection or inflammation, hypoxia, nociception, and hypotension and contribute to most glucoprivic responses. C1 cells also stimulate breathing and activate brain stem noradrenergic neurons including the locus coeruleus. Based on the various effects attributed to the C1 cells, their axonal projections and what is currently known of their synaptic inputs, subsets of C1 cells appear to be differentially recruited by pain, hypoxia, infection/inflammation, hemorrhage, and hypoglycemia to produce a repertoire of stereotyped autonomic, metabolic, and neuroendocrine responses that help the organism survive physical injury and its associated cohort of acute infection, hypoxia, hypotension, and blood loss. C1 cells may also contribute to glucose and cardiovascular homeostasis in the absence of such physical stresses, and C1 cell hyperactivity may contribute to the increase in sympathetic nerve activity associated with diseases such as hypertension. PMID:23697799

  13. Electrophysiological evidence of increased glycine receptor-mediated phasic and tonic inhibition by blockade of glycine transporters in spinal superficial dorsal horn neurons of adult mice

    Directory of Open Access Journals (Sweden)

    Misa Oyama

    2017-03-01

    Full Text Available To understand the synaptic and/or extrasynaptic mechanisms underlying pain relief by blockade of glycine transporter subtypes GlyT1 and GlyT2, whole-cell recordings were made from dorsal horn neurons in spinal slices from adult mice, and the effects of NFPS and ALX-1393, selective GlyT1 and GlyT2 inhibitors, respectively, on phasic evoked or miniature glycinergic inhibitory postsynaptic currents (eIPSCs or mIPSCs were examined. NFPS and ALX-1393 prolonged the decay phase of eIPSCs without affecting their amplitude. In the presence of tetrodotoxin to record mIPSCs, NFPS and ALX-1393 induced a tonic inward current that was reversed by strychnine. Although NFPS had no statistically significant influences on mIPSCs, ALX-1393 significantly increased their frequency. We then further explored the role of GlyTs in the maintenance of glycinergic IPSCs. To facilitate vesicular release of glycine, repetitive high-frequency stimulation (HFS was applied at 10 Hz for 3 min during continuous recordings of eIPSCs at 0.1 Hz. Prominent suppression of eIPSCs was evident after HFS in the presence of ALX-1393, but not NFPS. Thus, it appears that phasic and tonic inhibition may contribute to the analgesic effects of GlyT inhibitors. However, reduced glycinergic inhibition due to impaired vesicular refilling could hamper the analgesic efficacy of GlyT2 inhibitors.

  14. Role of renal sympathetic nerve activity in prenatal programming of hypertension.

    Science.gov (United States)

    Baum, Michel

    2018-03-01

    Prenatal insults, such as maternal dietary protein deprivation and uteroplacental insufficiency, lead to small for gestational age (SGA) neonates. Epidemiological studies from many different parts of the world have shown that SGA neonates are at increased risk for hypertension and early death from cardiovascular disease as adults. Animal models, including prenatal administration of dexamethasone, uterine artery ligation and maternal dietary protein restriction, result in SGA neonates with fewer nephrons than controls. These models are discussed in this educational review, which provides evidence that prenatal insults lead to altered sodium transport in multiple nephron segments. The factors that could result in increased sodium transport are discussed, focusing on new information that there is increased renal sympathetic nerve activity that may be responsible for augmented renal tubular sodium transport. Renal denervation abrogates the hypertension in programmed rats but has no effect on control rats. Other potential factors that could cause hypertension in programmed rats, such as the renin-angiotensin system, are also discussed.

  15. Sympathetic influence on cerebral blood flow and metabolism during exercise in humans

    DEFF Research Database (Denmark)

    Seifert, Thomas; Secher, Niels H

    2011-01-01

    This review focuses on the possibility that autonomic activity influences cerebral blood flow (CBF) and metabolism during exercise in humans. Apart from cerebral autoregulation, the arterial carbon dioxide tension, and neuronal activation, it may be that the autonomic nervous system influences CBF...... perfusion and reduces the near-infrared determined cerebral oxygenation at rest, but not during exercise associated with an increased cerebral metabolic rate for oxygen (CMRO(2)), suggesting competition between CMRO(2) and sympathetic control of CBF. CMRO(2) does not change during even intense handgrip......-oxidative carbohydrate uptake during exercise. Adrenaline appears to accelerate cerebral glycolysis through a beta2-adrenergic receptor mechanism since noradrenaline is without such an effect. In addition, the exercise-induced cerebral non-oxidative carbohydrate uptake is blocked by combined beta 1/2-adrenergic blockade...

  16. Transportation

    National Research Council Canada - National Science Library

    Adams, James; Carr, Ron; Chebl, Maroun; Coleman, Robert; Costantini, William; Cox, Robert; Dial, William; Jenkins, Robert; McGovern, James; Mueller, Peter

    2006-01-01

    ...., trains, ships, etc.) and maximizing intermodal efficiency. A healthy balance must be achieved between the flow of international commerce and security requirements regardless of transportation mode...

  17. 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-D-pyranoside confers neuroprotection in cell and animal models of ischemic stroke through calpain1/PKA/CREB-mediated induction of neuronal glucose transporter 3

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Shu; Cheng, Qiong; Li, Lu; Liu, Mei; Yang, Yumin; Ding, Fei, E-mail: dingfei@ntu.edu.cn

    2014-06-15

    Salidroside is proven to be a neuroprotective agent of natural origin, and its analog, 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-D-pyranoside (named SalA-4 g), has been synthesized in our lab. In this study, we showed that SalA-4 g promoted neuronal survival and inhibited neuronal apoptosis in primary hippocampal neurons exposed to oxygen and glucose deprivation (OGD) and in rats subjected to ischemia by transient middle cerebral artery occlusion (MCAO), respectively, and that SalA-4 g was more neuroprotective than salidroside. We further found that SalA-4 g elevated glucose uptake in OGD-injured primary hippocampal neurons and increased the expression and recruitment of glucose transporter 3 (GLUT3) in ischemic brain. Signaling analysis revealed that SalA-4 g triggered the phosphorylation of CREB, and increased the expression of PKA RII in primary hippocampal neurons exposed to OGD injury, while inhibition of PKA/CREB by H-89 alleviated the elevation in glucose uptake and GLUT3 expression, and blocked the protective effects of SalA-4 g. Moreover, SalA-4 g was noted to inhibit intracellular Ca{sup 2+} influx and calpain1 activation in OGD-injured primary hippocampal neurons. Our results suggest that SalA-4 g neuroprotection might be mediated by increased glucose uptake and elevated GLUT3 expression through calpain1/PKA/CREB pathway. - Highlights: • A salidroside (Sal) analog (SalA-4 g) is prepared to be more neuroprotective than Sal. • SalA-4 g protected hippocampal neurons from oxygen and glucose deprivation insult. • SalA-4 g reduced ischemic injury after transient middle cerebral artery occlusion in rats. • Neuroprotection of SalA-4 g was mediated by GLUT3 level via calpain/PKA/CREB pathway.

  18. 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-D-pyranoside confers neuroprotection in cell and animal models of ischemic stroke through calpain1/PKA/CREB-mediated induction of neuronal glucose transporter 3

    International Nuclear Information System (INIS)

    Yu, Shu; Cheng, Qiong; Li, Lu; Liu, Mei; Yang, Yumin; Ding, Fei

    2014-01-01

    Salidroside is proven to be a neuroprotective agent of natural origin, and its analog, 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-D-pyranoside (named SalA-4 g), has been synthesized in our lab. In this study, we showed that SalA-4 g promoted neuronal survival and inhibited neuronal apoptosis in primary hippocampal neurons exposed to oxygen and glucose deprivation (OGD) and in rats subjected to ischemia by transient middle cerebral artery occlusion (MCAO), respectively, and that SalA-4 g was more neuroprotective than salidroside. We further found that SalA-4 g elevated glucose uptake in OGD-injured primary hippocampal neurons and increased the expression and recruitment of glucose transporter 3 (GLUT3) in ischemic brain. Signaling analysis revealed that SalA-4 g triggered the phosphorylation of CREB, and increased the expression of PKA RII in primary hippocampal neurons exposed to OGD injury, while inhibition of PKA/CREB by H-89 alleviated the elevation in glucose uptake and GLUT3 expression, and blocked the protective effects of SalA-4 g. Moreover, SalA-4 g was noted to inhibit intracellular Ca 2+ influx and calpain1 activation in OGD-injured primary hippocampal neurons. Our results suggest that SalA-4 g neuroprotection might be mediated by increased glucose uptake and elevated GLUT3 expression through calpain1/PKA/CREB pathway. - Highlights: • A salidroside (Sal) analog (SalA-4 g) is prepared to be more neuroprotective than Sal. • SalA-4 g protected hippocampal neurons from oxygen and glucose deprivation insult. • SalA-4 g reduced ischemic injury after transient middle cerebral artery occlusion in rats. • Neuroprotection of SalA-4 g was mediated by GLUT3 level via calpain/PKA/CREB pathway

  19. Noninvasive evaluation of sympathetic nervous system in human heart by positron emission tomography

    International Nuclear Information System (INIS)

    Schwaiger, M.; Kalff, V.; Rosenspire, K.; Haka, M.S.; Molina, E.; Hutchins, G.D.; Deeb, M.; Wolfe, E. Jr.; Wieland, D.M.

    1990-01-01

    The noninvasive functional characterization of the cardiac sympathetic nervous system by imaging techniques may provide important pathophysiological information in various cardiac disease states. Hydroxyephedrine labeled with carbon 11 has been developed as a new catecholamine analogue to be used in the in vivo evaluation of presynaptic adrenergic nerve terminals by positron emission tomography (PET). To determine the feasibility of this imaging approach in the human heart, six normal volunteers and five patients with recent cardiac transplants underwent dynamic PET imaging after intravenous injection of 20 mCi [11C]hydroxyephedrine. Blood and myocardial tracer kinetics were assessed using a regions-of-interest approach. In normal volunteers, blood 11C activity cleared rapidly, whereas myocardium retained 11C activity with a long tissue half-life. Relative tracer retention in the myocardium averaged 79 +/- 31% of peak activity at 60 minutes after tracer injection. The heart-to-blood 11C activity ratio exceeded 6:1 as soon as 30 minutes after tracer injection, yielding excellent image quality. Little regional variation of tracer retention was observed, indicating homogeneous sympathetic innervation throughout the left ventricle. In the transplant recipients, myocardial [11C]hydroxyephedrine retention at 60 minutes was significantly less (-82%) than that of normal volunteers, indicating only little non-neuronal binding of the tracer in the denervated human heart. Thus, [11C]hydroxyephedrine, in combination with dynamic PET imaging, allows the noninvasive delineation of myocardial adrenergic nerve terminals. Tracer kinetic modeling may permit quantitative assessment of myocardial catecholamine uptake, which will in turn provide insights into the effects of various disease processes on the neuronal integrity of the heart

  20. Vasovagal oscillations and vasovagal responses produced by the Vestibulo-Sympathetic Reflex in the rat

    Directory of Open Access Journals (Sweden)

    Sergei B. Yakushin

    2014-04-01

    Full Text Available Sinusoidal galvanic vestibular stimulation (sGVS induces oscillations in blood pressure (BP and heart rate (HR i.e., vasovagal oscillations, and decreases in BP and HR i.e., vasovagal responses, in isoflurane-anesthetized rats. We determined the characteristics of the vasovagal oscillations, assessed their role in the generation of vasovagal responses and determined whether they could be induced by monaural as well as by binaural sGVS and by oscillation in pitch. Wavelet analyses were used to determine the power distributions of the waveforms. Monaural and binaural sGVS and pitch generated vasovagal oscillations at the frequency and at twice the frequency of stimulation. Vasovagal oscillations and vasovagal responses were maximally induced at low stimulus frequencies (0.025-0.05 Hz. The oscillations were attenuated and the responses were rarely induced at higher stimulus frequencies. Vasovagal oscillations could occur without induction of vasovagal responses, but vasovagal responses were always associated with a vasovagal oscillation. We posit that the vasovagal oscillations originate in a low frequency band that, when appropriately activated by strong sympathetic stimulation, can generate vasovagal oscillations as a precursor for vasovagal responses and syncope. We further suggest that the activity responsible for the vasovagal oscillations arises in low frequency, otolith neurons with orientation vectors close to the vertical axis of the head. These neurons are likely to provide critical input to the Vestibulo-Sympathetic Reflex to increase BP and HR upon changes in head position relative to gravity, and to contribute to the production of vasovagal oscillations and vasovagal responses and syncope when the baroreflex is inactivated.

  1. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41).

    Science.gov (United States)

    Kimura, Ikuo; Inoue, Daisuke; Maeda, Takeshi; Hara, Takafumi; Ichimura, Atsuhiko; Miyauchi, Satoshi; Kobayashi, Makio; Hirasawa, Akira; Tsujimoto, Gozoh

    2011-05-10

    The maintenance of energy homeostasis is essential for life, and its dysregulation leads to a variety of metabolic disorders. Under a fed condition, mammals use glucose as the main metabolic fuel, and short-chain fatty acids (SCFAs) produced by the colonic bacterial fermentation of dietary fiber also contribute a significant proportion of daily energy requirement. Under ketogenic conditions such as starvation and diabetes, ketone bodies produced in the liver from fatty acids are used as the main energy sources. To balance energy intake, dietary excess and starvation trigger an increase or a decrease in energy expenditure, respectively, by regulating the activity of the sympathetic nervous system (SNS). The regulation of metabolic homeostasis by glucose is well recognized; however, the roles of SCFAs and ketone bodies in maintaining energy balance remain unclear. Here, we show that SCFAs and ketone bodies directly regulate SNS activity via GPR41, a Gi/o protein-coupled receptor for SCFAs, at the level of the sympathetic ganglion. GPR41 was most abundantly expressed in sympathetic ganglia in mouse and humans. SCFA propionate promoted sympathetic outflow via GPR41. On the other hand, a ketone body, β-hydroxybutyrate, produced during starvation or diabetes, suppressed SNS activity by antagonizing GPR41. Pharmacological and siRNA experiments indicated that GPR41-mediated activation of sympathetic neurons involves Gβγ-PLCβ-MAPK signaling. Sympathetic regulation by SCFAs and ketone bodies correlated well with their respective effects on energy consumption. These findings establish that SCFAs and ketone bodies directly regulate GPR41-mediated SNS activity and thereby control body energy expenditure in maintaining metabolic homeostasis.

  2. Transportation

    International Nuclear Information System (INIS)

    Anon.

    1998-01-01

    Here is the decree of the thirtieth of July 1998 relative to road transportation, to trade and brokerage of wastes. It requires to firms which carry out a road transportation as well as to traders and to brokers of wastes to declare their operations to the prefect. The declaration has to be renewed every five years. (O.M.)

  3. Dietary plant lectins appear to be transported from the gut to gain access to and alter dopaminergic neurons of Caenorhabditis elegans, a potential etiology of Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Jolene eZheng

    2016-03-01

    Full Text Available Lectins from dietary plants have been shown to enhance drug absorption in the gastrointestinal tract of rats, be transported trans-synaptically as shown by tracing of axonal and dendritic paths, and enhance gene delivery. Other carbohydrate-binding protein toxins are known to traverse the gut intact in dogs. Post-feeding rhodamine- or TRITC-tagged dietary lectins, the lectins were tracked from gut to dopaminergic neurons (DAergic-N in transgenic Caenorhabditis elegans (C. elegans (egIs1[Pdat-1::GFP] where the mutant has the Green Fluorescent Protein (GFP gene fused to a dopamine transport protein gene labeling dopaminergic neurons, The lectins were supplemented along with the food organism Escherichia coli (OP50. Among nine tested rhodamine/TRITC-tagged lectins, four, including Phaseolus vulgaris erythroagglutinin (PHA-E, Bandeiraea simplicifolia (BS-I, Dolichos biflorus agglutinin (DBA, and Arachis hypogaea (PNA, appeared to be transported from gut to the GFP-DAergic-N. Griffonia Simplicifolia (GSL-I and PHA-E, reduced the number of GFP-DAergic-N suggesting a toxic activity. PHA-E, BS-I, Pisum Sativum (PSA, and Triticum vulgaris agglutinin (Succinylated reduced fluorescent intensity of GFP-DAergic-N. PHA-E, PSA, Concanavalin A, and Triticum vulgaris agglutinin decreased the size of GFP-DAergic-N, while BS-I increased neuron size. These observations suggest that dietary plant lectins are transported to and affect DAergic-N in C. elegans, which support Braak and Hawkes’ hypothesis, suggesting one alternate potential dietary etiology of Parkinson’s disease (PD. A recent Danish study showed that vagotomy resulted in 40% lower incidence of PD over 20 years. Differences in inherited sugar structures of gut and neuronal cell surfaces may make some individuals more susceptible in this conceptual disease etiology model.

  4. Inflammation in CRPS: role of the sympathetic supply.

    Science.gov (United States)

    Schlereth, Tanja; Drummond, Peter D; Birklein, Frank

    2014-05-01

    Acute Complex Regional Pain Syndrome (CRPS) is associated with signs of inflammation such as increased skin temperature, oedema, skin colour changes and pain. Pro-inflammatory cytokines (tumour necrosis factor-α (TNF-α), interleukin-2 (IL-2), IL-1beta, IL-6) are up-regulated, whereas anti-inflammatory cytokines (IL-4, IL-10) are diminished. Adaptive immunity seems to be involved in CRPS pathophysiology as many patients have autoantibodies directed against β2 adrenergic and muscarinic-2 receptors. In an animal tibial fracture model changes in the innate immune response such as up-regulation of keratinocytes are also found. Additionally, CRPS is accompanied by increased neurogenic inflammation which depends mainly on neuropeptides such as CGRP and Substance P. Besides inflammatory signs, sympathetic nervous system involvement in CRPS results in cool skin, increased sweating and sympathetically-maintained pain. The norepinephrine level is lower in the CRPS-affected than contralateral limb, but sympathetic sprouting and up-regulation of alpha-adrenoceptors may result in an adrenergic supersensitivity. The sympathetic nervous system and inflammation interact: norepinephrine influences the immune system and the production of cytokines. There is substantial evidence that this interaction contributes to the pathophysiology and clinical presentation of CRPS, but this interaction is not straightforward. How inflammation in CRPS might be exaggerated by sympathetic transmitters requires further elucidation. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. The articulo-cardiac sympathetic reflex in spinalized, anesthetized rats.

    Science.gov (United States)

    Nakayama, Tomohiro; Suzuki, Atsuko; Ito, Ryuzo

    2006-04-01

    Somatic afferent regulation of heart rate by noxious knee joint stimulation has been proven in anesthetized cats to be a reflex response whose reflex center is in the brain and whose efferent arc is a cardiac sympathetic nerve. In the present study we examined whether articular stimulation could influence heart rate by this efferent sympathetic pathway in spinalized rats. In central nervous system (CNS)-intact rats, noxious articular movement of either the knee or elbow joint resulted in an increase in cardiac sympathetic nerve activity and heart rate. However, although in acutely spinalized rats a noxious movement of the elbow joint resulted in a significant increase in cardiac sympathetic nerve activity and heart rate, a noxious movement of the knee joint had no such effect and resulted in only a marginal increase in heart rate. Because this marginal increase was abolished by adrenalectomy suggests that it was due to the release of adrenal catecholamines. In conclusion, the spinal cord appears to be capable of mediating, by way of cardiac sympathetic nerves, the propriospinally induced reflex increase in heart rate that follows noxious stimulation of the elbow joint, but not the knee joint.

  6. Sympathetic Innervation Promotes Arterial Fate by Enhancing Endothelial ERK Activity.

    Science.gov (United States)

    Pardanaud, Luc; Pibouin-Fragner, Laurence; Dubrac, Alexandre; Mathivet, Thomas; English, Isabel; Brunet, Isabelle; Simons, Michael; Eichmann, Anne

    2016-08-19

    Arterial endothelial cells are morphologically, functionally, and molecularly distinct from those found in veins and lymphatic vessels. How arterial fate is acquired during development and maintained in adult vessels is incompletely understood. We set out to identify factors that promote arterial endothelial cell fate in vivo. We developed a functional assay, allowing us to monitor and manipulate arterial fate in vivo, using arteries isolated from quails that are grafted into the coelom of chick embryos. Endothelial cells migrate out from the grafted artery, and their colonization of host arteries and veins is quantified. Here we show that sympathetic innervation promotes arterial endothelial cell fate in vivo. Removal of sympathetic nerves decreases arterial fate and leads to colonization of veins, whereas exposure to sympathetic nerves or norepinephrine imposes arterial fate. Mechanistically, sympathetic nerves increase endothelial ERK (extracellular signal-regulated kinase) activity via adrenergic α1 and α2 receptors. These findings show that sympathetic innervation promotes arterial endothelial fate and may lead to novel approaches to improve arterialization in human disease. © 2016 American Heart Association, Inc.

  7. Enhanced astroglial GABA uptake attenuates tonic GABAA inhibition of the presympathetic hypothalamic paraventricular nucleus neurons in heart failure.

    Science.gov (United States)

    Pandit, Sudip; Jo, Ji Yoon; Lee, Sang Ung; Lee, Young Jae; Lee, So Yeong; Ryu, Pan Dong; Lee, Jung Un; Kim, Hyun-Woo; Jeon, Byeong Hwa; Park, Jin Bong

    2015-08-01

    γ-Aminobutyric acid (GABA) generates persistent tonic inhibitory currents (Itonic) and conventional inhibitory postsynaptic currents in the hypothalamic paraventricular nucleus (PVN) via activation of GABAA receptors (GABAARs). We investigated the pathophysiological significance of astroglial GABA uptake in the regulation of Itonic in the PVN neurons projecting to the rostral ventrolateral medulla (PVN-RVLM). The Itonic of PVN-RVLM neurons were significantly reduced in heart failure (HF) compared with sham-operated (SHAM) rats. Reduced Itonic sensitivity to THIP argued for the decreased function of GABAAR δ subunits in HF, whereas similar Itonic sensitivity to benzodiazepines argued against the difference of γ2 subunit-containing GABAARs in SHAM and HF rats. HF Itonic attenuation was reversed by a nonselective GABA transporter (GAT) blocker (nipecotic acid, NPA) and a GAT-3 selective blocker, but not by a GAT-1 blocker, suggesting that astroglial GABA clearance increased in HF. Similar and minimal Itonic responses to bestrophin-1 blockade in SHAM and HF neurons further argued against a role for astroglial GABA release in HF Itonic attenuation. Finally, the NPA-induced inhibition of spontaneous firing was greater in HF than in SHAM PVN-RVLM neurons, whereas diazepam induced less inhibition of spontaneous firing in HF than in SHAM neurons. Overall, our results showed that combined with reduced GABAARs function, the enhanced astroglial GABA uptake-induced attenuation of Itonic in HF PVN-RVLM neurons explains the deficit in tonic GABAergic inhibition and increased sympathetic outflow from the PVN during heart failure. Copyright © 2015 the American Physiological Society.

  8. Sympathetic nerve damage and restoration after ischemia-reperfusion injury as assessed by {sup 11}C-hydroxyephedrine

    Energy Technology Data Exchange (ETDEWEB)

    Werner, Rudolf A.; Higuchi, Takahiro [University of Wuerzburg, Department of Nuclear Medicine, Wuerzburg (Germany); University of Wuerzburg, Comprehensive Heart Failure Center, Wuerzburg (Germany); Maya, Yoshifumi [University of Wuerzburg, Department of Nuclear Medicine, Wuerzburg (Germany); Nihon Medi-Physics Co., Ltd., Research Centre, Chiba (Japan); Rischpler, Christoph [Technische Universitaet Muenchen, Department of Nuclear Medicine, Klinikum rechts der Isar, Muenchen (Germany); Javadi, Mehrbod S. [Johns Hopkins University, Division of Nuclear Medicine, Russell H. Morgan Department of Radiology, Baltimore, MD (United States); Fukushima, Kazuhito [Hyogo College of Medicine, Department of Radiology, Hyogo (Japan); Lapa, Constantin [University of Wuerzburg, Department of Nuclear Medicine, Wuerzburg (Germany); Herrmann, Ken [University of Wuerzburg, Department of Nuclear Medicine, Wuerzburg (Germany); David Geffen School of Medicine at UCLA, Department of Molecular and Medical Pharmacology, Los Angeles, CA (United States)

    2016-02-15

    An altered state of the cardiac sympathetic nerves is an important prognostic factor in patients with coronary artery disease. The aim of this study was to investigate regional sympathetic nerve damage and restoration utilizing a rat model of myocardial transient ischemia and a catecholamine analog PET tracer, {sup 11}C-hydroxyephedrine ({sup 11}C-HED). Transient myocardial ischemia was induced by coronary occlusion for 20 min and reperfusion in male Wistar rats. Dual-tracer autoradiography was performed subacutely (7 days) and chronically (2 months) after ischemia, and in control rats without ischemia using {sup 11}C-HED as a marker of sympathetic innervation and {sup 201}TI for perfusion. Additional serial in vivo cardiac {sup 11}C-HED and {sup 18}F-FDG PET scans were performed in the subacute and chronic phases after ischemia. After transient ischemia, the {sup 11}C-HED uptake defect areas in both the subacute and chronic phases were clearly larger than the perfusion defect areas in the midventricular wall. The subacute {sup 11}C-HED uptake defect showed a transmural pattern, whereas uptake recovered in the subepicardial portion in the chronic phase. Tyrosine hydroxylase antibody nerve staining confirmed regional denervation corresponding to areas of decreased {sup 11}C-HED uptake. Serial in vivo PET imaging visualized reductions in the area of the {sup 11}C-HED uptake defects in the chronic phase consistent with autoradiography and histology. Higher susceptibility of sympathetic neurons compared to myocytes was confirmed by a larger {sup 11}C-HED defect with a corresponding histologically identified region of denervation. Furthermore, partial reinnervation was observed in the chronic phase as shown by recovery of subepicardial {sup 11}C-HED uptake. (orig.)

  9. Vesicle-mediated transport and release of CCL21 in endangered neurons : A possible explanation for microglia activation remote from a primary lesion

    NARCIS (Netherlands)

    de Jong, EK; Dijkstra, IM; Hensens, M; Brouwer, N; van Amerongen, M; Liem, RSB; Boddeke, HWGM; Biber, K

    2005-01-01

    Whenever neurons in the CNS are injured, microglia become activated. In addition to local activation, microglia remote from the primary lesion site are stimulated. Because this so-called secondary activation of microglia is instrumental for long-term changes after neuronal injury, it is important to

  10. Transportation

    National Research Council Canada - National Science Library

    Allshouse, Michael; Armstrong, Frederick Henry; Burns, Stephen; Courts, Michael; Denn, Douglas; Fortunato, Paul; Gettings, Daniel; Hansen, David; Hoffman, D. W; Jones, Robert

    2007-01-01

    .... The ability of the global transportation industry to rapidly move passengers and products from one corner of the globe to another continues to amaze even those wise to the dynamics of such operations...

  11. Role of sympathetic nervous system and neuropeptides in obesity hypertension

    Directory of Open Access Journals (Sweden)

    J.E. Hall

    2000-06-01

    Full Text Available Obesity is the most common cause of human essential hypertension in most industrialized countries. Although the precise mechanisms of obesity hypertension are not fully understood, considerable evidence suggests that excess renal sodium reabsorption and a hypertensive shift of pressure natriuresis play a major role. Sympathetic activation appears to mediate at least part of the obesity-induced sodium retention and hypertension since adrenergic blockade or renal denervation markedly attenuates these changes. Recent observations suggest that leptin and its multiple interactions with neuropeptides in the hypothalamus may link excess weight gain with increased sympathetic activity. Leptin is produced mainly in adipocytes and is believed to regulate energy balance by acting on the hypothalamus to reduce food intake and to increase energy expenditure via sympathetic activation. Short-term administration of leptin into the cerebral ventricles increases renal sympathetic activity, and long-term leptin infusion at rates that mimic plasma concentrations found in obesity raises arterial pressure and heart rate via adrenergic activation in non-obese rodents. Transgenic mice overexpressing leptin also develop hypertension. Acute studies suggest that the renal sympathetic effects of leptin may depend on interactions with other neurochemical pathways in the hypothalamus, including the melanocortin-4 receptor (MC4-R. However, the role of this pathway in mediating the long-term effects of leptin on blood pressure is unclear. Also, it is uncertain whether there is resistance to the chronic renal sympathetic and blood pressure effects of leptin in obese subjects. In addition, leptin also has other cardiovascular and renal actions, such as stimulation of nitric oxide formation and improvement of insulin sensitivity, which may tend to reduce blood pressure in some conditions. Although the role of these mechanisms in human obesity has not been elucidated, this

  12. Mapping monoaminergic neurons with (/sup 3/H) reserpine by autoradiography

    Energy Technology Data Exchange (ETDEWEB)

    Richards, J G; Da Prada, M; Wuersch, J; Lorez, H P; Pieri, L [Hoffmann-La Roche (F.) and Co., Basel (Switzerland)

    1979-01-01

    The synthesis of (/sup 3/H) reserpine of high specific activity is described. The accumulation of radioactivity in peripheral sympathetically innervated organs and in the brain after intravenous injection of (/sup 3/H) reserpine to rats was measured biochemically and its localization studied by light-microscopic autoradiography. In most of the organs and tissues investigated minute quantities of (/sup 3/H) reserpine persisted up to 10 days after injection. By autoradiography, it was observed that silver grains were unevenly distributed in various brain regions and peripheral organs 18 h and up to 10 days after administration of (/sup 3/H) reserpine. Pretreating (but not post-treating) animals with non-radioactive reserpine prevented by up to 80% the accumulation of radiolabel and abolished to a great extent the autoradiographic localization. The fact that the persistently bound radiolabel is confined to monoaminergic neurons suggests that it is irreversibly bound to its target site, the amine-storing vesicle. Support for this interpretation comes from studies demonstrating a fast anterograde axonal transport of (/sup 3/H) reserpine in the nigrostriatal tract after intranigral injection of the radiolabel. These findings demonstrate that (/sup 3/H) reserpine of high specific activity is a useful tool in studies designed to map monoaminergic pathways in the brain and to further characterize amine-storing mechanisms.

  13. Exposure to a high-fat diet alters leptin sensitivity and elevates renal sympathetic nerve activity and arterial pressure in rabbits.

    Science.gov (United States)

    Prior, Larissa J; Eikelis, Nina; Armitage, James A; Davern, Pamela J; Burke, Sandra L; Montani, Jean-Pierre; Barzel, Benjamin; Head, Geoffrey A

    2010-04-01

    The activation of the sympathetic nervous system through the central actions of the adipokine leptin has been suggested as a major mechanism by which obesity contributes to the development of hypertension. However, direct evidence for elevated sympathetic activity in obesity has been limited to muscle. The present study examined the renal sympathetic nerve activity and cardiovascular effects of a high-fat diet (HFD), as well as the changes in the sensitivity to intracerebroventricular leptin. New Zealand white rabbits fed a 13.5% HFD for 4 weeks showed modest weight gain but a 2- to 3-fold greater accumulation of visceral fat compared with control rabbits. Mean arterial pressure, heart rate, and plasma norepinephrine concentration increased by 8%, 26%, and 87%, respectively (Pdiet rabbits and was correlated to plasma leptin (r=0.87; Pfat accumulation through consumption of a HFD leads to marked sympathetic activation, which is related to increased responsiveness to central sympathoexcitatory effects of leptin. The paradoxical reduction in hypothalamic neuronal activation by leptin suggests a marked "selective leptin resistance" in these animals.

  14. A hepatic amino acid/mTOR/S6K-dependent signalling pathway modulates systemic lipid metabolism via neuronal signals.

    Science.gov (United States)

    Uno, Kenji; Yamada, Tetsuya; Ishigaki, Yasushi; Imai, Junta; Hasegawa, Yutaka; Sawada, Shojiro; Kaneko, Keizo; Ono, Hiraku; Asano, Tomoichiro; Oka, Yoshitomo; Katagiri, Hideki

    2015-08-13

    Metabolism is coordinated among tissues and organs via neuronal signals. Levels of circulating amino acids (AAs), which are elevated in obesity, activate the intracellular target of rapamycin complex-1 (mTORC1)/S6kinase (S6K) pathway in the liver. Here we demonstrate that hepatic AA/mTORC1/S6K signalling modulates systemic lipid metabolism via a mechanism involving neuronal inter-tissue communication. Hepatic expression of an AA transporter, SNAT2, activates the mTORC1/S6K pathway, and markedly elevates serum triglycerides (TGs), while downregulating adipose lipoprotein lipase (LPL). Hepatic Rheb or active-S6K expression have similar metabolic effects, whereas hepatic expression of dominant-negative-S6K inhibits TG elevation in SNAT2 mice. Denervation, pharmacological deafferentation and β-blocker administration suppress obesity-related hypertriglyceridemia with adipose LPL upregulation, suggesting that signals are transduced between liver and adipose tissue via a neuronal pathway consisting of afferent vagal and efferent sympathetic nerves. Thus, the neuronal mechanism uncovered here serves to coordinate amino acid and lipid levels and contributes to the development of obesity-related hypertriglyceridemia.

  15. Neurotransmitter transporters

    DEFF Research Database (Denmark)

    Gether, Ulrik; Andersen, Peter H; Larsson, Orla M

    2006-01-01

    The concentration of neurotransmitters in the extracellular space is tightly controlled by distinct classes of membrane transport proteins. This review focuses on the molecular function of two major classes of neurotransmitter transporter that are present in the cell membrane of neurons and....... Recent research has provided substantial insight into the structure and function of these transporters. In particular, the recent crystallizations of bacterial homologs are of the utmost importance, enabling the first reliable structural models of the mammalian neurotransmitter transporters...

  16. The pedunculopontine tegmentum controls renal sympathetic nerve activity and cardiorespiratory activities in nembutal-anesthetized rats.

    Directory of Open Access Journals (Sweden)

    Anne M Fink

    Full Text Available Elevated renal sympathetic nerve activity (RSNA accompanies a variety of complex disorders, including obstructive sleep apnea, heart failure, and chronic kidney disease. Understanding pathophysiologic renal mechanisms is important for determining why hypertension is both a common sequelae and a predisposing factor of these disorders. The role of the brainstem in regulating RSNA remains incompletely understood. The pedunculopontine tegmentum (PPT is known for regulating behaviors including alertness, locomotion, and rapid eye movement sleep. Activation of PPT neurons in anesthetized rats was previously found to increase splanchnic sympathetic nerve activity and blood pressure, in addition to altering breathing. The present study is the first investigation of the PPT and its potential role in regulating RSNA. Microinjections of DL-homocysteic acid (DLH were used to probe the PPT in 100-μm increments in Nembutal-anesthetized rats to identify effective sites, defined as locations where changes in RSNA could be evoked. A total of 239 DLH microinjections were made in 18 rats, which identified 20 effective sites (each confirmed by the ability to evoke a repeatable sympathoexcitatory response. Peak increases in RSNA occurred within 10-20 seconds of PPT activation, with RSNA increasing by 104.5 ± 68.4% (mean ± standard deviation from baseline. Mean arterial pressure remained significantly elevated for 30 seconds, increasing from 101.6 ± 18.6 mmHg to 135.9 ± 36.4 mmHg. DLH microinjections also increased respiratory rate and minute ventilation. The effective sites were found throughout the rostal-caudal extent of the PPT with most located in the dorsal regions of the nucleus. The majority of PPT locations tested with DLH microinjections did not alter RSNA (179 sites, suggesting that the neurons that confer renal sympathoexcitatory functions comprise a small component of the PPT. The study also underscores the importance of further investigation to

  17. Dietary Plant Lectins Appear to Be Transported from the Gut to Gain Access to and Alter Dopaminergic Neurons of Caenorhabditis elegans, a Potential Etiology of Parkinson’s Disease

    Science.gov (United States)

    Zheng, Jolene; Wang, Mingming; Wei, Wenqian; Keller, Jeffrey N.; Adhikari, Binita; King, Jason F.; King, Michael L.; Peng, Nan; Laine, Roger A.

    2016-01-01

    Lectins from dietary plants have been shown to enhance drug absorption in the gastrointestinal tract of rats, be transported trans-synaptically as shown by tracing of axonal and dendritic paths, and enhance gene delivery. Other carbohydrate-binding protein toxins are known to traverse the gut intact in dogs. Post-feeding rhodamine- or TRITC-tagged dietary lectins, the lectins were tracked from gut to dopaminergic neurons (DAergic-N) in transgenic Caenorhabditis elegans (C. elegans) [egIs1(Pdat-1:GFP)] where the mutant has the green fluorescent protein (GFP) gene fused to a dopamine transport protein gene labeling DAergic-N. The lectins were supplemented along with the food organism Escherichia coli (OP50). Among nine tested rhodamine/TRITC-tagged lectins, four, including Phaseolus vulgaris erythroagglutinin (PHA-E), Bandeiraea simplicifolia (BS-I), Dolichos biflorus agglutinin (DBA), and Arachis hypogaea agglutinin (PNA), appeared to be transported from gut to the GFP-DAergic-N. Griffonia Simplicifolia and PHA-E, reduced the number of GFP-DAergic-N, suggesting a toxic activity. PHA-E, BS-I, Pisum sativum (PSA), and Triticum vulgaris agglutinin (Succinylated) reduced fluorescent intensity of GFP-DAergic-N. PHA-E, PSA, Concanavalin A, and Triticum vulgaris agglutinin decreased the size of GFP-DAergic-N, while BS-I increased neuron size. These observations suggest that dietary plant lectins are transported to and affect DAergic-N in C. elegans, which support Braak and Hawkes’ hypothesis, suggesting one alternate potential dietary etiology of Parkinson’s disease (PD). A recent Danish study showed that vagotomy resulted in 40% lower incidence of PD over 20 years. Differences in inherited sugar structures of gut and neuronal cell surfaces may make some individuals more susceptible in this conceptual disease etiology model. PMID:27014695

  18. Dynamic resistance training decreases sympathetic tone in hypertensive ovariectomized rats

    International Nuclear Information System (INIS)

    Shimojo, G.L.; Palma, R.K.; Brito, J.O.; Sanches, I.C.; Irigoyen, M.C.; De Angelis, K.

    2015-01-01

    The aim of this study was to investigate the effects of resistance exercise training on hemodynamics and cardiac autonomic control in ovariectomized spontaneously hypertensive rats. Female rats were divided into 4 groups: sedentary control (SC), sedentary hypertensive (SH), sedentary hypertensive ovariectomized (SHO), and resistance-trained hypertensive ovariectomized (RTHO). Resistance exercise training was performed on a vertical ladder (5 days/week, 8 weeks) at 40-60% maximal load. Direct arterial pressure was recorded. Vagal and sympathetic tones were measured by heart rate (HR) responses to methylatropine (3 mg/kg, iv) and propranolol (4 mg/kg, iv). Ovariectomy resulted in additional increases in blood pressure in hypertensive rats and was associated with decreased vagal tone. Resistance exercise trained rats had lower mean arterial pressure than untrained rats (RTHO: 159±2.2 vs SHO: 177±3.4 mmHg), as well as resting bradycardia (RTHO: 332±9.0 vs SHO: 356±5 bpm). Sympathetic tone was also lower in the trained group. Moreover, sympathetic tone was positively correlated with resting HR (r=0.7, P<0.05). The additional arterial pressure increase in hypertensive rats caused by ovarian hormone deprivation was attenuated by moderate-intensity dynamic resistance training. This benefit may be associated with resting bradycardia and reduced cardiac sympathetic tone after training, which suggests potential benefits of resistance exercise for the management of hypertension after ovarian hormone deprivation

  19. Dynamic resistance training decreases sympathetic tone in hypertensive ovariectomized rats

    Energy Technology Data Exchange (ETDEWEB)

    Shimojo, G.L.; Palma, R.K.; Brito, J.O.; Sanches, I.C. [Laboratório de Fisiologia Translacional, Programa de Ciências da Reabilitação, Universidade Nove de Julho, São Paulo, SP (Brazil); Irigoyen, M.C. [Instituto do Coração, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); De Angelis, K. [Laboratório de Fisiologia Translacional, Programa de Ciências da Reabilitação, Universidade Nove de Julho, São Paulo, SP (Brazil)

    2015-03-27

    The aim of this study was to investigate the effects of resistance exercise training on hemodynamics and cardiac autonomic control in ovariectomized spontaneously hypertensive rats. Female rats were divided into 4 groups: sedentary control (SC), sedentary hypertensive (SH), sedentary hypertensive ovariectomized (SHO), and resistance-trained hypertensive ovariectomized (RTHO). Resistance exercise training was performed on a vertical ladder (5 days/week, 8 weeks) at 40-60% maximal load. Direct arterial pressure was recorded. Vagal and sympathetic tones were measured by heart rate (HR) responses to methylatropine (3 mg/kg, iv) and propranolol (4 mg/kg, iv). Ovariectomy resulted in additional increases in blood pressure in hypertensive rats and was associated with decreased vagal tone. Resistance exercise trained rats had lower mean arterial pressure than untrained rats (RTHO: 159±2.2 vs SHO: 177±3.4 mmHg), as well as resting bradycardia (RTHO: 332±9.0 vs SHO: 356±5 bpm). Sympathetic tone was also lower in the trained group. Moreover, sympathetic tone was positively correlated with resting HR (r=0.7, P<0.05). The additional arterial pressure increase in hypertensive rats caused by ovarian hormone deprivation was attenuated by moderate-intensity dynamic resistance training. This benefit may be associated with resting bradycardia and reduced cardiac sympathetic tone after training, which suggests potential benefits of resistance exercise for the management of hypertension after ovarian hormone deprivation.

  20. Sympathetic neural responses to smoking are age dependent

    Czech Academy of Sciences Publication Activity Database

    Hering, D.; Somers, V. K.; Kára, T.; Kucharska, W.; Jurák, Pavel; Bieniaszewski, L.; Narkiewicz, K.

    2006-01-01

    Roč. 24, č. 4 (2006), s. 691-695 ISSN 0263-6352 R&D Projects: GA ČR(CZ) GA102/05/0402 Institutional research plan: CEZ:AV0Z20650511 Keywords : sympathetic neural response * blood pressure * heart rate * smoking Subject RIV: FS - Medical Facilities ; Equipment Impact factor: 4.021, year: 2006

  1. Sympathetic Overactivity in Chronic Kidney Disease: Consequences and Mechanisms

    Directory of Open Access Journals (Sweden)

    Jasdeep Kaur

    2017-08-01

    Full Text Available The incidence of chronic kidney disease (CKD is increasing worldwide, with more than 26 million people suffering from CKD in the United States alone. More patients with CKD die of cardiovascular complications than progress to dialysis. Over 80% of CKD patients have hypertension, which is associated with increased risk of cardiovascular morbidity and mortality. Another common, perhaps underappreciated, feature of CKD is an overactive sympathetic nervous system. This elevation in sympathetic nerve activity (SNA not only contributes to hypertension but also plays a detrimental role in the progression of CKD independent of any increase in blood pressure. Indeed, high SNA is associated with poor prognosis and increased cardiovascular morbidity and mortality independent of its effect on blood pressure. This brief review will discuss some of the consequences of sympathetic overactivity and highlight some of the potential pathways contributing to chronically elevated SNA in CKD. Mechanisms leading to chronic sympathoexcitation in CKD are complex, multifactorial and to date, not completely understood. Identification of the mechanisms and/or signals leading to sympathetic overactivity in CKD are crucial for development of effective therapeutic targets to reduce the increased cardiovascular risk in this patient group.

  2. Sympathetic Wigner-function tomography of a dark trapped ion

    DEFF Research Database (Denmark)

    Mirkhalaf, Safoura; Mølmer, Klaus

    2012-01-01

    A protocol is provided to reconstruct the Wigner function for the motional state of a trapped ion via fluorescence detection on another ion in the same trap. This “sympathetic tomography” of a dark ion without optical transitions suitable for state measurements is based on the mapping of its...

  3. Reflex sympathetic dystrophy/complex regional pain syndrome, type 1

    African Journals Online (AJOL)

    Enrique

    with MRI every 3 months and the bone marrow oedema disappeared after 6 months. Introduction ... SA JOURNAL OF RADIOLOGY • August 2004. Reflex sympathetic dystrophy/complex regional pain syndrome, type 1 ... may be either trauma of external origin or iatrogenic, post surgery. In some patients particularly children ...

  4. The clinical value of cardiac sympathetic imaging in heart failure

    DEFF Research Database (Denmark)

    Christensen, Thomas Emil; Kjaer, Andreas; Hasbak, Philip

    2014-01-01

    The autonomic nervous system plays an important role in the pathology of heart failure. The single-photon emission computed tomography tracer iodine-123-metaiodobenzylguanidine ((123) I-MIBG) can be used to investigate the activity of the predominant neurotransmitter of the sympathetic nervous...

  5. Baroreflex control of sympathetic activity in experimental hypertension

    Directory of Open Access Journals (Sweden)

    M.C.C. Irigoyen

    1998-09-01

    Full Text Available The arterial baroreceptor reflex system is one of the most powerful and rapidly acting mechanisms for controlling arterial pressure. The purpose of the present review is to discuss data relating sympathetic activity to the baroreflex control of arterial pressure in two different experimental models: neurogenic hypertension by sinoaortic denervation (SAD and high-renin hypertension by total aortic ligation between the renal arteries in the rat. SAD depresses baroreflex regulation of renal sympathetic activity in both the acute and chronic phases. However, increased sympathetic activity (100% was found only in the acute phase of sinoaortic denervation. In the chronic phase of SAD average discharge normalized but the pattern of discharges was different from that found in controls. High-renin hypertensive rats showed overactivity of the renin angiotensin system and a great depression of the baroreflexes, comparable to the depression observed in chronic sinoaortic denervated rats. However, there were no differences in the average tonic sympathetic activity or changes in the pattern of discharges in high-renin rats. We suggest that the difference in the pattern of discharges may contribute to the increase in arterial pressure lability observed in chronic sinoaortic denervated rats.

  6. Nav1.7-related small fiber neuropathy: impaired slow-inactivation and DRG neuron hyperexcitability.

    NARCIS (Netherlands)

    Han, C.; Hoeijmakers, J.G.; Ahn, H.S.; Zhao, P.; Shah, P.; Lauria, G.; Gerrits, M.M.; Morsche, R.H.M. te; Dib-Hajj, S.D.; Drenth, J.P.H.; Faber, C.G.; Merkies, I.S.; Waxman, S.G.

    2012-01-01

    OBJECTIVES: Although small fiber neuropathy (SFN) often occurs without apparent cause, the molecular etiology of idiopathic SFN (I-SFN) has remained enigmatic. Sodium channel Na(v)1.7 is preferentially expressed within dorsal root ganglion (DRG) and sympathetic ganglion neurons and their

  7. Nitric Oxide Orchestrates a Power-Law Modulation of Sympathetic Firing Behaviors in Neonatal Rat Spinal Cords

    Directory of Open Access Journals (Sweden)

    Chun-Kuei Su

    2018-03-01

    Full Text Available Nitric oxide (NO is a diffusible gas and has multifarious effects on both pre- and postsynaptic events. As a consequence of complex excitatory and inhibitory integrations, NO effects on neuronal activities are heterogeneous. Using in vitro preparations of neonatal rats that retain the splanchnic sympathetic nerves and the thoracic spinal cord as an experimental model, we report here that either enhancement or attenuation of NO production in the neonatal rat spinal cords could increase, decrease, or not change the spontaneous firing behaviors recorded from splanchnic sympathetic single fibers. To elucidate the mathematical features of NO-mediated heterogeneous responses, the ratios of changes in firing were plotted against their original firing rates. In log-log plots, a linear data distribution demonstrated that NO-mediated heterogeneity in sympathetic firing responses was well described by a power function. Selective antagonists were applied to test if glycinergic, GABAergic, glutamatergic, and cholinergic neurotransmission in the spinal cord are involved in NO-mediated power-law firing modulations (plFM. NO-mediated plFM diminished in the presence of mecamylamine (an open-channel blocker of nicotinic cholinergic receptors, indicating that endogenous nicotinic receptor activities were essential for plFM. Applications of strychnine (a glycine receptor blocker, gabazine (a GABAA receptor blocker, or kynurenate (a broad-spectrum ionotropic glutamate receptor blocker also caused plFM. However, strychnine- or kynurenate-induced plFM was diminished by L-NAME (an NO synthase inhibitor pretreatments, indicating that the involvements of glycine or ionotropic glutamate receptor activities in plFM were secondary to NO signaling. To recapitulate the arithmetic natures of the plFM, the plFM were simulated by firing changes in two components: a step increment and a fractional reduction of their basal firing activities. Ionotropic glutamate receptor

  8. In vivo measurement of neuronal dopamine transporter in tobacco and cannabis dependents subjects with positron tomography and [{sup 11}C]P E 2 I

    Energy Technology Data Exchange (ETDEWEB)

    Leroy, C; Ribeiro, M J; Trichard, C; Martinot, J L [Institut National de la Sante et de la Recherche Medicale (INSERM), U797, Research Unit, Neuroimaging and Psychiatry, IFR49, 91 - Orsay (France); CEA, Neuroimaging and Psychiatry, Unit, Hospital Dept. Frederic Joliot, I2BM, 91 - Orsay (France); Ribeiro, M J; Comtat, C; Dolle, F [Hospital Dept. Frederic Joliot, Research Medical Dept., I2BM, 91 - Orsay (France); Karila, L; Lukasiewicz, M; Reynaud, M [Paul Brousse Hospital, APHP, Psychiatry and Addictology Dept., 94 - Villejuif (France)

    2008-02-15

    Modifications of dopamine neurotransmission are classically involved in addictive behaviors and drug reinforcement. However, to date no data are available concerning the effects of cannabis addiction on dopaminergic neurotransmission in Human. The neuronal dopamine transporter (D.A.T.) is essential for the maintenance of normal dopamine homeostasis in the brain by ensuring the re-uptake of extracellular dopamine. Therefore, observation of D.A.T. availability abnormalities in cannabis-dependents subjects could provide further evidence for the implication of dopaminergic dysfunction in this addiction. Thus, as the cannabis dependent subjects are also most of time tobacco-dependents, this work aims studying the D.A.T. availability in age-paired control, tobacco-dependent and cannabis-dependent male subjects using Positron Emission Tomography (PET). Subjects are scanned on High Resolution Research Tomograph (H.R.R.T.) for one hour after injection of a selective D.A.T. radioligand ([{sup 11}C]P.E. 2 I.) [1]. The binding potential (B.P.) is calculated in order to obtained the specific binding of [{sup 11}C]P.E. 2 I. to the D.A.T. using the simplified reference tissue model of Lammertsma (S.R.T.M.) [2] and B.P. maps were generated according to Gunn model [3]. Comparison of mean B.P. obtained in Region Of Interest and voxel to voxel comparison of B.P. maps using S.P.M.5 were performed with M.A.N.C.O.V.A. controlled for age between control, tobacco-dependent and cannabis-dependent groups. Preliminary results are concordant between both approaches and shown significant decreases of the D.A.T. availability in the both groups of addicted subjects in comparison to controls at the level of dorsal and ventral striatum and the dorsal midbrain including substantia nigra and ventral tegmental area. However, no difference in D.A.T. binding between tobacco and cannabis dependents subjects was observed. These widespread modifications of D.A.T. availability in the dependents subjects

  9. Transportation

    Science.gov (United States)

    2007-01-01

    Faculty ii INDUSTRY TRAVEL Domestic Assistant Deputy Under Secretary of Defense (Transportation Policy), Washington, DC Department of...developed between the railroad and trucking industries. Railroads: Today’s seven Class I freight railroad systems move 42% of the nation’s intercity ...has been successfully employed in London to reduce congestion and observed by this industry study during its travels . It is currently being

  10. Direct projections from hypothalamic orexin neurons to brainstem cardiac vagal neurons.

    Science.gov (United States)

    Dergacheva, Olga; Yamanaka, Akihiro; Schwartz, Alan R; Polotsky, Vsevolod Y; Mendelowitz, David

    2016-12-17

    Orexin neurons are known to augment the sympathetic control of cardiovascular function, however the role of orexin neurons in parasympathetic cardiac regulation remains unclear. To test the hypothesis that orexin neurons contribute to parasympathetic control we selectively expressed channelrhodopsin-2 (ChR2) in orexin neurons in orexin-Cre transgenic rats and examined postsynaptic currents in cardiac vagal neurons (CVNs) in the dorsal motor nucleus of the vagus (DMV). Simultaneous photostimulation and recording in ChR2-expressing orexin neurons in the lateral hypothalamus resulted in reliable action potential firing as well as large whole-cell currents suggesting a strong expression of ChR2 and reliable optogenetic excitation. Photostimulation of ChR2-expressing fibers in the DMV elicited short-latency (ranging from 3.2ms to 8.5ms) postsynaptic currents in 16 out of 44 CVNs tested. These responses were heterogeneous and included excitatory glutamatergic (63%) and inhibitory GABAergic (37%) postsynaptic currents. The results from this study suggest different sub-population of orexin neurons may exert diverse influences on brainstem CVNs and therefore may play distinct functional roles in parasympathetic control of the heart. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  11. Chewing reduces sympathetic nervous response to stress and prevents poststress arrhythmias in rats.

    Science.gov (United States)

    Koizumi, So; Minamisawa, Susumu; Sasaguri, Kenichi; Onozuka, Minoru; Sato, Sadao; Ono, Yumie

    2011-10-01

    Reducing stress is important in preventing sudden death in patients with cardiovascular disease, as stressful events may cause autonomic imbalance and trigger fatal arrhythmias. Since chewing has been shown to inhibit stress-induced neuronal responses in the hypothalamus, we hypothesized that chewing could ameliorate stress-induced autonomic imbalance and prevent arrhythmias. To test this hypothesis, we analyzed changes in radiotelemetered electrocardiograms in rats that were allowed to chew a wooden stick during a 1-h period of immobilization stress. Chewing significantly reduced the occurrence of ventricular premature beats (VPBs) and complex ventricular ectopy after immobilization and prevented stress-induced prolongation of the QT interval of VPBs throughout the 10-h experimental period. It also prevented prolongation of the QRS complex and fluctuations in the QT interval in normal sinus rhythm beats preceding VPBs during both immobilization and in the poststress period. Fast Fourier transform-based spectral analysis of heart-rate variability further showed that chewing significantly inhibited the stress-induced increase in the power ratio of low-to-high frequency activity (LF/HF: a marker of sympathetic activity) during immobilization and in addition was associated with blunting of the stress-induced increase in plasma noradrenaline observed at the termination of immobilization. Similar suppressive effects on the occurrence of VPBs and the LF/HF were observed in rats that were administered the β-adrenergic blocker propranolol before immobilization. These results indicate that chewing can ameliorate sympathetic hyperactivity during stress and prevent poststress arrhythmias and suggest that chewing may provide a nonpharmacological and cost-effective treatment option for patients with a high risk of stress-induced fatal arrhythmia.

  12. Motor Neurons

    DEFF Research Database (Denmark)

    Hounsgaard, Jorn

    2017-01-01

    Motor neurons translate synaptic input from widely distributed premotor networks into patterns of action potentials that orchestrate motor unit force and motor behavior. Intercalated between the CNS and muscles, motor neurons add to and adjust the final motor command. The identity and functional...... in in vitro preparations is far from complete. Nevertheless, a foundation has been provided for pursuing functional significance of intrinsic response properties in motoneurons in vivo during motor behavior at levels from molecules to systems....

  13. Bradykinin Contributes to Sympathetic and Pressor Responses Evoked by Activation of Skeletal Muscle Afferents P2X in Heart Failure

    Directory of Open Access Journals (Sweden)

    Jihong Xing

    2016-11-01

    Full Text Available Background/Aims: Published data suggest that purinergic P2X receptors of muscle afferent nerves contribute to the enhanced sympathetic nervous activity (SNA and blood pressure (BP responses during static exercise in heart failure (HF. In this study, we examined engagement of bradykinin (BK in regulating responses of SNA and BP evoked by P2X stimulation in rats with HF. We further examined cellular mechanisms responsible for BK. We hypothesized that BK potentiates P2X currents of muscle dorsal root ganglion (DRG neurons, and this effect is greater in HF due to upregulation of BK kinin B2 and P2X3 receptor. As a result, BK amplifies muscle afferents P2X-mediated SNA and BP responses. Methods: Renal SNA and BP responses were recorded in control rats and rats with HF. Western Blot analysis and patch-clamp methods were employed to examine the receptor expression and function of DRG neurons involved in the effects of BK. Results: BK injected into the arterial blood supply of the hindlimb muscles heightened the reflex SNA and BP responses induced by P2X activation with α,β-methylene ATP to a greater degree in HF rats. In addition, HF upregulated the protein expression of kinin B2 and P2X3 in DRG and the prior application of BK increased the magnitude of α,β-methylene ATP-induced currents in muscle DRG neurons from HF rats. Conclusion: BK plays a facilitating role in modulating muscle afferent P2X-engaged reflex sympathetic and pressor responses. In HF, P2X responsivness is augmented due to increases in expression of kinin B2 and P2X3 receptors and P2X current activity.

  14. Continuous Thoracic Sympathetic Ganglion Block in Complex Regional Pain Syndrome Patients with Spinal Cord Stimulation Implantation

    Directory of Open Access Journals (Sweden)

    EungDon Kim

    2016-01-01

    Full Text Available The sympathetic block is widely used for treating neuropathic pain such as complex regional pain syndrome (CRPS. However, single sympathetic block often provides only short-term effect. Moreover, frequent procedures for sympathetic block may increase the risk of complications. The use of epidural route may be limited by concern of infection in case of previous implantation of the spinal cord stimulation (SCS. In contrast, a continuous sympathetic block can be administered without such concerns. The continuous thoracic sympathetic block (TSGB has been used to treat the ischemic disease and other neuropathic conditions such as postherpetic neuralgia. We administered continuous thoracic sympathetic block using catheter in CRPS patients who underwent SCS implantations and achieved desirable outcomes. We believe a continuous sympathetic block is a considerable option before performing neurolysis or radiofrequency rhizotomy and even after SCS implantation.

  15. Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis.

    Science.gov (United States)

    Nordström, Viola; Willershäuser, Monja; Herzer, Silke; Rozman, Jan; von Bohlen Und Halbach, Oliver; Meldner, Sascha; Rothermel, Ulrike; Kaden, Sylvia; Roth, Fabian C; Waldeck, Clemens; Gretz, Norbert; de Angelis, Martin Hrabě; Draguhn, Andreas; Klingenspor, Martin; Gröne, Hermann-Josef; Jennemann, Richard

    2013-01-01

    Hypothalamic neurons are main regulators of energy homeostasis. Neuronal function essentially depends on plasma membrane-located gangliosides. The present work demonstrates that hypothalamic integration of metabolic signals requires neuronal expression of glucosylceramide synthase (GCS; UDP-glucose:ceramide glucosyltransferase). As a major mechanism of central nervous system (CNS) metabolic control, we demonstrate that GCS-derived gangliosides interacting with leptin receptors (ObR) in the neuronal membrane modulate leptin-stimulated formation of signaling metabolites in hypothalamic neurons. Furthermore, ganglioside-depleted hypothalamic neurons fail to adapt their activity (c-Fos) in response to alterations in peripheral energy signals. Consequently, mice with inducible forebrain neuron-specific deletion of the UDP-glucose:ceramide glucosyltransferase gene (Ugcg) display obesity, hypothermia, and lower sympathetic activity. Recombinant adeno-associated virus (rAAV)-mediated Ugcg delivery to the arcuate nucleus (Arc) significantly ameliorated obesity, specifying gangliosides as seminal components for hypothalamic regulation of body energy homeostasis.

  16. Neuropeptide Y-like immunoreactivity in rat cranial parasympathetic neurons: coexistence with vasoactive intestinal peptide and choline acetyltransferase

    International Nuclear Information System (INIS)

    Leblanc, G.C.; Trimmer, B.A.; Landis, S.C.

    1987-01-01

    Neuropeptide Y (NPY) is widely distributed in the sympathetic nervous system, where it is colocalized with norepinephrine. The authors report here that NPY-immunoreactive neurons are also abundant in three cranial parasympathetic ganglia, the otic, sphenopalatine, and ciliary, in the rat measured by radioimmunoassay. High-performance liquid chromatographic analysis of the immunoreactive material present in the otic ganglion indicates that this material is very similar to porcine NPY and indistinguishable from the NPY-like immunoreactivity present in rat sympathetic neurons. These findings raise the possibility that NPY acts as a neuromodulator in the parasympathetic as well as the sympathetic nervous system. In contrast to what had been observed for sympathetic neurons, NPY-immunoreactive neurons in cranial parasympathetic ganglia do not contain detectable catecholamines or tyrosine hydroxylase immunoreactivity, and many do contain immunoreactivity for vasoactive intestinal peptide and/or choline acetyltransferase. These findings suggest that there is no simple rule governing coexpression of NPY with norepinephrine, acetylcholine, or vasoactive intestinal peptide in autonomic neurons. Further, while functional studies have indicated that NPY exerts actions on the peripheral vasculature which are antagonistic to those of acetylcholine and vasoactive intestinal peptide, the present results raise the possibility that these three substances may have complementary effects on other target tissues

  17. Optogenetic identification of hypothalamic orexin neuron projections to paraventricular spinally projecting neurons.

    Science.gov (United States)

    Dergacheva, Olga; Yamanaka, Akihiro; Schwartz, Alan R; Polotsky, Vsevolod Y; Mendelowitz, David

    2017-04-01

    Orexin neurons, and activation of orexin receptors, are generally thought to be sympathoexcitatory; however, the functional connectivity between orexin neurons and a likely sympathetic target, the hypothalamic spinally projecting neurons (SPNs) in the paraventricular nucleus of the hypothalamus (PVN) has not been established. To test the hypothesis that orexin neurons project directly to SPNs in the PVN, channelrhodopsin-2 (ChR2) was selectively expressed in orexin neurons to enable photoactivation of ChR2-expressing fibers while examining evoked postsynaptic currents in SPNs in rat hypothalamic slices. Selective photoactivation of orexin fibers elicited short-latency postsynaptic currents in all SPNs tested ( n = 34). These light-triggered responses were heterogeneous, with a majority being excitatory glutamatergic responses (59%) and a minority of inhibitory GABAergic (35%) and mixed glutamatergic and GABAergic currents (6%). Both glutamatergic and GABAergic responses were present in the presence of tetrodotoxin and 4-aminopyridine, suggesting a monosynaptic connection between orexin neurons and SPNs. In addition to generating postsynaptic responses, photostimulation facilitated action potential firing in SPNs (current clamp configuration). Glutamatergic, but not GABAergic, postsynaptic currents were diminished by application of the orexin receptor antagonist almorexant, indicating orexin release facilitates glutamatergic neurotransmission in this pathway. This work identifies a neuronal circuit by which orexin neurons likely exert sympathoexcitatory control of cardiovascular function. NEW & NOTEWORTHY This is the first study to establish, using innovative optogenetic approaches in a transgenic rat model, that there are robust heterogeneous projections from orexin neurons to paraventricular spinally projecting neurons, including excitatory glutamatergic and inhibitory GABAergic neurotransmission. Endogenous orexin release modulates glutamatergic, but not

  18. Simulating sympathetic detonation using the hydrodynamic models and constitutive equations

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Bo Hoon; Kim, Min Sung; Yoh, Jack J. [Dept. of Mechanical and Aerospace Engineering, Seoul National University, Seoul (Korea, Republic of); Sun, Tae Boo [Hanwha Corporation Defense Rand D Center, Daejeon (Korea, Republic of)

    2016-12-15

    A Sympathetic detonation (SD) is a detonation of an explosive charge by a nearby explosion. Most of times it is unintended while the impact of blast fragments or strong shock waves from the initiating donor explosive is the cause of SD. We investigate the SD of a cylindrical explosive charge (64 % RDX, 20 % Al, 16 % HTPB) contained in a steel casing. The constitutive relations for high explosive are obtained from a thermo-chemical code that provides the size effect data without the rate stick data typically used for building the rate law and equation of state. A full size SD test of eight pallet-packaged artillery shells is performed that provides the pressure data while the hydrodynamic model with proper constitutive relations for reactive materials and the fragmentation model for steel casing is conducted to replicate the experimental findings. The work presents a novel effort to accurately model and reproduce the sympathetic detonation event with a reduced experimental effort.

  19. Experiencing Physical Pain Leads to More Sympathetic Moral Judgments

    Science.gov (United States)

    Xiao, Qianguo; Zhu, Yi; Luo, Wen-bo

    2015-01-01

    Previous studies have shown that observing another’s pain can evoke other-oriented emotions, which instigate empathic concern for another’s needs. It is not clear whether experiencing first-hand physical pain may also evoke other-oriented emotion and thus influence people’s moral judgment. Based on the embodied simulation literature and neuroimaging evidence, the present research tested the idea that participants who experienced physical pain would be more sympathetic in their moral judgments. Study 1 showed that ice-induced physical pain facilitated higher self-assessments of empathy, which motivated participants to be more sympathetic in their moral judgments. Study 2 confirmed findings in study 1 and also showed that State Perspective Taking subscale of the State Empathy Scale mediated the effects of physical pain on moral judgment. These results provide support for embodied view of morality and for the view that pain can serve a positive psychosocial function. PMID:26465603

  20. The biophysics of renal sympathetic denervation using radiofrequency energy.

    Science.gov (United States)

    Patel, Hitesh C; Dhillon, Paramdeep S; Mahfoud, Felix; Lindsay, Alistair C; Hayward, Carl; Ernst, Sabine; Lyon, Alexander R; Rosen, Stuart D; di Mario, Carlo

    2014-05-01

    Renal sympathetic denervation is currently performed in the treatment of resistant hypertension by interventionists who otherwise do not typically use radiofrequency (RF) energy ablation in their clinical practice. Adequate RF lesion formation is dependent upon good electrode-tissue contact, power delivery, electrode-tissue interface temperature, target-tissue impedance and the size of the catheter's active electrode. There is significant interplay between these variables and hence an appreciation of the biophysical determinants of RF lesion formation is required to provide effective and safe clinical care to our patients. In this review article, we summarize the biophysics of RF ablation and explain why and how complications of renal sympathetic denervation may occur and discuss methods to minimise them.

  1. Does transcutaneous nerve stimulation have effect on sympathetic skin response?

    Science.gov (United States)

    Okuyucu, E Esra; Turhanoğlu, Ayşe Dicle; Guntel, Murat; Yılmazer, Serkan; Savaş, Nazan; Mansuroğlu, Ayhan

    2018-01-01

    This study examined the effects of transcutaneous electrical nerve stimulation (TENS) on the sympathetic nerve system by sympathetic skin response test. Fifty-five healthy volunteers received either: (i) 30minutes TENS (25 participants) (ii) 30minutes sham TENS (30 participants) and SSR test was performed pre- and post-TENS. The mean values of latency and peak-to-peak amplitude of five consecutive SSRs were calculated. A significant amplitude difference was found between TENS and sham TENS group both in right and left hand (p=0.04, p=0.01, respectively). However there was no significant latancy difference between two groups (p>0.05 ). TENS has an inhibitory effect on elicited SNS responses when compared with sham TENS control group. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Increased sympathetic tone in forearm subcutaneous tissue in primary hypothyroidism

    DEFF Research Database (Denmark)

    Vagn Nielsen, H; Hasselström, K; Feldt-Rasmussen, U

    1987-01-01

    vasoconstriction normally seen after lowering the forearm 40 cm below heart level was absent since SBF only decreased by 4% (+/- 7%, P greater than 0.1) during these conditions. In head-up vertical position we noticed a diminished baroreceptor response as SBF at heart level was reduced by 11% (+/- 7%, P greater...... than 0.1) compared to supine position. After proximal local anaesthesia SBF increased by 351% (+/- 81%, P less than 0.01) and disclosed a normal vasoconstrictor response as SBF was reduced by 53% (+/- 5%, P less than 0.01) during arm lowering. Five of the treated patients were restudied.......02)). In conclusion sympathetic vasoconstrictor activity in adipose tissue is markedly increased in primary hypothyroidism. Sympathetic tone and arterial pressure are reduced during treatment....

  3. Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB₁ receptor blockade.

    Science.gov (United States)

    Bellocchio, Luigi; Soria-Gómez, Edgar; Quarta, Carmelo; Metna-Laurent, Mathilde; Cardinal, Pierre; Binder, Elke; Cannich, Astrid; Delamarre, Anna; Häring, Martin; Martín-Fontecha, Mar; Vega, David; Leste-Lasserre, Thierry; Bartsch, Dusan; Monory, Krisztina; Lutz, Beat; Chaouloff, Francis; Pagotto, Uberto; Guzman, Manuel; Cota, Daniela; Marsicano, Giovanni

    2013-03-19

    Complex interactions between periphery and the brain regulate food intake in mammals. Cannabinoid type-1 (CB1) receptor antagonists are potent hypophagic agents, but the sites where this acute action is exerted and the underlying mechanisms are not fully elucidated. To dissect the mechanisms underlying the hypophagic effect of CB1 receptor blockade, we combined the acute injection of the CB1 receptor antagonist rimonabant with the use of conditional CB1-knockout mice, as well as with pharmacological modulation of different central and peripheral circuits. Fasting/refeeding experiments revealed that CB1 receptor signaling in many specific brain neurons is dispensable for the acute hypophagic effects of rimonabant. CB1 receptor antagonist-induced hypophagia was fully abolished by peripheral blockade of β-adrenergic transmission, suggesting that this effect is mediated by increased activity of the sympathetic nervous system. Consistently, we found that rimonabant increases gastrointestinal metabolism via increased peripheral β-adrenergic receptor signaling in peripheral organs, including the gastrointestinal tract. Blockade of both visceral afferents and glutamatergic transmission in the nucleus tractus solitarii abolished rimonabant-induced hypophagia. Importantly, these mechanisms were specifically triggered by lipid-deprivation, revealing a nutrient-specific component acutely regulated by CB1 receptor blockade. Finally, peripheral blockade of sympathetic neurotransmission also blunted central effects of CB1 receptor blockade, such as fear responses and anxiety-like behaviors. These data demonstrate that, independently of their site of origin, important effects of CB1 receptor blockade are expressed via activation of peripheral sympathetic activity. Thus, CB1 receptors modulate bidirectional circuits between the periphery and the brain to regulate feeding and other behaviors.

  4. Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB1 receptor blockade

    Science.gov (United States)

    Bellocchio, Luigi; Soria-Gómez, Edgar; Quarta, Carmelo; Metna-Laurent, Mathilde; Cardinal, Pierre; Binder, Elke; Cannich, Astrid; Delamarre, Anna; Häring, Martin; Martín-Fontecha, Mar; Vega, David; Leste-Lasserre, Thierry; Bartsch, Dusan; Monory, Krisztina; Lutz, Beat; Chaouloff, Francis; Pagotto, Uberto; Guzman, Manuel; Cota, Daniela; Marsicano, Giovanni

    2013-01-01

    Complex interactions between periphery and the brain regulate food intake in mammals. Cannabinoid type-1 (CB1) receptor antagonists are potent hypophagic agents, but the sites where this acute action is exerted and the underlying mechanisms are not fully elucidated. To dissect the mechanisms underlying the hypophagic effect of CB1 receptor blockade, we combined the acute injection of the CB1 receptor antagonist rimonabant with the use of conditional CB1-knockout mice, as well as with pharmacological modulation of different central and peripheral circuits. Fasting/refeeding experiments revealed that CB1 receptor signaling in many specific brain neurons is dispensable for the acute hypophagic effects of rimonabant. CB1 receptor antagonist-induced hypophagia was fully abolished by peripheral blockade of β-adrenergic transmission, suggesting that this effect is mediated by increased activity of the sympathetic nervous system. Consistently, we found that rimonabant increases gastrointestinal metabolism via increased peripheral β-adrenergic receptor signaling in peripheral organs, including the gastrointestinal tract. Blockade of both visceral afferents and glutamatergic transmission in the nucleus tractus solitarii abolished rimonabant-induced hypophagia. Importantly, these mechanisms were specifically triggered by lipid-deprivation, revealing a nutrient-specific component acutely regulated by CB1 receptor blockade. Finally, peripheral blockade of sympathetic neurotransmission also blunted central effects of CB1 receptor blockade, such as fear responses and anxiety-like behaviors. These data demonstrate that, independently of their site of origin, important effects of CB1 receptor blockade are expressed via activation of peripheral sympathetic activity. Thus, CB1 receptors modulate bidirectional circuits between the periphery and the brain to regulate feeding and other behaviors. PMID:23487769

  5. Central vs. peripheral neuraxial sympathetic control of porcine ventricular electrophysiology

    Science.gov (United States)

    Yamakawa, Kentaro; Howard-Quijano, Kimberly; Zhou, Wei; Rajendran, Pradeep; Yagishita, Daigo; Vaseghi, Marmar; Ajijola, Olujimi A.; Armour, J. Andrew; Shivkumar, Kalyanam; Ardell, Jeffrey L.

    2015-01-01

    Sympathoexcitation is associated with ventricular arrhythmogenesis. The aim of this study was to determine the role of thoracic dorsal root afferent neural inputs to the spinal cord in modulating ventricular sympathetic control of normal heart electrophysiology. We hypothesize that dorsal root afferent input tonically modulates basal and evoked efferent sympathetic control of the heart. A 56-electrode sock placed on the epicardial ventricle in anesthetized Yorkshire pigs (n = 17) recorded electrophysiological function, as well as activation recovery interval (ARI) and dispersion in ARI, at baseline conditions and during stellate ganglion electrical stimulation. Measures were compared between intact states and sequential unilateral T1–T4 dorsal root transection (DRTx), ipsilateral ventral root transection (VRTx), and contralateral dorsal and ventral root transections (DVRTx). Left or right DRTx decreased global basal ARI [Lt.DRTx: 369 ± 12 to 319 ± 13 ms (P < 0.01) and Rt.DRTx: 388 ± 19 to 356 ± 15 ms (P < 0.01)]. Subsequent unilateral VRTx followed by contralateral DRx+VRTx induced no further change. In intact states, left and right stellate ganglion stimulation shortened ARIs (6 ± 2% vs. 17 ± 3%), while increasing dispersion (+139% vs. +88%). There was no difference in magnitude of ARI or dispersion change with stellate stimulation following spinal root transections. Interruption of thoracic spinal afferent signaling results in enhanced basal cardiac sympathoexcitability without diminishing the sympathetic response to stellate ganglion stimulation. This suggests spinal dorsal root transection releases spinal cord-mediated tonic inhibitory control of efferent sympathetic tone, while maintaining intrathoracic cardiocentric neural networks. PMID:26661096

  6. Temperament affects sympathetic nervous function in a normal population.

    Science.gov (United States)

    Kim, Bora; Lee, Jae-Hon; Kang, Eun-Ho; Yu, Bum-Hee

    2012-09-01

    Although specific temperaments have been known to be related to autonomic nervous function in some psychiatric disorders, there are few studies that have examined the relationship between temperaments and autonomic nervous function in a normal population. In this study, we examined the effect of temperament on the sympathetic nervous function in a normal population. Sixty eight healthy subjects participated in the present study. Temperament was assessed using the Korean version of the Cloninger Temperament and Character Inventory (TCI). Autonomic nervous function was determined by measuring skin temperature in a resting state, which was recorded for 5 minutes from the palmar surface of the left 5th digit using a thermistor secured with a Velcro® band. Pearson's correlation analysis and multiple linear regression were used to examine the relationship between temperament and skin temperature. A higher harm avoidance score was correlated with a lower skin temperature (i.e. an increased sympathetic tone; r=-0.343, p=0.004) whereas a higher persistence score was correlated with a higher skin temperature (r=0.433, p=0.001). Hierarchical linear regression analysis revealed that harm avoidance was able to predict the variance of skin temperature independently, with a variance of 7.1% after controlling for sex, blood pressure and state anxiety and persistence was the factor predicting the variance of skin temperature with a variance of 5.0%. These results suggest that high harm avoidance is related to an increased sympathetic nervous function whereas high persistence is related to decreased sympathetic nervous function in a normal population.

  7. Temperament Affects Sympathetic Nervous Function in a Normal Population

    OpenAIRE

    Kim, Bora; Lee, Jae-Hon; Kang, Eun-Ho; Yu, Bum-Hee

    2012-01-01

    Objective Although specific temperaments have been known to be related to autonomic nervous function in some psychiatric disorders, there are few studies that have examined the relationship between temperaments and autonomic nervous function in a normal population. In this study, we examined the effect of temperament on the sympathetic nervous function in a normal population. Methods Sixty eight healthy subjects participated in the present study. Temperament was assessed using the Korean vers...

  8. Cardiorespiratory Coupling: Common Rhythms in Cardiac, Sympathetic, and Respiratory Activities

    Science.gov (United States)

    Dick, Thomas E.; Hsieh, Yee-Hsee; Dhingra, Rishi R.; Baekey, David M.; Galán, Roberto F.; Wehrwein, Erica; Morris, Kendall F.

    2014-01-01

    Cardiorespiratory coupling is an encompassing term describing more than the well-recognized influences of respiration on heart rate and blood pressure. Our data indicate that cardiorespiratory coupling reflects a reciprocal interaction between autonomic and respiratory control systems, and the cardiovascular system modulates the ventilatory pattern as well. For example, cardioventilatory coupling refers to the influence of heart beats and arterial pulse pressure on respiration and is the tendency for the next inspiration to start at a preferred latency after the last heart beat in expiration. Multiple complementary, well-described mechanisms mediate respiration’s influence on cardiovascular function, whereas mechanisms mediating the cardiovascular system’s influence on respiration may only be through the baroreceptors but are just being identified. Our review will describe a differential effect of conditioning rats with either chronic intermittent or sustained hypoxia on sympathetic nerve activity but also on ventilatory pattern variability. Both intermittent and sustained hypoxia increase sympathetic nerve activity after 2 weeks but affect sympatho-respiratory coupling differentially. Intermittent hypoxia enhances sympatho-respiratory coupling, which is associated with low variability in the ventilatory pattern. In contrast, after constant hypobaric hypoxia, 1-to-1 coupling between bursts of sympathetic and phrenic nerve activity is replaced by 2-to-3 coupling. This change in coupling pattern is associated with increased variability of the ventilatory pattern. After baro-denervating hypobaric hypoxic-conditioned rats, splanchnic sympathetic nerve activity becomes tonic (distinct bursts are absent) with decreases during phrenic nerve bursts and ventilatory pattern becomes regular. Thus, conditioning rats to either intermittent or sustained hypoxia accentuates the reciprocal nature of cardiorespiratory coupling. Finally, identifying a compelling physiologic

  9. Paroxysmal sympathetic hyperactivity: An entity to keep in mind.

    Science.gov (United States)

    Godoy, D A; Panhke, P; Guerrero Suarez, P D; Murillo-Cabezas, F

    2017-12-15

    Paroxysmal sympathetic hyperactivity (PSH) is a potentially life-threatening neurological emergency secondary to multiple acute acquired brain injuries. It is clinically characterized by the cyclic and simultaneous appearance of signs and symptoms secondary to exacerbated sympathetic discharge. The diagnosis is based on the clinical findings, and high alert rates are required. No widely available and validated homogeneous diagnostic criteria have been established to date. There have been recent consensus attempts to shed light on this obscure phenomenon. Its physiopathology is complex and has not been fully clarified. However, the excitation-inhibition model is the theory that best explains the different aspects of this condition, including the response to treatment with the available drugs. The key therapeutic references are the early recognition of the disorder, avoiding secondary injuries and the triggering of paroxysms. Once sympathetic crises occur, they must peremptorily aborted and prevented. of the later the syndrome is recognized, the poorer the patient outcome. Copyright © 2017 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.

  10. Sympathetic cooling of ions in a hybrid atom ion trap

    Energy Technology Data Exchange (ETDEWEB)

    Hoeltkemeier, Bastian

    2016-10-27

    In this thesis the dynamics of a trapped ion immersed in a spatially localized buffer gas is investigated. For a homogeneous buffer gas, the ion's energy distribution reaches a stable equilibrium only if the mass of the buffer gas atoms is below a critical value. This limitation can be overcome by using multipole traps in combination and/or a spatially confined buffer gas. Using a generalized model for elastic collisions of the ion with the buffer gas atoms, the ion's energy distribution is numerically determined for arbitrary buffer gas distributions and trap parameters. Three regimes characterized by the respective analytic form of the ion's equilibrium energy distribution are found. One of these is a novel regime at large atom-to-ion mass ratios where the final ion temperature can tuned by adiabatically decreasing the spatial extension of the buffer gas and the effective ion trap depth (forced sympathetic cooling). The second part of the thesis presents a hybrid atom ion trap designed for sympathetic cooling of hydroxide anions. In this hybrid trap the anions are immersed in a cloud of laser cooled rubidium atoms. The translational and rovibrational temperatures of the anions is probed by photodetachment tomography and spectroscopy which shows the first ever indication of sympathetic cooling of anions by laser cooled atoms.

  11. [Mirror neurons].

    Science.gov (United States)

    Rubia Vila, Francisco José

    2011-01-01

    Mirror neurons were recently discovered in frontal brain areas of the monkey. They are activated when the animal makes a specific movement, but also when the animal observes the same movement in another animal. Some of them also respond to the emotional expression of other animals of the same species. These mirror neurons have also been found in humans. They respond to or "reflect" actions of other individuals in the brain and are thought to represent the basis for imitation and empathy and hence the neurobiological substrate for "theory of mind", the potential origin of language and the so-called moral instinct.

  12. Distinct functional and temporal requirements for zebrafish Hdac1 during neural crest-derived craniofacial and peripheral neuron development.

    Science.gov (United States)

    Ignatius, Myron S; Unal Eroglu, Arife; Malireddy, Smitha; Gallagher, Glen; Nambiar, Roopa M; Henion, Paul D

    2013-01-01

    The regulation of gene expression is accomplished by both genetic and epigenetic means and is required for the precise control of the development of the neural crest. In hdac1(b382) mutants, craniofacial cartilage development is defective in two distinct ways. First, fewer hoxb3a, dlx2 and dlx3-expressing posterior branchial arch precursors are specified and many of those that are consequently undergo apoptosis. Second, in contrast, normal numbers of progenitors are present in the anterior mandibular and hyoid arches, but chondrocyte precursors fail to terminally differentiate. In the peripheral nervous system, there is a disruption of enteric, DRG and sympathetic neuron differentiation in hdac1(b382) mutants compared to wildtype embryos. Specifically, enteric and DRG-precursors differentiate into neurons in the anterior gut and trunk respectively, while enteric and DRG neurons are rarely present in the posterior gut and tail. Sympathetic neuron precursors are specified in hdac1(b382) mutants and they undergo generic neuronal differentiation but fail to undergo noradrenergic differentiation. Using the HDAC inhibitor TSA, we isolated enzyme activity and temporal requirements for HDAC function that reproduce hdac1(b382) defects in craniofacial and sympathetic neuron development. Our study reveals distinct functional and temporal requirements for zebrafish hdac1 during neural crest-derived craniofacial and peripheral neuron development.

  13. Distinct functional and temporal requirements for zebrafish Hdac1 during neural crest-derived craniofacial and peripheral neuron development.

    Directory of Open Access Journals (Sweden)

    Myron S Ignatius

    Full Text Available The regulation of gene expression is accomplished by both genetic and epigenetic means and is required for the precise control of the development of the neural crest. In hdac1(b382 mutants, craniofacial cartilage development is defective in two distinct ways. First, fewer hoxb3a, dlx2 and dlx3-expressing posterior branchial arch precursors are specified and many of those that are consequently undergo apoptosis. Second, in contrast, normal numbers of progenitors are present in the anterior mandibular and hyoid arches, but chondrocyte precursors fail to terminally differentiate. In the peripheral nervous system, there is a disruption of enteric, DRG and sympathetic neuron differentiation in hdac1(b382 mutants compared to wildtype embryos. Specifically, enteric and DRG-precursors differentiate into neurons in the anterior gut and trunk respectively, while enteric and DRG neurons are rarely present in the posterior gut and tail. Sympathetic neuron precursors are specified in hdac1(b382 mutants and they undergo generic neuronal differentiation but fail to undergo noradrenergic differentiation. Using the HDAC inhibitor TSA, we isolated enzyme activity and temporal requirements for HDAC function that reproduce hdac1(b382 defects in craniofacial and sympathetic neuron development. Our study reveals distinct functional and temporal requirements for zebrafish hdac1 during neural crest-derived craniofacial and peripheral neuron development.

  14. Orexin inputs to caudal raphé neurons involved in thermal, cardiovascular, and gastrointestinal regulation.

    Science.gov (United States)

    Berthoud, Hans-Rudolf; Patterson, Laurel M; Sutton, Gregory M; Morrison, Christopher; Zheng, Huiyuan

    2005-02-01

    Orexin-expressing neurons in the lateral hypothalamus with their wide projections throughout the brain are important for the regulation of sleep and wakefulness, ingestive behavior, and the coordination of these behaviors in the environmental context. To further identify downstream effector targets of the orexin system, we examined in detail orexin-A innervation of the caudal raphe nuclei in the medulla, known to harbor sympathetic preganglionic motor neurons involved in thermal, cardiovascular, and gastrointestinal regulation. All three components of the caudal raphe nuclei, raphe pallidus, raphe obscurus, and parapyramidal nucleus, are innervated by orexin-A-immunoreactive fibers. Using confocal microscopy, we demonstrate close anatomical appositions between varicose orexin-A immunoreactive axon profiles and sympathetic premotor neurons identified with either a transneuronal retrograde pseudorabies virus tracer injected into the interscapular brown fat pads, or with in situ hybridization of pro-TRH mRNA. Furthermore, orexin-A injected into the fourth ventricle induced c-Fos expression in the raphe pallidus and parapyramidal nucleus. These findings suggest that orexin neurons in the hypothalamus can modulate brown fat thermogenesis, cardiovascular, and gastrointestinal functions by acting directly on neurons in the caudal raphe nuclei, and support the idea that orexin's simultaneous stimulation of food intake and sympathetic activity might have evolved as a mechanism to stay alert while foraging.

  15. Glutamate neurons are intermixed with midbrain dopamine neurons in nonhuman primates and humans

    Science.gov (United States)

    Root, David H.; Wang, Hui-Ling; Liu, Bing; Barker, David J.; Mód, László; Szocsics, Péter; Silva, Afonso C.; Maglóczky, Zsófia; Morales, Marisela

    2016-01-01

    The rodent ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) contain dopamine neurons intermixed with glutamate neurons (expressing vesicular glutamate transporter 2; VGluT2), which play roles in reward and aversion. However, identifying the neuronal compositions of the VTA and SNC in higher mammals has remained challenging. Here, we revealed VGluT2 neurons within the VTA and SNC of nonhuman primates and humans by simultaneous detection of VGluT2 mRNA and tyrosine hydroxylase (TH; for identification of dopamine neurons). We found that several VTA subdivisions share similar cellular compositions in nonhuman primates and humans; their rostral linear nuclei have a high prevalence of VGluT2 neurons lacking TH; their paranigral and parabrachial pigmented nuclei have mostly TH neurons, and their parabrachial pigmented nuclei have dual VGluT2-TH neurons. Within nonhuman primates and humans SNC, the vast majority of neurons are TH neurons but VGluT2 neurons were detected in the pars lateralis subdivision. The demonstration that midbrain dopamine neurons are intermixed with glutamate or glutamate-dopamine neurons from rodents to humans offers new opportunities for translational studies towards analyzing the roles that each of these neurons play in human behavior and in midbrain-associated illnesses such as addiction, depression, schizophrenia, and Parkinson’s disease. PMID:27477243

  16. Systemic Glucoregulation by Glucose-Sensing Neurons in the Ventromedial Hypothalamic Nucleus (VMH).

    Science.gov (United States)

    Shimazu, Takashi; Minokoshi, Yasuhiko

    2017-05-01

    The ventromedial hypothalamic nucleus (VMH) regulates glucose production in the liver as well as glucose uptake and utilization in peripheral tissues, including skeletal muscle and brown adipose tissue, via efferent sympathetic innervation and neuroendocrine mechanisms. The action of leptin on VMH neurons also increases glucose uptake in specific peripheral tissues through the sympathetic nervous system, with improved insulin sensitivity. On the other hand, subsets of VMH neurons, such as those that express steroidogenic factor 1 (SF1), sense changes in the ambient glucose concentration and are characterized as glucose-excited (GE) and glucose-inhibited (GI) neurons whose action potential frequency increases and decreases, respectively, as glucose levels rise. However, how these glucose-sensing (GE and GI) neurons in the VMH contribute to systemic glucoregulation remains poorly understood. In this review, we provide historical background and discuss recent advances related to glucoregulation by VMH neurons. In particular, the article describes the role of GE neurons in the control of peripheral glucose utilization and insulin sensitivity, which depend on mitochondrial uncoupling protein 2 of the neurons, as well as that of GI neurons in the control of hepatic glucose production through hypoglycemia-induced counterregulatory mechanisms.

  17. Orexin neurons receive glycinergic innervations.

    Directory of Open Access Journals (Sweden)

    Mari Hondo

    Full Text Available Glycine, a nonessential amino-acid that acts as an inhibitory neurotransmitter in the central nervous system, is currently used as a dietary supplement to improve the quality of sleep, but its mechanism of action is poorly understood. We confirmed the effects of glycine on sleep/wakefulness behavior in mice when administered peripherally. Glycine administration increased non-rapid eye movement (NREM sleep time and decreased the amount and mean episode duration of wakefulness when administered in the dark period. Since peripheral administration of glycine induced fragmentation of sleep/wakefulness states, which is a characteristic of orexin deficiency, we examined the effects of glycine on orexin neurons. The number of Fos-positive orexin neurons markedly decreased after intraperitoneal administration of glycine to mice. To examine whether glycine acts directly on orexin neurons, we examined the effects of glycine on orexin neurons by patch-clamp electrophysiology. Glycine directly induced hyperpolarization and cessation of firing of orexin neurons. These responses were inhibited by a specific glycine receptor antagonist, strychnine. Triple-labeling immunofluorescent analysis showed close apposition of glycine transporter 2 (GlyT2-immunoreactive glycinergic fibers onto orexin-immunoreactive neurons. Immunoelectron microscopic analysis revealed that GlyT2-immunoreactive terminals made symmetrical synaptic contacts with somata and dendrites of orexin neurons. Double-labeling immunoelectron microscopy demonstrated that glycine receptor alpha subunits were localized in the postsynaptic membrane of symmetrical inhibitory synapses on orexin neurons. Considering the importance of glycinergic regulation during REM sleep, our observations suggest that glycine injection might affect the activity of orexin neurons, and that glycinergic inhibition of orexin neurons might play a role in physiological sleep regulation.

  18. Intrathecal infusion of a Ca(2+)-permeable AMPA channel blocker slows loss of both motor neurons and of the astrocyte glutamate transporter, GLT-1 in a mutant SOD1 rat model of ALS.

    Science.gov (United States)

    Yin, Hong Z; Tang, Darryl T; Weiss, John H

    2007-10-01

    Elevated extracellular glutamate, resulting from a loss of astrocytic glutamate transport capacity, may contribute to excitotoxic motor neuron (MN) damage in ALS. Accounting for their high excitotoxic vulnerability, MNs possess large numbers of unusual Ca(2+)-permeable AMPA channels (Ca-AMPA channels), the activation of which triggers mitochondrial Ca(2+) overload and strong reactive oxygen species (ROS) generation. However, the causes of the astrocytic glutamate transport loss remain unexplained. To assess the role of Ca-AMPA channels on the evolution of pathology in vivo, we have examined effects of prolonged intrathecal infusion of the Ca-AMPA channel blocker, 1-naphthyl acetylspermine (NAS), in G93A transgenic rat models of ALS. In wild-type animals, immunoreactivity for the astrocytic glutamate transporter, GLT-1, was particularly strong around ventral horn MNs. However, a marked loss of ventral horn GLT-1 was observed, along with substantial MN damage, prior to onset of symptoms (90-100 days) in the G93A rats. Conversely, labeling with the oxidative marker, nitrotyrosine, was increased in the neuropil surrounding MNs in the transgenic animals. Compared to sham-treated G93A animals, 30-day NAS infusions (starting at 67+/-2 days of age) markedly diminished the loss of both MNs and of astrocytic GLT-1 labeling. These observations are compatible with the hypothesis that activation of Ca-AMPA channels on MNs contributes, likely in part through oxidative mechanisms, to loss of glutamate transporter in surrounding astrocytes.

  19. Free fatty acid receptor 3 is a key target of short chain fatty acid. What is the impact on the sympathetic nervous system?

    Science.gov (United States)

    López Soto, Eduardo Javier; Gambino, Luisina Ongaro; Mustafá, Emilio Román

    2014-01-01

    Nervous system (NS) activity participates in metabolic homeostasis by detecting peripheral signal molecules derived from food intake and energy balance. High quality diets are thought to include fiber-rich foods like whole grain rice, breads, cereals, and grains. Several studies have associated high consumption of fiber-enriched diets with a reduced risk of diabetes, obesity, and gastrointestinal disorders. In the lower intestine, anaerobic fermentation of soluble fibers by microbiota produces short chain fatty acids (SCFAs), key energy molecules that have a recent identified leading role in the intestinal gluconeogenesis, promoting beneficial effects on glucose tolerance and insulin resistance. SCFAs are also signaling molecules that bind to specific G-protein coupled receptors (GPCRs) named Free Fatty Acid Receptor 3 (FFA3, GPR41) and 2 (FFA2, GPR43). However, how SCFAs impact NS activity through their GPCRs is poorly understood. Recently, studies have demonstrated the presence of FFA2 and FFA3 in the sympathetic NS of rat, mouse and human. Two studies have showed that FFA3 activation by SCFAs increases firing and norepinephrine (NE) release from sympathetic neurons. However, the recent study from the Ikeda Laboratory revealed that activation of FFA3 by SCFAs impairs N-type calcium channel (NTCC) activity, which contradicts the idea of FFA3 activation leading to increased action potential evoked NE release. Here we will discuss the scope of the latter study and the putative physiological role of SCFAs and FFAs in the sympathetic NS.

  20. Exercise training preserves vagal preganglionic neurones and restores parasympathetic tonus in heart failure.

    Science.gov (United States)

    Ichige, Marcelo H A; Santos, Carla R; Jordão, Camila P; Ceroni, Alexandre; Negrão, Carlos E; Michelini, Lisete C

    2016-11-01

    Heart Failure (HF) is accompanied by reduced ventricular function, activation of compensatory neurohormonal mechanisms and marked autonomic dysfunction characterized by exaggerated sympathoexcitation and reduced parasympathetic activity. With 6 weeks of exercise training, HF-related loss of choline acetyltransferase (ChAT)-positive vagal preganglionic neurones is avoided, restoring the parasympathetic tonus to the heart, and the immunoreactivity of dopamine β-hydroxylase-positive premotor neurones that drive sympathetic outflow to the heart is reduced. Training-induced correction of autonomic dysfunction occurs even with the persistence of abnormal ventricular function. Strong positive correlation between improved parasympathetic tonus to the heart and increased ChAT immunoreactivity in vagal preganglionic neurones after training indicates this is a crucial mechanism to restore autonomic function in heart failure. Exercise training is an efficient tool to attenuate sympathoexcitation, a hallmark of heart failure (HF). Although sympathetic modulation in HF is widely studied, information regarding parasympathetic control is lacking. We examined the combined effects of sympathetic and vagal tonus to the heart in sedentary (Sed) and exercise trained (ET) HF rats and the contribution of respective premotor and preganglionic neurones. Wistar rats submitted to coronary artery ligation or sham surgery were assigned to training or sedentary protocols for 6 weeks. After haemodynamic, autonomic tonus (atropine and atenolol i.v.) and ventricular function determinations, brains were collected for immunoreactivity assays (choline acetyltransferase, ChATir; dopamine β-hydroxylase, DBHir) and neuronal counting in the dorsal motor nucleus of vagus (DMV), nucleus ambiguus (NA) and rostroventrolateral medulla (RVLM). HF-Sed vs. SHAM-Sed exhibited decreased exercise capacity, reduced ejection fraction, increased left ventricle end diastolic pressure, smaller positive and negative

  1. Marital conflict and children's externalizing behavior: interactions between parasympathetic and sympathetic nervous system activity

    National Research Council Canada - National Science Library

    El-Sheikh, Mona; Beauchaine, Theodore P; Moore, Ginger A

    2009-01-01

    "Toward greater specificity in the prediction of externalizing problems in the context of interparental conflict, interactions between children's parasympathetic and sympathetic nervous system (PNS and SNS...

  2. Burst Activity and Heart Rhythm Modulation in the Sympathetic Outflow to the Heart

    National Research Council Canada - National Science Library

    Baselli, G

    2001-01-01

    In 13 decerebrate, artificially ventilated cats preganglionic sympathetic outflow to the heart was recorded with ECG and ventilation signal, A novel algorithm was implemented that extracts weighted...

  3. Sympathetic activity induced by naloxone-precipitated morphine withdrawal is blocked in genetically engineered mice lacking functional CRF1 receptor

    International Nuclear Information System (INIS)

    García-Carmona, Juan-Antonio; Martínez-Laorden, Elena; Milanés, María-Victoria; Laorden, María-Luisa

    2015-01-01

    There is large body evidence indicating that stress can lead to cardiovascular disease. However, the exact brain areas and the mechanisms involved remain to be revealed. Here, we performed a series of experiments to characterize the role of CRF1 receptor (CRF1R) in the stress response induced by naloxone-precipitated morphine withdrawal. The experiments were performed in the hypothalamic paraventricular nucleus (PVN) ventrolateral medulla (VLM), brain regions involved in the regulation of cardiovascular activity, and in the right ventricle by using genetically engineered mice lacking functional CRF1R levels (KO). Mice were treated with increasing doses of morphine and withdrawal was precipitated by naloxone administration. Noradrenaline (NA) turnover, c-Fos, expression, PKA and TH phosphorylated at serine 40, was evaluated by high-performance liquid chromatography (HPLC), immunohistochemistry and immunoblotting. Morphine withdrawal induced an enhancement of NA turnover in PVN in parallel with an increase in TH neurons expressing c-Fos in VLM in wild-type mice. In addition we have demonstrated an increase in NA turnover, TH phosphorylated at serine 40 and PKA levels in heart. The main finding of the present study was that NA turnover, TH positive neurons that express c-Fos, TH phosphorylated at serine 40 and PKA expression observed during morphine withdrawal were significantly inhibited in CRF1R KO mice. Our results demonstrate that CRF/CRF1R activation may contribute to the adaptive changes induced by naloxone-precipitated withdrawal in the heart and in the brain areas which modulate the cardiac sympathetic function and suggest that CRF/CRF1R pathways could be contributing to cardiovascular disease associated to opioid addiction. - Highlights: • Naloxone-precipitated morphine withdrawal increases sympathetic activity in the PVN and heart. • Co-localization of TH phosphorylated at serine 40/c-Fos in the VLM after morphine withdrawal • Naloxone

  4. Sympathetic activity induced by naloxone-precipitated morphine withdrawal is blocked in genetically engineered mice lacking functional CRF1 receptor

    Energy Technology Data Exchange (ETDEWEB)

    García-Carmona, Juan-Antonio; Martínez-Laorden, Elena; Milanés, María-Victoria; Laorden, María-Luisa

    2015-02-15

    There is large body evidence indicating that stress can lead to cardiovascular disease. However, the exact brain areas and the mechanisms involved remain to be revealed. Here, we performed a series of experiments to characterize the role of CRF1 receptor (CRF1R) in the stress response induced by naloxone-precipitated morphine withdrawal. The experiments were performed in the hypothalamic paraventricular nucleus (PVN) ventrolateral medulla (VLM), brain regions involved in the regulation of cardiovascular activity, and in the right ventricle by using genetically engineered mice lacking functional CRF1R levels (KO). Mice were treated with increasing doses of morphine and withdrawal was precipitated by naloxone administration. Noradrenaline (NA) turnover, c-Fos, expression, PKA and TH phosphorylated at serine 40, was evaluated by high-performance liquid chromatography (HPLC), immunohistochemistry and immunoblotting. Morphine withdrawal induced an enhancement of NA turnover in PVN in parallel with an increase in TH neurons expressing c-Fos in VLM in wild-type mice. In addition we have demonstrated an increase in NA turnover, TH phosphorylated at serine 40 and PKA levels in heart. The main finding of the present study was that NA turnover, TH positive neurons that express c-Fos, TH phosphorylated at serine 40 and PKA expression observed during morphine withdrawal were significantly inhibited in CRF1R KO mice. Our results demonstrate that CRF/CRF1R activation may contribute to the adaptive changes induced by naloxone-precipitated withdrawal in the heart and in the brain areas which modulate the cardiac sympathetic function and suggest that CRF/CRF1R pathways could be contributing to cardiovascular disease associated to opioid addiction. - Highlights: • Naloxone-precipitated morphine withdrawal increases sympathetic activity in the PVN and heart. • Co-localization of TH phosphorylated at serine 40/c-Fos in the VLM after morphine withdrawal • Naloxone

  5. Percutaneous renal sympathetic nerve ablation for loin pain haematuria syndrome.

    Science.gov (United States)

    Gambaro, Giovanni; Fulignati, Pierluigi; Spinelli, Alessio; Rovella, Valentina; Di Daniele, Nicola

    2013-09-01

    Loin pain haematuria syndrome (LPHS) is a severe renal pain condition of uncertain origin and often resistant to treatment. Nephrectomy and renal autotrasplantation have occasionally been performed in very severe cases. Its pathogenesis is controversial. A 40-year-old hypertensive lady was diagnosed with LPHS after repeated diagnostic imaging procedures had ruled out any renal, abdominal or spinal conditions to justify pain. Notwithstanding treatment with three drugs, she had frequent hypertensive crises during which the loin pain was dramatically exacerbated. Vascular causes of the pain and hypertension were investigated and excluded. Her renal function was normal. The patient was referred to a multidisciplinary pain clinic, but had no significant improvement in her pain symptoms despite the use of non-steroidal anti-inflammatory drugs, adjuvant antidepressants and opioid-like agents. The pain and the discomfort were so severe that her quality of life was very poor, and her social and professional activities were compromised. Nephrectomy and renal autotransplantation have occasionally been performed in these cases. Since visceral pain signals flow through afferent sympathetic fibres, we felt that percutaneous catheter-based radiofrequency ablation of the renal sympathetic nerve fibres (recently introduced for the treatment of drug-resistant hypertension) could be valuable for pain relief. We treated the patient with radiofrequency ablation (Medtronic Symplicity Catheter) applied only to the right renal artery. After a 6-month follow-up, the patient is pain free and normotensive with all drugs withdrawn. She has experienced no hypertensive crises in the meantime. This observation suggests that percutaneous sympathetic denervation could prove to be an effective mini-invasive strategy for the treatment of chronic renal pain, and LPHS in particular.

  6. Study of sympathetic nerve activity in young Indian obese individuals

    Directory of Open Access Journals (Sweden)

    B Kalpana

    2013-01-01

    Full Text Available Background: Obesity is the culmination of a chronic imbalance between energy intake and energy expenditure. This energy balance can be potentially affected by the activity of autonomic nervous system (ANS. Altered sympathetic nerve function may be of importance in obesity. Objective: The present study is an attempt to pinpoint the defect (if any in the activity of sympathetic limb of the ANS in obesity, by subjecting to isometric exercise stress. Materials and Methods: A total of 81 females belonging to the age group of 18-22 years were recruited for the study. The participants were divided into two groups as normal weight and obese based on WHO guidelines for Asia Pacific region. After recording the resting blood pressure, they were subjected to isometric exercise by Handgrip dynamometer. Blood pressure was recorded again, and the difference was noted down. All recorded parameters were compared between two groups using unpaired t test. The relationship between body mass index (BMI and rise in diastolic pressure was quantified by Pearson′s correlation test. A P value less than 0.05 was considered as significant. Results: In obese, the diastolic pressure was significantly higher at rest, but showed reduced rise during handgrip test in comparison with normal weight individuals. Also, the rise in diastolic pressure exhibited a negative relation with BMI. Conclusion: The result is suggestive of impaired autonomic function at rest and reduced sympathetic activity in the group of obese when subjected to stress. This could make them more prone for future development of hypertension or other cardiovascular disorders.

  7. TARGETED STELLATE DECENTRALIZATION: IMPLICATIONS FOR SYMPATHETIC CONTROL OF VENTRICULAR ELECTROPHYSIOLOGY

    Science.gov (United States)

    Buckley, Una; Yamakawa, Kentaro; Takamiya, Tatsuo; Armour, J. Andrew; Shivkumar, Kalyanam; Ardell, Jeffrey L.

    2015-01-01

    Background Selective, bilateral cervicothoracic sympathectomy has proven to be effective for managing ventricular arrhythmias in the setting of structural heart disease. The procedure currently employed removes the caudal portions of both stellate ganglia, along with thoracic chain ganglia down to T4 ganglia. Objective To define the relative contributions of T1-T2 and the T3-T4 paravertebral ganglia in modulating ventricular electrical function. Methods In anesthetized vagotomised porcine subjects (n=8), the heart was exposed via sternotomy along with right and left paravertebral sympathetic ganglia to the T4 level. A 56-electrode epicardial sock was placed over both ventricles to assess epicardial activation recovery intervals (ARI) in response to individually stimulating right and left stellate vs T3 paravertebral ganglia. Responses to T3 stimuli were repeated following surgical removal of the caudal portions of stellate ganglia and T2 bilaterally. Results In intact preparations, stellate ganglion vs T3 stimuli (4Hz, 4ms duration) were titrated to produce equivalent decreases in global ventricular ARIs (right-side 85±6 vs 55±10 ms; left-side 24±3 vs 17±7 ms). Threshold of stimulus intensity applied to T3 ganglia to achieve threshold was 3 times that of T1 threshold. ARIs in unstimulated states were unaffected by bilateral stellate-T2 ganglion removal. Following acute decentralization, T3 stimulation failed to change ARIs. Conclusion Preganglionic sympathetic efferents arising from the T1-T4 spinal cord that project to the heart transit through stellate ganglia via the paravertebral chain. T1-T2 surgical excision is thus sufficient to functionally interrupt central control of peripheral sympathetic efferent activity. PMID:26282244

  8. Sympathetic ophthalmia after 23-gauge transconjunctival sutureless vitrectomy

    Directory of Open Access Journals (Sweden)

    Masatoshi Haruta

    2010-11-01

    Full Text Available Masatoshi Haruta1, Hirokazu Mukuno2, Kazuaki Nishijima3, Hitoshi Takagi4, Mihori Kita51Department of Ophthalmology, Kurume University School of Medicine, Kurume, Fukuoka, Japan; 2Department of Ophthalmology, Konan Hospital, Kobe, Hyogo, Japan; 3Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Kyoto, Japan; 4Department of Ophthalmology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan; 5Department of Ophthalmology, Hyogo Prefectural Amagasaki Hospital, Amagasaki, Hyogo, JapanPurpose: We report a case of a sympathetic ophthalmia that occurred after 23-gauge transconjunctival sutureless vitrectomy for a retinal detachment.Case report: A 41-year-old Japanese woman underwent combined phacoemulsification with intraocular lens implantation and 23-gauge transconjunctival sutureless vitrectomy for a rhegmatogenous retinal detachment in the right eye. Endolaser photocoagulation and silicone oil tamponade were used to manage inferior retinal holes. Four weeks after the surgery, she returned with a 5-day history of reduced vision and metamorphopsia in her left eye. Slit-lamp examination showed a shallow anterior chamber in the right eye and moderate anterior uveitis bilaterally. Silicone oil bubbles and pigment dispersion were observed in the subconjunctival space adjacent to the right eye’s superonasal sclerotomy site. Fundus examination showed multifocal serous retinal detachments in both eyes. A diagnosis of sympathetic ophthalmia was made and the patient was treated with intensive topical and systemic steroids. The subretinal fluid cleared in both eyes following treatment. Twelve months after the onset of inflammation, the patient’s condition was stable on a combination of oral cyclosporine and topical steroids. Sunset glow retinal changes remain, but there has been no evidence of recurrent inflammation.Conclusion: Sympathetic ophthalmia can develop after 23-gauge

  9. Activation of afferent renal nerves modulates RVLM-projecting PVN neurons.

    Science.gov (United States)

    Xu, Bo; Zheng, Hong; Liu, Xuefei; Patel, Kaushik P

    2015-05-01

    Renal denervation for the treatment of hypertension has proven to be successful; however, the underlying mechanism/s are not entirely clear. To determine if preautonomic neurons in the paraventricular nucleus (PVN) respond to afferent renal nerve (ARN) stimulation, extracellular single-unit recording was used to investigate the contribution of the rostral ventrolateral medulla (RVLM)-projecting PVN (PVN-RVLM) neurons to the response elicited during stimulation of ARN. In 109 spontaneously active neurons recorded in the PVN of anesthetized rats, 25 units were antidromically activated from the RVLM. Among these PVN-RVLM neurons, 84% (21/25) were activated by ARN stimulation. The baseline discharge rate was significantly higher in these neurons than those PVN-RVLM neurons not activated by ARN stimulation (16%, 4/25). The responsiveness of these neurons to baroreflex activation induced by phenylephrine and activation of cardiac sympathetic afferent reflex (CSAR) was also examined. Almost all of the PVN neurons that responded to ARN stimulation were sensitive to baroreflex (95%) and CSAR (100%). The discharge characteristics for nonevoked neurons (not activated by RVLM antidromic stimulation) showed that 23% of these PVN neurons responded to ARN stimulation. All the PVN neurons that responded to ARN stimulation were activated by N-methyl-D-aspartate, and these responses were attenuated by the glutamate receptor blocker AP5. These experiments demonstrated that sensory information originating in the kidney is integrated at the level of preautonomic neurons within the PVN, providing a novel mechanistic insight for use of renal denervation in the modulation of sympathetic outflow in disease states such as hypertension and heart failure. Copyright © 2015 the American Physiological Society.

  10. Memory coherence of a sympathetically cooled trapped-ion qubit

    International Nuclear Information System (INIS)

    Home, J. P.; McDonnell, M. J.; Szwer, D. J.; Keitch, B. C.; Lucas, D. M.; Stacey, D. N.; Steane, A. M.

    2009-01-01

    We demonstrate sympathetic cooling of a 43 Ca + trapped-ion 'memory' qubit by a 40 Ca + 'coolant' ion sufficiently near the ground state of motion for fault-tolerant quantum logic, while maintaining coherence of the qubit. This is an essential ingredient in trapped-ion quantum computers. The isotope shifts are sufficient to suppress decoherence and phase shifts of the memory qubit due to the cooling light which illuminates both ions. We measure the qubit coherence during ten cycles of sideband cooling, finding a coherence loss of 3.3% per cooling cycle. The natural limit of the method is O(10 -4 ) infidelity per cooling cycle.

  11. Neurons other than motor neurons in motor neuron disease.

    Science.gov (United States)

    Ruffoli, Riccardo; Biagioni, Francesca; Busceti, Carla L; Gaglione, Anderson; Ryskalin, Larisa; Gambardella, Stefano; Frati, Alessandro; Fornai, Francesco

    2017-11-01

    Amyotrophic lateral sclerosis (ALS) is typically defined by a loss of motor neurons in the central nervous system. Accordingly, morphological analysis for decades considered motor neurons (in the cortex, brainstem and spinal cord) as the neuronal population selectively involved in ALS. Similarly, this was considered the pathological marker to score disease severity ex vivo both in patients and experimental models. However, the concept of non-autonomous motor neuron death was used recently to indicate the need for additional cell types to produce motor neuron death in ALS. This means that motor neuron loss occurs only when they are connected with other cell types. This concept originally emphasized the need for resident glia as well as non-resident inflammatory cells. Nowadays, the additional role of neurons other than motor neurons emerged in the scenario to induce non-autonomous motor neuron death. In fact, in ALS neurons diverse from motor neurons are involved. These cells play multiple roles in ALS: (i) they participate in the chain of events to produce motor neuron loss; (ii) they may even degenerate more than and before motor neurons. In the present manuscript evidence about multi-neuronal involvement in ALS patients and experimental models is discussed. Specific sub-classes of neurons in the whole spinal cord are reported either to degenerate or to trigger neuronal degeneration, thus portraying ALS as a whole spinal cord disorder rather than a disease affecting motor neurons solely. This is associated with a novel concept in motor neuron disease which recruits abnormal mechanisms of cell to cell communication.

  12. Hindbrain Catecholamine Neurons Activate Orexin Neurons During Systemic Glucoprivation in Male Rats.

    Science.gov (United States)

    Li, Ai-Jun; Wang, Qing; Elsarelli, Megan M; Brown, R Lane; Ritter, Sue

    2015-08-01

    Hindbrain catecholamine neurons are required for elicitation of feeding responses to glucose deficit, but the forebrain circuitry required for these responses is incompletely understood. Here we examined interactions of catecholamine and orexin neurons in eliciting glucoprivic feeding. Orexin neurons, located in the perifornical lateral hypothalamus (PeFLH), are heavily innervated by hindbrain catecholamine neurons, stimulate food intake, and increase arousal and behavioral activation. Orexin neurons may therefore contribute importantly to appetitive responses, such as food seeking, during glucoprivation. Retrograde tracing results showed that nearly all innervation of the PeFLH from the hindbrain originated from catecholamine neurons and some raphe nuclei. Results also suggested that many catecholamine neurons project collaterally to the PeFLH and paraventricular hypothalamic nucleus. Systemic administration of the antiglycolytic agent, 2-deoxy-D-glucose, increased food intake and c-Fos expression in orexin neurons. Both responses were eliminated by a lesion of catecholamine neurons innervating orexin neurons using the retrogradely transported immunotoxin, anti-dopamine-β-hydroxylase saporin, which is specifically internalized by dopamine-β-hydroxylase-expressing catecholamine neurons. Using designer receptors exclusively activated by designer drugs in transgenic rats expressing Cre recombinase under the control of tyrosine hydroxylase promoter, catecholamine neurons in cell groups A1 and C1 of the ventrolateral medulla were activated selectively by peripheral injection of clozapine-N-oxide. Clozapine-N-oxide injection increased food intake and c-Fos expression in PeFLH orexin neurons as well as in paraventricular hypothalamic nucleus neurons. In summary, catecholamine neurons are required for the activation of orexin neurons during glucoprivation. Activation of orexin neurons may contribute to appetitive responses required for glucoprivic feeding.

  13. Increased Sympathetic Renal Innervation in Hemodialysis Patients Is the Anatomical Substrate of Sympathetic Hyperactivity in End-Stage Renal Disease.

    Science.gov (United States)

    Mauriello, Alessandro; Rovella, Valentina; Anemona, Lucia; Servadei, Francesca; Giannini, Elena; Bove, Pierluigi; Anselmo, Alessandro; Melino, Gerry; Di Daniele, Nicola

    2015-11-26

    Renal denervation represents an emerging treatment for resistant hypertension in patients with end-stage renal disease, but data about the anatomic substrate of this treatment are lacking. Therefore, the aim of this study was to investigate the morphological basis of sympathetic hyperactivity in the setting of hemodialysis patients to identify an anatomical substrate that could warrant the use of this new therapeutic approach. The distribution of sympathetic nerves was evaluated in the adventitia of 38 renal arteries that were collected at autopsy or during surgery from 25 patients: 9 with end-stage renal disease on dialysis (DIAL group) and 16 age-matched control nondialysis patients (CTRL group). Patients in the DIAL group showed a significant increase in nerve density in the internal area of the peri-adventitial tissue (within the first 0.5 mm of the beginning of the adventitia) compared with the CTRL group (4.01±0.30 versus 2.87±0.28×mm(2), P=0.01). Regardless of dialysis, hypertensive patients with signs of severe arteriolar damage had a greater number of nerve endings in the most internal adventitia, and this number was significantly higher than in patients without hypertensive arteriolar damage (3.90±0.36 versus 2.87±0.41×mm(2), P=0.04), showing a correlation with hypertensive arteriolar damage rather than with hypertensive clinical history. The findings from this study provide a morphological basis underlying sympathetic hyperactivity in patients with end-stage renal disease and might offer useful information to improve the use of renal denervation in this group of patients. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  14. Carotid body (Thermoreceptors, sympathetic neural activation, and cardiometabolic disease

    Directory of Open Access Journals (Sweden)

    Rodrigo Iturriaga

    Full Text Available The carotid body (CB is the main peripheral chemoreceptor that senses the arterial PO2, PCO2 and pH. In response to hypoxemia, hypercapnia and acidosis, carotid chemosensory discharge elicits reflex respiratory, autonomic and cardiovascular adjustments. The classical construct considers the CB as the main peripheral oxygen sensor, triggering reflex physiological responses to acute hypoxemia and facilitating the ventilatory acclimation to chronic hypoxemia at high altitude. However, a growing body of experimental evidence supports the novel concept that an abnormally enhanced CB chemosensory input to the brainstem contributes to overactivation of the sympathetic nervous system, and consequent pathology. Indeed, the CB has been implicated in several diseases associated with increases in central sympathetic outflow. These include hypertension, heart failure, sleep apnea, chronic obstructive pulmonary disease and metabolic syndrome. Indeed, ablation of the CB has been proposed for the treatment of severe and resistant hypertension in humans. In this review, we will analyze and discuss new evidence supporting an important role for the CB chemoreceptor in the progression of autonomic and cardiorespiratory alterations induced by heart failure, obstructive sleep apnea, chronic obstructive pulmonary disease and metabolic syndrome.

  15. Patterns of Sympathetic Responses Induced by Different Stress Tasks

    Science.gov (United States)

    Fechir, M; Schlereth, T; Purat, T; Kritzmann, S; Geber, C; Eberle, T; Gamer, M; Birklein, F

    2008-01-01

    Stress tasks are used to induce sympathetic nervous system (SNS) arousal. However, the efficacy and the patterns of SNS activation have not been systematically compared between different tasks. Therefore, we analyzed SNS activation during the following stress tasks: Presentation of negative, positive, and – as a control – neutral affective pictures, Color-Word interference test (CWT), mental arithmetic under time limit, singing a song aloud, and giving a spontaneous talk. We examined 11 healthy subjects and recorded the following SNS parameters: Activation of emotional sweating by quantitative sudometry, skin vasoconstriction by laser-Doppler flowmetry, heart rate by ECG, blood pressure by determination of pulse wave transit time (PWTT), and electromyographic (EMG) activity of the trapezius muscle. Moreover, subjective stress ratings were acquired for each task using a visual analog scale. All tasks were felt significantly stressful when compared to viewing neutral pictures. However, SNS activation was not reliable: Affective pictures did not induce a significant SNS response; singing, giving a talk and mental arithmetic selectively increased heart rate and emotional sweating. Only the CWT globally activated the SNS. Regarding all tasks, induction of emotional sweating, increase of heart rate and blood pressure significantly correlated with subjective stress ratings, in contrast to EMG and skin vasoconstriction. Our results show that the activation of the SNS widely varies depending on the stress task. Different stress tasks differently activate the SNS, which is an important finding when considering sympathetic reactions - in clinical situations and in research. PMID:19018304

  16. Acute sex hormone suppression reduces skeletal muscle sympathetic nerve activity.

    Science.gov (United States)

    Day, Danielle S; Gozansky, Wendolyn S; Bell, Christopher; Kohrt, Wendy M

    2011-10-01

    Comparisons of sympathetic nervous system activity (SNA) between young and older women have produced equivocal results, in part due to inadequate control for potential differences in sex hormone concentrations, age, and body composition. The aim of the present study was to determine the effect of a short-term reduction in sex hormones on tonic skeletal muscle sympathetic nerve activity (MSNA), an indirect measure of whole body SNA, using an experimental model of sex hormone deficiency in young women. We also assessed the independent effects of estradiol and progesterone add-back therapy on MSNA. MSNA was measured in 9 women (30±2 years; mean±SE) on three separate occasions: during the mid-luteal menstrual cycle phase, on the fifth day of gonadotropin-releasing hormone antagonist (GnRHant) administration, and after 5 days add-back of either estradiol (n=4) or progesterone (n=3) during continued GnRHant administration. In response to GnRHant, there were significant reductions in serum estradiol and progesterone (both psuppression attenuates MSNA and that this may be related to the suppression of progesterone rather than estradiol.

  17. Renal sympathetic denervation in the treatment of resistant hypertension.

    Science.gov (United States)

    Sánchez-Álvarez, Catalina; González-Vélez, Miguel; Stilp, Erik; Ward, Charisse; Mena-Hurtado, Carlos

    2014-12-01

    Arterial hypertension (HTN) is a major health problem worldwide. Treatment-resistant hypertension (trHTN) is defined as the failure to achieve target blood pressure despite the concomitant use of maximally tolerated doses of three different antihypertensive medications, including a diuretic. trHTN is associated with considerable morbidity and mortality. Renal sympathetic denervation (RDn) is available and implemented abroad as a strategy for the treatment of trHTN and is currently under clinical investigation in the United States. Selective renal sympathectomy via an endovascular approach effectively decreases renal sympathetic nerve hyperactivity leading to a decrease in blood pressure. The Symplicity catheter, currently under investigation in the United States, is a 6-French compatible system advanced under fluoroscopic guidance via percutaneous access of the common femoral artery to the distal lumen of each of the main renal arteries. Radiofrequency (RF) energy is then applied to the endoluminal surface of the renal arteries via an electrode located at the tip of the catheter. Two clinical trials (Symplicity HTN 1 and Symplicity HTN 2) have shown the efficacy of RDn with a post-procedure decline of 27/17 mmHg at 12 months and 32/12 mmHg at 6 months, respectively, with few minor adverse events. Symplicity HTN-3 study is a, multi-center, prospective, single-blind, randomized, controlled study currently under way and will provide further insights about the safety and efficacy of renal denervation in patients with trHTN.

  18. Gudmundur Finnbogason, "sympathetic understanding," and early Icelandic psychology.

    Science.gov (United States)

    Pind, Jörgen L

    2008-05-01

    Gudmundur Finnbogason (1873-1944) was a pioneer of Icelandic psychology. He was educated at the University of Copenhagen where he finished his M.A. in 1901 in philosophy, specializing in psychology. During the years 1901-1905, Finnbogason played a major role in establishing and shaping the future of primary education in Iceland. He defended his doctoral thesis on "sympathetic understanding" at the University of Copenhagen in 1911. This work deals with the psychology of imitation. In it Finnbogason defends the view that imitation is basically perception so that there is a direct link from perception to motor behavior. Through imitation people tend to assume the countenance and demeanor of other people, thus showing, in Finnbogason's terminology, "sympathetic understanding." Finnbogason's theory of imitation in many respects anticipates contemporary approaches to the psychology of imitation. In 1918 Finnbogason became professor of applied psychology at the recently founded University of Iceland. Here he attempted to establish psychology as an independent discipline. In this he was unsuccessful; his chair was abolished in 1924.

  19. The Relevance of AgRP Neuron-Derived GABA Inputs to POMC Neurons Differs for Spontaneous and Evoked Release.

    Science.gov (United States)

    Rau, Andrew R; Hentges, Shane T

    2017-08-02

    Hypothalamic agouti-related peptide (AgRP) neurons potently stimulate food intake, whereas proopiomelanocortin (POMC) neurons inhibit feeding. Whether AgRP neurons exert their orexigenic actions, at least in part, by inhibiting anorexigenic POMC neurons remains unclear. Here, the connectivity between GABA-releasing AgRP neurons and POMC neurons was examined in brain slices from male and female mice. GABA-mediated spontaneous IPSCs (sIPSCs) in POMC neurons were unaffected by disturbing GABA release from AgRP neurons either by cell type-specific deletion of the vesicular GABA transporter or by expression of botulinum toxin in AgRP neurons to prevent vesicle-associated membrane protein 2-dependent vesicle fusion. Additionally, there was no difference in the ability of μ-opioid receptor (MOR) agonists to inhibit sIPSCs in POMC neurons when MORs were deleted from AgRP neurons, and activation of the inhibitory designer receptor hM4Di on AgRP neurons did not affect sIPSCs recorded from POMC neurons. These approaches collectively indicate that AgRP neurons do not significantly contribute to the strong spontaneous GABA input to POMC neurons. Despite these observations, optogenetic stimulation of AgRP neurons reliably produced evoked IPSCs in POMC neurons, leading to the inhibition of POMC neuron firing. Thus, AgRP neurons can potently affect POMC neuron function without contributing a significant source of spontaneous GABA input to POMC neurons. Together, these results indicate that the relevance of GABAergic inputs from AgRP to POMC neurons is state dependent and highlight the need to consider different types of transmitter release in circuit mapping and physiologic regulation. SIGNIFICANCE STATEMENT Agouti-related peptide (AgRP) neurons play an important role in driving food intake, while proopiomelanocortin (POMC) neurons inhibit feeding. Despite the importance of these two well characterized neuron types in maintaining metabolic homeostasis, communication between these

  20. Renal Sympathetic Denervation System via Intraluminal Ultrasonic Ablation: Therapeutic Intravascular Ultrasound Design and Preclinical Evaluation.

    Science.gov (United States)

    Chernin, Gil; Szwarcfiter, Iris; Bausback, Yvonne; Jonas, Michael

    2017-05-01

    To assess the safety and performance of a nonfocused and nonballooned ultrasonic (US) catheter-based renal sympathetic denervation (RDN) system in normotensive swine. RDN with the therapeutic intravascular US catheter was evaluated in 3 experiments: (i) therapeutic intravascular US RDN vs a control group of untreated animals with follow-up of 30, 45, and 90 days (n = 6; n = 12 renal arteries for each group); (ii) therapeutic intravascular US RDN vs radiofrequency (RF) RDN in the contralateral artery in the same animal (n = 2; n = 4 renal arteries); and (iii) therapeutic intravascular US RDN in a recently stent-implanted renal artery (n = 2; n = 4 renal arteries). In the first experiment, therapeutic intravascular US RDN was safe, without angiographic evidence of dissection or renal artery stenosis. Neuronal tissue vacuolization, nuclei pyknosis, and perineuronal inflammation were evident after RDN, without renal artery wall damage. Norepinephrine levels were significantly lower after therapeutic intravascular US RDN after 30, 45, and 90 days compared with the control group (200.17 pg/mg ± 63.35, 184.75 pg/mg ± 44.51, and 203.43 pg/mg ± 58.54, respectively, vs 342.42 pg/mg ± 79.97). In the second experiment, deeper neuronal ablation penetrance was found with therapeutic intravascular US RDN vs RF RDN (maximal penetrance from endothelium of 7.0 mm vs 3.5 mm, respectively). There was less damage to the artery wall after therapeutic intravascular US RDN than with RF RDN, after which edema and injured endothelium were seen. In the third experiment, denervation inside the stent-implanted segments was feasible without damage to the renal artery wall or stent. The therapeutic intravascular US system performed safely and reduced norepinephrine levels. Deeper penetrance and better preservation of vessel wall were observed with therapeutic intravascular US RDN vs RF RDN. Neuronal ablations were observed in stent-implanted renal arteries. Copyright © 2017 SIR. Published

  1. Cardiac sympathetic nervous system imaging with (123)I-meta-iodobenzylguanidine: Perspectives from Japan and Europe

    NARCIS (Netherlands)

    Nakajima, K.; Scholte, A.; Nakata, T.; Dimitriu-Leen, A.C.; Chikamori, T.; Vitola, J.V.; Yoshinaga, K.

    2017-01-01

    Cardiac sympathetic nervous system dysfunction is closely associated with risk of serious cardiac events in patients with heart failure (HF), including HF progression, pump-failure death, and sudden cardiac death by lethal ventricular arrhythmia. For cardiac sympathetic nervous system imaging,

  2. Regional sympathetic denervation after myocardial infarction in humans detected noninvasively using I-123-metaiodobenzylguanidine

    Energy Technology Data Exchange (ETDEWEB)

    Stanton, M.S.; Tuli, M.M.; Radtke, N.L.; Heger, J.J.; Miles, W.M.; Mock, B.H.; Burt, R.W.; Wellman, H.N.; Zipes, D.P. (Indiana Univ. School of Medicine, IN (USA))

    1989-11-15

    Transmural myocardial infarction in dogs produces denervation of sympathetic nerves in viable myocardium apical to the infarct that may be arrhythmogenic. It is unknown whether sympathetic denervation occurs in humans. The purpose of this study was to use iodine-123-metaiodobenzylguanidine (MIBG), a radiolabeled guanethidine analog that is actively taken up by sympathetic nerve terminals, to image noninvasively the cardiac sympathetic nerves in patients with and without ventricular arrhythmias after myocardial infarction. Results showed that 10 of 12 patients with spontaneous ventricular tachyarrhythmias after myocardial infarction exhibited regions of thallium-201 uptake indicating viable perfused myocardium, with no MIBG uptake. Such a finding is consistent with sympathetic denervation. One patient had frequent episodes of nonsustained ventricular tachycardia induced at exercise testing that was eliminated by beta-adrenoceptor blockade. Eleven of the 12 patients had ventricular tachycardia induced at electrophysiologic study and metoprolol never prevented induction. Sympathetic denervation was also detected in two of seven postinfarction patients without ventricular arrhythmias. Normal control subjects had no regions lacking MIBG uptake. This study provides evidence that regional sympathetic denervation occurs in humans after myocardial infarction and can be detected noninvasively by comparing MIBG and thallium-201 images. Although the presence of sympathetic denervation may be related to the onset of spontaneous ventricular tachyarrhythmias in some patients, it does not appear to be related to sustained ventricular tachycardia induced at electrophysiologic study.

  3. The Sympathetic Release Test: A Test Used to Assess Thermoregulation and Autonomic Control of Blood Flow

    Science.gov (United States)

    Tansey, E. A.; Roe, S. M.; Johnson, C. J.

    2014-01-01

    When a subject is heated, the stimulation of temperature-sensitive nerve endings in the skin, and the raising of the central body temperature, results in the reflex release of sympathetic vasoconstrictor tone in the skin of the extremities, causing a measurable temperature increase at the site of release. In the sympathetic release test, the…

  4. Sympathetic mediated vasomotion and skin capillary permeability in diabetic patients with peripheral neuropathy

    NARCIS (Netherlands)

    Lefrandt, JD; Hoeven, JH; Roon, AM; Smit, AJ; Hoogenberg, K

    Aims/hypothesis. A loss of sympathetic function could lead to changes in capillary fluid filtration in diabetic patients. We investigated whether a decreased sympathetically mediated vasomotion in the skin in diabetic patients with peripheral neuropathy is associated with an abnormal capillary

  5. Effects of Antidepressants, but not Psychopathology, on Cardiac Sympathetic Control : A Longitudinal Study

    NARCIS (Netherlands)

    Licht, Carmilla M. M.; Penninx, Brenda W. J. H.; de Geus, Eco J. C.

    2012-01-01

    Increased sympathetic activity has been hypothesized to have a role in the elevated somatic disease risk in persons with depressive or anxiety disorders. However, it remains unclear whether increased sympathetic activity reflects a direct effect of anxiety or depression or an indirect effect of

  6. Lipid nanocapsules containing the non-ionic surfactant Solutol HS15 inhibit the transport of calcium through hyperforin-activated channels in neuronal cells.

    Science.gov (United States)

    Chauvet, Sylvain; Barras, Alexandre; Boukherroub, Rabah; Bouron, Alexandre

    2015-12-01

    Hyperforin is described as a natural antidepressant inhibiting the reuptake of neurotransmitters and also activating cation channels. However the blood-brain barrier limits the access to the brain of this biomolecule. To circumvent this problem it was envisaged to encapsulate hyperforin into biomimetic lipid nano-carriers like lipid nanocapsules (LNCs). When testing the safety of 25 nm LNCs it appeared that they strongly blocked hyperforin-activated Ca2+ channels of cultured cortical neurons. This inhibition was due to one of their main component: solutol HS15 (polyoxyethylene-660-12-hydroxy stearate), a non-ionic soluble surfactant. Solutol HS15 rapidly depresses in a concentration-dependent manner the entry of Ca2+ through hyperforin-activated channels without influencing store-operated channels. This effect is mimicked by Brij58 but not by PEG600, indicating that the lipid chain of Solutol HS15 is important in determining its effects on the channels. The inhibition of the Ca2+ fluxes depends on the cellular cholesterol content; it is stronger after depleting cholesterol with methyl-β-cyclodextrin and is nearly absent on cells cultured in a cholesterol-rich medium. When chronically applied for 24 h, Solutol HS15 slightly up-regulates the entry of Ca2+ through hyperforin-activated channels. Similar observations were made when testing 25 nm lipid nanocapsules containing the surfactant Solutol HS15. Altogether, this study shows that Solutol HS15 perturbs in a cholesterol-dependent manner the activity of some neuronal channels. This is the first demonstration that LNCs containing this surfactant can influence cellular calcium signaling in the brain, a finding that can have important clinical implications. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. In vivo high-affinity uptake and axonal transport of D-(2,3-/sup 3/H)aspartate in excitatory neurons

    Energy Technology Data Exchange (ETDEWEB)

    Storm-Mathisen, J.; Wold, J.E. (Oslo Univ. (Norway))

    1981-12-28

    D-(2,3-/sup 3/H)aspartate ((/sup 3/H)D-Asp) at ..mu..M concentrations in Krebs' solution was infused intracerebrally in rats, mice and hamsters. Neuropil sites in the hippocampal formation, septum and neostriatum, known to receive excitatory nerve inputs with glutamate and aspartate as putative transmitters, showed strong autoradiographic labeling after intraventricular infusions. There was evidence for retrograde axonal transport to pyramidal cell bodies in hippocampus CA3 and neocortex. Infusions into the hilus fasciae dentatae led to anterograde axonal transport of (/sup 3/H)D-Asp in the mossy fibers.

  8. Effect of sympathetic nerve block on acute inflammatory pain and hyperalgesia

    DEFF Research Database (Denmark)

    Pedersen, J L; Rung, G W; Kehlet, H

    1997-01-01

    BACKGROUND: Sympathetic nerve blocks relieve pain in certain chronic pain states, but the role of the sympathetic pathways in acute pain is unclear. Thus the authors wanted to determine whether a sympathetic block could reduce acute pain and hyperalgesia after a heat injury in healthy volunteers....... The duration and quality of blocks were evaluated by the sympatogalvanic skin response and skin temperature. Bilateral heat injuries were produced on the medial surfaces of the calves with a 50 x 25 mm thermode (47 degrees C, 7 min) 45 min after the blocks. Pain intensity induced by heat, pain thresholds...... between sympathetic block and placebo for pain or mechanical allodynia during injury, or pain thresholds, pain responses to heat, or areas of secondary hyperalgesia after the injury. The comparisons were done for the period when the block was effective. CONCLUSION: Sympathetic nerve block did not change...

  9. Temporal resolution of misfolded prion protein transport, accumulation, glial activation, and neuronal death in the retinas of mice inoculated with scrapie

    Science.gov (United States)

    Currently, there is a lack of pathologic landmarks to describe the progression of prion disease in vivo. The goal of this work was to determine the temporal relationship between the transport of misfolded prion protein from the brain to the retina, the accumulation of PrPSc in the retina, the respon...

  10. Alpha2delta-1 in SF1+ Neurons of the Ventromedial Hypothalamus Is an Essential Regulator of Glucose and Lipid Homeostasis

    Directory of Open Access Journals (Sweden)

    Jennifer A. Felsted

    2017-12-01

    Full Text Available Summary: The central mechanisms controlling glucose and lipid homeostasis are inadequately understood. We show that α2δ-1 is an essential regulator of glucose and lipid balance, acting in steroidogenic factor-1 (SF1 neurons of the ventromedial hypothalamus (VMH. These effects are body weight independent and involve regulation of SF1+ neuronal activity and sympathetic output to metabolic tissues. Accordingly, mice with α2δ-1 deletion in SF1 neurons exhibit glucose intolerance, altered lipolysis, and decreased cholesterol content in adipose tissue despite normal energy balance regulation. Profound reductions in the firing rate of SF1 neurons, decreased sympathetic output, and elevated circulating levels of serotonin are associated with these alterations. Normal calcium currents but reduced excitatory postsynaptic currents in mutant SF1 neurons implicate α2δ-1 in the promotion of excitatory synaptogenesis separate from its canonical role as a calcium channel subunit. Collectively, these findings identify an essential mechanism that regulates VMH neuronal activity and glycemic and lipid control and may be a target for tackling metabolic disease. : Felsted et al. show a required role of the calcium channel subunit and thrombospondin receptor α2δ-1 in regulating glucose and lipid homeostasis in the ventromedial hypothalamus (VMH. These effects are caused by regulation of SF1+ neuronal activity in the VMH through non-canonical mechanisms and concomitant influences on sympathetic output. Keywords: diabetes, VMH, hypothalamus, glucose, norepinephrine, serotonin, excitability, lipid, SF1

  11. Production and sympathetic cooling of complex molecular ions

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Chaobo

    2008-06-24

    This thesis reports on experimental and theoretical studies of the sympathetic cooling of complex molecular ions demonstrating that this general method for cooling atomic and molecular ions is reliable and efficient. For this purpose, complex molecular ions and barium ions have been confined simultaneously in a linear Paul trap. The complex molecular ions are generated in an electrospray ionization system and transferred to the trap via a 2 m long octopole ion guide. These molecular ions are pre-cooled by room temperature helium buffer gas so that they can be captured by the trap. The atomic barium ions are loaded from a barium evaporator oven and are laser-cooled by a 493 nm cooling laser and a 650 nm repumping laser. Due to the mutual Coulomb interaction among these charged particles, the kinetic energy of the complex molecular ions can be reduced significantly. In our experiments we have demonstrated the sympathetic cooling of various molecules (CO{sub 2}, Alexa Fluor 350, glycyrrhetinic acid, cytochrome c) covering a wide mass range from a few tens to 13000 amu. In every case the molecular ions could be cooled down to millikelvin temperatures. Photo-chemical reactions of the {sup 138}Ba{sup +} ions in the ({sup 2}P{sub 1/2}) excited state with gases such as O{sub 2}, CO{sub 2}, or N{sub 2}O, could be observed. If the initial {sup 138}Ba{sup +} ion ensemble is cold, the produced {sup 138}BaO{sup +} ions are cold as well, with a similar temperature as the laser-cooled barium ions (a few tens of millikelvin). The back-reaction of {sup 138}BaO{sup +} ions with neutral CO to {sup 138}Ba{sup +} is possible and was observed in our experiments as well. A powerful molecular dynamics (MD) simulation program has been developed. With this program dynamic properties of ion ensembles, such as sympathetic interactions or heating effects, have been investigated and experimental results have been analyzed to obtain, for example, ion numbers and temperatures. Additionally, the

  12. Production and sympathetic cooling of complex molecular ions

    International Nuclear Information System (INIS)

    Zhang, Chaobo

    2008-01-01

    This thesis reports on experimental and theoretical studies of the sympathetic cooling of complex molecular ions demonstrating that this general method for cooling atomic and molecular ions is reliable and efficient. For this purpose, complex molecular ions and barium ions have been confined simultaneously in a linear Paul trap. The complex molecular ions are generated in an electrospray ionization system and transferred to the trap via a 2 m long octopole ion guide. These molecular ions are pre-cooled by room temperature helium buffer gas so that they can be captured by the trap. The atomic barium ions are loaded from a barium evaporator oven and are laser-cooled by a 493 nm cooling laser and a 650 nm repumping laser. Due to the mutual Coulomb interaction among these charged particles, the kinetic energy of the complex molecular ions can be reduced significantly. In our experiments we have demonstrated the sympathetic cooling of various molecules (CO 2 , Alexa Fluor 350, glycyrrhetinic acid, cytochrome c) covering a wide mass range from a few tens to 13000 amu. In every case the molecular ions could be cooled down to millikelvin temperatures. Photo-chemical reactions of the 138 Ba + ions in the ( 2 P 1/2 ) excited state with gases such as O 2 , CO 2 , or N 2 O, could be observed. If the initial 138 Ba + ion ensemble is cold, the produced 138 BaO + ions are cold as well, with a similar temperature as the laser-cooled barium ions (a few tens of millikelvin). The back-reaction of 138 BaO + ions with neutral CO to 138 Ba + is possible and was observed in our experiments as well. A powerful molecular dynamics (MD) simulation program has been developed. With this program dynamic properties of ion ensembles, such as sympathetic interactions or heating effects, have been investigated and experimental results have been analyzed to obtain, for example, ion numbers and temperatures. Additionally, the feasibility of nondestructive spectroscopy via an optical dipole excitation

  13. Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury

    DEFF Research Database (Denmark)

    Jansen, Pernille; Giehl, Klaus; Nyengaard, Jens R

    2007-01-01

    Neurotrophins are essential for development and maintenance of the vertebrate nervous system. Paradoxically, although mature neurotrophins promote neuronal survival by binding to tropomyosin receptor kinases and p75 neurotrophin receptor (p75(NTR)), pro-neurotrophins induce apoptosis in cultured......)/sortilin receptor complex to neuronal viability. In the developing retina, Sortilin 1 (Sort1)(-/-) mice showed reduced neuronal apoptosis that was indistinguishable from that observed in p75(NTR)-deficient (Ngfr(-/-)) mice. To our surprise, although sortilin deficiency did not affect developmentally regulated...... apoptosis of sympathetic neurons, it did prevent their age-dependent degeneration. Furthermore, in an injury protocol, lesioned corticospinal neurons in Sort1(-/-) mice were protected from death. Thus, the sortilin pathway has distinct roles in pro-neurotrophin-induced apoptotic signaling in pathological...

  14. Anatomy and physiology of phrenic afferent neurons.

    Science.gov (United States)

    Nair, Jayakrishnan; Streeter, Kristi A; Turner, Sara M F; Sunshine, Michael D; Bolser, Donald C; Fox, Emily J; Davenport, Paul W; Fuller, David D

    2017-12-01

    Large-diameter myelinated phrenic afferents discharge in phase with diaphragm contraction, and smaller diameter fibers discharge across the respiratory cycle. In this article, we review the phrenic afferent literature and highlight areas in need of further study. We conclude that 1 ) activation of both myelinated and nonmyelinated phrenic sensory afferents can influence respiratory motor output on a breath-by-breath basis; 2 ) the relative impact of phrenic afferents substantially increases with diaphragm work and fatigue; 3 ) activation of phrenic afferents has a powerful impact on sympathetic motor outflow, and 4 ) phrenic afferents contribute to diaphragm somatosensation and the conscious perception of breathing. Much remains to be learned regarding the spinal and supraspinal distribution and synaptic contacts of myelinated and nonmyelinated phrenic afferents. Similarly, very little is known regarding the potential role of phrenic afferent neurons in triggering or modulating expression of respiratory neuroplasticity. Copyright © 2017 the American Physiological Society.

  15. Chronic Hyperinsulinaemic Hypoglycaemia in Rats Is Accompanied by Increased Body Weight, Hyperleptinaemia, and Decreased Neuronal Glucose Transporter Levels in the Brain

    DEFF Research Database (Denmark)

    Jensen, Vivi F. H.; Molck, Anne-Marie; Chapman, Melissa

    2017-01-01

    of cerebral glucose transporters. Compensatory measures in the brain during chronic insulin-induced hypoglycaemia are less well understood. The present study investigated how the brain of nondiabetic rats copes with chronic insulin-induced hypoglycaemia for up to eight weeks. Brain level of different...... substrate transporters and redox homeostasis was evaluated. Hyperinsulinaemia for 8 weeks consistently lowered blood glucose levels by 30–50% (4–6 mM versus 7–9 mM in controls). The animals had increased food consumption, body weights, and hyperleptinaemia. During infusion, protein levels of the brain......The brain is vulnerable to hypoglycaemia due to a continuous need of energy substrates to meet its high metabolic demands. Studies have shown that severe acute insulin-induced hypoglycaemia results in oxidative stress in the rat brain, when neuroglycopenia cannot be evaded despite increased levels...

  16. Depletion of catecholaminergic neurons of the rostral ventrolateral medulla in multiple systems atrophy with autonomic failure

    Science.gov (United States)

    Benarroch, E. E.; Smithson, I. L.; Low, P. A.; Parisi, J. E.

    1998-01-01

    The ventrolateral portion of the intermediate reticular formation of the medulla (ventrolateral medulla, VLM), including the C1/A1 groups of catecholaminergic neurons, is thought to be involved in control of sympathetic cardiovascular outflow, cardiorespiratory interactions, and reflex control of vasopressin release. As all these functions are affected in patients with multiple systems atrophy (MSA) with autonomic failure, we sought to test the hypothesis that catecholaminergic (tyrosine hydroxylase [TH]-positive) neurons of the VLM are depleted in these patients. Medullas were obtained at autopsy from 4 patients with MSA with prominent autonomic failure and 5 patients with no neurological disease. Patients with MSA had laboratory evidence of severe adrenergic sudomotor and cardiovagal failure. Tissue was immersion fixed in 2% paraformaldehyde at 4 degrees C for 24 hours and cut into 1-cm blocks in the coronal plane from throughout the medulla. Serial 50-microm sections were collected and one section every 300 microm was stained for TH. There was a pronounced depletion of TH neurons in the rostral VLM in all cases of MSA. There was also significant reduction of TH neurons in the caudal VLM in 3 MSA patients compared with 3 control subjects. In 2 MSA cases and in 2 control subjects, the thoracic spinal cord was available for study. There was also depletion of TH fibers and sympathetic preganglionic neurons (SPNs) in the 2 MSA cases examined. Thus, depletion of catecholaminergic neurons in the VLM may provide a substrate for some of the autonomic and endocrine manifestations of MSA.

  17. Pathophysiology of Resistant Hypertension: The Role of Sympathetic Nervous System

    Directory of Open Access Journals (Sweden)

    Costas Tsioufis

    2011-01-01

    Full Text Available Resistant hypertension (RH is a powerful risk factor for cardiovascular morbidity and mortality. Among the characteristics of patients with RH, obesity, obstructive sleep apnea, and aldosterone excess are covering a great area of the mosaic of RH phenotype. Increased sympathetic nervous system (SNS activity is present in all these underlying conditions, supporting its crucial role in the pathophysiology of antihypertensive treatment resistance. Current clinical and experimental knowledge points towards an impact of several factors on SNS activation, namely, insulin resistance, adipokines, endothelial dysfunction, cyclic intermittent hypoxaemia, aldosterone effects on central nervous system, chemoreceptors, and baroreceptors dysregulation. The further investigation and understanding of the mechanisms leading to SNS activation could reveal novel therapeutic targets and expand our treatment options in the challenging management of RH.

  18. Cardiac Sympathetic Hyperactivity after Chemotherapy: Early Sign of Cardiotoxicity?

    Energy Technology Data Exchange (ETDEWEB)

    Guimarães, Sarita Lígia Pessoa de Melo Machado [Pós-Graduação em Ciências da Saúde da Universidade Federal de Pernambuco (PGCS-UFPE), Recife, PE (Brazil); Hospital Agamenon Magalhães (HAM), Recife, PE (Brazil); Brandão, Simone Cristina Soares, E-mail: simonecordis@yahoo.com.br [Pós-Graduação em Ciências da Saúde da Universidade Federal de Pernambuco (PGCS-UFPE), Recife, PE (Brazil); Andrade, Luciana Raposo [Hospital Santa Joana, Recife, PE (Brazil); Maia, Rafael José Coelho [Pós-Graduação em Ciências da Saúde da Universidade Federal de Pernambuco (PGCS-UFPE), Recife, PE (Brazil); Hospital Agamenon Magalhães (HAM), Recife, PE (Brazil); Markman Filho, Brivaldo [Pós-Graduação em Ciências da Saúde da Universidade Federal de Pernambuco (PGCS-UFPE), Recife, PE (Brazil)

    2015-09-15

    Chemotherapy with anthracyclines and trastuzumab can cause cardiotoxicity. Alteration of cardiac adrenergic function assessed by metaiodobenzylguanidine labeled with iodine-123 ({sup 123}I-mIBG) seems to precede the drop in left ventricular ejection fraction. To evaluate and to compare the presence of cardiovascular abnormalities among patients with breast cancer undergoing chemotherapy with anthracyclines and trastuzumab, and only with anthracycline. Patients with breast cancer were analyzed clinical, laboratory, electrocardiographic and echocardiographic and cardiac sympathetic activity. In scintigraphic images, the ratio of {sup 123}I-mIBG uptake between the heart and mediastinum, and the washout rate were calculated. The variables were compared between patients who received anthracyclines and trastuzumab (Group 1) and only anthracyclines (Group 2). Twenty patients, with mean age 57 ± 14 years, were studied. The mean left ventricular ejection fraction by echocardiography was 67.8 ± 4.0%. Mean washout rate was 28.39 ± 9.23% and the ratio of {sup 123}I-mIBG uptake between the heart and mediastinum was 2.07 ± 0.28. Of the patients, 82% showed an increased in washout rate, and the ratio of {sup 123}I-mIBG uptake between the heart and mediastinum decreased in 25%. Concerning the groups, the mean washout rate of Group 1 was 32.68 ± 9.30% and of Group 2 was 24.56 ± 7.72% (p = 0,06). The ratio of {sup 123}I-mIBG uptake between the heart and mediastinum was normal in all patients in Group 2, however, the Group 1, showed 50% the ratio of {sup 123}I-mIBG uptake between the heart and mediastinum ≤ 1.8 (p = 0.02). In women with breast cancer undergoing chemotherapy, assessment of cardiac sympathetic activity with {sup 123}I-mIBG appears to be an early marker of cardiotoxicity. The combination of chemotherapy showed higher risk of cardiac adrenergic hyperactivity.

  19. Developmental neurotoxicity targeting hepatic and cardiac sympathetic innervation: effects of organophosphates are distinct from those of glucocorticoids.

    Science.gov (United States)

    Seidler, Frederic J; Slotkin, Theodore A

    2011-05-30

    Early-life exposure to organophosphate pesticides leads to subsequent hyperresponsiveness of β-adrenergic receptor-mediated cell signaling that regulates hepatic gluconeogenesis, culminating in metabolic abnormalities resembling prediabetes. In the current study, we evaluated the effects of chlorpyrifos or parathion on presynaptic sympathetic innervation to determine whether the postsynaptic signaling effects are accompanied by defects in neuronal input. We administered either chlorpyrifos or parathion to newborn rats using exposure paradigms known to elicit the later metabolic changes but found no alterations in either hepatic or cardiac norepinephrine levels in adolescence or adulthood. However, shifting chlorpyrifos exposure to the prenatal period did evoke changes: exposure early in gestation produced subsequent elevations in norepinephrine, whereas later gestational exposure produced significant deficits. We also distinguished the organophosphate effects from those of the glucocorticoid, dexamethasone, a known endocrine disruptor that leads to later-life metabolic and cardiovascular disruption. Postnatal exposure to dexamethasone elicited deficits in peripheral norepinephrine levels but prenatal exposure did not. Our results indicate that early-life exposure to organophosphates leads to subsequent abnormalities of peripheral sympathetic innervation through mechanisms entirely distinct from those of glucocorticoids, ruling out the possibility that the organophosphate effects are secondary to stress or disruption of the HPA axis. Further, the effects on innervation were separable from those on postsynaptic signaling, differing in critical period as well as tissue- and sex-selectivity. Organophosphate targeting of both presynaptic and postsynaptic β-adrenergic sites, each with different critical periods of vulnerability, thus sets the stage for compounding of hepatic and cardiac functional abnormalities. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. Sympathetic nerves: How do they affect angiogenesis, particularly during wound healing of soft tissues?

    Science.gov (United States)

    Pan, Liangli; Tang, Jianbing; Liu, Hongwei; Cheng, Biao

    2016-01-01

    Angiogenesis is essential for wound healing, and angiogenesis impairment can result in chronic ulcers. Studies have shown that the sympathetic nervous system has an important role in angiogenesis. In recent years, researchers have focused on the roles of sympathetic nerves in tumor angiogenesis. In fact, sympathetic nerves can affect angiogenesis in the wound healing of soft tissues, and may have a similar mechanism of action as that seen in tumorigenesis. Sympathetic nerves act primarily through interactions between the neurotransmitters released from nerve endings and receptors present in target organs. Among this, activation or inhibition of adrenergic receptors (mainly β-adrenergic receptors) influence formation of new blood vessels considerably. As sympathetic nerves locate near pericytes in microvessel, go along the capillaries and there are adrenergic receptors present in endothelial cells and pericytes, sympathetic nerves may participate in angiogenesis by influencing the endothelial cells and pericytes of new capillaries. Studying the roles of sympathetic nerves on the angiogenesis of wound healing can contribute to understanding the mechanisms of tissue repair, tissue regeneration, and tumorigenesis, thereby providing new therapeutic perspectives.

  1. Sympathetic Blocks Provided Sustained Pain Relief in a Patient with Refractory Painful Diabetic Neuropathy

    Directory of Open Access Journals (Sweden)

    Jianguo Cheng

    2012-01-01

    Full Text Available The sympathetic nervous system has been implicated in pain associated with painful diabetic neuropathy. However, therapeutic intervention targeted at the sympathetic nervous system has not been established. We thus tested the hypothesis that sympathetic nerve blocks significantly reduce pain in a patient with painful diabetic neuropathy who has failed multiple pharmacological treatments. The diagnosis of small fiber sensory neuropathy was based on clinical presentations and confirmed by skin biopsies. A series of 9 lumbar sympathetic blocks over a 26-month period provided sustained pain relief in his legs. Additional thoracic paravertebral blocks further provided control of the pain in the trunk which can occasionally be seen in severe diabetic neuropathy cases, consequent to extensive involvement of the intercostal nerves. These blocks provided sustained and significant pain relief and improvement of quality of life over a period of more than two years. We thus provided the first clinical evidence supporting the notion that sympathetic nervous system plays a critical role in painful diabetic neuropathy and sympathetic blocks can be an effective management modality of painful diabetic neuropathy. We concluded that the sympathetic nervous system is a valuable therapeutic target of pharmacological and interventional modalities of treatments in painful diabetic neuropathy patients.

  2. Bipotential precursors of putative fibrous astrocytes and oligodendrocytes in rat cerebellar cultures express distinct surface features and neuron-like γ-aminobutyric acid transport

    International Nuclear Information System (INIS)

    Levi, G.; Gallo, V.; Ciotti, T.

    1986-01-01

    When postnatal rat cerebellar cells were cultured in a chemically defined, serum-free medium, the only type of astrocyte present was unable to accumulate γ-[ 3 H]aminobutyric acid (GABA), did not express surface antigens recognized by two monoclonal antibodies, A2B5 and LB1, and showed minimal proliferation. In these cultures, nonneuronal A2B5 + , LB1 + stellate cells exhibiting neuron-like [ 3 H]GABA uptake formed cell colonies of increasing size and were GFAP - . After about one week of culturing, the A2B5 + , LB1 + , GABA-uptake positive cell groups became galactocerebroside (GalCer) positive. Immunocytolysis of the A2B5 + cells at 3 and 4 days in vitro prevented the appearance of the A2B5 + , LB1 + , GABA-uptake positive cell colonies, and also of the GalCer + cell groups. If 10% (vol/vol) fetal calf serum was added to 6-day cultures, the A2B5 + , LB1 + , GABA-uptake positive cell groups expressed GFAP and not GalCer. If the serum was added to the cultures 2 days after lysing the A2B5 + cells, only A2B5 - , LB1 - , GABA-uptake negative astrocytes proliferated. It is concluded that the putative fibrous astrocytes previously described in serum-containing cultures derive from bipotential precursors that differentiate into oligodendrocytes (GalCer + ) in serum-free medium or into astrocytes (GFAP + ) in the presence of serum, while the epithelioid A2B5 - , LB1 - , GABA-uptake negative astrocytes originate from a different precursor not yet identified

  3. The role of sympathetic nervous system in the progression of chronic kidney disease in the era of catheter based sympathetic renal denervation.

    Science.gov (United States)

    Petras, Dimitrios; Koutroutsos, Konstantinos; Kordalis, Athanasios; Tsioufis, Costas; Stefanadis, Christodoulos

    2013-08-01

    The kidney has been shown to be critically involved as both trigger and target of sympathetic nervous system overactivity in both experimental and clinical studies. Renal injury and ischemia, activation of renin angiotensin system and dysfunction of nitric oxide system have been implicated in adrenergic activation from kidney. Conversely, several lines of evidence suggest that sympathetic overactivity, through functional and morphological alterations in renal physiology and structure, may contribute to kidney injury and chronic kidney disease progression. Pharmacologic modulation of sympathetic nervous system activity has been found to have a blood pressure independent renoprotective effect. The inadequate normalization of sympathoexcitation by pharmacologic treatment asks for novel treatment options. Catheter based renal denervation targets selectively both efferent and afferent renal nerves and functionally denervates the kidney providing blood pressure reduction in clinical trials and renoprotection in experimental models by ameliorating the effects of excessive renal sympathetic drive. This review will focus on the role of sympathetic overactivity in the pathogenesis of kidney injury and CKD progression and will speculate on the effect of renal denervation to these conditions.

  4. Spiking Neurons for Analysis of Patterns

    Science.gov (United States)

    Huntsberger, Terrance

    2008-01-01

    Artificial neural networks comprising spiking neurons of a novel type have been conceived as improved pattern-analysis and pattern-recognition computational systems. These neurons are represented by a mathematical model denoted the state-variable model (SVM), which among other things, exploits a computational parallelism inherent in spiking-neuron geometry. Networks of SVM neurons offer advantages of speed and computational efficiency, relative to traditional artificial neural networks. The SVM also overcomes some of the limitations of prior spiking-neuron models. There are numerous potential pattern-recognition, tracking, and data-reduction (data preprocessing) applications for these SVM neural networks on Earth and in exploration of remote planets. Spiking neurons imitate biological neurons more closely than do the neurons of traditional artificial neural networks. A spiking neuron includes a central cell body (soma) surrounded by a tree-like interconnection network (dendrites). Spiking neurons are so named because they generate trains of output pulses (spikes) in response to inputs received from sensors or from other neurons. They gain their speed advantage over traditional neural networks by using the timing of individual spikes for computation, whereas traditional artificial neurons use averages of activity levels over time. Moreover, spiking neurons use the delays inherent in dendritic processing in order to efficiently encode the information content of incoming signals. Because traditional artificial neurons fail to capture this encoding, they have less processing capability, and so it is necessary to use more gates when implementing traditional artificial neurons in electronic circuitry. Such higher-order functions as dynamic tasking are effected by use of pools (collections) of spiking neurons interconnected by spike-transmitting fibers. The SVM includes adaptive thresholds and submodels of transport of ions (in imitation of such transport in biological

  5. A Simple Picaxe Microcontroller Pulse Source for Juxtacellular Neuronal Labelling.

    Science.gov (United States)

    Verberne, Anthony J M

    2016-10-19

    Juxtacellular neuronal labelling is a method which allows neurophysiologists to fill physiologically-identified neurons with small positively-charged marker molecules. Labelled neurons are identified by histochemical processing of brain sections along with immunohistochemical identification of neuropeptides, neurotransmitters, neurotransmitter transporters or biosynthetic enzymes. A microcontroller-based pulser circuit and associated BASIC software script is described for incorporation into the design of a commercially-available intracellular electrometer for use in juxtacellular neuronal labelling. Printed circuit board construction has been used for reliability and reproducibility. The current design obviates the need for a separate digital pulse source and simplifies the juxtacellular neuronal labelling procedure.

  6. Racemic ketamine decreases muscle sympathetic activity but maintains the neural response to hypotensive challenges in humans

    NARCIS (Netherlands)

    Kienbaum, P.; Heuter, T.; Michel, M. C.; Peters, J.

    2000-01-01

    BACKGROUND: Cardiovascular stimulation and increased catecholamine plasma concentrations during ketamine anesthesia have been attributed to increased central sympathetic activity as well as catecholamine reuptake inhibition in various experimental models. However, direct recordings of efferent

  7. Sympathetic neural adaptation to hypocaloric diet with or without exercise training in obese metabolic syndrome subjects

    DEFF Research Database (Denmark)

    Straznicky, Nora E; Lambert, Elisabeth A; Nestel, Paul J

    2010-01-01

    Sympathetic nervous system (SNS) overactivity contributes to the pathogenesis and target organ complications of obesity. This study was conducted to examine the effects of lifestyle interventions (weight loss alone or together with exercise) on SNS function....

  8. Subtle involvement of the sympathetic nervous system in amyotrophic lateral sclerosis.

    NARCIS (Netherlands)

    Oey, P.L.; Vos, P.E.; Wieneke, G.H.; Wokke, J.H.J.; Blankestijn, P.J.; Karemaker, J.M.

    2002-01-01

    The literature on the involvement of the autonomic nervous system (ANS) in amyotrophic lateral sclerosis (ALS) is conflicting. We therefore investigated several aspects of autonomic function, namely muscle sympathetic nerve activity (MSNA), blood pressure, cardiac function (electrocardiogram; ECG),

  9. Subtle involvement of the sympathetic nervous system in amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    Oey, P. Liam; Vos, Pieter E.; Wieneke, George H.; Wokke, John H. J.; Blankestijn, Peter J.; Karemaker, John M.

    2002-01-01

    The literature on the involvement of the autonomic nervous system (ANS) in amyotrophic lateral sclerosis (ALS) is conflicting. We therefore investigated several aspects of autonomic function, namely muscle sympathetic nerve activity (MSNA), blood pressure, cardiac function (electrocardiogram; ECG),

  10. Effect of experimental hyperinsulinemia on sympathetic nervous system activity in the rat

    International Nuclear Information System (INIS)

    Young, J.B.

    1988-01-01

    Since insulin acutely stimulates the sympathetic nervous system, a role for sympathetic overactivity has been hypothesized to underlie the association between chronic hyperinsulinemia and hypertension. To assess the effect of sustained hyperinsulinemia on sympathetic function, [ 3 H]norepinephrine (NE) turnover was measured in rats injected with insulin for 14d. NE turnover in insulin-treated animals given free access to lab chow and a 10% sucrose solution was compared with that obtained in rats fed chow alone or chow plus sucrose. Sucrose ingestion increased NE turnover in heart, brown adipose tissue, and liver, but exogenous insulin did not augment turnover beyond that seen in animals given sucrose alone. This study, therefore, provides no evidence that chronic hyperinsulinemia, sufficient to induce peripheral insulin resistance, stimulates sympathetic activity more than that produced by chronic sucrose ingestion

  11. ACE INHIBITION ATTENUATES SYMPATHETIC CORONARY VASOCONSTRICTION IN PATIENTS WITH CORONARY-ARTERY DISEASE

    NARCIS (Netherlands)

    PERONDI, R; SAINO, A; TIO, RA; POMIDOSSI, G; GREGORINI, L; ALESSIO, P; MORGANTI, A; ZANCHETTI, A; MANCIA, G

    Background. In humans, angiotensin converting enzyme (ACE) inhibition attenuates the vasoconstriction induced by sympathetic stimulation in a number of peripheral districts. Whether this is also the case in the coronary circulation is unknown, however. Methods and Results. In nine normotensive

  12. Factitious lymphoedema as a psychiatric condition mimicking reflex sympathetic dystrophy: a case report

    Directory of Open Access Journals (Sweden)

    Nwaejike Nnamdi

    2008-06-01

    Full Text Available Abstract Introduction Reflex sympathetic dystrophy can result in severe disability with only one in five patients able to fully resume prior activities. Therefore, it is important to diagnose this condition early and begin appropriate treatment. Factitious lymphoedema can mimic reflex sympathetic dystrophy and is caused by self-inflicted tourniquets, blows to the arm or repeated skin irritation. Patients with factitious lymphoedema have an underlying psychiatric disorder but usually present to emergency or orthopaedics departments. Factitious lymphoedema can then be misdiagnosed as reflex sympathetic dystrophy. The treatment for factitious lymphoedema is dealing with the underlying psychiatric condition. Case presentation We share our experience of treating a 33-year-old man, who presented with factitious lymphoedema, initially diagnosed as reflex sympathetic dystrophy. Conclusion Awareness of this very similar differential diagnosis allows early appropriate treatment to be administered.

  13. Structural remodeling of the heart and its premotor cardioinhibitory vagal neurons following T(5) spinal cord transection.

    Science.gov (United States)

    Lujan, Heidi L; Janbaih, Hussein; DiCarlo, Stephen E

    2014-05-01

    Midthoracic spinal cord injury (SCI) is associated with enhanced cardiac sympathetic activity and reduced cardiac parasympathetic activity. The enhanced cardiac sympathetic activity is associated with sympathetic structural plasticity within the stellate ganglia, spinal cord segments T1-T4, and heart. However, changes to cardiac parasympathetic centers rostral to an experimental SCI are relatively unknown. Importantly, reduced vagal activity is a predictor of high mortality. Furthermore, this autonomic dysregulation promotes progressive left ventricular (LV) structural remodeling. Accordingly, we hypothesized that midthoracic spinal cord injury is associated with structural plasticity in premotor (preganglionic parasympathetic neurons) cardioinhibitory vagal neurons located within the nucleus ambiguus as well as LV structural remodeling. To test this hypothesis, dendritic arborization and morphology (cholera toxin B immunohistochemistry and Sholl analysis) of cardiac projecting premotor cardioinhibitory vagal neurons located within the nucleus ambiguus were determined in intact (sham transected) and thoracic level 5 transected (T5X) rats. In addition, LV chamber size, wall thickness, and collagen content (Masson trichrome stain and structural analysis) were determined. Midthoracic SCI was associated with structural changes within the nucleus ambiguus and heart. Specifically, following T5 spinal cord transection, there was a significant increase in cardiac parasympathetic preganglionic neuron dendritic arborization, soma area, maximum dendritic length, and number of intersections/animal. This parasympathetic structural remodeling was associated with a profound LV structural remodeling. Specifically, T5 spinal cord transection increased LV chamber area, reduced LV wall thickness, and increased collagen content. Accordingly, results document a dynamic interaction between the heart and its parasympathetic innervation.

  14. Intracellular loop 5 is important for the transport mechanism and molecular pharmacology of the human serotonin transporter

    DEFF Research Database (Denmark)

    Said, Saida; Neubauer, Henrik Amtoft; Müller, Heidi Kaastrup

    2015-01-01

    The serotonin transporter (SERT) belongs to a family of transport proteins called the neurotransmitter:sodium symporters. The specialized members of this family transport different neurotransmitters across the cell membrane, thereby regulating signaling between neurons. Most of these transporters...

  15. Sympathetic and parasympathetic regulation of rectal motility in rats.

    Science.gov (United States)

    Ridolfi, Timothy J; Tong, Wei-Dong; Takahashi, Toku; Kosinski, Lauren; Ludwig, Kirk A

    2009-11-01

    The colon and rectum are regulated by the autonomic nervous system (ANS). Abnormalities of the ANS are associated with diseases of the colon and rectum while its modulation is a putative mechanism for sacral nerve stimulation. The purpose of this study is to establish a rat model elucidating the role of the efferent ANS on rectal motility. Rectal motility following transection or stimulation of parasympathetic pelvic nerves (PN) or sympathetic hypogastric nerves (HGN) was measured with rectal strain gauge transducers and quantified as a motility index (MI). Colonic transit was measured 24 hours after transection by calculating the geometric center (GC) of distribution of (51)Cr Transection of PN and HGN decreased MI to 518 +/- 185 g*s (p < 0.05) and increased MI to 5,029 +/- 1,954 g*s (p < 0.05), respectively, compared to sham (975 +/- 243 g*s). Sectioning of PN and HGN decreased transit with GC = 4.9 +/- 0.2 (p < 0.05) and increased transit with GC = 8.1 +/- 0.7 (p < 0.02), respectively, compared to sham (GC = 5.8 +/- 0.3). Stimulation of PN and HGN increased MI to 831 +/- 157% (p < 0.01) and decreased MI to 251 +/- 24% (p < 0.05), respectively. Rectal motility is significantly altered by sectioning or stimulating either HGN or PN. This model may be useful in studying how sacral nerve stimulation exerts its effects and provide insight into the maladies of colonic motility.

  16. High-resolution Observations of Sympathetic Filament Eruptions by NVST

    Energy Technology Data Exchange (ETDEWEB)

    Li, Shangwei; Su, Yingna; Zhou, Tuanhui; Ji, Haisheng [Key Laboratory for Dark Matter and Space Science, Purple Mountain Observatory, CAS, Nanjing 210008 (China); Van Ballegooijen, Adriaan [5001 Riverwood Avenue, Sarasota, FL 34231 (United States); Sun, Xudong, E-mail: ynsu@pmo.ac.cn [W. W. Hansen Experimental Physics Laboratory, Stanford University, Stanford, CA 94305 (United States)

    2017-07-20

    We investigate two sympathetic filament eruptions observed by the New Vacuum Solar Telescope on 2015 October 15. The full picture of the eruptions is obtained from the corresponding Solar Dynamics Observatory ( SDO )/Atmospheric Imaging Assembly (AIA) observations. The two filaments start from active region NOAA 12434 in the north and end in one large quiescent filament channel in the south. The left filament erupts first, followed by the right filament eruption about 10 minutes later. Clear twist structure and rotating motion are observed in both filaments during the eruption. Both eruptions failed, since the filaments first rise up, then flow toward the south and merge into the southern large quiescent filament. We also observe repeated activations of mini filaments below the right filament after its eruption. Using magnetic field models constructed based on SDO /HMI magnetograms via the flux rope insertion method, we find that the left filament eruption is likely to be triggered by kink instability, while the weakening of overlying magnetic fields due to magnetic reconnection at an X-point between the two filament systems might play an important role in the onset of the right filament eruption.

  17. Sympathetic Tone Induced by High Acoustic Tempo Requires Fast Respiration.

    Directory of Open Access Journals (Sweden)

    Ken Watanabe

    Full Text Available Many studies have revealed the influences of music, and particularly its tempo, on the autonomic nervous system (ANS and respiration patterns. Since there is the interaction between the ANS and the respiratory system, namely sympatho-respiratory coupling, it is possible that the effect of musical tempo on the ANS is modulated by the respiratory system. Therefore, we investigated the effects of the relationship between musical tempo and respiratory rate on the ANS. Fifty-two healthy people aged 18-35 years participated in this study. Their respiratory rates were controlled by using a silent electronic metronome and they listened to simple drum sounds with a constant tempo. We varied the respiratory rate-acoustic tempo combination. The respiratory rate was controlled at 15 or 20 cycles per minute (CPM and the acoustic tempo was 60 or 80 beats per minute (BPM or the environment was silent. Electrocardiograms and an elastic chest band were used to measure the heart rate and respiratory rate, respectively. The mean heart rate and heart rate variability (HRV were regarded as indices of ANS activity. We observed a significant increase in the mean heart rate and the low (0.04-0.15 Hz to high (0.15-0.40 Hz frequency ratio of HRV, only when the respiratory rate was controlled at 20 CPM and the acoustic tempo was 80 BPM. We suggest that the effect of acoustic tempo on the sympathetic tone is modulated by the respiratory system.

  18. Sympathetic Tone Induced by High Acoustic Tempo Requires Fast Respiration.

    Science.gov (United States)

    Watanabe, Ken; Ooishi, Yuuki; Kashino, Makio

    2015-01-01

    Many studies have revealed the influences of music, and particularly its tempo, on the autonomic nervous system (ANS) and respiration patterns. Since there is the interaction between the ANS and the respiratory system, namely sympatho-respiratory coupling, it is possible that the effect of musical tempo on the ANS is modulated by the respiratory system. Therefore, we investigated the effects of the relationship between musical tempo and respiratory rate on the ANS. Fifty-two healthy people aged 18-35 years participated in this study. Their respiratory rates were controlled by using a silent electronic metronome and they listened to simple drum sounds with a constant tempo. We varied the respiratory rate-acoustic tempo combination. The respiratory rate was controlled at 15 or 20 cycles per minute (CPM) and the acoustic tempo was 60 or 80 beats per minute (BPM) or the environment was silent. Electrocardiograms and an elastic chest band were used to measure the heart rate and respiratory rate, respectively. The mean heart rate and heart rate variability (HRV) were regarded as indices of ANS activity. We observed a significant increase in the mean heart rate and the low (0.04-0.15 Hz) to high (0.15-0.40 Hz) frequency ratio of HRV, only when the respiratory rate was controlled at 20 CPM and the acoustic tempo was 80 BPM. We suggest that the effect of acoustic tempo on the sympathetic tone is modulated by the respiratory system.

  19. Inorganic phosphate inhibits sympathetic neurotransmission in canine saphenous veins

    International Nuclear Information System (INIS)

    Edoute, Y.; Vanhoutte, P.M.; Shepherd, J.T.

    1987-01-01

    Inorganic phosphate has been proposed as the initiator of metabolic vasodilatation in active skeletal muscle. The present study was primarily designed to determine if this substance has an inhibitory effect on adrenergic neurotransmission. Rings of canine saphenous veins were suspended for isometric tension recording in organ chambers. A comparison was made of the ability of inorganic phosphate (3 to 14 mM) to relax rings contracted to the same degree by electrical stimulation, exogenous norepinephrine, and prostaglandin F/sub 2α/. The relaxation during electrical stimulation was significantly greater at all concentrations of phosphate. In strips of saphenous veins previously incubated with [ 3 H]norepinephrine, the depression of the contractile response caused by phosphate during electrical stimulated was accompanied by a significant reduction in the overflow of labeled neurotransmitter. Thus inorganic phosphate inhibits sympathetic neurotransmission and hence may have a key role in the sympatholysis in the active skeletal muscles during exercise. By contrast, in this preparation, it has a modest direct relaxing action on the vascular smooth muscle

  20. Reflex sympathetic dystrophy/complex regional pain syndrome, type 1

    Directory of Open Access Journals (Sweden)

    S.H. Botha

    2004-06-01

    Full Text Available Complex regional pain syndrome (CPRS, type 1 is a pain disorder that develops unpredictably and can follow a minor injury. A 12-year-old boy presented with severe pain in the feet and could not walk or stand weight bearing. Normal X-rays showed osteopenic changes and radiolucent lines, which appeared to be stress fractures. Three-phase bone scintigraphy showed no uptake in the left lower leg on the blood pool phase or on the immediate or delayed images. This indicated typical CPRS type 1 in children. The uptake in the right foot was increased and the stress fracture and other illness could not be differentiated. Computed tomography was done to exclude stress fractures. Only osteopenic changes in both calcaneus bones were found and there was no evidence of cortical stress fractures. Magnetic resonance images revealed oedema in the calcaneus and talus bones of both feet. The patient received epidural narcotic infusion with sympathetic blockage for 1 week combined with extensive physiotherapy. The blood pool phase of the bone scan became normal within 2 weeks, and increased uptake in both feet was noticed. The patient was followed up with MRI every 3 months and the bone marrow oedema disappeared after 6 months.

  1. Renal sympathetic denervation for treatment of patients with heart failure: summary of the available evidence.

    Science.gov (United States)

    Nammas, Wail; Koistinen, Juhani; Paana, Tuomas; Karjalainen, Pasi P

    2017-08-01

    Heart failure syndrome results from compensatory mechanisms that operate to restore - back to normal - the systemic perfusion pressure. Sympathetic overactivity plays a pivotal role in heart failure; norepinephrine contributes to maintenance of the systemic blood pressure and increasing preload. Cardiac norepinephrine spillover increases in patients with heart failure; norepinephrine exerts direct toxicity on cardiac myocytes resulting in a decrease of synthetic activity and/or viability. Importantly, cardiac norepinephrine spillover is a powerful predictor of mortality in patients with moderate to severe HF. This provided the rationale for trials that demonstrated survival benefit associated with the use of beta adrenergic blockers in heart failure with reduced ejection fraction. Nevertheless, the MOXCON trial demonstrated that rapid uptitration of moxonidine (inhibitor of central sympathetic outflow) in patients with heart failure was associated with excess mortality and morbidity, despite reduction of plasma norepinephrine. Interestingly, renal norepinephrine spillover was the only independent predictor of adverse outcome in patients with heart failure, in multivariable analysis. Recently, renal sympathetic denervation has emerged as a novel approach for control of blood pressure in patients with treatment-resistant hypertension. This article summarizes the available evidence for the effect of renal sympathetic denervation in the setting of heart failure. Key messages Experimental studies supported a beneficial effect of renal sympathetic denervation in heart failure with reduced ejection fraction. Clinical studies demonstrated improvement of symptoms, and left ventricular function. In heart failure and preserved ejection fraction, renal sympathetic denervation is associated with improvement of surrogate endpoints.

  2. The sympathetic nervous system in polycystic ovary syndrome: a novel therapeutic target?

    Science.gov (United States)

    Lansdown, Andrew; Rees, D Aled

    2012-12-01

    Polycystic ovary syndrome (PCOS) is a common endocrine condition associated with long-term health risks, including type 2 diabetes and vascular dysfunction in addition to reproductive sequelae. Many of the common features of PCOS, such as central obesity, hyperinsulinaemia and obstructive sleep apnoea (OSA), are associated with chronic sympathetic overactivity, suggesting that sympathoexcitation may be involved in the pathogenesis of this condition. Rodent models of polycystic ovaries have shown that ovarian sympathetic outflow may be increased, accompanied by elevated intra-ovarian synthesis of nerve growth factor (NGF) which may be involved in initiation of ovarian pathology. Patients with PCOS have evidence of increased muscle sympathetic nerve activity (MSNA), altered heart rate variability and attenuated heart rate recovery postexercise, compared with age- and BMI-matched controls, suggesting a generalized increase in sympathetic nerve activity. Active weight loss can reduce MSNA and whole body noradrenaline spillover, whereas low-frequency electroacupuncture decreased MSNA in overweight women with PCOS. Treatment of OSA with continuous positive airways pressure may reduce plasma noradrenaline levels and diastolic blood pressure and improve cardiac sympathovagal balance. Renal sympathetic denervation also reduced MSNA, noradrenaline spillover and blood pressure in two PCOS subjects with hypertension, accompanied by improved insulin sensitivity. The sympathetic nervous system may thus offer a new therapeutic target in PCOS but larger and longer-term studies are needed before these treatments can be considered in clinical practice. © 2012 Blackwell Publishing Ltd.

  3. Functional Characterization of Lamina X Neurons in ex-Vivo Spinal Cord Preparation

    Directory of Open Access Journals (Sweden)

    Volodymyr Krotov

    2017-11-01

    Full Text Available Functional properties of lamina X neurons in the spinal cord remain unknown despite the established role of this area for somatosensory integration, visceral nociception, autonomic regulation and motoneuron output modulation. Investigations of neuronal functioning in the lamina X have been hampered by technical challenges. Here we introduce an ex-vivo spinal cord preparation with both dorsal and ventral roots still attached for functional studies of the lamina X neurons and their connectivity using an oblique LED illumination for resolved visualization of lamina X neurons in a thick tissue. With the elaborated approach, we demonstrate electrophysiological characteristics of lamina X neurons by their membrane properties, firing pattern discharge and fiber innervation (either afferent or efferent. The tissue preparation has been also probed using Ca2+ imaging with fluorescent Ca2+ dyes (membrane-impermeable or -permeable to demonstrate the depolarization-induced changes in intracellular calcium concentration in lamina X neurons. Finally, we performed visualization of subpopulations of lamina X neurons stained by retrograde labeling with aminostilbamidine dye to identify sympathetic preganglionic and projection neurons in the lamina X. Thus, the elaborated approach provides a reliable tool for investigation of functional properties and connectivity in specific neuronal subpopulations, boosting research of lamina X of the spinal cord.

  4. Activity-Dependent Regulation of Surface Glucose Transporter-3

    OpenAIRE

    Ferreira, Jainne M.; Burnett, Arthur L.; Rameau, Gerald A.

    2011-01-01

    Glucose transporter 3 (GLUT3) is the main facilitative glucose transporter in neurons. Glucose provides neurons with a critical energy source for neuronal activity. However, the mechanism by which neuronal activity controls glucose influx via GLUT3 is unknown. We investigated the influence of synaptic stimulation on GLUT3 surface expression and glucose import in primary cultured cortical and hippocampal neurons. Synaptic activity increased surface expression of GLUT3 leading to an elevation o...

  5. A study of signalling events regulating the retrograde axonal transport of neurotrophic factors in vivo

    International Nuclear Information System (INIS)

    Reynolds, A.J.; Bartlett, S.E.; Hendry, I.A.

    1998-01-01

    Full text: Soluble neurotrophic factors such as NGF promote the survival of sympathetic and sensory neuronal populations by binding to receptors present on the nerve terminal and transported to the cell body. This study aimed to establish the molecular mechanisms regulating this process by identifying potential signalling molecules that may be involved using specific pharmacological inhibitors. Adult Balb/c or CBA mice were anaesthetized using 88 μg/g ketamine and 16 μg/g rompun (i.p.) and 1 μl containing 4 μCi of 125 I-labelled NT-3 (37 ng) or pNGF (22 ng) was co-injected with inhibitors into the anterior eye chamber. After 20 hours the accumulated radioactivity was measured in the superior cervical and trigeminal ganglia. The PI3-kinase inhibitor Wortmannin inhibited 125 I-NT-3 transport in the range of 0.1-1 nmol/eye as previously shown with 125 I-βOeGF. The cPLA 2 inhibitor AACOCF3 did not significantly affect the retrograde transport of either 125 I-NT-3 or 125 I-βNGF suggesting that Wortmannin is not influencing the transport of these neurotrophins by inhibiting cPLA 2 activity. The dynein ATPase inhibitor erythro-9-[3-(2-hydroxynonyl)]adenine (1 mM) also selectively reduced 125 I-βNGF transport. Non-specific tyrosine kinase inhibitors did not have a significant effect. These results further suggest that PI3-kinase might regulate the intracellular transport of neurotrophic factors, and that retrograde axonal transport of these proteins relies on the dynein motor protein in vivo. Copyright (1998) Australian Neuroscience Society

  6. Clonidine, an alpha2-receptor agonist, diminishes GABAergic neurotransmission to cardiac vagal neurons in the nucleus ambiguus.

    Science.gov (United States)

    Philbin, Kerry E; Bateman, Ryan J; Mendelowitz, David

    2010-08-06

    In hypertension, there is an autonomic imbalance in which sympathetic activity dominates over parasympathetic control. Parasympathetic activity to the heart originates from cardiac vagal neurons located in the nucleus ambiguus. Presympathetic neurons that project to sympathetic neurons in the spinal cord are located in the ventral brainstem in close proximity to cardiac vagal neurons, and many of these presympathetic neurons are catecholaminergic. In addition to their projection to the spinal cord, many of these presympathetic neurons have axon collaterals that arborize into neighboring cardiorespiratory locations and likely release norepinephrine onto nearby neurons. Activation of alpha(2)-adrenergic receptors in the central nervous system evokes a diverse range of physiological effects, including reducing blood pressure. This study tests whether clonidine, an alpha(2)-adrenergic receptor agonist, alters excitatory glutamatergic, and/or inhibitory GABAergic or glycinergic synaptic neurotransmission to cardiac vagal neurons in the nucleus ambiguus. Cardiac vagal neurons were identified in an in vitro brainstem slice preparation, and synaptic events were recording using whole cell voltage clamp methodologies. Clonidine significantly inhibited GABAergic neurotransmission but had no effect on glycinergic or glutamatergic pathways to cardiac vagal neurons. This diminished inhibitory GABAergic neurotransmission to cardiac vagal neurons would increase parasympathetic activity to the heart, decreasing heart rate and blood pressure. The results presented here provide a cellular substrate for the clinical use of clonidine as a treatment for hypertension as well as a role in alleviating posttraumatic stress disorder by evoking an increase in parasympathetic cardiac vagal activity, and a decrease in heart rate and blood pressure. Copyright 2010 Elsevier B.V. All rights reserved.

  7. Retrograde and transganglionic transport of horseradish peroxidase-conjugated cholera toxin B subunit, wheatgerm agglutinin and isolectin B4 from Griffonia simplicifolia I in primary afferent neurons innervating the rat urinary bladder.

    Science.gov (United States)

    Wang, H F; Shortland, P; Park, M J; Grant, G

    1998-11-01

    myelinated fibres). Double labelling with other neuronal markers showed that 71%, 43% and 36% of the cholera toxin B subunit-immunoreactive cells were calcitonin gene-related peptide-, isolectin B4-binding- and substance P-positive, respectively. A few cholera toxin B subunit cells showed galanin-immunoreactivity, but none were somatostatin-, vasoactive intestinal polypeptide-, or neuropeptide Y-immunoreactive or contained fluoride-resistant acid phosphatase. The results show that cholera toxin B subunit-horseradish peroxidase is a more effective retrograde and transganglionic tracer for pelvic primary afferents from the urinary bladder than wheat germ agglutinin-horseradish peroxidase and isolectin B4-horseradish peroxidase, but in contrast to somatic nerves, it is transported mainly by unmyelinated fibres in the visceral afferents.

  8. Overactivity of Liver-Related Neurons in the Paraventricular Nucleus of the Hypothalamus: Electrophysiological Findings in db/db Mice.

    Science.gov (United States)

    Gao, Hong; Molinas, Adrien J R; Miyata, Kayoko; Qiao, Xin; Zsombok, Andrea

    2017-11-15

    Preautonomic neurons in the paraventricular nucleus (PVN) of the hypothalamus play a large role in the regulation of hepatic functions via the autonomic nervous system. Activation of hepatic sympathetic nerves increases glucose and lipid metabolism and contributes to the elevated hepatic glucose production observed in the type 2 diabetic condition. This augmented sympathetic output could originate from altered activity of liver-related PVN neurons. Remarkably, despite the importance of the brain-liver pathway, the cellular properties of liver-related neurons are not known. In this study, we provide the first evidence of overall activity of liver-related PVN neurons. Liver-related PVN neurons were identified with a retrograde, trans-synaptic, viral tracer in male lean and db/db mice and whole-cell patch-clamp recordings were conducted. In db/db mice, the majority of liver-related PVN neurons fired spontaneously; whereas, in lean mice the majority of liver-related PVN neurons were silent, indicating that liver-related PVN neurons are more active in db/db mice. Persistent, tonic inhibition was identified in liver-related PVN neurons; although, the magnitude of tonic inhibitory control was not different between lean and db/db mice. In addition, our study revealed that the transient receptor potential vanilloid type 1-dependent increase of excitatory neurotransmission was reduced in liver-related PVN neurons of db/db mice. These findings demonstrate plasticity of liver-related PVN neurons and a shift toward excitation in a diabetic mouse model. Our study suggests altered autonomic circuits at the level of the PVN, which can contribute to autonomic dysfunction and dysregulation of neural control of hepatic functions including glucose metabolism. SIGNIFICANCE STATEMENT A growing body of evidence suggests the importance of the autonomic control in the regulation of hepatic metabolism, which plays a major role in the development and progression of type 2 diabetes mellitus

  9. Renal sympathetic denervation for treatment of resistant hypertension: Egyptian experience.

    Science.gov (United States)

    Hamza, Mohamed; Khamis, Hazem

    2014-08-01

    Among the Egyptian population with essential hypertension, a minority are under control (systolic pressure renal artery radiofrequency (RF) ablation. To evaluate the feasibility, efficacy, and safety of catheter-based radiofrequency renal sympathetic denervation for treatment of resistant hypertension in Egyptian patients. Patients with essential hypertension unresponsive to at least 3 types of antihypertensive medical therapy (baseline office systolic blood pressure ≥160 mmHg) (n = 55) were enrolled between February 2012 and June 2013 and received percutaneous RF ablation. Patients were followed up for 6 months after treatment to detect any change in office-based measurement of blood pressure. Urine and blood samples were taken to evaluate the effects on renal function. A reduction of mean office blood pressure was seen from 174/103 ± 9/5 mmHg at baseline to 150/91 ± 8/5 mmHg at 6 months follow-up (P = 0.001). Also, we noted a significant decrease in plasma renin activity (3.66 ± 0.64 vs. 3.37 ± 0.47 ng/mL per hour; P = 0.003), and there were no periprocedural complications, no adverse events, and no change in renal function during the follow-up period. Also, no change was noted in the number of medications after 6 months (3.95 ± 1.64 vs. 3.67 ± 0.72; P = 0.27). In this observational study, catheter-based renal denervation causes sustained blood pressure reduction in patients with resistant hypertension, without serious adverse events. © 2014, Wiley Periodicals, Inc.

  10. THE WAYS OF SYMPATHETIC SYSTEM OVERACTIVITY BLOCKING: RILMENIDINE VERSUS ATENOLOL

    Directory of Open Access Journals (Sweden)

    Y. R. Kasherininov

    2006-01-01

    Full Text Available Aim. To evaluate effects of long-term treatment with rilmenidine compared with atenolol on lipid and glucose metabolism and cardiovascular remodeling in hypertension. Material and methods. 37 patients with hypertension were randomized to rilmenidine 1-2 mg/day or atenolol 50-100 mg/day for 26 weeks. Standard oral glucose tolerance test with a parallel measurement of insulin and glucose levels was performed. The “areas under the curve” (AUC for insulin and glucose were calculated. Plasma lipids, left ventricular mass index (LVMI and intima-media thickness (IMT were measured. Brachial artery diameter during reactive hyperemia was used to test endothelium-dependent vasodilatation (EDVD. Results. Blood pressure reduction was equally achieved in both treatment arms. The fasting glucose level increased in the atenolol group from 4.8±0.6 to 5.2±0.7 mmol/l (p<0.01. The AUC of glucose in rilmenidine group decreased from 860±93 to 737±66 mmol/min/l (p<0.05, and it increased from 937±86 to 989±88 mmol/min/l (p<0.05 in the atenolol group. Rilmenidine showed a positive effect on lipid levels, while in the atenolol group a significant decrease of high density lipoprotein was observed. LVMI decreased with rilmenidine by 9.6% (p<0.05 and by 6,9% (not significantly with atenolol. IMT significantly decreased in the rilmenidine. EDVD slightly increased on rilmenidine, while on atenolol group it remained unchanged. Conclusion. Our data suggest that in hypertensive patients central inhibition of sympathetic drive can produce favorable effects on glucose and lipid metabolism compared with standard β-blockade with a similar antihypertensive efficacy. Rilmenidine also provides beneficial effects on cardiovascular remodeling and altered endothelial function in hypertension.

  11. Increased vascular sympathetic modulation in mice with Mas receptor deficiency

    Science.gov (United States)

    Rabello Casali, Karina; Ravizzoni Dartora, Daniela; Moura, Marina; Bertagnolli, Mariane; Bader, Michael; Haibara, Andrea; Alenina, Natalia; Irigoyen, Maria Claudia; Santos, Robson A

    2016-01-01

    Introduction: The angiotensin-converting enzyme 2 (ACE2)/angiotensin (Ang)-(1–7)/Mas axis could modulate the heart rate (HR) and blood pressure variabilities (BPV) which are important predictors of cardiovascular risk and provide information about the autonomic modulation of the cardiovascular system. Therefore we investigated the effect of Mas deficiency on autonomic modulation in wild type and Mas-knockout (KO) mice. Methods: Blood pressure was recorded at high sample rate (4000 Hz). Stationary sequences of 200–250 beats were randomly chosen. Frequency domain analysis of HR and BPV was performed with an autoregressive algorithm on the pulse interval sequences and on respective systolic sequences. Results: The KO group presented an increase of systolic arterial pressure (SAP; 127.26±11.20 vs 135.07±6.98 mmHg), BPV (3.54±1.54 vs 5.87±2.12 mmHg2), and low-frequency component of systolic BPV (0.12±0.11 vs 0.47±0.34 mmHg2). Conclusions: The deletion of Mas receptor is associated with an increase of SAP and with an increased BPV, indicating alterations in autonomic control. Increase of sympathetic vascular modulation in absence of Mas evidences the important role of Ang-(1–7)/Mas on cardiovascular regulation. Moreover, the absence of significant changes in HR and HRV can indicate an adaptation of autonomic cardiac balance. Our results suggest that the Ang-(1–7)/Mas axis seems more important in autonomic modulation of arterial pressure than HR. PMID:27080540

  12. Neuronal Migration Disorders

    Science.gov (United States)

    ... Understanding Sleep The Life and Death of a Neuron Genes At Work In The Brain Order Publications ... birth defects caused by the abnormal migration of neurons in the developing brain and nervous system. In ...

  13. Motor Neuron Diseases

    Science.gov (United States)

    ... and other neurodegenerative diseases to better understand the function of neurons and other support cells and identify candidate therapeutic ... and other neurodegenerative diseases to better understand the function of neurons and other support cells and identify candidate therapeutic ...

  14. Cardiorespiratory adaptations induced by aerobic training in middle-aged men: the importance of a decrease in sympathetic stimulation for the contribution of dynamic exercise tachycardia

    Directory of Open Access Journals (Sweden)

    Chacon-Mikahil M.P.T.

    1998-01-01

    Full Text Available We investigated the effects of aerobic training on the efferent autonomic control of heart rate (HR during dynamic exercise in middle-aged men, eight of whom underwent exercise training (T while the other seven continued their sedentary (S life style. The training was conducted over 10 months (three 1-h sessions/week on a field track at 70-85% of the peak HR. The contribution of sympathetic and parasympathetic exercise tachycardia was determined in terms of differences in the time constant effects on the HR response obtained using a discontinuous protocol (4-min tests at 25, 50, 100 and 125 watts on a cycle ergometer, and a continuous protocol (25 watts/min until exhaustion allowed the quantification of the parameters (anaerobic threshold, VO2 AT; peak O2 uptake, VO2 peak; power peak that reflect oxygen transport. The results obtained for the S and the T groups were: 1 a smaller resting HR in T (66 beats/min when compared to S (84 beats/min; 2 during exercise, a small increase in the fast tachycardia (D0-10 s related to vagal withdrawal (P<0.05, only at 25 watts was observed in T at all powers; at middle and higher powers a significant decrease (P<0.05 at 50, 100 and 125 watts in the slow tachycardia (D1-4 min related to a sympathetic-dependent mechanism was observed in T; 3 the VO2 AT (S = 1.06 and T = 1.33 l/min and VO2 peak (S = 1.97 and T = 2.47 l/min were higher in T (P<0.05. These results demonstrate that aerobic training can induce significant physiological adaptations in middle-aged men, mainly expressed as a decrease in the sympathetic effects on heart rate associated with an increase in oxygen transport during dynamic exercise.

  15. Accurate counting of neurons in frozen sections: some necessary precautions.

    OpenAIRE

    Cooper, J D; Payne, J N; Horobin, R W

    1988-01-01

    In 30 microns frozen sections of rat midbrain the retrograde axonal transport of diamidino yellow, a fluorescent tracer, was used to demonstrate a population of neurons in the substantia nigra. However, when visualisation was carried out using the routine Nissl method a significant proportion of neurons failed to stain. As the presence of the retrograde tracer did not affect Nissl staining of such cells, such incomplete staining, with consequent underestimation of neuronal populations, is pro...

  16. Recurrent postoperative CRPS I in patients with abnormal preoperative sympathetic function.

    Science.gov (United States)

    Ackerman, William E; Ahmad, Mahmood

    2008-02-01

    A complex regional pain syndrome of an extremity that has previously resolved can recur after repeat surgery at the same anatomic site. Complex regional pain syndrome is described as a disease of the autonomic nervous system. The purpose of this study was to evaluate preoperative and postoperative sympathetic function and the recurrence of complex regional pain syndrome type I (CRPS I) in patients after repeat carpal tunnel surgery. Thirty-four patients who developed CRPS I after initial carpal tunnel releases and required repeat open carpal tunnel surgeries were studied. Laser Doppler imaging (LDI) was used to assess preoperative sympathetic function 5-7 days prior to surgery and to assess postoperative sympathetic function 19-22 days after surgery or 20-22 days after resolution of the CRPS I. Sympathetic nervous system function was prospectively examined by testing reflex-evoked vasoconstrictor responses to sympathetic stimuli recorded with LDI of both hands. Patients were assigned to 1 of 2 groups based on LDI responses to sympathetic provocation. Group I (11 of 34) patients had abnormal preoperative LDI studies in the hands that had prior surgeries, whereas group II (23 of 34) patients had normal LDI studies. Each patient in this study had open repeat carpal tunnel surgery. In group I, 8 of 11 patients had recurrent CRPS I, whereas in group II, 3 of 23 patients had recurrent CRPS I. All of the recurrent CRPS I patients were successfully treated with sympathetic blockade, occupational therapy, and pharmacologic modalities. Repeat LDI after recurrent CRPS I resolution was abnormal in 8 of 8 group I patients and in 1 of 3 group II patients. CRPS I can recur after repeat hand surgery. Our study results may, however, identify those individuals who may readily benefit from perioperative therapies. Prognostic I.

  17. Muscle sympathetic nerve activity is related to a surrogate marker of endothelial function in healthy individuals.

    Directory of Open Access Journals (Sweden)

    Yrsa Bergmann Sverrisdóttir

    Full Text Available BACKGROUND: Evidence from animal studies indicates the importance of an interaction between the sympathetic nervous system and the endothelium for cardiovascular regulation. However the interaction between these two systems remains largely unexplored in humans. The aim of this study was to investigate whether directly recorded sympathetic vasoconstrictor outflow is related to a surrogate marker of endothelial function in healthy individuals. METHODS AND RESULTS: In 10 healthy normotensive subjects (3 f/7 m, (age 37+/-11 yrs, (BMI 24+/-3 kg/m(2 direct recordings of sympathetic action potentials to the muscle vascular bed (MSNA were performed and endothelial function estimated with the Reactive Hyperaemia- Peripheral Arterial Tonometry (RH-PAT technique. Blood samples were taken and time spent on leisure-time physical activities was estimated. In all subjects the rate between resting flow and the maximum flow, the Reactive Hyperemic index (RH-PAT index, was within the normal range (1.9-3.3 and MSNA was as expected for age and gender (13-44 burst/minute. RH-PAT index was inversely related to MSNA (r = -0.8, p = 0.005. RH-PAT index and MSNA were reciprocally related to time (h/week spent on physical activity (p = 0.005 and p = 0.006 respectively and platelet concentration (PLT (p = 0.02 and p = 0.004 respectively. CONCLUSIONS: Our results show that sympathetic nerve activity is related to a surrogate marker of endothelial function in healthy normotensive individuals, indicating that sympathetic outflow may be modulated by changes in endothelial function. In this study time spent on physical activity is identified as a predictor of sympathetic nerve activity and endothelial function in a group of healthy individuals. The results are of importance in understanding mechanisms underlying sympathetic activation in conditions associated with endothelial dysfunction and emphasise the importance of a daily exercise routine for maintenance of cardiovascular

  18. SYMPATHETIC NEURAL AND HEMODYNAMIC RESPONSES DURING COLD PRESSOR TEST IN ELDERLY BLACKS AND WHITES

    Science.gov (United States)

    Okada, Yoshiyuki; Jarvis, Sara S.; Best, Stuart A.; Edwards, Jeffrey G.; Hendrix, Joseph M.; Adams-Huet, Beverley; Vongpatanasin, Wanpen; Levine, Benjamin D.; Fu, Qi

    2016-01-01

    The sympathetic response during the cold pressor test (CPT) has been reported to be greater in young blacks than whites, especially in those with a family history of hypertension. Since blood pressure (BP) increases with age, we evaluated whether elderly blacks have greater sympathetic activation during CPT than age-matched whites. BP, heart rate (HR), cardiac output (Qc), and muscle sympathetic nerve activity (MSNA) were measured during supine baseline, 2-min CPT, and 3-min recovery in 47 elderly [68±7 (SD) yrs] volunteers (12 blacks, 35 whites). Baseline BP, HR, Qc, or MSNA did not differ between races. Systolic and diastolic BP (DBP) and HR increased during CPT (all P0.05). Qc increased during CPT and up to 30 sec of recovery in both groups, but was lower in blacks than whites. MSNA increased during CPT in both groups (both P<0.001); the increase in burst frequency was similar between groups, while the increase in total activity was smaller in blacks (P=0.030 for interaction). Peak change (Δ) in DBP was correlated with Δ total activity at 1 min into CPT in both blacks (r=0.78, P=0.003) and whites (r=0.43, P=0.009), while the slope was significantly greater in blacks (P=0.007). Thus, elderly blacks have smaller sympathetic and central hemodynamic (e.g., Qc) responses, but a greater pressor response for a given sympathetic activation during CPT than elderly whites. This response may stem from augmented sympathetic vascular transduction, greater sympathetic activation to other vascular bed(s), and/or enhanced non-adrenergically mediated vasoconstriction in elderly blacks. PMID:27021009

  19. Primary culture of glial cells from mouse sympathetic cervical ganglion: a valuable tool for studying glial cell biology.

    Science.gov (United States)

    de Almeida-Leite, Camila Megale; Arantes, Rosa Maria Esteves

    2010-12-15

    Central nervous system glial cells as astrocytes and microglia have been investigated in vitro and many intracellular pathways have been clarified upon various stimuli. Peripheral glial cells, however, are not as deeply investigated in vitro despite its importance role in inflammatory and neurodegenerative diseases. Based on our previous experience of culturing neuronal cells, our objective was to standardize and morphologically characterize a primary culture of mouse superior cervical ganglion glial cells in order to obtain a useful tool to study peripheral glial cell biology. Superior cervical ganglia from neonatal C57BL6 mice were enzymatically and mechanically dissociated and cells were plated on diluted Matrigel coated wells in a final concentration of 10,000cells/well. Five to 8 days post plating, glial cell cultures were fixed for morphological and immunocytochemical characterization. Glial cells showed a flat and irregular shape, two or three long cytoplasm processes, and round, oval or long shaped nuclei, with regular outline. Cell proliferation and mitosis were detected both qualitative and quantitatively. Glial cells were able to maintain their phenotype in our culture model including immunoreactivity against glial cell marker GFAP. This is the first description of immunocytochemical characterization of mouse sympathetic cervical ganglion glial cells in primary culture. This work discusses the uses and limitations of our model as a tool to study many aspects of peripheral glial cell biology. Copyright © 2010 Elsevier B.V. All rights reserved.

  20. Heart failure-induced changes of voltage-gated Ca2+ channels and cell excitability in rat cardiac postganglionic neurons.

    Science.gov (United States)

    Tu, Huiyin; Liu, Jinxu; Zhang, Dongze; Zheng, Hong; Patel, Kaushik P; Cornish, Kurtis G; Wang, Wei-Zhong; Muelleman, Robert L; Li, Yu-Long

    2014-01-15

    Chronic heart failure (CHF) is characterized by decreased cardiac parasympathetic and increased cardiac sympathetic nerve activity. This autonomic imbalance increases the risk of arrhythmias and sudden death in patients with CHF. We hypothesized that the molecular and cellular alterations of cardiac postganglionic parasympathetic (CPP) neurons located in the intracardiac ganglia and sympathetic (CPS) neurons located in the stellate ganglia (SG) possibly link to the cardiac autonomic imbalance in CHF. Rat CHF was induced by left coronary artery ligation. Single-cell real-time PCR and immunofluorescent data showed that L (Ca(v)1.2 and Ca(v)1.3), P/Q (Ca(v)2.1), N (Ca(v)2.2), and R (Ca(v)2.3) types of Ca2+ channels were expressed in CPP and CPS neurons, but CHF decreased the mRNA and protein expression of only the N-type Ca2+ channels in CPP neurons, and it did not affect mRNA and protein expression of all Ca2+ channel subtypes in the CPS neurons. Patch-clamp recording confirmed that CHF reduced N-type Ca2+ currents and cell excitability in the CPP neurons and enhanced N-type Ca2+ currents and cell excitability in the CPS neurons. N-type Ca2+ channel blocker (1 μM ω-conotoxin GVIA) lowered Ca2+ currents and cell excitability in the CPP and CPS neurons from sham-operated and CHF rats. These results suggest that CHF reduces the N-type Ca2+ channel currents and cell excitability in the CPP neurons and enhances the N-type Ca2+ currents and cell excitability in the CPS neurons, which may contribute to the cardiac autonomic imbalance in CHF.

  1. Pseudorabies virus infection alters neuronal activity and connectivity in vitro.

    Directory of Open Access Journals (Sweden)

    Kelly M McCarthy

    2009-10-01

    Full Text Available Alpha-herpesviruses, including human herpes simplex virus 1 & 2, varicella zoster virus and the swine pseudorabies virus (PRV, infect the peripheral nervous system of their hosts. Symptoms of infection often include itching, numbness, or pain indicative of altered neurological function. To determine if there is an in vitro electrophysiological correlate to these characteristic in vivo symptoms, we infected cultured rat sympathetic neurons with well-characterized strains of PRV known to produce virulent or attenuated symptoms in animals. Whole-cell patch clamp recordings were made at various times after infection. By 8 hours of infection with virulent PRV, action potential (AP firing rates increased substantially and were accompanied by hyperpolarized resting membrane potentials and spikelet-like events. Coincident with the increase in AP firing rate, adjacent neurons exhibited coupled firing events, first with AP-spikelets and later with near identical resting membrane potentials and AP firing. Small fusion pores between adjacent cell bodies formed early after infection as demonstrated by transfer of the low molecular weight dye, Lucifer Yellow. Later, larger pores formed as demonstrated by transfer of high molecular weight Texas red-dextran conjugates between infected cells. Further evidence for viral-induced fusion pores was obtained by infecting neurons with a viral mutant defective for glycoprotein B, a component of the viral membrane fusion complex. These infected neurons were essentially identical to mock infected neurons: no increased AP firing, no spikelet-like events, and no electrical or dye transfer. Infection with PRV Bartha, an attenuated circuit-tracing strain delayed, but did not eliminate the increased neuronal activity and coupling events. We suggest that formation of fusion pores between infected neurons results in electrical coupling and elevated firing rates, and that these processes may contribute to the altered neural

  2. Sensory neurons do not induce motor neuron loss in a human stem cell model of spinal muscular atrophy.

    Science.gov (United States)

    Schwab, Andrew J; Ebert, Allison D

    2014-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder leading to paralysis and early death due to reduced SMN protein. It is unclear why there is such a profound motor neuron loss, but recent evidence from fly and mouse studies indicate that cells comprising the whole sensory-motor circuit may contribute to motor neuron dysfunction and loss. Here, we used induced pluripotent stem cells derived from SMA patients to test whether sensory neurons directly contribute to motor neuron loss. We generated sensory neurons from SMA induced pluripotent stem cells and found no difference in neuron generation or survival, although there was a reduced calcium response to depolarizing stimuli. Using co-culture of SMA induced pluripotent stem cell derived sensory neurons with control induced pluripotent stem cell derived motor neurons, we found no significant reduction in motor neuron number or glutamate transporter boutons on motor neuron cell bodies or neurites. We conclude that SMA sensory neurons do not overtly contribute to motor neuron loss in this human stem cell system.

  3. Neuronal imaging using SPECT

    International Nuclear Information System (INIS)

    Yamashina, Shohei; Yamazaki, Jun-ichi

    2007-01-01

    123 I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy is one of only a few methods available for objective evaluation of cardiac sympathetic function at the clinical level. Disorders of cardiac sympathetic function play an important role in various heart diseases, and MIBG provides an abundance of useful information for the evaluation of severity, prognosis and therapeutic effects; this is particularly useful in cases of heart failure, ischaemic heart disease and arrhythmic disease. On the other hand, the quantitative indices for MIBG differ between institutions, and evidence has not been sufficiently well established for MIBG scintigraphy when compared with myocardial perfusion imaging in ischaemic heart diseases. In consideration of these difficulties, this review provides fundamental information regarding MIBG, its usefulness for various diseases and future difficulties. (orig.)

  4. Neuronal imaging using SPECT

    International Nuclear Information System (INIS)

    Yamashina, Shohei; Yamazaki, Jun-ichi

    2007-01-01

    123 I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy is one of only a few methods available for objective evaluation of cardiac sympathetic function at a clinical level. Disorders in cardiac sympathetic function play an important role in various heart diseases, and MIBG provides an abundance of useful information for evaluation of disease severity, prognosis, and therapeutic effects; this information is of particular value in patients with heart failure, ischemic heart diseases, or arrhythmic disorders. On the other hand, the quantitative indices for MIBG differ between institutions, and evidence has not been sufficiently well established for MIBG, compared with myocardial perfusion imaging, in ischemic heart diseases. In view of these difficulties, this review provides fundamental information regarding MIBG, its usefulness for various diseases and future difficulties. (orig.)

  5. Hypertrophy of Neurons Within Cardiac Ganglia in Human, Canine, and Rat Heart Failure: The Potential Role of Nerve Growth Factor

    OpenAIRE

    Singh, Sanjay; Sayers, Scott; Walter, James S.; Thomas, Donald; Dieter, Robert S.; Nee, Lisa M.; Wurster, Robert D.

    2013-01-01

    Background Autonomic imbalances including parasympathetic withdrawal and sympathetic overactivity are cardinal features of heart failure regardless of etiology; however, mechanisms underlying these imbalances remain unknown. Animal model studies of heart and visceral organ hypertrophy predict that nerve growth factor levels should be elevated in heart failure; whether this is so in human heart failure, though, remains unclear. We tested the hypotheses that neurons in cardiac ganglia are hyper...

  6. Imaging neuronal pathways with 52Mn PET

    DEFF Research Database (Denmark)

    Napieczynska, Hanna; Severin, Gregory; Fonslet, Jesper

    2017-01-01

    Manganese in its divalent state (Mn2+) has features that make it a unique tool for tracing neuronal pathways. It is taken up and transported by neurons in an activity dependent manner and it can cross synapses. It also acts as a contrast agent for magnetic resonance imaging (MRI) enabling visuali...

  7. Endovascular ultrasound for renal sympathetic denervation in patients with therapy-resistant hypertension not responding to radiofrequency renal sympathetic denervation.

    Science.gov (United States)

    Stiermaier, Thomas; Okon, Thomas; Fengler, Karl; Mueller, Ulrike; Hoellriegel, Robert; Schuler, Gerhard; Desch, Steffen; Lurz, Philipp

    2016-06-12

    Recent studies have reported a considerable number of non-responders after renal sympathetic de-nervation (RSD) with radiofrequency technology. Here we report our results of repeat RSD using ultrasound in these patients. A cohort study was performed in patients who underwent ultrasound RSD after non-response to RSD with radiofrequency. Non-response was defined as mean daytime systolic blood pressure ≥140 mmHg and/or a reduction of ≤10 mmHg in ambulatory blood pressure measurement (ABPM) ≥6 months after radiofrequency denervation. ABPM was recorded at baseline, post radiofrequency RSD as well as at three and six months post ultrasound RSD. A total of 24 non-responders underwent retreatment with the ultrasound device at a mean 15.3±8.2 months after radiofrequency RSD. Ultrasound RSD was performed successfully in all patients without severe adverse events. Mean daytime systolic blood pressure changed from 161.7±14.6 mmHg at baseline to 158.5±9.5 mmHg post radiofrequency RSD and to 150.5±10.4 mmHg and 151.6±11.0 mmHg at three and six months, respectively, post ultrasound RSD (pmeasures analysis of variance). The main results of post hoc testing were as follows: baseline versus post radiofrequency RSD, p=0.83; baseline versus three months post ultrasound RSD, p=0.01; and baseline versus six months post ultrasound RSD, p=0.04. Ultrasound RSD appears to be safe and an effective therapeutic approach in patients not responding to previous RSD with radiofrequency technology.

  8. Change in sympathetic nerve firing pattern associated with dietary weight loss in the metabolic syndrome

    Directory of Open Access Journals (Sweden)

    Elisabeth Annie Lambert

    2011-08-01

    Full Text Available Sympathetic activation in subjects with the metabolic syndrome (MS plays a role in the pathogenesis of cardiovascular disease development. Diet-induced weight loss decreases sympathetic outflow. However the mechanisms that account for sympathetic inhibition are not known. We sought to provide a detailed description of the sympathetic response to diet by analyzing the firing behavior of single-unit sympathetic nerve fibres. Fourteen subjects (57±2 years, 9 men, 5 females fulfilling ATP III criteria for the MS underwent a 3-month low calorie diet. Metabolic profile, hemodynamic parameters and multi-unit and single unit muscle sympathetic nerve activity (MSNA, microneurography were assessed prior to and at the end of the diet. Patients’ weight dropped from 96±4 to 88±3 kg (P<0.001. This was associated with a decrease in systolic and diastolic blood pressure (-12 ±3 and -5±2 mmHg, P<0.05, and in heart rate (-7±2 bpm, P<0.01 and an improvement in all metabolic parameters (fasting glucose: -0.302.1±0.118 mmol/l, total cholesterol: -0.564±0.164 mmol/l, triglycerides: -0.414±0.137 mmol/l, P<0.05. Multi-unit MSNA decreased from 68±4 to 59±5 bursts per 100 heartbeats (P<0.05. Single-unit MSNA indicated that the firing rate of individual vasoconstrictor fibres decreased from 59±10 to 32±4 spikes per 100 heart beats (P<0.05. The probability of firing decreased from 34±5 to 23±3 % of heartbeats (P<0.05, and the incidence of multiple firing decreased from 14±4 to 6±1 % of heartbeats (P<0.05. Cardiac and sympathetic baroreflex function were significantly improved (cardiac slope: 6.57±0.69 to 9.57±1.20 msec.mmHg-1; sympathetic slope: -3.86±0.34 to -5.05±0.47 bursts per 100 heartbeats.mmHg-1 P<0.05 for both. Hypocaloric diet decreased sympathetic activity and improved hemodynamic and metabolic parameters. The sympathoinhibition associated with weight loss involves marked changes, not only in the rate but also in the firing pattern of

  9. Medullary Reticular Neurons Mediate Neuropeptide Y-Induced Metabolic Inhibition and Mastication.

    Science.gov (United States)

    Nakamura, Yoshiko; Yanagawa, Yuchio; Morrison, Shaun F; Nakamura, Kazuhiro

    2017-02-07

    Hypothalamic neuropeptide Y (NPY) elicits hunger responses to increase the chances of surviving starvation: an inhibition of metabolism and an increase in feeding. Here we elucidate a key central circuit mechanism through which hypothalamic NPY signals drive these hunger responses. GABAergic neurons in the intermediate and parvicellular reticular nuclei (IRt/PCRt) of the medulla oblongata, which are activated by NPY-triggered neural signaling from the hypothalamus, potentially through the nucleus tractus solitarius, mediate the NPY-induced inhibition of metabolic thermogenesis in brown adipose tissue (BAT) via their innervation of BAT sympathetic premotor neurons. Intriguingly, the GABAergic IRt/PCRt neurons innervating the BAT sympathetic premotor region also innervate the masticatory motor region, and stimulation of the IRt/PCRt elicits mastication and increases feeding as well as inhibits BAT thermogenesis. These results indicate that GABAergic IRt/PCRt neurons mediate hypothalamus-derived hunger signaling by coordinating both autonomic and feeding motor systems to reduce energy expenditure and to promote feeding. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. The Effects of Sympathetic Inhibition on Metabolic and Cardiopulmonary Responses to Exercise in Hypoxic Conditions.

    Science.gov (United States)

    Scalzo, Rebecca L; Peltonen, Garrett L; Binns, Scott E; Klochak, Anna L; Szallar, Steve E; Wood, Lacey M; Larson, Dennis G; Luckasen, Gary J; Irwin, David; Schroeder, Thies; Hamilton, Karyn L; Bell, Christopher

    2015-12-01

    Pre-exertion skeletal muscle glycogen content is an important physiological determinant of endurance exercise performance: low glycogen stores contribute to premature fatigue. In low-oxygen environments (hypoxia), the important contribution of carbohydrates to endurance performance is further enhanced as glucose and glycogen dependence is increased; however, the insulin sensitivity of healthy adult humans is decreased. In light of this insulin resistance, maintaining skeletal muscle glycogen in hypoxia becomes difficult, and subsequent endurance performance is impaired. Sympathetic inhibition promotes insulin sensitivity in hypoxia but may impair hypoxic exercise performance, in part due to suppression of cardiac output. Accordingly, we tested the hypothesis that hypoxic exercise performance after intravenous glucose feeding in a low-oxygen environment will be attenuated when feeding occurs during sympathetic inhibition. On 2 separate occasions, while breathing a hypoxic gas mixture, 10 healthy men received 1 hour of parenteral carbohydrate infusion (20% glucose solution in saline; 75 g), after which they performed stationary cycle ergometer exercise (~65% maximal oxygen uptake) until exhaustion. Forty-eight hours before 1 visit, chosen randomly, sympathetic inhibition via transdermal clonidine (0.2 mg/d) was initiated. The mean time to exhaustion after glucose feeding both with and without sympathetic inhibition was not different (22.7 ± 5.4 minutes vs 23.5 ± 5.1 minutes; P = .73). Sympathetic inhibition protects against hypoxia-mediated insulin resistance without influencing subsequent hypoxic endurance performance. Copyright © 2015 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.

  11. Changes in the Skin Conductance Monitor as an End Point for Sympathetic Nerve Blocks.

    Science.gov (United States)

    Gungor, Semih; Rana, Bhumika; Fields, Kara; Bae, James J; Mount, Lauren; Buschiazzo, Valeria; Storm, Hanne

    2017-11-01

    There is a lack of objective methods for determining the achievement of sympathetic block. This study validates the skin conductance monitor (SCM) as an end point indicator of successful sympathetic blockade as compared with traditional monitors. This interventional study included 13 patients undergoing 25 lumbar sympathetic blocks to compare time to indication of successful blockade between the SCM indices and traditional measures, clinically visible hyperemia, clinically visible engorgement of veins, subjective skin temperature difference, unilateral thermometry monitoring, bilateral comparative thermometry monitoring, and change in waveform amplitude in pulse oximetry plethysmography, within a 30-minute observation period. Differences in the SCM indices were studied pre- and postblock to validate the SCM. SCM showed substantially greater odds of indicating achievement of sympathetic block in the next moment (i.e., hazard rate) compared with all traditional measures (clinically visible hyperemia, clinically visible engorgement of veins, subjective temperature difference, unilateral thermometry monitoring, bilateral comparative thermometry monitoring, and change in waveform amplitude in pulse oximetry plethysmography; P ≤ 0.011). SCM indicated successful block for all (100%) procedures, while the traditional measures failed to indicate successful blocks in 16-84% of procedures. The SCM indices were significantly higher in preblock compared with postblock measurements (P SCM is a more reliable and rapid response indicator of a successful sympathetic blockade when compared with traditional monitors. © 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  12. RESISTIN, AN ADIPOKINE WITH NON-GENERALISED ACTIONS ON SYMPATHETIC NERVE ACTIVITY

    Directory of Open Access Journals (Sweden)

    Emilio eBadoer

    2015-11-01

    Full Text Available The World Health Organisation has called obesity a global epidemic. There is a strong association between body weight gain and blood pressure. A major determinant of blood pressure is the level of activity in sympathetic nerves innervating cardiovascular organs. A characteristic of obesity, in both humans and in animal models, is an increase in sympathetic nerve activity to the skeletal muscle vasculature and to the kidneys. Obesity is now recognised as a chronic, low level inflammatory condition and pro-inflammatory cytokines are elevated including those produced by adipose tissue. The most well known adipokine released from fat tissue is leptin. The adipokine, resistin,, is also released from adipose tissue. Resistin can act in the central nervous system to influence the sympathetic nerve activity. Here, we review the effects of resistin on sympathetic nerve activity and compare them with leptin. We build an argument that resistin and leptin may have complex interactions. Firstly, they may augment each other as both are excitatory on sympathetic nerves innervating cardiovascular organs; In contrast, they could antagonize each other’s actions on brown adipose tissue, a key metabolic organ. These interactions may be important in conditions in which leptin and resistin are elevated, such as in obesity.

  13. SYMPATHETIC FILAMENT ERUPTIONS FROM A BIPOLAR HELMET STREAMER IN THE SUN

    International Nuclear Information System (INIS)

    Yang Jiayan; Jiang Yunchun; Zheng Ruisheng; Bi Yi; Hong Junchao; Yang Bo

    2012-01-01

    On 2005 August 5, two solar filaments erupted successively from different confined arcades underlying a common overarching multiple-arcade bipolar helmet streamer. We present detailed observations of these two events and identify them as sympathetic filament eruptions. The first (F1) is a small active-region filament located near the outskirts of the streamer arcade. It underwent a nonradial eruption, initially moving in the interior of the streamer arcade and resulting in an over-and-out coronal mass ejection. The second filament (F2), a larger quiescent one far away from F1, was clearly disturbed during the F1 eruption. It then underwent a very slow eruption and finally disappeared completely and permanently. Because two belt-shaped diffuse dimmings formed along the footprints of the streamer arcade in the first eruption and persisted throughout the complete disappearance of F2, the eruption series are interpreted as sympathetic: the simple expansion of the common streamer arcade forced by the F1 eruption weakened magnetic flux overlying F2 and thus led to its slow eruption, with the dimming formation indicating their physical connection. Our observations suggest that multiple-arcade bipolar helmet-streamer configurations are appropriate to producing sympathetic eruptions. Combined with the recent observations of unipolar-streamer sympathetic events, it appears that a multiple-arcade unipolar or bipolar helmet streamer can serve as a common magnetic configuration for sympathetic eruptions.

  14. Alterations of sympathetic nerve fibers in avascular necrosis of femoral head.

    Science.gov (United States)

    Li, Deqiang; Liu, Peilai; Zhang, Yuankai; Li, Ming

    2015-01-01

    Avascular necrosis of the femoral head (ANFH) was mainly due to alterations of bone vascularity. And noradrenaline (NA), as the neurotransmitter of the sympathetic nervous system (SNS), leads to the vasoconstriction by activating its α-Receptor. This study was to explore the nerve fiber density of the femoral head in the rabbit model of ANFH. Twenty New Zealand white rabbits were used in this study. The rabbit model of ANFH was established by the injection of methylprednisolone acetate. The nerve fiber density and distribution in the femoral head was determined using an Olympus BH2 microscope. Significant fewer sympathetic nerve fibers was found in the ANFH intertrochanteric bone samples (P = 0.036) with osteonecrosis. The number of sympathetic nerve fibers was compared between the two groups. And less sympathetic nerve fibers were found in later stage ANFH samples in comparison with those of early stages. ANFH might be preceded by an inflammatory reaction, and an inflammatory response might lead to arthritic changes in tissue samples, which in turn reduces the number of sympathetic nerve fibers.

  15. Neural correlates of fear-induced sympathetic response associated with the peripheral temperature change rate.

    Science.gov (United States)

    Yoshihara, Kazufumi; Tanabe, Hiroki C; Kawamichi, Hiroaki; Koike, Takahiko; Yamazaki, Mika; Sudo, Nobuyuki; Sadato, Norihiro

    2016-07-01

    Activation of the sympathetic nervous system is essential for coping with environmental stressors such as fearful stimuli. Recent human imaging studies demonstrated that activity in some cortical regions, such as the anterior cingulate cortex (ACC) and anterior insula cortex (aIC), is related to sympathetic activity. However, little is known about the functional brain connectivity related to sympathetic response to fearful stimuli. The participants were 32 healthy, right-handed volunteers. Functional magnetic resonance imaging (fMRI) was used to examine brain activity when watching horror and control movies. Fingertip temperature was taken during the scanning as a measure of sympathetic response. The movies were watched a second time, and the degree of fear (9-point Likert-type scale) was evaluated every three seconds. The brain activity of the ACC, bilateral aIC, and bilateral anterior prefrontal cortex (aPFC) was correlated with the change rate of fingertip temperature, with or without fearful stimuli. Functional connectivity analysis revealed significantly greater positive functional connectivity between the amygdala and the ACC and between the amygdala and the aIC when watching the horror movie than when watching the control movie. Whole-brain psycho-physiological interaction (PPI) analysis revealed that the functional connectivity between the left amygdala and the ACC was modulated according to the fear rating. Our results indicate that the increased functional connectivity between the left amygdala and the ACC represents a sympathetic response to fearful stimuli. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Astrocytic GABA Transporters

    DEFF Research Database (Denmark)

    Schousboe, Arne; Wellendorph, Petrine; Frølund, Bente

    2017-01-01

    , and several of these compounds have been shown to exhibit pronounced anticonvulsant activity in a variety of animal seizure models. As proof of concept of the validity of this drug development approach, one GABA-transport inhibitor, tiagabine, has been developed as a clinically active antiepileptic drug......Inactivation of GABA-mediated neurotransmission is achieved by high-affinity transporters located at both GABAergic neurons and the surrounding astrocytes. Early studies of the pharmacological properties of neuronal and glial GABA transporters suggested that different types of transporters might...... be expressed in the two cell types, and such a scenario was confirmed by the cloning of four distinctly different GABA transporters from a number of different species. These GABA-transport entities have been extensively characterized using a large number of GABA analogues of restricted conformation...

  17. Role of autoinhibitory feedback in cardiac sympathetic transmission

    International Nuclear Information System (INIS)

    Angus, J.A.; Korner, P.I.; Jackman, G.P.; Bobik, A.; Kopin, I.J.

    1984-01-01

    The relationship between two indices of transmitter release measured simultaneously and the frequency of 4 field pulses (0.125-2 Hz) were obtained from superfused guinea pig right atria after labelling with 3 H-noradrenaline. The relationships between 3 H-efflux or rate responses and frequency were hyperbolic. Autoinhibitory feedback did not play a role since phentolamine (1 microM) did not alter the 3 H-efflux or rate responses to 4 field pulses that gave 50-60% of the maximum rate response. In the presence of neuronal uptake block (desipramine (0.1 microM) phentolamine enhanced 3 H-efflux and rate responses to 4 field pulses at all frequencies. In the absence of desipramine prolonged trains of field pulses (8-12 pulses) at low frequency (0.25 Hz) were not sufficient to activate autoinhibitory feedback. At 2 Hz phentolamine enhanced both responses at 12 field pulses. We conclude that in the right atrium autoinhibitory feedback plays little role in the modulation of transmitter release at levels of stimulation that cause 50-60% of maximum tissue response. The presence of neuronal uptake inhibition or high stimulus strengths are necessary to evoke autoinhibitory feedback

  18. Pain increases during sympathetic arousal in patients with complex regional pain syndrome.

    Science.gov (United States)

    Drummond, P D; Finch, P M; Skipworth, S; Blockey, P

    2001-10-09

    To investigate the effect of sympathetic arousal on pain and vasomotor responses in healthy control subjects and patients with complex regional pain syndrome (CRPS), and to determine whether pain increases in patients with particular symptoms. In experiments 1 and 2, capsaicin was applied to the forearm of 24 healthy subjects to induce thermal hyperalgesia. Vascular responses were monitored and subjects rated thermal hyperalgesia before and after being startled (experiment 1), and before, during, and after mental arithmetic, breath holding, forehead cooling, the Valsalva maneuver, and a cold pressor test in experiment 2. In a third experiment, sensitivity to heat, cold, and mechanical stimulation was investigated in 61 patients with CRPS. Pain ratings and vascular and electrodermal responses were recorded after patients were startled and during forehead cooling. In experiment 1, thermal hyperalgesia decreased in healthy control subjects after they were startled, and digital blood vessels constricted symmetrically. In experiment 2, thermal hyperalgesia decreased during and after other forms of sympathetic arousal. However, in experiment 3, ratings of clinical pain increased during forehead cooling or after being startled in over 70% of patients with CRPS. Pain increased most consistently during forehead cooling in patients with cold allodynia or punctate allodynia. Digital blood vessels constricted more intensely on the symptomatic than the nonsymptomatic side in patients with CRPS during sympathetic arousal. Normal inhibitory influences on pain during sympathetic arousal are compromised in the majority of patients with CRPS. The augmented vasoconstrictor response in the symptomatic limb during sympathetic arousal is consistent with adrenergic supersensitivity. An adrenergic sensitivity in nociceptive afferents might contribute to pain and hyperalgesia during sympathetic arousal in certain patients with CRPS.

  19. Insulin resistance is associated with impaired cardiac sympathetic innervation in patients with heart failure.

    Science.gov (United States)

    Paolillo, S; Rengo, G; Pellegrino, T; Formisano, R; Pagano, G; Gargiulo, P; Savarese, G; Carotenuto, R; Petraglia, L; Rapacciuolo, A; Perrino, C; Piscitelli, S; Attena, E; Del Guercio, L; Leosco, D; Trimarco, B; Cuocolo, A; Perrone-Filardi, P

    2015-10-01

    Insulin resistance (IR) represents, at the same time, cause and consequence of heart failure (HF) and affects prognosis in HF patients, but pathophysiological mechanisms remain unclear. Hyperinsulinemia, which characterizes IR, enhances sympathetic drive, and it can be hypothesized that IR is associated with impaired cardiac sympathetic innervation in HF. Yet, this hypothesis has never been investigated. Aim of the present observational study was to assess the relationship between IR and cardiac sympathetic innervation in non-diabetic HF patients. One hundred and fifteen patients (87% males; 65 ± 11.3 years) with severe-to-moderate HF (ejection fraction 32.5 ± 9.1%) underwent iodine-123 meta-iodobenzylguanidine ((123)I-MIBG) myocardial scintigraphy to assess sympathetic innervation and Homeostasis Model Assessment Insulin Resistance (HOMA-IR) evaluation to determine the presence of IR. From (123)I-MIBG imaging, early and late heart to mediastinum (H/M) ratios and washout rate were calculated. Seventy-two (63%) patients showed IR and 43 (37%) were non-IR. Early [1.68 (IQR 1.53-1.85) vs. 1.79 (IQR 1.66-1.95); P = 0.05] and late H/M ratio [1.50 (IQR 1.35-1.69) vs. 1.65 (IQR 1.40-1.85); P = 0.020] were significantly reduced in IR compared with non-IR patients. Early and late H/M ratio showed significant inverse correlation with fasting insulinemia and HOMA-IR. Cardiac sympathetic innervation is more impaired in patients with IR and HF compared with matched non-IR patients. These findings shed light on the relationship among IR, HF, and cardiac sympathetic nervous system. Additional studies are needed to clarify the pathogenetic relationship between IR and HF. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

  20. Sympathetic nerve-derived ATP regulates renal medullary blood flow via vasa recta pericytes

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    Scott S Wildman

    2013-10-01

    Full Text Available Pericyte cells are now known to be a novel locus of blood flow control, being able to regulate capillary diameter via their unique morphology and expression of contractile proteins. We have previously shown that exogenous ATP causes constriction of vasa recta via renal pericytes, acting at a variety of membrane bound P2 receptors on descending vasa recta, and therefore may be able to regulate medullary blood flow (MBF. Regulation of MBF is essential for appropriate urine concentration and providing essential oxygen and nutrients to this region of high, and variable, metabolic demand. Various sources of endogenous ATP have been proposed, including from epithelial, endothelial and red blood cells in response to stimuli such as mechanical stimulation, local acidosis, hypoxia, and exposure to various hormones. Extensive sympathetic innervation of the nephron has previously been shown, however the innervation reported has focused around the proximal and distal tubules, and ascending loop of Henle. We hypothesise that sympathetic nerves are an additional source of ATP acting at renal pericytes and therefore regulate MBF. Using a rat live kidney slice model in combination with video imaging and confocal microscopy techniques we firstly show sympathetic nerves in close proximity to vasa recta pericytes in both the outer and inner medulla. Secondly, we demonstrate pharmacological stimulation of sympathetic nerves in situ (by tyramine evokes pericyte-mediated vasoconstriction of vasa recta capillaries; inhibited by the application of the P2 receptor antagonist suramin. Lastly, tyramine-evoked vasoconstriction of vasa recta by pericytes is significantly less than ATP-evoked vasoconstriction. Sympathetic innervation may provide an additional level of functional regulation in the renal medulla that is highly localized. It now needs to be determined under which physiological/pathophysiological circumstances that sympathetic innervation of renal pericytes is

  1. Role of nucleus of the solitary tract noradrenergic neurons in post-stress cardiovascular and hormonal control in male rats.

    Science.gov (United States)

    Bundzikova-Osacka, Jana; Ghosal, Sriparna; Packard, Benjamin A; Ulrich-Lai, Yvonne M; Herman, James P

    2015-01-01

    Chronic stress causes hypothalamo-pituitary-adrenal (HPA) axis hyperactivity and cardiovascular dyshomeostasis. Noradrenergic (NA) neurons in the nucleus of the solitary tract (NTS) are considered to play a role in these changes. In this study, we tested the hypothesis that NTS NA A2 neurons are required for cardiovascular and HPA axis responses to both acute and chronic stress. Adult male rats received bilateral microinjection into the NTS of 6-hydroxydopamine (6-OHDA) to lesion A2 neurons [cardiovascular study, n = 5; HPA study, n = 5] or vehicle [cardiovascular study, n = 6; HPA study, n = 4]. Rats were exposed to acute restraint stress followed by 14 d of chronic variable stress (CVS). On the last day of testing, rats were placed in a novel elevated plus maze (EPM) to test post-CVS stress responses. Lesions of NTS A2 neurons reduced the tachycardic response to acute restraint, confirming that A2 neurons promote sympathetic activation following acute stress. In addition, CVS increased the ratio of low-frequency to high-frequency power for heart rate variability, indicative of sympathovagal imbalance, and this effect was significantly attenuated by 6-OHDA lesion. Lesions of NTS A2 neurons reduced acute restraint-induced corticosterone secretion, but did not affect the corticosterone response to the EPM, indicating that A2 neurons promote acute HPA axis responses, but are not involved in CVS-mediated HPA axis sensitization. Collectively, these data indicate that A2 neurons promote both cardiovascular and HPA axis responses to acute stress. Moreover, A2 catecholaminergic neurons may contribute to the potentially deleterious enhancement of sympathetic drive following chronic stress.

  2. Cytoskeleton Molecular Motors: Structures and Their Functions in Neuron.

    Science.gov (United States)

    Xiao, Qingpin; Hu, Xiaohui; Wei, Zhiyi; Tam, Kin Yip

    2016-01-01

    Cells make use of molecular motors to transport small molecules, macromolecules and cellular organelles to target region to execute biological functions, which is utmost important for polarized cells, such as neurons. In particular, cytoskeleton motors play fundamental roles in neuron polarization, extension, shape and neurotransmission. Cytoskeleton motors comprise of myosin, kinesin and cytoplasmic dynein. F-actin filaments act as myosin track, while kinesin and cytoplasmic dynein move on microtubules. Cytoskeleton motors work together to build a highly polarized and regulated system in neuronal cells via different molecular mechanisms and functional regulations. This review discusses the structures and working mechanisms of the cytoskeleton motors in neurons.

  3. Treatment of Reflex sympathetic dystrophy with Bee venom -Using Digital Infrared Thermographic Imaging-

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    Myung-jang Lim

    2006-12-01

    Full Text Available Objectives : The purpose of this case is to report the patient with Reflex sympathetic dystrophy, who is improved by Bee venom. Method : We treated the patient with Bee venom who was suffering from Reflex sympathetic dystrophy, using Digital Infrared Thermographic Imaging and Verbal Numerical Rating Scale(VNRS to evaluate the therapeutic effects. We compared the temperature of the patient body before and after treatment. Result and Conclusion : We found that Bee venom had excellent outcome to relieve pain, atrophy and ankle joint ROM, and that Bee venom also had clinical effect on hypothermia on the Digital Infrared Thermographic Imaging.

  4. Renal sympathetic denervation attenuates hypertension and vascular remodeling in renovascular hypertensive rats.

    Science.gov (United States)

    Li, Peng; Huang, Pei-Pei; Yang, Yun; Liu, Chi; Lu, Yan; Wang, Fang; Sun, Wei; Kong, Xiang-Qing

    2017-01-01

    Li P, Huang P, Yang Y, Liu C, Lu Y, Wang F, Sun W, Kong X. Renal sympathetic denervation attenuates hypertension and vascular remodeling in renovascular hypertensive rats. J Appl Physiol 122: 121-129, 2017. First published October 14, 2016; doi:10.1152/japplphysiol.01019.2015-Sympathetic activity is enhanced in patients with essential or secondary hypertension, as well as in various hypertensive animal models. Therapeutic targeting of sympathetic activation is considered an effective antihypertensive strategy. We hypothesized that renal sympathetic denervation (RSD) attenuates hypertension and improves vascular remodeling and renal disease in the 2-kidney, 1-clip (2K1C) rat model. Rats underwent 2K1C modeling or sham surgery; then rats underwent RSD or sham surgery 4 wk later, thus resulting in four groups (normotensive-sham, normotensive-RSD, 2K1C-sham, and 2K1C-RSD). Norepinephrine was measured by ELISA. Echocardiography was used to assess heart function. Fibrosis and apoptosis were assessed by Masson and TUNEL staining. Changes in mean arterial blood pressure in response to hexamethonium and plasma norepinephrine levels were used to evaluate basal sympathetic nerve activity. The 2K1C modeling success rate was 86.8%. RSD reversed the elevated systolic blood pressure induced by 2K1C, but had no effect on body weight. Compared with rats in the 2K1C-sham group, rats in the 2K1C-RSD group showed lower left ventricular mass/body weight ratio, interventricular septal thickness in diastole, left ventricular end-systolic diameter, and left ventricular posterior wall thickness in systole, whereas fractional shortening and ejection fraction were higher. Right kidney apoptosis and left kidney hypertrophy were not changed by RSD. Arterial fibrosis was lower in animals in the 2K1C-RSD group compared with those in the 2K1C-sham group. RSD reduced plasma norepinephrine and basal sympathetic activity in rats in the 2K1C-RSD group compared with rats in the 2K1C-sham group. These

  5. Chronic renin inhibition lowers blood pressure and reduces upright muscle sympathetic nerve activity in hypertensive seniors

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    Okada, Yoshiyuki; Jarvis, Sara S; Best, Stuart A; Bivens, Tiffany B; Adams-Huet, Beverley; Levine, Benjamin D; Fu, Qi

    2013-01-01

    Cardiovascular risk remains high in patients with hypertension even with adequate blood pressure (BP) control. One possible mechanism may be sympathetic activation via the baroreflex. We tested the hypothesis that chronic inhibition of renin reduces BP without sympathetic activation, but diuresis augments sympathetic activity in elderly hypertensives. Fourteen patients with stage-I hypertension (66 ± 5 (SD) years) were treated with a direct renin inhibitor, aliskiren (n= 7), or a diuretic, hydrochlorothiazide (n= 7), for 6 months. Muscle sympathetic nerve activity (MSNA), BP, direct renin and aldosterone were measured during supine and a graded head-up tilt (HUT; 5 min 30° and 20 min 60°), before and after treatment. Sympathetic baroreflex sensitivity (BRS) was assessed. Both groups had similar BP reductions after treatment (all P < 0.01), while MSNA responses were different between hydrochlorothiazide and aliskiren (P= 0.006 pre/post × drug). Both supine and upright MSNA became greater after hydrochlorothiazide treatment (supine, 72 ± 18 post vs. 64 ± 15 bursts (100 beats)−1 pre; 60° HUT, 83 ± 10 vs. 78 ± 13 bursts (100 beats)−1; P= 0.002). After aliskiren treatment, supine MSNA remained unchanged (69 ± 13 vs. 64 ± 8 bursts (100 beats)−1), but upright MSNA was lower (74 ± 15 vs. 85 ± 10 bursts (100 beats)−1; P= 0.012 for pre/post × posture). Direct renin was greater after both treatments (both P < 0.05), while upright aldosterone was greater after hydrochlorothiazide only (P= 0.002). The change in upright MSNA by the treatment was correlated with the change of aldosterone (r= 0.74, P= 0.002). Upright sympathetic BRS remained unchanged after either treatment. Thus, chronic renin inhibition may reduce upright MSNA through suppressed renin activity, while diuresis may evoke sympathetic activation via the upregulated renin–angiotensin–aldosterone system, without changing intrinsic sympathetic baroreflex function in elderly hypertensive

  6. Understanding metal homeostasis in primary cultured neurons. Studies using single neuron subcellular and quantitative metallomics.

    Science.gov (United States)

    Colvin, Robert A; Lai, Barry; Holmes, William R; Lee, Daewoo

    2015-07-01

    The purpose of this study was to demonstrate how single cell quantitative and subcellular metallomics inform us about both the spatial distribution and cellular mechanisms of metal buffering and homeostasis in primary cultured neurons from embryonic rat brain, which are often used as models of human disease involving metal dyshomeostasis. The present studies utilized synchrotron radiation X-ray fluorescence (SRXRF) and focused primarily on zinc and iron, two abundant metals in neurons that have been implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Total single cell contents for calcium, iron, zinc, copper, manganese, and nickel were determined. Resting steady state zinc showed a diffuse distribution in both soma and processes, best defined by the mass profile of the neuron with an enrichment in the nucleus compared with the cytoplasm. Zinc buffering and homeostasis was studied using two modes of cellular zinc loading - transporter and ionophore (pyrithione) mediated. Single neuron zinc contents were shown to statistically significantly increase by either loading method - ionophore: 160 million to 7 billion; transporter 160 million to 280 million atoms per neuronal soma. The newly acquired and buffered zinc still showed a diffuse distribution. Soma and processes have about equal abilities to take up zinc via transporter mediated pathways. Copper levels are distributed diffusely as well, but are relatively higher in the processes relative to zinc levels. Prior studies have observed iron puncta in certain cell types, but others have not. In the present study, iron puncta were characterized in several primary neuronal types. The results show that iron puncta could be found in all neuronal types studied and can account for up to 50% of the total steady state content of iron in neuronal soma. Although other metals can be present in iron puncta, they are predominantly iron containing and do not appear to be

  7. Sympathetic regulation and anterior cingulate cortex volume are altered in a rat model of chronic back pain.

    Science.gov (United States)

    Touj, Sara; Houle, Sébastien; Ramla, Djamel; Jeffrey-Gauthier, Renaud; Hotta, Harumi; Bronchti, Gilles; Martinoli, Maria-Grazia; Piché, Mathieu

    2017-06-03

    Chronic pain is associated with autonomic disturbance. However, specific effects of chronic back pain on sympathetic regulation remain unknown. Chronic pain is also associated with structural changes in the anterior cingulate cortex (ACC), which may be linked to sympathetic dysregulation. The aim of this study was to determine whether sympathetic regulation and ACC surface and volume are affected in a rat model of chronic back pain, in which complete Freund Adjuvant (CFA) is injected in back muscles. Sympathetic regulation was assessed with renal blood flow (RBF) changes induced by electrical stimulation of a hind paw, while ACC structure was examined by measuring cortical surface and volume. RBF changes and ACC volume were compared between control rats and rats injected with CFA in back muscles segmental (T10) to renal sympathetic innervation or not (T2). In rats with CFA, chronic inflammation was observed in the affected muscles in addition to increased nuclear factor-kappa B (NF-kB) protein expression in corresponding spinal cord segments (p=0.01) as well as decreased ACC volume (pchronic pain at T2 (p'schronic back pain alters sympathetic functions through non-segmental mechanisms, possibly by altering descending regulatory pathways from ACC. Yet, segmental somato-sympathetic reflexes may compete with non-segmental processes depending on the back region affected by pain and according to the segmental organization of the sympathetic nervous system. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  8. Nucleus Ambiguus Cholinergic Neurons Activated by Acupuncture: Relation to Enkephalin

    Science.gov (United States)

    Guo, Zhi-Ling; Li, Min; Longhurst, John C.

    2012-01-01

    Acupuncture regulates autonomic function. Our previous studies have shown that electroacupuncture (EA) at the Jianshi–Neiguan acupoints (P5–P6, underlying the median nerve) inhibits central sympathetic outflow and attenuates excitatory cardiovascular reflexes, in part, through an opioid mechanism. It is unknown if EA at these acupoints influences the parasympathetic system. Thus, using c-Fos expression, we examined activation of nucleus ambiguus (NAmb) neurons by EA, their relation to cholinergic (preganglionic parasympathetic) neurons and those containing enkephalin. To enhance detection of cell bodies containing enkephalin, colchicine (90–100 μg/kg) was administered into the subarachnoid space of cats 30 hr prior to EA or sham-operated controls for EA. Following bilateral barodenervation and cervical vagotomy, either EA for 30 min at P5–P6 acupoints or control stimulation (needle placement at P5–P6 without stimulation) was applied. While perikarya containing enkephalin were observed in some medullary nuclei (e.g., râphe), only enkephalin-containing neuronal processes were found in the NAmb. Compared to controls (n=4), more c-Fos immunoreactivity, located principally in close proximity to fibers containing enkephalin was noted in the NAmb of EA-treated cats (n=5; P<0.01). Moreover, neurons double-labeled with c-Fos and choline acetyltransferase in the NAmb were identified in EA-treated, but not the control animals. These data demonstrate for the first time that EA activates preganglionic parasympathetic neurons in the NAmb. Because of their close proximity, these EA-activated neurons likely interact with nerve fibers containing enkephalin. These results suggest that EA at the P5–P6 acupoints has the potential to influence parasympathetic outflow and cardiovascular function, likely through an enkephalinergic mechanism. PMID:22306033

  9. Neuron-glia crosstalk in the autonomic nervous system and its possible role in the progression of metabolic syndrome: A new hypothesis

    Directory of Open Access Journals (Sweden)

    RODRIGO eDEL RIO

    2015-12-01

    Full Text Available Metabolic syndrome (MS is characterized by the following physiological alterations: increase in abdominal fat, insulin resistance, high concentration of triglycerides, low levels of HDL, high blood pressure and a generalized inflammatory state. One of the pathophysiological hallmarks of this syndrome is the presence of neurohumoral activation, which involve autonomic imbalance associated to hyperactivation of the sympathetic nervous system. Indeed, enhanced sympathetic drive has been linked to the development of endothelial dysfunction, hypertension, stroke, myocardial infarct and obstructive sleep apnea. Glial cells, the most abundant cells in the central nervous system, control synaptic transmission and regulate neuronal function by releasing bioactive molecules called gliotransmitters. Recently, a new family of plasma membrane channels called hemichannels has been described to allow the release of gliotransmitters and modulate neuronal firing rate. Moreover, a growing amount of evidence indicates that uncontrolled hemichannel opening could impair glial cell functions, affecting synaptic transmission and neuronal survival. Given that glial cell functions are disturbed in various metabolic diseases, we hypothesize that progression of MS may relies on hemichannel-dependent impairment of glial-to-neuron communication by a mechanism related to dysfunction of inflammatory response and mitochondrial metabolism of glial cells. In this manuscript, we discuss how glial cells may contribute to the enhanced sympathetic drive observed in MS, and shed light about the possible role of hemichannels in this process.

  10. Dexmedetomidine decreases inhibitory but not excitatory neurotransmission to cardiac vagal neurons in the nucleus ambiguus.

    Science.gov (United States)

    Sharp, Douglas B; Wang, Xin; Mendelowitz, David

    2014-07-29

    Dexmedetomidine, an α2 adrenergic agonist, is a useful sedative but can also cause significant bradycardia. This decrease in heart rate may be due to decreased central sympathetic output as well as increased parasympathetic output from brainstem cardiac vagal neurons. In this study, using whole cell voltage clamp methodology, the actions of dexmedetomidine on excitatory glutamatergic and inhibitory GABAergic and glycinergic neurotransmission to parasympathetic cardiac vagal neurons in the rat nucleus ambiguus was determined. The results indicate that dexmedetomidine decreases both GABAergic and glycinergic inhibitory input to cardiac vagal neurons, with no significant effect on excitatory input. These results provide a mechanism for dexmedetomidine induced bradycardia and has implications for the management of this potentially harmful side effect. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Calcitonin gene-related peptide alters the firing rates of hypothalamic temperature sensitive and insensitive neurons

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    Grimm Eleanor R

    2008-07-01

    Full Text Available Abstract Background Transient hyperthermic shifts in body temperature have been linked to the endogenous hormone calcitonin gene-related peptide (CGRP, which can increase sympathetic activation and metabolic heat production. Recent studies have demonstrated that these centrally mediated responses may result from CGRP dependent changes in the activity of thermoregulatory neurons in the preoptic and anterior regions of the hypothalamus (POAH. Results Using a tissue slice preparation, we recorded the single-unit activity of POAH neurons from the adult male rat, in response to temperature and CGRP (10 μM. Based on the slope of firing rate as a function of temperature, neurons were classified as either warm sensitive or temperature insensitive. All warm sensitive neurons responded to CGRP with a significant decrease in firing rate. While CGRP did not alter the firing rates of some temperature insensitive neurons, responsive neurons showed an increase in firing rate. Conclusion With respect to current models of thermoregulatory control, these CGRP dependent changes in firing rate would result in hyperthermia. This suggests that both warm sensitive and temperature insensitive neurons in the POAH may play a role in producing this hyperthermic shift in temperature.

  12. Enlarged superior cervical sympathetic ganglion mimicking a metastatic lymph node in the retropharyngeal space: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jae Min; Kim, Jin Na; Kim, Se Hoon; Choi, Eun Chang [Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2017-04-15

    The superior cervical sympathetic ganglion, the largest and most cranial of the three cervical sympathetic ganglia, transfers sympathetic signals to specific targets on the head and neck. This ganglion is located just lateral to the retropharyngeal space along the medial margin of the carotid sheath. Located thus, an enlarged superior cervical sympathetic ganglion can mimic a metastatic lymph node in the retropharyngeal space of the suprahyoid neck in head and neck cancer patients. However, this is often disregarded by radiologists due to lack of interest in its anatomic location. We present a case of an enlarged superior cervical sympathetic ganglion mimicking a retropharyngeal metastatic lymph node in a 42-year-old man with oral tongue cancer.

  13. Eppur Si Muove: The dynamic nature of physiological control of renal blood flow by the renal sympathetic nerves.

    Science.gov (United States)

    Schiller, Alicia M; Pellegrino, Peter Ricci; Zucker, Irving H

    2017-05-01

    Tubuloglomerular feedback and the myogenic response are widely appreciated as important regulators of renal blood flow, but the role of the sympathetic nervous system in physiological renal blood flow control remains controversial. Where classic studies using static measures of renal blood flow failed, dynamic approaches have succeeded in demonstrating sympathetic control of renal blood flow under normal physiological conditions. This review focuses on transfer function analysis of renal pressure-flow, which leverages the physical relationship between blood pressure and flow to assess the underlying vascular control mechanisms. Studies using this approach indicate that the renal nerves are important in the rapid regulation of the renal vasculature. Animals with intact renal innervation show a sympathetic signature in the frequency range associated with sympathetic vasomotion that is eliminated by renal denervation. In conscious rabbits, this sympathetic signature exerts vasoconstrictive, baroreflex control of renal vascular conductance, matching well with the rhythmic, baroreflex-influenced control of renal sympathetic nerve activity and complementing findings from other studies employing dynamic approaches to study renal sympathetic vascular control. In this light, classic studies reporting that nerve stimulation and renal denervation do not affect static measures of renal blood flow provide evidence for the strength of renal autoregulation rather than evidence against physiological renal sympathetic control of renal blood flow. Thus, alongside tubuloglomerular feedback and the myogenic response, renal sympathetic outflow should be considered an important physiological regulator of renal blood flow. Clinically, renal sympathetic vasomotion may be important for solving the problems facing the field of therapeutic renal denervation. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Norepinephrine metabolism in neuronal cultures is increased by angiotensin II

    International Nuclear Information System (INIS)

    Sumners, C.; Shalit, S.L.; Kalberg, C.J.; Raizada, M.K.

    1987-01-01

    In this study the authors have examined the actions of angiotensin II (ANG II) on catecholamine metabolism in neuronal brain cell cultures prepared from the hypothalamus and brain stem. Neuronal cultures prepared from the brains of 1-day-old Sprague-Dawley rats exhibit specific neuronal uptake mechanisms for both norepinephrine (NE) and dopamine (DA), and also monoamine oxidase (MAO) and catechol O-methyltransferase (COMT) activity. Separate neuronal uptake sites for NE and DA were identified by using specific neuronal uptake inhibitors for each amine. In previous studies, they determined that ANG II (10 nM-1 μM) stimulates increased neuronal [ 3 H]NE uptake by acting as specific receptors. They have confirmed these results here and in addition have shown that ANG II has not significant effects on neuronal [ 3 H]DA uptake. These results suggest that the actions of ANG II are restricted to the NE transporter in neuronal cultures. It is possible that ANG II stimulates the intraneuronal metabolism of at least part of the NE that is taken up, because the peptide stimulates MAO activity, an effect mediated by specific ANG II receptors. ANG II had no effect on COMT activity in neuronal cultures. Therefore, the use of neuronal cultures of hypothalamus and brain stem they have determined that ANG II can specifically alter NE metabolism in these areas, while apparently not altering DA metabolism

  15. Vagal and sympathetic activity in burnouts during a mentally demanding workday

    NARCIS (Netherlands)

    Zanstra, Ydwine J.; Schellekens, Jan M. H.; Schaap, Cas; Kooistra, Libbe

    2006-01-01

    Objective: We study differences in task performance and related sympathetic-vagal reaction patterns between burnouts and controls during a mentally demanding workday. Method: Thirty-nine adults with burnout and 40 healthy controls performed mental tasks during a simulated workday. At pretest, just

  16. Early life stress sensitizes the renal and systemic sympathetic system in rats.

    Science.gov (United States)

    Loria, Analia S; Brands, Michael W; Pollock, David M; Pollock, Jennifer S

    2013-08-01

    We hypothesized that maternal separation (MS), an early life stress model, induces a sensitization of the sympathetic system. To test this hypothesis, we evaluated the renal and systemic sympathetic system in 12- to 14-wk-old male control or MS rats with the following parameters: 1) effect of renal denervation on conscious renal filtration capacity, 2) norepinephrine (NE) content in key organs involved in blood pressure control, and 3) acute systemic pressor responses to adrenergic stimulation or ganglion blockade. MS was performed by separating pups from their mothers for 3 h/day from day 2 to 14; controls were nonhandled littermates. Glomerular filtration rate (GFR) was examined in renal denervated (DnX; within 2 wk) or sham rats using I¹²⁵-iothalamate plasma clearance. MS-DnX rats showed significantly increased GFR compared with MS-SHAM rats (3.8 ± 0.4 vs. 2.4 ± 0.2 ml/min, respectively, P renal nerves regulate GFR in MS rats. NE content was significantly increased in organ tissues from MS rats (P renal and systemic sympathetic system. Conscious MS rats displayed a significantly greater increase in mean arterial pressure (MAP) in response to NE (2 μg/kg ip) and a greater reduction in MAP in response to mecamylamine (2 mg/kg ip, P renal and systemic sympathetic system ultimately impairing blood pressure regulation.

  17. Renal sympathetic nervous system and the effects of denervation on renal arteries.

    Science.gov (United States)

    Kannan, Arun; Medina, Raul Ivan; Nagajothi, Nagapradeep; Balamuthusamy, Saravanan

    2014-08-26

    Resistant hypertension is associated with chronic activation of the sympathetic nervous system resulting in various comorbidities. The prevalence of resistant hypertension is often under estimated due to various reasons. Activation of sympathetic nervous system at the renal- as well as systemic- level contributes to the increased level of catecholamines and resulting increase in the blood pressure. This increased activity was demonstrated by increased muscle sympathetic nerve activity and renal and total body noradrenaline spillover. Apart from the hypertension, it is hypothesized to be associated with insulin resistance, congestive heart failure and obstructive sleep apnea. Renal denervation is a novel procedure where the sympathetic afferent and efferent activity is reduced by various techniques and has been used successfully to treat drug-resistant hypertension improvement of various metabolic derangements. Renal denervation has the unique advantage of offering the denervation at the renal level, thus mitigating the systemic side effects. Renal denervation can be done by various techniques including radiofrequency ablation, ultrasound guided ablation and chemical ablation. Various trials evaluated the role of renal denervation in the management of resistant hypertension and have found promising results. More studies are underway to evaluate the role of renal denervation in patients presenting with resistant hypertension in different scenarios. Appropriate patient selection might be the key in determining the effectiveness of the procedure.

  18. Increased cardiac sympathetic activity in patients with hypothyroidism as determined by iodine-123 metaiodobenzylguanidine scintigraphy

    International Nuclear Information System (INIS)

    Momose, Mitsuru; Inaba, Shigeki; Emori, Toshiaki; Imamura, Kimiharu; Kawano, Katsunori; Ueda, Tetsuro; Kobayashi, Hideki; Hosoda, Saichi

    1997-01-01

    Clinical manifestations of hypothyroidism, such as bradycardia, suggest decreased sympathetic tone. However, previous studies in patients with hypothyroidism have suggested that increased plasma noradrenaline (NA) levels represent enhanced general sympathetic activity. As yet, cardiac sympathetic activity (CSA) in hypothyroidism has not been clarified. To evaluate CSA in patients with hypothyroidism, iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy was performed in eight patients with hypothyroidism before therapy and in ten normal control patients. Planar images were obtained at 15 min and 4 h after injection of MIBG. The ratio of early myocardial uptake to the total injected dose (MU) and myocardial clearance of MIBG within 4 h p.i. (MC) were calculated. Plasma NA was also measured, and echocardiography was performed in all patients. Those patients with hypothyroidism in the euthyroid state after medical therapy were also evaluated in a similar manner. Left ventricular ejection fraction, measured by echocardiography, did not differ significantly between the groups. NA, MU and MC were significantly higher in patients with hypothyroidism than in controls, and all parameters were decreased after therapy. MC was well correlated with NA in hypothyroidism (r=0.86) before therapy. We conclude that CSA is increased in patients with hypothyroidism, in parallel with the enhanced general sympathetic activity. (orig.). With 4 figs., 2 tabs

  19. Sympathetic arousal, but not disturbed executive functioning, mediates the impairment of cognitive flexibility under stress.

    Science.gov (United States)

    Marko, Martin; Riečanský, Igor

    2018-05-01

    Cognitive flexibility emerges from an interplay of multiple cognitive systems, of which lexical-semantic and executive are thought to be the most important. Yet this has not been addressed by previous studies demonstrating that such forms of flexible thought deteriorate under stress. Motivated by these shortcomings, the present study evaluated several candidate mechanisms implied to mediate the impairing effects of stress on flexible thinking. Fifty-seven healthy adults were randomly assigned to psychosocial stress or control condition while assessed for performance on cognitive flexibility, working memory capacity, semantic fluency, and self-reported cognitive interference. Stress response was indicated by changes in skin conductance, hearth rate, and state anxiety. Our analyses showed that acute stress impaired cognitive flexibility via a concomitant increase in sympathetic arousal, while this mediator was positively associated with semantic fluency. Stress also decreased working memory capacity, which was partially mediated by elevated cognitive interference, but neither of these two measures were associated with cognitive flexibility or sympathetic arousal. Following these findings, we conclude that acute stress impairs cognitive flexibility via sympathetic arousal that modulates lexical-semantic and associative processes. In particular, the results indicate that stress-level of sympathetic activation may restrict the accessibility and integration of remote associates and bias the response competition towards prepotent and dominant ideas. Importantly, our results indicate that stress-induced impairments of cognitive flexibility and executive functions are mediated by distinct neurocognitive mechanisms. Copyright © 2018 Elsevier B.V. All rights reserved.

  20. Enhanced sympathetic arousal in response to FMRI scanning correlates with task induced activations and deactivations.

    Directory of Open Access Journals (Sweden)

    Markus Muehlhan

    Full Text Available It has been repeatedly shown that functional magnetic resonance imaging (fMRI triggers distress and neuroendocrine response systems. Prior studies have revealed that sympathetic arousal increases, particularly at the beginning of the examination. Against this background it appears likely that those stress reactions during the scanning procedure may influence task performance and neural correlates. However, the question how sympathetic arousal elicited by the scanning procedure itself may act as a potential confounder of fMRI data remains unresolved today. Thirty-seven scanner naive healthy subjects performed a simple cued target detection task. Levels of salivary alpha amylase (sAA, as a biomarker for sympathetic activity, were assessed in samples obtained at several time points during the lab visit. SAA increased two times, immediately prior to scanning and at the end of the scanning procedure. Neural activation related to motor preparation and timing as well as task performance was positively correlated with the first increase. Furthermore, the first sAA increase was associated with task induced deactivation (TID in frontal and parietal regions. However, these effects were restricted to the first part of the experiment. Consequently, this bias of scanner related sympathetic activation should be considered in future fMRI investigations. It is of particular importance for pharmacological investigations studying adrenergic agents and the comparison of groups with different stress vulnerabilities like patients and controls or adolescents and adults.

  1. Central Gi(2) proteins, sympathetic nervous system and blood pressure regulation

    Czech Academy of Sciences Publication Activity Database

    Zicha, Josef

    2016-01-01

    Roč. 216, č. 3 (2016), s. 258-259 ISSN 1748-1708 Institutional support: RVO:67985823 Keywords : inhibitory G proteins * sympathetic nervous system * central blood pressure control Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 4.867, year: 2016

  2. EXERCISE-INDUCED SYMPATHETIC FFA MOBILIZATION IN VMH-LESIONED RATS IS NORMALIZED BY FASTING

    NARCIS (Netherlands)

    Balkan, B.; Dijk, G. van; Strubbe, J.H.; Bruggink, J.E.; Steffens, A.B.

    This study investigates whether reduced sympathetic responses during physical exercise in ventromedial hypothalamus (VMH)-lesioned obese rats are the direct result of damage to hypothalamic circuits or a secondary effect of the altered metabolism in obesity. Obese, VMH-lesioned rats and lean

  3. Macrophage populations and cardiac sympathetic denervation during L-NAME-induced hypertension in rats

    DEFF Research Database (Denmark)

    Neves, S R S; Machado, C R S; Pinto, A M T

    2006-01-01

    The rat model of hypertension induced by prolonged treatment with Nomega-nitro-L-arginine methyl ester (L-NAME) has been extensively used. However, the effects on cardiac autonomic innervation are unknown. Here, the cardiac sympathetic innervation is analyzed in parallel with myocardial lesions a...

  4. Vibration sense and sympathetic vasoconstrictor activity in patients with occlusive arterial disease

    DEFF Research Database (Denmark)

    Bjerre-Jepsen, K; Henriksen, O; Parm, Martin Lehnsbo

    1983-01-01

    function was studied by the capability of the local sympathetic venoarteriolar reflex (Henriksen 1977) elicited by lowering the leg to induce an arteriolar constriction in subcutaneous tissue at the ankle level. Blood flow was measured by the local isotope washout technique. In only five patients with loss...

  5. Low plasma volume coincides with sympathetic hyperactivity and reduced baroreflex sensitivity in formerly preeclamptic patients.

    NARCIS (Netherlands)

    Courtar, D.A.; Spaanderman, M.E.A.; Aardenburg, R.; Janssen, B.J.; Peeters, L.L.

    2006-01-01

    BACKGROUND: Preeclampsia is associated with enhanced sympathetic activity as well as subnormal plasma volume. Meanwhile, in over 50% of these complicated pregnancies, the subnormal plasma volume has been found to persist for a prolonged period after pregnancy. The objective of this study is to test

  6. Adolescent sympathetic activity and salivary C-reactive protein: The effects of parental behavior.

    Science.gov (United States)

    Nelson, Benjamin W; Byrne, Michelle L; Simmons, Julian G; Whittle, Sarah; Schwartz, Orli S; Reynolds, Eric C; O'Brien-Simpson, Neil M; Sheeber, Lisa; Allen, Nicholas B

    2017-10-01

    This study utilized a novel multisystem approach to investigate the effect of observed parental behavior on the relationship between biological mechanisms associated with disease processes (i.e., autonomic physiology and immune response) among their adolescent children. Thirty-three adolescents (23 males), aged 11-13, and their parents participated in a laboratory session in which adolescents provided baseline measures of autonomic (sympathetic) activity, and adolescents and 1 parent participated in a laboratory based dyadic conflict resolution interaction task. This included 3 male parent/male adolescent dyads, 20 female parent/male adolescent dyads, 3 male parent/female adolescent dyads, and 7 female parent/female adolescent dyads. Approximately 3 years later, adolescents provided a salivary measure of C-Reactive Protein (sCRP) to index inflammation. Analyses revealed a positive association between sympathetic activity and sCRP, as well as a moderating role of positive parental behavior in this relationship, such that the association between sympathetic activity and sCRP was greater among adolescents whose parents displayed shorter duration of positive affect. Overall findings indicate parental behavior may influence the association between adolescent sympathetic activity and inflammatory processes. These findings have important implications for understanding the impact of psychosocial factors on biological mechanisms of disease. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  7. Lumbar Sympathetic Plexus Block as a Treatment for Postamputation Pain: Methodology for a Randomized Controlled Trial.

    Science.gov (United States)

    McCormick, Zachary L; Hendrix, Andrew; Dayanim, David; Clay, Bryan; Kirsling, Amy; Harden, Norman

    2018-03-08

    We present a technical protocol for rigorous assessment of patient-reported outcomes and psychophysical testing relevant to lumbar sympathetic blocks for the treatment of postamputation pain (PAP). This description is intended to inform future prospective investigation. Series of four participants from a blinded randomized sham-controlled trial. Tertiary, urban, academic pain medicine center. Four participants with a single lower limb amputation and associated chronic PAP. Participants were randomized to receive a lumbar sympathetic block with 0.25% bupivacaine or sham needle placement. Patient-rated outcome measures included the numerical rating scale (NRS) for pain, the McGill Pain Questionnaire-Short Form, Center for Epidemiological Studies Depression Scale, Pain and Anxiety Symptoms Scale-short version, and Pain Disability Index (PDI). Psychophysical and biometric testing was also performed, which included vibration sensation testing, pinprick sensation testing, brush sensation testing, Von Frey repeated weighted pinprick sensation, and thermal quantitative sensory testing. In the four described cases, treatment of PAP with a single lumbar sympathetic block but not sham intervention resulted in reduction of both residual limb pain and phantom limb pain as well as perceived disability on the PDI at three-month follow-up. An appropriately powered randomized controlled study using this methodology may not only aid in determining the possible clinical efficacy of lumbar sympathetic block in PAP, but could also improve our understanding of underlying pathophysiologic mechanisms of PAP.

  8. Mechanisms of sympathetic activation and blood pressure elevation by intermittent hypoxia.

    Science.gov (United States)

    Prabhakar, Nanduri R; Kumar, Ganesh K

    2010-11-30

    Sleep disordered breathing with recurrent apneas is one of the most frequently encountered breathing disorder in adult humans and preterm infants. Recurrent apnea patients exhibit several co-morbidities including hypertension and persistent sympathetic activation. Intermittent hypoxia (IH) resulting from apneas appears to be the primary stimulus for evoking autonomic changes. The purpose of this article is to briefly review the effects of IH on chemo- and baro-reflexes and circulating vasoactive hormones and their contribution to sympathetic activation and blood pressures. Sleep apnea patients and IH-treated rodents exhibit exaggerated arterial chemo-reflex. Studies on rodent models demonstrated that IH leads to hyperactive carotid body response to hypoxia. On the other hand, baro-reflex function is attenuated in patients with sleep apnea and in IH-treated rodents. Circulating vasoactive hormone levels are elevated in sleep apnea patients and in rodent models of IH. Thus, persistent sympathetic activation and hypertension associated with sleep apneas seems to be due to a combination of altered chemo- and baro-reflexes resulting in sympathetic activation and action of elevated circulating levels of vasoactive hormones on vasculature. Copyright © 2010 Elsevier B.V. All rights reserved.

  9. Exercise training attenuates sympathetic activation and oxidative stress in diet-induced obesity.

    Science.gov (United States)

    Li, G; Liu, J-Y; Zhang, H-X; Li, Q; Zhang, S-W

    2015-01-01

    It is known that excessive sympathetic activity and oxidative stress are enhanced in obesity. This study aimed to clarify whether exercise training (ET) attenuates sympathetic activation and oxidative stress in obesity. The obesity was induced by high-fat diet (HFD) for 12 weeks. Male Sprague-Dawley rats were assigned to four groups: regular diet (RD) plus sedentary (RD-S), RD plus ET (RD-ET), HFD plus sedentary (HFD-S), and HFD plus ET (HFD-ET). The rats in RD-ET and HFD-ET groups were trained on a motorized treadmill for 60 min/day, five days/week for 8 weeks. The sympathetic activity was evaluated by the plasma norepinephrine (NE) level. The superoxide anion, malondialdehyde and F2-isoprostanes levels in serum and muscles were measured to evaluate oxidative stress. The ET prevented the increases in the body weight, arterial pressure and white adipose tissue mass in HFD rats. The NE level in plasma and oxidative stress related parameters got lower in HFD-ET group compared with HFD-S group. We have found decreased mRNA and protein levels of toll-like receptor (TLR)-2 and TLR-4 by ET in HFD rats. These findings suggest that ET may be effective for attenuating sympathetic activation and oxidative stress in diet-induced obesity.

  10. Fostering College-Going Expectations of Immigrant Students through the Sympathetic Touch of School Leadership

    Science.gov (United States)

    Liou, Daniel D.

    2016-01-01

    This article intends to support the efforts of administrators, teachers, and community activists to center race, equity, and anti-deficit perspectives within the practice of school leadership. By drawing upon methods of critical race studies, and Du Bois's 1935 concept of the sympathetic touch, the author provides examples of anti-deficit…

  11. Marital Conflict and Children's Externalizing Behavior: Interactions between Parasympathetic and Sympathetic Nervous System Activity

    Science.gov (United States)

    El-Sheikh, Mona; Kouros, Chrystyna D.; Erath, Stephen; Cummings, E. Mark; Keller, Peggy; Staton, Lori

    2009-01-01

    Toward greater specificity in the prediction of externalizing problems in the context of interparental conflict, interactions between children's parasympathetic and sympathetic nervous system (PNS and SNS) activity were examined as moderators. PNS activity was indexed by respiratory sinus arrhythmia (RSA) and RSA reactivity (RSA-R) to lab…

  12. Voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans

    NARCIS (Netherlands)

    Kox, M.; Eijk, L.T.G.J. van; Zwaag, J.; Wildenberg, J. van den; Sweep, F.C.; Hoeven, J.G. van der; Pickkers, P.

    2014-01-01

    Excessive or persistent proinflammatory cytokine production plays a central role in autoimmune diseases. Acute activation of the sympathetic nervous system attenuates the innate immune response. However, both the autonomic nervous system and innate immune system are regarded as systems that cannot

  13. Sympathetic responses during saline infusion into the veins of an occluded limb.

    Science.gov (United States)

    Cui, Jian; McQuillan, Patrick; Moradkhan, Raman; Pagana, Charles; Sinoway, Lawrence I

    2009-07-15

    Animal studies have shown that the increased intravenous pressure stimulates the group III and IV muscle afferent fibres, and in turn induce cardiovascular responses. However, this pathway of autonomic regulation has not been examined in humans. The aim of this study was to examine the hypothesis that infusion of saline into the venous circulation of an arterially occluded vascular bed evokes sympathetic activation in healthy individuals. Blood pressure, heart rate, and muscle sympathetic nerve activity (MSNA) responses were assessed in 19 young healthy subjects during local infusion of 40 ml saline into a forearm vein in the circulatory arrested condition. From baseline (11.8 +/- 1.2 bursts min(-1)), MSNA increased significantly during the saline infusion (22.5 +/- 2.6 bursts min(-1), P Blood pressure also increased significantly during the saline infusion. Three control trials were performed during separate visits. The results from the control trial show that the observed MSNA and blood pressure responses were not due to muscle ischaemia. The present data show that saline infusion into the venous circulation of an arterially occluded vascular bed induces sympathetic activation and an increase in blood pressure. We speculate that the infusion under such conditions stimulates the afferent endings near the vessels, and evokes the sympathetic activation.

  14. Sensory and sympathetic correlates of heat pain sensitization and habituation in men and women.

    Science.gov (United States)

    Breimhorst, M; Hondrich, M; Rebhorn, C; May, A; Birklein, F

    2012-10-01

    Habituation and sensitization are important behavioural responses to repeated exposure to painful stimuli, but little is known about the factors determining sensory, affective and sympathetic habituation to repeated pain stimulation in men and women. Thirty volunteers (15 women) underwent a standardized heat pain paradigm spread over 8 consecutive days. At the beginning of the experiment, personality dimensions, coping strategies and pain catastrophizing thoughts were determined. Receiving a series of 10 blocks of six painful heat stimuli a day, participants rated pain intensity and unpleasantness. Skin conductance was recorded throughout the sessions. The results show similar habituation of both the sensory and affective dimensions of pain in men and women, although skin conductance did not undergo a significant decrease across the eight days. When focusing on single daily sessions, women showed pain sensitization but sympathetic habituation, while men showed pain sensitization but stable sympathetic activation. Our findings therefore indicate that the process of long-term habituation to painful heat stimuli is a common feature in both genders, whereas men and women might differently recruit their sympathetic nervous system for short-term pain processing. This study could potentially help to better evaluate gender-specific mechanisms in pain perception. © 2012 European Federation of International Association for the Study of Pain Chapters.

  15. Functional role of diverse changes in sympathetic nerve activity in regulating arterial pressure during REM sleep.

    Science.gov (United States)

    Yoshimoto, Misa; Yoshida, Ikue; Miki, Kenju

    2011-08-01

    This study aimed to investigate whether REM sleep evoked diverse changes in sympathetic outflows and, if so, to elucidate why REM sleep evokes diverse changes in sympathetic outflows. Male Wistar rats were chronically implanted with electrodes to measure renal (RSNA) and lumbar sympathetic nerve activity (LSNA), electroencephalogram, electromyogram, and electrocardiogram, and catheters to measure systemic arterial and central venous pressure; these parameters were measured simultaneously and continuously during the sleep-awake cycle in the same rat. REM sleep resulted in a step reduction in RNSA by 36.1% ± 2.7% (P sleep. In contrast to REM sleep, RSNA, LSNA, systemic arterial pressure, and heart rate increased in a unidirectional manner associated with increases in physical activity levels in the order from NREM sleep, quiet awake, moving, and grooming state. Thus, the relationship between RSNA vs. LSNA and systemic arterial pressure vs. heart rate observed during REM sleep was dissociated compared with that obtained during the other behavioral states. It is suggested that the diverse changes in sympathetic outflows during REM sleep may be needed to increase systemic arterial pressure by balancing vascular resistance between muscles and vegetative organs without depending on the heart.

  16. Using a forehead reflectance pulse oximeter to detect changes in sympathetic tone.

    Science.gov (United States)

    Wendelken, Suzanne M; McGrath, Susan P; Akay, Metin; Blike, George T

    2004-01-01

    The extreme conditions of combat and multi-casualty rescue often make field triage difficult and put the medic or first responder at risk. In an effort to improve field triage, we have developed an automated remote triage system called ARTEMIS (automated remote triage and emergency management information system) for use in the battlefield or disaster zone. Common to field injuries is a sudden change in arterial pressure resulting from massive blood loss or shock. In effort to stabilize the arterial pressure, the sympathetic system is strongly activated and sympathetic tone is increased. This preliminary research seeks to empirically demonstrate that a forehead reflectance pulse oximeter is a viable sensor for detecting sudden changes in sympathetic tone. We performed the classic supine-standing experiment and collected the raw waveform, the photoplethysmogram (PPG), continuously using a forehead reflectance pulse oximeter. The resulting waveform was processed in Matlab using various spectral analysis techniques (FFT and AR). Our preliminary results show that a relative ratio analysis (low frequency power/high frequency power) for both the raw PPG signal and its derived pulse statistics (height, beat-to-beat interval) is a useful technique for detecting change in sympathetic tone resulting from positional change.

  17. Kappe neurons, a novel population of olfactory sensory neurons

    OpenAIRE

    Ahuja, Gaurav; Nia, Shahrzad Bozorg; Zapilko, Veronika; Shiriagin, Vladimir; Kowatschew, Daniel; Oka, Yuichiro; Korsching, Sigrun I.

    2014-01-01

    Perception of olfactory stimuli is mediated by distinct populations of olfactory sensory neurons, each with a characteristic set of morphological as well as functional parameters. Beyond two large populations of ciliated and microvillous neurons, a third population, crypt neurons, has been identified in teleost and cartilaginous fishes. We report here a novel, fourth olfactory sensory neuron population in zebrafish, which we named kappe neurons for their characteristic shape. Kappe neurons ar...

  18. NEURON and Python.

    Science.gov (United States)

    Hines, Michael L; Davison, Andrew P; Muller, Eilif

    2009-01-01

    The NEURON simulation program now allows Python to be used, alone or in combination with NEURON's traditional Hoc interpreter. Adding Python to NEURON has the immediate benefit of making available a very extensive suite of analysis tools written for engineering and science. It also catalyzes NEURON software development by offering users a modern programming tool that is recognized for its flexibility and power to create and maintain complex programs. At the same time, nothing is lost because all existing models written in Hoc, including graphical user interface tools, continue to work without change and are also available within the Python context. An example of the benefits of Python availability is the use of the xml module in implementing NEURON's Import3D and CellBuild tools to read MorphML and NeuroML model specifications.

  19. Significance of cardiac sympathetic nervous system abnormality for predicting vascular events in patients with idiopathic paroxysmal atrial fibrillation

    International Nuclear Information System (INIS)

    Akutsu, Yasushi; Kaneko, Kyouichi; Kodama, Yusuke; Li, Hui-Ling; Kawamura, Mitsuharu; Asano, Taku; Hamazaki, Yuji; Tanno, Kaoru; Kobayashi, Youichi; Suyama, Jumpei; Shinozuka, Akira; Gokan, Takehiko

    2010-01-01

    Neuronal system activity plays an important role for the prognosis of patients with atrial fibrillation (AF). Using 123 I metaiodobenzylguanidine ( 123 I-MIBG) scintigraphy, we investigated whether a cardiac sympathetic nervous system (SNS) abnormality would be associated with an increased risk of vascular events in patients with paroxysmal AF. 123 I-MIBG scintigraphy was performed in 69 consecutive patients (67 ± 13 years, 62% men) with paroxysmal AF who did not have structural heart disease. SNS integrity was assessed from the heart to mediastinum (H/M) ratio on delayed imaging. Serum concentration of C-reactive protein (CRP) was measured before 123 I-MIBG study. During a mean of 4.5 ± 3.6 years follow-up, 19 patients had myocardial infarction, stroke or heart failure (range: 0.2-11.5 years). SNS abnormality (H/M ratio <2.7) and high CRP (≥0.3 mg/dl) were associated with the vascular events (58.3% in 14 of 24 patients with SNS abnormality vs 11.1% in 5 of 45 patients without SNS abnormality, p < 0.0001, 52.4% in 11 of 21 patients with high CRP vs 16.7% in 8 of 48 patients without high CRP, p < 0.0001). After adjustment for potential confounding variables such as age, left atrial dimension and left ventricular function, SNS abnormality was an independent predictor of vascular events with a hazard ratio of 4.1 [95% confidence interval (CI): 1.3-12.6, p = 0.014]. Further, SNS abnormality had an incremental and additive prognostic power in combination with high CRP with an adjusted hazard ratio of 4.1 (95% CI: 1.5-10.9, p = 0.006). SNS abnormality is predictive of vascular events in patients with idiopathic paroxysmal AF. (orig.)