Live-cell imaging methods for the study of vagal afferents within the nucleus of the solitary tract

Rogers, R. Curtis; Nasse, Jason S.; Hermann, Gerlinda E.

doi:10.1016/j.jneumeth.2005.05.020

Cited by 28 publications

(40 citation statements)

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“…Our data indicate that RyR2 facilitates presynaptic glutamate release in central parasympathetic dorsomotor vagal neurons. The involvement of RyR channels in this central autonomic microcircuit was previously demonstrated using RyR modulators to modify the excitability of dorsal premotor vagal neurons (53) and the sensory afferent vagal nerve inputs terminating in the NTS (54,55). Thus, abnormal hyperexcitability of the central excitatory input to the dorsal vagal brainstem microcircuit may contribute to episodic interictal bradycardia as well as depress cardiac function during seizures.…”

Section: Rq Mutation Selectively Enhances Excitatory Synaptic Transmimentioning

confidence: 94%

Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death

Aiba

Wehrens

Noebels

2016

Proc. Natl. Acad. Sci. U.S.A.

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Cardiorespiratory failure is the most common cause of sudden unexplained death in epilepsy (SUDEP). Genetic autopsies have detected "leaky" gain-of-function mutations in the ryanodine receptor-2 (RyR2) gene in both SUDEP and sudden cardiac death cases linked to catecholaminergic polymorphic ventricular tachycardia that feature lethal cardiac arrhythmias without structural abnormality. Here we find that a human leaky RyR2 mutation, R176Q (RQ), alters neurotransmitter release probability in mice and significantly lowers the threshold for spreading depolarization (SD) in dorsal medulla, leading to cardiorespiratory collapse. Rare episodes of sinus bradycardia, spontaneous seizure, and sudden death were detected in RQ/+ mutant mice in vivo; however, when provoked, cortical seizures frequently led to apneas, brainstem SD, cardiorespiratory failure, and death. In vitro studies revealed that the RQ mutation selectively strengthened excitatory, but not inhibitory, synapses and facilitated SD in both the neocortex as well as brainstem dorsal medulla autonomic microcircuits. These data link defects in neuronal intracellular calcium homeostasis to the vulnerability of central autonomic brainstem pathways to hypoxic stress and implicate brainstem SD as a previously unrecognized site and mechanism contributing to premature death in individuals with leaky RYR2 mutations.sudden unexpected death in epilepsy | SUDEP | catecholaminergic polymorphic ventricular tachycardia | CPVT | ryanodine receptor U p to 10% of individuals with seizures of unknown cause and without known structural cardiac pathology die of sudden unexpected death in epilepsy (SUDEP), and this morbidity is second only to stroke in the number of life-years lost (1). Despite the high mortality rate, comparable to that of sudden infant death syndrome (SIDS), the exact causes are unclear, and there is no effective prediction or intervention. Cardiorespiratory dysfunction and collapse have been observed following generalized tonicclonic seizures in a small number of monitored cases (2), "near SUDEP" cases (3), and mouse SUDEP models (4-6). Genes linked with the most common cardiac LQT syndromes including LQT1 (KCNQ1), LQT2 (KCNH2/HERG), and LQT3 (SCN5A) are expressed in both the human heart and brain, where mutations in the kinetics of these membrane ion channels prolong depolarization and produce combined seizure, cardiac arrhythmia, and sudden death phenotypes (7,8). Because mutations in these ion channel genes currently explain only a small fraction of SUDEP cases (7), the search for additional genes and mechanisms is a high priority to understand and treat sudden death risk.Along with cardiac arrhythmia, recent findings in voltage-gated ion channelopathy models point to an extracardiac, central autonomic involvement of these genes in the events leading to sudden cardiac death. Spreading depolarization (SD) is a slow propagating wave of cellular depolarization that occurs in human brain and is known to contribute to transient neurological deficits during migraine ...

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Section: Rq Mutation Selectively Enhances Excitatory Synaptic Transmimentioning

confidence: 94%

Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death

Aiba

Wehrens

Noebels

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Additionally, these calcium-imaging methods may be used in adult rodents, whereas in vitro whole-cell patch or intracellular recording methods are usually restricted to neonates and juveniles because of the overgrowth of the neuropil and glia. The development of methods for direct analysis of vagal afferent terminal calcium responses yielded a powerful tool for examining presynaptic regulatory mechanisms (Rogers, Nasse, and Hermann 2006).…”

Section: Mechanism Of Action Of Tnf α At Vagal Afferent Terminals In mentioning

confidence: 99%

TNF α: A Trigger of Autonomic Dysfunction

Hermann

Rogers

2007

Neuroscientist

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During disease, infection, or trauma, the cytokine tumor necrosis factor α (TNF α ) causes fever, fatigue, malaise, allodynia, anorexia, gastric stasis associated with nausea, and emesis via interactions with the central nervous system. Our studies have focused on how TNF α produces a profound gastric stasis by acting on vago-vagal reflex circuits in the brainstem. Sensory elements of this circuit (i.e., nucleus of the solitary tract [NST] and area postrema) are activated by TNF α . In response, the efferent elements (i.e., dorsal motor neurons of the vagus) cause gastroinhibition via their action on the gastric enteric plexus. We find that TNF α presynaptically modulates the release of glutamate from primary vagal afferents to the NST and can amplify vagal afferent responsiveness by sensitizing presynaptic intracellular calcium-release mechanisms. The constitutive presence of TNF α receptors on these afferents and their ability to amplify afferent signals may explain how TNF α can completely disrupt autonomic control of the gut. KeywordsImmune-neural interactions; Gastric stasis; Visceral malaise; Hypersensitivity; Potentiation; Allodynia; Illness behavior Immune system activation in response to infection or injury initiates a constellation of physiological and behavioral changes that include fever, fatigue, listlessness, loss of appetite, malaise, nausea, emesis, hypersensitivity to touch or pain, and significant changes in sleep patterns (Hermann, Holmes, and Rogers 2005). This Ȝsickness behaviorȝ represents an attempt by the host to reorganize its physiological priorities following injury or infection. For example with infection, an elevation in body temperature may help destroy the microorganisms, and the loss of appetite and emesis will minimize ingestion and cause elimination of pathogens and toxins. The reduction in activity caused by allodynia and increased sleep will act to immobilize the host, thus conserving available energy resources (Turrin and Plata-Salaman 2000).These physiological changes are caused by the endocrine-like and paracrine-like actions of signal molecules called cytokines. Cytokines are released by immune effector cells as well as a variety of nonimmune cell types (e.g., Guzik and others 2006;Muller and Meineke 2007). The production of cytokines by the immune system in response to infection or injury plays a critical role in coordinating the host's defense (e.g., Correa and others 2007;Kaisho and Akira 2006). The process is triggered by interactions with transmembrane proteins, Toll-like receptors that are mainly expressed on antigen-presenting cells such as macrophages or dendritic cells and provoke the release of proinflammatory cytokines (e.g., Copyright © 2008 Sage Publications Address correspondence to: Gerlinda E. Hermann and Richard C. Rogers, Laboratory of Autonomic Neurosciences, Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, LA 70808 (HermanGE@pbrc.edu; RogersRC@pbrc.edu). NIH Public Access Brainstem Visceral Autonomic ControlThe dorsal vaga...

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“…Importantly, neuromodulators acting at presynaptic receptors that reduce the probability of transmitter release can alter the filtering characteristic of these synapses rendering them more reliable. There are many autacoids, cytokines, and neurotransmitters that can presynaptically modulating vagal neurotransmission in the NTS (Andresen and Kunze, 1994; see also references in Rogers et al 2006). Thus, it is not too surprising that these synapses would also be regulated by lipid mediators such as PGE 2 .…”

mentioning

confidence: 99%

Prostaglandin E2 depresses solitary tract-mediated synaptic transmission in the nucleus tractus solitarius

Laaris¹,

Weinreich²

2007

Neuroscience

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Prostaglandin E 2 (PGE 2 ) is a prototypical inflammatory mediator that excites and sensitizes cell bodies (Kwong and Lee, 2002; and peripheral nerve terminals (Ho et al. 2000) of primary vagal sensory neurons. Nearly all central nerve terminals of vagal afferents are in the nucleus tractus solitarius (NTS), where they operate with a high probability of release (Doyle and Andresen, 2001). We studied the effect of PGE 2 on synaptic transmission between tractus solitarius afferent nerve terminals and the second order NTS neurons in brain stem slices of Sprague Dawley rats. Whole-cell patch recording in voltage clamp mode was used to study evoked excitatory postsynaptic glutamatergic currents (evEPSCs) from NTS neurons elicited by electrical stimulation of the solitary tract (ST). In 34 neurons, bath applied PGE 2 (200 nM) decreased the evEPSC amplitude by 49 ± 5 %. In 22 neurons, however, PGE 2 had no effect. We also tested 15 NTS neurons for capsaicin sensitivity. Seven neurons generated evEPSCs that were equally unaffected by PGE 2 and capsaicin. Conversely, evEPSCs of the other 8 neurons, which were PGE 2 -responsive, were abolished by 200 nM capsaicin. Furthermore, the PGE 2-induced depression of evEPSCs was associated with an increase in the paired pulse ratio and a decrease in both the frequency and amplitude of the spontaneous excitatory postsynaptic currents (sEPSCs) and TTX-independent spontaneous miniature excitatory postsynaptic currents (mEPSCs). These results suggest that PGE 2 acts both presynaptically on nerve terminals and postsynaptically on NTS neurons to reduce glutamatergic responses. KeywordsGlutamate; AMPA receptors; Presynaptic; Postsynaptic Many neurons in the nucleus of the tractus solitarius (NTS) receive nerve terminals whose axons arise from cell bodies of vagal primary afferent neurons located in the nodose and jugular vagal ganglia. These primary vagal afferents convey diverse sensory information from a variety of receptors located in cardiovascular, respiratory, gastrointestinal and other organs to the NTS neurons in the medulla (Contreras, 1982). Thus, the first monosynaptic contact for myelinated A-type and unmyelinated C-type axons of primary vagal afferent fibers are the second-order neurons in the NTS. These fibers reach second-order NTS neurons via the solitary tract (Doyle Corresponding author: Nora Laaris, Department Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, MD 21201, Tel: (410) 706-1409, Fax: (410) 706-0032, e-mail: nlaar001@umaryland.edu. Section Editor: Dr. Yoland Smith, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road NE, Atlanta, GA 30329, USA Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its fin...

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Live-cell imaging methods for the study of vagal afferents within the nucleus of the solitary tract

Cited by 28 publications

References 58 publications

Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death

Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death

TNF α: A Trigger of Autonomic Dysfunction

Prostaglandin E2 depresses solitary tract-mediated synaptic transmission in the nucleus tractus solitarius

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