Induction of c-Fos and ΔFosB Immunoreactivity in Rat Brain by Vagal Nerve Stimulation

Cunningham, J. Thomas; Mifflin, Steve; Gould, Georgianna G.; Frazer, Alan

doi:10.1038/sj.npp.1301570

Cited by 144 publications

(139 citation statements)

References 77 publications

(119 reference statements)

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“…Immunohistochemical studies demonstrate that hypoxia stimulates multiple types of neurons in numerous brain regions including both the noradrenergic LC and serotonergic raphe nuclei (Erickson and Millhorn, 1994;Teppema et al, 1997;Bodineau and Larnicol, 2001). In contrast, vagal modulation predominately activates LC cells that project to hypoglossal motoneurons (Naritoku et al, 1995;Cunningham et al, 2008). Therefore, we hypothesize that intermittent hypoxia recruits both serotonergic and noradrenergic mechanisms that cause both phrenic and hypoglossal LTF, whereas vagusmediated LTF specifically activates a noradrenergic pathway that only causes plasticity in hypoglossal motoneurons.…”

Section: Discussionmentioning

confidence: 87%

“…Anatomical tracing studies demonstrate that vagal afferents project to the nucleus of the solitary tract (NTS), which in turn innervates LC neurons (Cedarbaum and Aghajanian, 1978;Clavier, 1978;Kalia and Sullivan, 1982;Berthoud and Neuhuber, 2000). Importantly, vagal nerve modulation increases c-Fos activation of noradrenergic LC cells (Naritoku et al, 1995;Cunningham et al, 2008), which in turn project directly to hypoglossal motoneurons (Aldes et al, 1992). We hypothesize that obstructive apneas modulate vagal afferents, which indirectly (i.e., via NTS) activate LC neurons to increase noradrenaline release onto hypoglossal motoneurons.…”

Section: Discussionmentioning

confidence: 99%

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Identification of a Novel Form of Noradrenergic-Dependent Respiratory Motor Plasticity Triggered by Vagal Feedback

Tadjalli¹,

Duffin²,

Peever³

2010

J. Neurosci.

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The respiratory control system is not just reflexive, it is smart, it learns, and, in fact, it has a memory. The respiratory system listens to and carefully remembers how previous stimuli affect breathing. Respiratory memory is laid down by adjusting synaptic strength between respiratory neurons. For example, repeated hypoxic bouts trigger a form of respiratory memory that functions to strengthen the ability of respiratory motoneurons to trigger contraction of breathing muscles. This type of respiratory plasticity is known as long-term facilitation (LTF). Although chemical feedback, such as hypoxia, initiates LTF, it is unknown whether natural modulation of mechanical feedback (from vagal inputs) also causes motor plasticity. Here, we used reverse microdialysis, electrophysiology, neuropharmacology, and histology to determine whether episodic modulation of vagally mediated mechanical feedback is able to induce respiratory LTF in anesthetized adult rats. We show that repeated obstructive apneas disrupt vagal feedback and trigger LTF of hypoglossal motoneuron activity and genioglossus muscle tone. This same stimulus does not cause LTF of diaphragm activity. Hypoxic episodes do not cause apnea-induced LTF; instead, LTF is triggered by modulation of vagal feedback. Unlike hypoxia-induced respiratory plasticity, vagusinduced LTF does not require 5-HT 2 receptors but instead relies on activation of ␣1-adrenergic receptors on hypoglossal motoneurons. In summary, we identify a novel form of hypoxia-and 5-HT-independent respiratory motor plasticity that is triggered by physiological modulation of vagal feedback and is mediated by ␣1-adrenergic receptor activation on (or near) hypoglossal motoneurons.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Identification of a Novel Form of Noradrenergic-Dependent Respiratory Motor Plasticity Triggered by Vagal Feedback

Tadjalli¹,

Duffin²,

Peever³

2010

J. Neurosci.

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“…21 Recent studies have also shown VNS increase c-fos expression, which acutely activates the locus ceruleus and chronically activates the NTS, paraventricular nucleus of the hypothalamus, parabrachial nucleus, ventral bed nucleus of the stria terminalis, cingulated nucleus, and dorsal raphe nucleus. 22 VNS may also increase GABA release, which stimulates the vagus nerve and decreases seizure activity. These effects likely form the basic mechanism(s) by which VNS reduce seizure activity.…”

Section: Question 1: How Do Vagus Nerve Stimulators Work and What Armentioning

confidence: 99%

Obstructive Sleep Apnea and Respiratory Complications Associated with Vagus Nerve Stimulators

Parhizgar

Nugent

Raj

2011

Journal of Clinical Sleep Medicine

109

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Intermittent vagus nerve stimulation can reduce the frequency of seizures in patients with refractory epilepsy. Stimulation of vagus nerve afferent fi bers can also cause vocal cord dysfunction, laryngeal spasm, cough, dyspnea, nausea, and vomiting. Vagus nerve stimulation causes an increase in respiratory rate, decrease in respiratory amplitude, decrease in tidal volume, and decrease in oxygen saturation during periods of device activation. It usually does not cause an arousal, or a change in heart rate or blood pressure. Most patients have an increase in their apnea-hypopnea index (AHI). Patients with VNS can have central apneas, obstructive hypopneas, and obstructive apneas. These respiratory events can be reduced with changes in the vagus nerve stimulator operational parameters or with the use of CPAP. In summary, there are complex relationships between epilepsy and obstructive sleep apneas. In particular, patients with refractory epilepsy need assessment for undiagnosed and untreated obstructive sleep apnea before implantation of vagus nerve stimulator devices. Patients with vagus nerve stimulators often have an increase in apneic events after implantation, and these patients need screening for sleep apnea both before and after implantation. (VNS) to control refractory epilepsy in 1990. 1 Intermittent vagus nerve stimulation can reduce seizures by up to 50% in adult seizure patients and up to 90% in pediatric seizure patients. The FDA approved these devices for the treatment of refractory epilepsy in 1997 and for the treatment of refractory depression in 2005. VNS are currently under investigation for treatment of anxiety, obesity, bulimia, migraines, Alzheimer disease, chronic pain syndromes, obsessive-compulsive disorder, panic disorder, and posttraumatic stress disorder. 2 Vagus nerve stimulation can cause side effects involving the upper airway, lower respiratory tract, and upper gastrointestinal tract. These devices can decrease airfl ow, oxygen saturation, and respiratory amplitude during sleep. 3 Most patients with VNS have an increase in their apnea-hypopnea index (AHI) after implantation. 4 One-third of these patients develop mild obstructive sleep apnea post treatment, 4,5 and a minority of patients develop severe obstructive sleep apnea secondary to VNS therapy. 6 More than 50,000 patients have had VNS implants to date, and it is important for sleep medicine specialists to recognize the sleep disordered breathing and other respiratory complications related to VNS devices. We recently helped care for a patient who developed obstructive sleep apnea (OSA) after implantation of a VNS and then required discontinuation of the VNS. Our review of literature while attempting to answer some clinically relevant questions pertaining to this patient led to this review. This article focuses on six questions pertinent to the management of these patients and reviews the literature on sleep-related and respiratory complications associated with vagus nerve stimulators. mETHODSWe conducted a literature search with ...

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“…43 The observation of increased c-fos expression in response to acute and chronic VNS in rats also supports the role of locus coeruleus activation in the acute phase, along with long-term activation of the NTS, paraventricular nucleus of the hypothalamus, parabrachial nucleus, ventral bed nucleus of the stria terminalis, cingulate cortex, and dorsal raphe nucleus. 44 A marginal decrease in CSF aspartate with 3 months of VNS is also of interest, given the excitatory properties of aspartate. 41 Indeed, decreased levels of excitatory neurotransmitters may be one factor in the mechanisms underlying improved seizure control.…”

Section: Rationale and Proposed Mechanisms Of Vns In Epilepsy Controlmentioning

confidence: 99%

Vagus Nerve Stimulation in the Treatment of Refractory Epilepsy

2009

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Summary: Many patients with epilepsy suffer from persistent seizures despite maximal anti-epileptic drug therapy. Chronic, intermittent vagus nerve stimulation has been proven to be an effective option for many patients suffering from refractory seizures who are not candidates for surgical resection. Although only a small minority of patients will be entirely seizure-free, vagus nerve stimulation, as an adjunct to medical therapy, may result in significant improvements in quality of life. Vagus nerve stimulation is generally well-tolerated, as device implantation is associated with a low rate of perioperative complications, and the majority of side effects are stimulation-dependent and thus reversible.

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Induction of c-Fos and ΔFosB Immunoreactivity in Rat Brain by Vagal Nerve Stimulation

Cited by 144 publications

References 77 publications

Identification of a Novel Form of Noradrenergic-Dependent Respiratory Motor Plasticity Triggered by Vagal Feedback

Identification of a Novel Form of Noradrenergic-Dependent Respiratory Motor Plasticity Triggered by Vagal Feedback

Obstructive Sleep Apnea and Respiratory Complications Associated with Vagus Nerve Stimulators

Vagus Nerve Stimulation in the Treatment of Refractory Epilepsy

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