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      Vagus Nerve Stimulation in Rodent Models: An Overview of Technical Considerations

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          Abstract

          Over the last several decades, vagus nerve stimulation (VNS) has evolved from a treatment for select neuropsychiatric disorders to one that holds promise in treating numerous inflammatory conditions. Growing interest has focused on the use of VNS for other indications, such as heart failure, rheumatoid arthritis, inflammatory bowel disease, ischemic stroke, and traumatic brain injury. As pre-clinical research often guides expansion into new clinical avenues, animal models of VNS have also increased in recent years. To advance this promising treatment, however, there are a number of experimental parameters that must be considered when planning a study, such as physiology of the vagus nerve, electrical stimulation parameters, electrode design, stimulation equipment, and microsurgical technique. In this review, we discuss these important considerations and how a combination of clinically relevant stimulation parameters can be used to achieve beneficial therapeutic results in pre-clinical studies of sub-acute to chronic VNS, and provide a practical guide for performing this work in rodent models. Finally, by integrating clinical and pre-clinical research, we present indeterminate issues as opportunities for future research.

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          Most cited references 99

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          Electrical stimulation of excitable tissue: design of efficacious and safe protocols.

          The physical basis for electrical stimulation of excitable tissue, as used by electrophysiological researchers and clinicians in functional electrical stimulation, is presented with emphasis on the fundamental mechanisms of charge injection at the electrode/tissue interface. Faradaic and non-Faradaic charge transfer mechanisms are presented and contrasted. An electrical model of the electrode/tissue interface is given. The physical basis for the origin of electrode potentials is given. Various methods of controlling charge delivery during pulsing are presented. Electrochemical reversibility is discussed. Commonly used electrode materials and stimulation protocols are reviewed in terms of stimulation efficacy and safety. Principles of stimulation of excitable tissue are reviewed with emphasis on efficacy and safety. Mechanisms of damage to tissue and the electrode are reviewed.
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            Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia.

            The autonomic nervous system maintains homeostasis through its sympathetic and parasympathetic divisions. During infection, cells of the immune system release cytokines and other mediators that cause fever, hypotension, and tissue injury. Although the effect of cytokines on the nervous system has been known for decades, only recently has it become evident that the autonomic nervous system, in turn, regulates cytokine production through neural pathways. We have previously shown that efferent vagus nerve signals regulate cytokine production through the nicotinic acetylcholine receptor subunit alpha7, a mechanism termed "the cholinergic antiinflammatory pathway." Here, we show that vagus nerve stimulation during endotoxemia specifically attenuates TNF production by spleen macrophages in the red pulp and the marginal zone. Administration of nicotine, a pharmacological agonist of alpha7, attenuated TNF immunoreactivity in these specific macrophage subpopulations. Synaptophysin-positive nerve endings were observed in close apposition to red pulp macrophages, but they do not express choline acetyltransferase or vesicular acetylcholine transporter. Surgical ablation of the splenic nerve and catecholamine depletion by reserpine indicate that these nerves are catecholaminergic and are required for functional inhibition of TNF production by vagus nerve stimulation. Thus, the cholinergic antiinflammatory pathway regulates TNF production in discrete macrophage populations via two serially connected neurons: one preganglionic, originating in the dorsal motor nucleus of the vagus nerve, and the second postganglionic, originating in the celiac-superior mesenteric plexus, and projecting in the splenic nerve.
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              Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis

              The innate immune system protects against infection and tissue injury through the specialized organs of the reticuloendothelial system, including the lungs, liver, and spleen. The central nervous system regulates innate immune responses via the vagus nerve, a mechanism termed the cholinergic antiinflammatory pathway. Vagus nerve stimulation inhibits proinflammatory cytokine production by signaling through the α7 nicotinic acetylcholine receptor subunit. Previously, the functional relationship between the cholinergic antiinflammatory pathway and the reticuloendothelial system was unknown. Here we show that vagus nerve stimulation fails to inhibit tumor necrosis factor (TNF) production in splenectomized animals during lethal endotoxemia. Selective lesioning of the common celiac nerve abolishes TNF suppression by vagus nerve stimulation, suggesting that the cholinergic pathway is functionally hard wired to the spleen via this branch of the vagus nerve. Administration of nicotine, an α7 agonist that mimics vagus nerve stimulation, increases proinflammatory cytokine production and lethality from polymicrobial sepsis in splenectomized mice, indicating that the spleen is critical to the protective response of the cholinergic pathway. These results reveal a specific, physiological connection between the nervous and innate immune systems that may be exploited through either electrical vagus nerve stimulation or administration of α7 agonists to inhibit proinflammatory cytokine production during infection and tissue injury.
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                Author and article information

                Contributors
                Journal
                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                1662-4548
                1662-453X
                04 September 2019
                2019
                : 13
                Affiliations
                1The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami , Miami, FL, United States
                2Section of Neurosurgery, Department of Surgery, Dartmouth-Hitchcock Medical Center , Lebanon, NH, United States
                3Geisel School of Medicine, Dartmouth College , Hanover, NH, United States
                4SetPoint Medical Corporation , Valencia, CA, United States
                5Department of Neurological Surgery, Miller School of Medicine, University of Miami , Miami, FL, United States
                6Jackson Memorial Hospital , Miami, FL, United States
                7Department of Physical Medicine and Rehabilitation, Miller School of Medicine, University of Miami , Miami, FL, United States
                Author notes

                Edited by: Mikhail Lebedev, Duke University, United States

                Reviewed by: Stefan Kampusch, Vienna University of Technology, Austria; Ivan N. Pigarev, Institute for Information Transmission Problems (RAS), Russia; Ilknur Ay, Harvard Medical School, United States

                *Correspondence: Crystal M. Noller, Crystal.M.Noller@ 123456dartmouth.edu

                This article was submitted to Neural Technology, a section of the journal Frontiers in Neuroscience

                Article
                10.3389/fnins.2019.00911
                6738225
                Copyright © 2019 Noller, Levine, Urakov, Aronson and Nash.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 113, Pages: 11, Words: 0
                Funding
                Funded by: National Institute on Disability, Independent Living, and Rehabilitation Research 10.13039/100009157
                Funded by: Morton Cure Paralysis Fund 10.13039/100003146
                Categories
                Neuroscience
                Review

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