Modulation of neuroinflammation and memory dysfunction using percutaneous vagus nerve stimulation in mice.

Author: Huffman WJ1, Subramaniyan S2, Rodriguiz RM3, Wetsel WC4, Grill WM5, Terrando N6
Affiliation:
1Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA; Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, 27710, USA.
2Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, 27710, USA.
3Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, 27710, USA.
4Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, 27710, USA; Department of Neurobiology and Cell Biology, Duke University Medical Center, Durham, NC, 27710, USA.
5Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA; Department of Electrical and Computer Engineering, Neurobiology, and Neurosurgery, Duke University, Durham, NC, 27708, USA.
6Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, 27710, USA. Electronic address: niccolo.terrando@duke.edu.
Conference/Journal: Brain Stimul.
Date published: 2018 Oct 9
Other: Pages: S1935-861X(18)30351-6 , Special Notes: doi: 10.1016/j.brs.2018.10.005. [Epub ahead of print] , Word Count: 273

BACKGROUND: The vagus nerve is involved in regulating immunity and resolving inflammation. Current strategies aimed at modulating neuroinflammation and cognitive decline, in many cases, are limited and ineffective.

OBJECTIVE: We sought to develop a minimally invasive, targeted, vagus nerve stimulation approach (pVNS), and we tested its efficacy with respect to microglial activation and amelioration of cognitive dysfunction following lipopolysaccharide (LPS) endotoxemia in mice.

METHODS: We stimulated the cervical vagus nerve in mice using an ultrasound-guided needle electrode under sevoflurane anesthesia. The concentric bipolar needle electrode was percutaneously placed adjacent to the carotid sheath and stimulation was verified in real-time using bradycardia as a biomarker. Activation of vagal fibers was confirmed with immunostaining in relevant brainstem structures, including the dorsal motor nucleus and nucleus tractus solitarius. Efficacy of pVNS was evaluated following administration of LPS and analyses of changes in inflammation and behavior.

RESULTS: pVNS enabled stimulation of the vagus nerve as demonstrated by changes in bradycardia and histological evaluation of c-Fos and choline acetyltransferase expression in brainstem nuclei. Following LPS administration, pVNS significantly reduced plasma levels of tumor necrosis factor-α at 3 h post-injection. pVNS prevented LPS-induced hippocampal microglial activation as analyzed by changes in Iba-1 immunoreactivity, including cell body enlargement and shortened ramifications. Cognitive dysfunction following endotoxemia was also restored by pVNS.

CONCLUSION: Targeted cervical VNS using this novel percutaneous approach reduced LPS-induced systemic and brain inflammation and significantly improved cognitive responses. These results provide a novel therapeutic approach using bioelectronic medicine to modulate neuro-immune interactions that affect cognition.

Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

KEYWORDS: Cognition; Cytokines; Microglia; Neuroinflammation; Percutaneous; Vagus nerve stimulation

PMID: 30337243 DOI: 10.1016/j.brs.2018.10.005

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