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Modulation of neuroinflammation and memory dysfunction using percutaneous vagus nerve stimulation in mice
Open accessAbstract
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.
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“Peripheral inflammation triggers central cytokine release via vagus nerve-mediated signal transduction, forming a vicious neuro-immune cycle [94].”
From Research Advances in the Pathogenesis of Sepsis-Associated Encephalopathy (2026) · cites this paper as [94]
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“Cholinergic system dysfunction is manifested by reduced ChAT-positive neurons and abnormal AChE activity, leading to dysregulated microglial activation thresholds and accelerated transformation towards neurotoxic phenotypes [94].”
From Research Advances in the Pathogenesis of Sepsis-Associated Encephalopathy (2026) · cites this paper as [94]
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“Cholinergic system dysfunction is manifested by reduced ChAT-positive neurons and abnormal AChE activity, leading to dysregulated microglial activation thresholds and accelerated transformation towards neurotoxic phenotypes [94].”
From Research Advances in the Pathogenesis of Sepsis-Associated Encephalopathy (2026) · cites this paper as [94]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Cholinergic system dysfunction is manifested by reduced ChAT-positive neurons and abnormal AChE activity, leading to dysregulated microglial activation thresholds and accelerated transformation towards neurotoxic phenotypes [94].”
From Research Advances in the Pathogenesis of Sepsis-Associated Encephalopathy (2026) · cites this paper as [94]
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Metadata
- Authors
- Huffman, W. J., Subramaniyan, S., Rodriguiz, R. M., Wetsel, W. C., Grill, W. M., & Terrando, N.
- Affiliations
- Duke University (US)
- Corresponding author
- Terrando, Niccolò
- ORCID
- Venue
- Brain Stimulation
- Publisher
- Elsevier BV
- Published
- 2019-01
- Volume
- 12
- Issue
- 1
- Pages
- 19-29
- ISSN
- 1876-4754 (ISSN-L)
- 1935-861X
- PMC
- PMC6301148
- OpenAlex
- W2897533172
- Cited by
- 181
- References
- 49
- Citations by year
- 2026: 17 · 2025: 27 · 2024: 22 · 2023: 29 · 2022: 33 · 2021: 24 · 2020: 18 · 2019: 11
- FWCI
- 5.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain stimulation (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Aging (R21AG055877, R01AG057525)
- Topics
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- neuroinflammation, memory impairment, microglial activation, hippocampus, bioelectronic medicine, neuroimmune interactions, TNF-α, dorsal motor nucleus of the vagus, nucleus tractus solitarius, cognitive impairment
- MeSH terms
- Animals, Inflammation, Lipopolysaccharides, Male, Cytokines, Solitary Nucleus, Endotoxemia, Mice, Vagus Nerve Stimulation, Cognitive Dysfunction
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