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

Huffman, William J.; Subramaniyan, Saraswathi; Rodriguiz, Ramona M.; Wetsel, William C.; Grill, Warren M.; Terrando, Niccolò

doi:10.1016/j.brs.2018.10.005

Cited by 119 publications

(82 citation statements)

References 49 publications

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“…Alternatively, those 2 animals could simply be non-responders seen often in acute studies [38,40]. Our data also suggest that the presence of a heart rate response in an implant does not necessarily predict engagement of the anti-inflammatory pathway, which is consistent with previous findings in acute studies [40,84].…”

Section: Discussionsupporting

confidence: 88%

“…Previous research using VNS in mouse models of disease has been limited to acute, or singleevent, stimulation [40,45,60]. These studies, although of translational value, provide limited insight into the role of long-term stimulation in the treatment of chronic conditions.…”

Section: Discussionmentioning

confidence: 99%

“…This is of particular importance when VNS is delivered therapeutically, wherein standardized doses are desirable within and in between animals, and across time. Previous reports from rat and large animal models implemented a similar approach to adjust stimulation intensity using respiratory twitching [15,71], and heart rate [40,72,73] to standardize stimulation protocols, but not on a dose-by-dose basis. Notably, electrical impedance, which is commonly used as a measure of electrode integrity and performance [74], did not correlate well with changes in HRT on an individual implant basis as implants aged (Fig 3E).…”

Section: Discussionmentioning

confidence: 99%

“…Experimental testing of VNS as therapy for chronic diseases requires a long-term VN implant and, as of yet, has been mostly limited to neurological and cardiovascular diseases modeled in rats and large animals [11,13,15,[27][28][29][30][31][32][33][34]. Even though the mouse is the species of choice in the study of disease mechanisms and is considered the standard for pre-clinical therapeutic screening [35,36], translational VNS research in mice has been limited to acute delivery of stimulation [37][38][39][40][41][42][43][44][45]. This is mainly due to the significant surgical and technical challenges associated with a mechanically- [46][47][48] and electrochemically- [49,50] stable long-term interface with the microscopic anatomy of the mouse vagus nerve.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

An implant for long-term cervical vagus nerve stimulation in mice

Mughrabi

Hickman

Jayaprakash

et al. 2020

Preprint

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Vagus nerve stimulation (VNS) is a neuromodulation therapy with the potential to treat a wide range of chronic conditions in which inflammation is implicated, including type 2 diabetes, obesity and atherosclerosis. Many of these diseases have well-established mouse models, but due to the significant surgical and engineering challenges that accompany a reliable interface for long-term VNS in mice, the therapeutic implications of this bioelectronic therapy remain unexplored. Here, we describe a long-term VNS implant in mice, developed at 3 research laboratories and validated for across-lab reproducibility. Implant functionality was evaluated over 3-8 weeks in 81 anesthetized or behaving mice by determining the stimulus intensity required to elicit a change in heart rate (heart rate threshold, HRT). HRT was also used as a method to standardize stimulation dosing. Overall, 60-90% of implants produced stimulusevoked physiological responses for at least 4 weeks, with HRT values stabilizing after the second week of implantation. Furthermore, stimulation delivered through 6-week-old implants decreased TNF levels in a subset of mice with acute inflammation caused by endotoxemia. Histological examination of 4-to 6-weekold implants revealed fibrotic encapsulation and no gross fiber loss. This implantation and dosing approach provides a tool to systematically investigate the therapeutic potential of long-term VNS in chronic diseases modeled in the mouse, the most widely used vertebrate species in biomedical research.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

An implant for long-term cervical vagus nerve stimulation in mice

Mughrabi

Hickman

Jayaprakash

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Hippocampal-dependent memory was assessed with two mnemonic tasks (Huffman et al, 2019;Miller-Rhodes et al, 2019). The first task assessed memory for objects ("what"), their locations ("where"), and the order in which they were presented ("when").…”

Section: Behavioral Assays: "What-where-when" Memory and Memory Loadmentioning

confidence: 99%

Annexin-A1 tripeptide attenuates surgery-induced neuroinflammation and memory deficits through regulation of the NLRP3 inflammasome

Zhang

Velagapudi

et al. 2020

Preprint

Self Cite

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Neuroinflammation is a growing hallmark of perioperative neurocognitive disorders (PNDs), including delirium and longer-lasting cognitive deficits. We have developed a clinically-relevant orthopedic mouse model to study the impact of a common surgical procedure on the vulnerable brain. The mechanism underlying PNDs remain unknown. Here we evaluated the impact of surgical trauma on the NLRP3 inflammasome signaling, including the expression of apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, and IL-1β in the hippocampus of C57BL6/J male mice, adult (3-months) and aged (>18-months). Surgery triggered ASC specks formation in CA1 hippocampal microglia, but without inducing significant morphological changes in NLRP3 and ASC knockout mice. Since no therapies are currently available to treat PNDs, we assessed the neuroprotective effects of a biomimetic peptide derived from the endogenous inflammation-ending molecule, Annexin-A1 (ANXA1). We tested the hypothesis that this peptide (ANXA1sp) inhibits NLRP3 inflammasome activation, thus preventing microglial activation and hippocampal-dependent memory deficits. Together these results uncover a previously underrecognized role of the NLRP3 inflammasome in triggering postoperative neuroinflammation and offer a new target for advancing treatment of PNDs through resolution of inflammation.

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Comparative localization of colorectal sensory afferent central projections in the mouse spinal cord dorsal horn and caudal medulla dorsal vagal complex

Wang,

Caraballo,

Rychkov

et al. 2023

J of Comparative Neurology

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The distal colon and rectum (colorectum) are innervated by spinal and vagal afferent pathways. The central circuits into which vagal and spinal afferents relay colorectal nociceptive information remain to be comparatively assessed. To address this, regional colorectal retrograde tracing and colorectal distension (CRD)‐evoked neuronal activation were used to compare the circuits within the dorsal vagal complex (DVC) and dorsal horn (thoracolumbar [TL] and lumbosacral [LS] spinal levels) into which vagal and spinal colorectal afferents project. Vagal afferent projections were observed in the nucleus tractus solitarius (NTS), area postrema (AP), and dorsal motor nucleus of the vagus (DMV), labeled from the rostral colorectum. In the NTS, projections were opposed to catecholamine and pontine parabrachial nuclei (PbN)‐projecting neurons. Spinal afferent projections were labeled from rostral through to caudal aspects of the colorectum. In the dorsal horn, the number of neurons activated by CRD was linked to pressure intensity, unlike in the DVC. In the NTS, 13% ± 0.6% of CRD‐activated neurons projected to the PbN. In the dorsal horn, at the TL spinal level, afferent input was associated with PbN‐projecting neurons in lamina I (LI), with 63% ± 3.15% of CRD‐activated neurons in LI projecting to the PbN. On the other hand, at the LS spinal level, only 18% ± 0.6% of CRD‐activated neurons in LI projected to the PbN. The collective data identify differences in the central neuroanatomy that support the disparate roles of vagal and spinal afferent signaling in the facilitation and modulation of colorectal nociceptive responses.

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

Cited by 119 publications

References 49 publications

An implant for long-term cervical vagus nerve stimulation in mice

An implant for long-term cervical vagus nerve stimulation in mice

Annexin-A1 tripeptide attenuates surgery-induced neuroinflammation and memory deficits through regulation of the NLRP3 inflammasome

Comparative localization of colorectal sensory afferent central projections in the mouse spinal cord dorsal horn and caudal medulla dorsal vagal complex

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