Sensory Vagus Nerve Signalling in Inflammation
Başlık:
Sensory Vagus Nerve Signalling in Inflammation
Yazar:
Silverman, Harold A., author.
ISBN:
9780438037519
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (142 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Kevin J. Tracey; Sangeeta S. Chavan Committee members: Peter Davies; Barbra Sherry; Bruce T. Volpe; Ping Wang.
Özet:
The nervous system maintains homeostasis through many different reflex pathways. One such mechanism is the inflammatory reflex that regulates the immunological homeostasis. Pathogenic molecules, cytokines, and other inflammatory mediators activate the afferent signals in the vagus nerve that travel to the brainstem. These signals in turn result in an efferent response that is transmitted by the vagus nerve to the spleen. The splenic nerve signals activate choline acetyltransferase (ChAT)+ T-cells to release acetylcholine which binds to nicotinic acetylcholine receptor (?7 nAChR) expressed on macrophages to block the production of pro-inflammatory cytokines. Although the motor arc of the inflammatory reflex has been well defined, the sensory or afferent arm of this reflex has been much less so. Accordingly, the purpose of this thesis is to understand the afferent arm of the inflammatory reflex.
In Aim 1, we standardized a method for recording cervical vagus nerve activity in real time in mice. Cuff electrodes significantly reduced background noise and increased the signal to noise ratio as compared to hook electrodes. Using these standardized methods, we analyzed vagus neurograms in different mouse strains (Balb/c and C57BL/6), effect of the depth of anesthesia and food intake on the baseline vagus nerve activity. Vagus neurogram activity in wild type and TLR4 receptor knock out mice revealed receptor dependency of endotoxin mediated signals. Next, we analyzed vagus nerve activity in response to different cytokine challenges. Our studies demonstrated that TNF and IL-1beta induce a dose-dependent and receptor-dependent activation of the vagus nerve signals. To better understand these signals, we then developed an algorithm to isolate and decode specific neural signals and discriminate between the two cytokines. The algorithm utilized neural recordings from mice exposed to both TNF and IL-1beta (30 minutes apart) and groups the corresponding compound action potentials by shape and amplitude. Analysis revealed that different action potential shapes corresponded to each cytokine; identifying sensory neural groups specific to TNF and IL-1beta. We reasoned that based on these results, cytokine specific signals are carried through neural fibers that can be identified by molecular markers.
In Aim 2, we identified TRPA1 as a marker for afferent vagus nerve signaling of the inflammatory reflex. Selective stimulation of TRPA1+ fibers of the vagus nerve by optopharmacology significantly reduced levels of TNF in a model of endotoxemia, acting on afferent vagus nerve fibers. When administering IL-1beta to TRPA1 KO mice the thermoregulatory response seen in wildtype mice is ablated. Utilizing the methodology of vagus nerve recording, as previously seen IL-1? induces an increase in vagus nerve activity, this significant increase is not observed in TRPA1 knockout mice. In a model of polymicrobial sepsis, cecal ligation and puncture, TRPA1 knockout mice had significantly higher mortality rate. These mice also exhibited significantly higher percent weight loss and disease severity scores for sickness behavior. Identifying TRPA1 as a molecular marker for vagus nerve fibers in which specific inflammatory signals are transmitted, and a necessary component in maintaining inflammatory homeostasis.
In conclusion, these studies describe previously unknown mechanisms of afferent vagus nerve signaling through the inflammatory reflex and suggest that there is fiber specificity to inflammatory signaling from the periphery to the brain. In addition, this study identified a potential target for therapeutic intervention both electrically and chemically, by targeting TRPA1 specific vagus nerve fibers.
Notlar:
School code: 1983
Tüzel Kişi Ek Girişi:
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(680910.1) | 680910-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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