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dc.contributor.authorPradhananga, Sabindraen
dc.date.accessioned2019-09-26T23:31:30Z
dc.date.available2019-09-26T23:31:30Z
dc.identifier.urihttp://hdl.handle.net/1974/26619
dc.description.abstractIncreasing evidence has suggested that vagal afferent neurons can mediate gut microbiota induced effects in the brain and immune modulation during gut inflammation. However, the mechanisms behind the alteration in the activity of vagal afferent neurons by gut bacteria and during inflammation are yet to be fully characterized. The present thesis tests the hypothesis that the gut microbiota and inflammation modulate the excitability of the vagal afferent neurons. Perforated and whole-cell patch-clamp recordings were performed on dissociated nodose ganglia (NG) neurons to measure rheobase and to study the properties of voltage-gated ion channels respectively. I examined the effect of intestinal microbiota on mouse vagal afferent neurons in two ways: 1) incubating dissociated neurons in vitro in supernatant from a community of commensal gastrointestinal bacteria derived from a healthy human donor (Microbial Ecosystem Therapeutics; MET-1); and 2) by inducing microbial dysbiosis in vivo by oral administration of a non-absorbable antibiotic (vancomycin 50 ng/ml). Both exposures to MET-1 supernatant (1:100) in vitro and vancomycin-induced microbial dysbiosis increased the excitability of NG neurons, decreasing the mean rheobase by over 25%. The increase in excitability was reversed using a cysteine protease inhibitor (E-64, 30 nM) and a protease-activated receptor 2 antagonist (PAR2) (GB-83, 10 µM). Furthermore, voltage-clamp recordings revealed that incubation of NG neurons with MET-1 and antibiotic treatment hyperpolarized the voltage dependence of half-activation of Na+ conductance. Together, these findings suggest that cysteine proteases, in vitro and in vivo, increase the excitability of vagal afferent neurons by the activation of PAR2. To determine the effect of inflammation on vagal afferent neurons, the excitability of dissociated NG neurons from mice with DSS-induced colitis was measured. DSS treatment increased the excitability of NG neurons by decreasing the rheobase by almost 30%. The serum from DSS treated mice recapitulated the effect of DSS administration on NG neurons, which was blocked by a nuclear factor-κB (NF-κB) antagonist suggesting that circulating mediators that activated NF- κB signaling pathway increased the excitability of NG neurons. Taken together, these studies suggest modulation in activity of vagus nerve can influence the effect of gut microbiota and inflammation on brain.en
dc.language.isoengen
dc.relation.ispartofseriesCanadian thesesen
dc.rightsAttribution-NoDerivs 3.0 United Statesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
dc.rightsProQuest PhD and Master's Theses International Dissemination Agreementen
dc.rightsIntellectual Property Guidelines at Queen's Universityen
dc.rightsCopying and Preserving Your Thesisen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.rights.urihttp://creativecommons.org/licenses/by-nd/3.0/us/
dc.subjectPlasticityen
dc.subjectVagal afferent neuronsen
dc.subjectInflammationen
dc.subjectGut microbiotaen
dc.subjectProteaseen
dc.subjectExcitabilityen
dc.titlePlasticity of Vagal Afferent Neurons During Gut Microbial Dysbiosis and Inflammationen
dc.typethesisen
dc.description.degreePhDen
dc.contributor.supervisorLomax, Alan E.en
dc.contributor.departmentNeuroscience Studiesen
dc.degree.grantorQueen's University at Kingstonen


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Except where otherwise noted, this item's license is described as Attribution-NoDerivs 3.0 United States