Spinal Oxygen Sensors: location, function and mechanism

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dc.contributor.advisorWilson, Richard JA.; Whelan, Patrick.
dc.contributor.authorOrsi Barioni, Nicole
dc.contributor.committeememberZocal, Daniel B
dc.contributor.committeememberOusman, Shalina S
dc.contributor.committeememberThompson, Roger J
dc.contributor.committeememberGordon, Grant RJ.
dc.dateSpring Convocation
dc.date.accessioned2022-06-17T20:48:05Z
dc.date.available2022-06-17T20:48:05Z
dc.date.issued2021-04-05
dc.description.abstractIn hypoxic conditions, the mammalian body composes cardiorespiratory responses aimed to increase oxygen supply to vital organs. Although the carotid bodies are the primary oxygen chemoreceptors for breathing, data in the literature show that hypoxia-triggered cardiovascular responses remain in their absence, suggesting the existence of an additional hypoxia sensor responsible to elicit those responses. In the present work, my objectives were to determine 1) the origin of the cardiovascular responses to hypoxia in the absence of the carotid bodies; 2) the function of these oxygen sensors in rescuing cardiorespiratory control under hypoxia; and 3) the oxygen sensing mechanism through which these cells compose the hypoxic response. Using in vivo, in situ, en bloc and patch clamp preparations combined with pharmacological, immunological and genetic approaches, our data show that thoracic spinal preganglionic neurons (SPNs) are highly oxygen sensitive and this sensitivity is not mediated by surrounding glia (although spinal glia also seem to be oxygen sensitive). Additionally, these spinal oxygen sensors (SOS) are not only capable of increasing phrenic activity independent of the brainstem, but also modulating the brainstem’s process of gasp generation under asphyxia by increasing sympathetic output and promoting autoresuscitation – in some cases producing gasps on its own. Furthermore, our results suggest that the SOS are equipped with a novel oxygen sensing mechanism involving neuronal nitric oxide synthase (NOS1), expressed abundantly in SPNs. The high expression levels of NOS1 in SPNs causes high levels of NADPH consumption. However, as oxygenation decays in hypoxia, NOS1 becomes dormant due to its high KmO2, making NADPH available for NOX2 in the production of ROS. The increased ROS concentration inside the SPNs triggers TRP channels and IP3R, culminating in elevated intracellular calcium and, consequently, neuronal depolarization. In conclusion, the present thesis investigates a spinal oxygen sensor which potentially contributes to survival behaviours and appears to use a novel oxygen sensing mechanism.
dc.identifier.citationOrsi Barioni, N. (2021). Spinal Oxygen Sensors: location, function and mechanism (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/39832
dc.identifier.urihttp://hdl.handle.net/1880/114744
dc.language.isoenen
dc.language.isoEnglish
dc.publisher.facultyGraduate Studiesen
dc.publisher.facultyCumming School of Medicine
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en
dc.subjectOxygen sensing
dc.subjectPreganglionic neurons
dc.subjectAutonomic nervous system
dc.subjectBreathing
dc.subjectRespiratory
dc.subjectNOS1
dc.subjectNOX2
dc.subjectGasp
dc.subject.classificationHealth And Environmental Sciences
dc.subject.classificationBiological Sciences
dc.titleSpinal Oxygen Sensors: location, function and mechanism
dc.typedoctoral thesis
thesis.degree.disciplineMedicine – Neuroscience
thesis.degree.grantorUniversity of Calgaryen
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
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