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No description available.

The caudal solitary complex (cSC) is a cardiorespiratory integrative center in the dorsal medulla oblongata that plays a vital role in the central CO2-chemoreceptive network. Neurons in this area respond to hypercapnic acidosis (HA) by a depolarization of the membrane potential and increase in firing rate, however a definitive mechanism for this response remains unknown. Likewise, CO2-chemoreceptive neurons in the cSC respond to hyperoxia in a similar fashion, but via a free radical mediated mechanism. It remains unknown if the response to increased pO2 is merely an increase in redox signaling, or if it’s the result of a pathological state of redox stress. Importantly, free radical production is known to be stimulated by increasing pO2, and can be exacerbated downstream by the addition of CO2 and its subsequent acidosis. Conditions of hyperoxia in combination with HA can therefore become detrimental in several scenarios, including O2 toxicity seizures in divers and stranded submariners, as well as in cases of ischemia-reperfusion injury and sleep apneas. As such, we sought to not only determine how O2 and CO2 interact to affect cellular excitability in the cSC, but also if these cells exhibited increases in redox signaling and/or stress. We employed sharp-electrode intracellular electrophysiology to study whole-cell electrical responses to varied combinations of hyperoxia (0.4 0.95/1.95 ATA O2) and HA (0.05 0.1 ATA CO2). Additionally, we used fluorescence microscopy under similar conditions to study changes in the production rates of various free radicals, including superoxide (˙O2-), nitric oxide (˙NO), and a downstream aggregate pool of CO2/H+-dependent reactive oxygen and nitrogen species (RONS). Finally, we used several colorimetric assays to measure markers of oxidative and nitrosative stress, including malondialdehyde, 3-nitrotyrosine, and protein carbonyls. Our hypothesis for these experiments was that hyperoxia and HA alone could produce effects, but would be more pronounced when used together. As such, we saw that ~89% of cells tested that were sensitive to both hyperoxia and HA showed larger firing rate responses to HA during an increased background O2 (0.9 and/or 1.9 ATA) after showing a smaller response or no response to HA during control levels O2 (0.4 ATA). Additionally, we noted that the rate of ˙O2- fluorescence increased in response to hyperoxia, but only during pharmacological inhibition of its reactions with ˙NO and SOD. Likewise, the rate of ˙NO fluorescence increased during hyperoxia compared to control O2, but only during pharmacological scavenging of ˙O2-. Downstream, our aggregate pool of RONS showed increased rates of fluorescence during both hyperoxia alone and HA in control O2, however the most prominent increases were seen during hypercapnic hyperoxia. Finally, no significant effects were seen when probing for markers of redox stress in response to hyperoxia and hypercapnic hyperoxia. Overall, these results suggest that the increased excitability seen in cSC neurons during hypercapnic hyperoxia is the result of physiological redox signaling rather than pathological redox stress. Further research needs to be done to determine how this redox mechanism is specifically resulting in increased cellular excitability.

De nouveaux enjeux émergent dans le domaine de la Santé en raison du vieillissement de la population et du développement inquiétant de la Maladie d’Alzheimer (MA). Chez le sujet sain ou pathologique, peu d’études ont porté sur le vieillissement du contrôle nerveux de la respiration, en dépit de son rôle crucial pour l’oxygénation du cerveau. Cette thèse présente des recherches translationnelles, réalisées chez la souris, pour étudier le vieillissement physiologique et pathologique du contrôle nerveux de la respiration. Chez des souris transgéniques, modèles reconnus de la MA et du syndrome de Rett, nous décrivons le développement de neuropathologies respiratoires graves, conduisant à un décès prématuré. Nous montrons pour la première fois qu’une tauopathie du tronc cérébral altère le fonctionnement des voies aériennes supérieures, la vocalisation et la respiration. De plus, nos travaux suggèrent un rôle délétère de l’anesthésie pour la MA et identifient des pistes thérapeutiques nouvelles. En conclusion, nos travaux chez la souris peuvent avoir des retombées particulièrement intéressantes notamment pour la MA. / New issues are emerging in the field of Health care due to ageing of the population and the alarming development of Alzheimer’s Disease (AD). In healthy or pathological living being, very few studies are dealing with the ageing of the respiratory nervous control, in spite of the crucial role of respiration for brain oxygenation. This thesis presents translational research performed in mice to examine the physiological and pathological ageing of the respiratory nervous control. In mice from two transgenic strains, recognized models for AD and Rett syndrome, we describe the development of drastic respiratory neuropathologies leading to premature death. In the AD mouse model, we show for the first time that brainstem tauopathy triggers dysfunctions of the upper airways, impairs vocalization and alters respiration and respiratory control. In addition, our work suggests a deleterious effect of anaesthesia for AD and identifies new therapeutic strategies. This mouse research could well contribute to significant improvements in AD care.