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<p>Aortic bodies (ABs) are putative peripheral arterial chemoreceptors located near the aortic arch. They are hypothesized to contribute to O₂ homeostasis by sensing arterial O₂ content and initiating cardiovascular reflexes during hypoxia; however, information on their cellular physiology is lacking. The primary goal of this thesis was to elucidate chemosensory mechanisms among mammalian (rat) AB cells, located specifically at the bifurcation of the left vagus nerve and recurrent laryngeal nerve (RLN), where they are found in association with a group of local neurons (>30). In vagus nerve-RLN whole-mounts, AB chemoreceptor (type I) cells were immunoreactive against the vesicular acetylcholine (ACh) transporter, and were surrounded by nerve terminals immunopositive for purinergic P2X2 and P2X3 receptor subunits, suggesting that ACh and ATP may act as neurotransmitters as in the related carotid body. In a novel dissociated AB culture model, subsets of type I cells exhibited elevated intracellular Ca²⁺ responses to hypoxia, isohydric hypercapnia, isocapnic acidosis, and acidic hypercapnia, demonstrating their direct chemosensitivity for the first time. Interestingly, surviving local neurons also responded to these chemostimuli, suggesting that they are sensory. Patch clamp electrophysiological and Ca²⁺ imaging studies revealed functional heteromeric P2X2/3 and nicotinic ACh receptors on local neurons, consistent with ACh and/or ATP mediating chemotransmission between receptor cells and local neurons. These neurons were also found to be interconnected by electrical synapses. Finally, the short-term survival of red blood cells (RBCs) in AB cultures, along with the finding that blood-borne factors (e.g. ATP released from RBCs) may have access to AB nerve terminals <em>in situ</em>, implicates RBCs as O₂-sensors in AB function. Altogether, these results suggest an important role for purinergic P2X2/3 receptors on local neurons/nerve terminals and ATP release from type I cells and RBCs, in the unique ability of ABs to sense and process information about blood O₂ content.</p> / Doctor of Philosophy (PhD)

<p>Valproic acid (VPA) is clinically utilized as an anti-convulsant and mood stabilizer, though its mechanism of action has not been fully elucidated.<strong> </strong>Evidence suggests an interaction between VPA and the melatonergic system as VPA up-regulated the melatonin MT₁ receptor subtype in rat C6 glioma cells. To determine if the observed effects can translate to an <em>in vivo </em>model, we investigated the effects of chronic VPA administration in a rat model on the expression of MT₁ and MT₂ receptors in the hippocampus. We also investigated the effect of chronic VPA treatment on the expression of the neurotrophic factors BDNF and GDNF in the rat hippocampus and striatum.</p> <p>(1) Animals were separated into two groups with the experimental group receiving VPA (4 mg/mL) for 17 days, and the control receiving vehicle. The hippocampus was dissected and MT₁, MT₂, BDNF and GDNF mRNA were analyzed with RT-PCR. (2) Animals were separated into three groups with the first group receiving VPA (4 mg/mL), the second receiving VPA (3 mg/mL) for 16 days, and the control receiving vehicle. MT₂ mRNA in the hippocampal subregions were analyzed with in situ hybridization.</p> <p>VPA induced the expression of MT₁ and MT₂ mRNA in the hippocampus in the experimental group compared to the control group. VPA also increased MT₂ mRNA expression in the subregions of the hippocampus. Additionally, BDNF and GDNF mRNA expression were increased in the VPA treatment group.</p> <p>These findings raise the interesting question of whether the diverse clinical effects of VPA involve an interaction with the melatonergic system.</p> / Master of Science (MSc)

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