Lipid signaling in cardiovascular afferent transmission

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Project Summary Transient Receptor Potential Vanilloid Type 1 Receptors (TRPV1) are present in the central terminals of cranial visceral afferents including arterial baroreceptors and airway afferents within the solitary tract nucleus (NTS) but the function of central TRPV1 is unclear. TRPV1 is a calcium channel with three separate “openers” vanilloids, pH, and heat. Our recent cellular investigations demonstrate that TRPV1 calcium controls an independently regulated pool of glutamate vesicles that is distinct from the pool of vesicles released by action potentials. TRPV1-operated vesicles generate spontaneous excitatory synaptic events (EPSCs). Action potential evoked EPSCs are triggered by voltage activated calcium channels separately from TRPV1-operated glutamate release. Cooling to unphysiologically low temperatures 30°C suppresses TRPV1 release and vanilloid agonists sensitize thermal sensitivity. The present proposal stems from the observation that in animals fed a high fat diet (HFD), blockade of TRPV1 receptors within medial NTS reduces blood pressure and heart rate. Animals fed control diets do not respond to TRPV1 blockade suggesting an endogenous lipid agonist induced in NTS by the HFD. We will examine the mechanisms by which ST TRPV1 drives glutamate transmission normally and during exposure to a HFD. Our in vivo preliminary results suggest that HFD generates a vanilloid-like mediator which controls afferent triggered reflex function within NTS. The Research Plan proposes to establish the mechanisms of action of vanilloids in ST afferent transmission with a focus on CNS function in aortic baroreflex control. Our global hypothesis proposes that ST TRPV1 serves as a focal integrator of multiple signals in NTS with a primary reporting output of glutamate release. The Specific Aims will investigate whether TRPV1-operated glutamate activates metabotropic glutamate receptors on GABA release, whether postsynaptic depolarization modulates presynaptic TRPV1 mediated glutamate release, whether B-type GABA receptors alter myelinated baroreceptor transmission during HFD and how TRPV1 activation in NTS during HFD alters baroreflex responses. My laboratory has extensive experience with TRPV1 mechanisms in peripheral baroreceptors, baroreceptor reflexes, and central ST transmission. We will rely on methods including electrophysiological, live cell imaging, dye tracing and assays of whole animal reflex characteristics to understand TRPV1 function from cell to reflex. We will team with the Madden lab for whole animal assessments. The proposed research will help us to better understand the normal basis of these neural control mechanisms as well as identify pathophysiological changes and shed light on homeostatic control that include consequences for central nervous system inflammation, hypertension, stroke, metabolic syndrome, and heart failure to alter autonomic reflexes to detrimental effect.