Intermittent hypoxia and hypertension: Role of the lamina terminalis

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The central objective of this research program is to determine the role of the CNS in hypertension associated with chronic intermittent hypoxia (CIH), a model of hypoxemia associated with sleep apnea. Our previous results indicate that the median preoptic nucleus (MnPO) contributes to the sustained hypertension produced by CIH in rat. These experiments will investigate 3 novel mechanisms that may allow the MnPO to contribute to CIH hypertension. Our working hypothesis, based on our previous studies, is that CIH triggers FosB transcriptional activity involving angiotensin II (ANG II) and NO signaling to increase excitation causing BDNF-driven increases in intracellular chloride. These effects would further increase excitation and reduce or reverse inhibition from arterial baroreceptors promoting sustained CIH HTN during normoxic periods of the day. Specific Aim 1: Test the role of angiotensin signaling in increased MnPO excitation in CIH HTN. Hypothesis: Increased angiotensin signaling increases the activity of PVN-projecting MnPO neurons. Aim 1 will quantify the contribution of the brain angiotensin system to increased activity in PVN-projecting MnPO neurons using angiotensin “sniffer cells” 19 combined with optogenetics, patch clamp electrophysiology, in vivo recording of sympathetic nerve activity, and MnPO single unit activity. Specific Aim 2: Test the role of NO in increasing MnPO excitation in CIH HTN. Hypothesis: Increased expression and activity of nos1 in MnPO increases presynaptic excitation to drive sustained CIH hypertension. Aim 2 will test the hypothesis that the increase of nos1 expression and activity triggered by CIH increases presynaptic excitation in PVN projecting MnPO neurons. This mechanism will be tested using in vitro electrophysiology and paired real-time measurements of NO with carbon fiber electrodes and DAF-2 imaging, in vivo recording of sympathetic nerve activity, and chronic blood pressure recording with radio telemetry. Specific Aim 3: Determine the contribution of reduced/reversed GABA inhibition and BDNF to changes in MnPO excitability, synaptic efficacy, and CIH HTN. Hypothesis: CIH triggers BDNF neurons that reduces/reverses GABA inhibition in MnPO neurons. Aim 3 will determine if BDNF reduces/reverses baroreceptor inhibition by GABA in PVN-projecting MnPO neurons though chloride transports such as sodium potassium chloride cotransporter 1 (NKCC1) and/or potassium chloride cotransporter2 (KCC2). These experiments will use live cell chloride imaging, brain slice and in vivo electrophysiology, and channel rhodopsin assisted circuit mapping.