PROJECT 2 (Pickel): Hypothalamic plasticity enabling slow pressor hypertension Neurohumoral output neurons in the hypothalamic paraventricular nucleus (PVN) are activated by glutamateand Angll-containing neuronal inputs from the subfornical organ (SFO), a brain structure responsive to circulating angiotensin 11 (Angll). These inputs target PVN output neurons that increase hormonal release from the pituitary and sympathetic activity through monosynaptic projections to the thoracic spinal cord. Slow pressor hypertension can be induced by chronic systemic infusion of low doses of Angll (600 ng/kg/min) or by chronic exposure to intermittent hypoxia (CIH). The CIH-induced sympathetic activation and elevation in arterial pressure is dependent on plasticity in the carotid body, but also on changes in glutamate NMDA receptor-dependent transmission in the brain. Chronic exposure to Angll or CIH may result in NMDA receptor-dependent long-term facilitation of glutamatergic transmission in the PVN spinal projection neurons, which is enabled in part by suppression of opposing inhibitory neurons. NADPH oxidase generated reactive oxygen species (ROS) are important modulators of NMDA receptor mediated synaptic plasticity, and are also mediators of the intracellular signaling for Angll, a neuropeptide present in the glutamatergic SFO inputs to the PVN and active mainly through the Angll type-1 (ATi) receptor. Project 2 will test the central hvpothes s that plasticitv in pre-svmpathetic output and inhibitorv neurons of the PVN enables the development of slow pressor hvpertension through mechanisms that are dependent on postsvnaptic NMDA receptors and influenced bv both Angll and ROS.
Aim 1 will examine the basal distribution and function of NMDA and ATi receptors in PVN neurons identified as projecting to the thoracic spinal cord by retrograde transport.
Aim 2 will determine whether changes in the surface/synaptic availability of the essential NMDA NR1 subunit and NMDA currents are concomitants of Angll or CIH hypertension, both of which are attenuated by a spatial-temporal deletion of postsynaptic NR1 in the PVN.
Aim 3 will determine whether the development of Angll and/or CIH hypertension is linked to NADPH oxidase generated ROS in the PVN. This research will be conducted in male mouse models using in vivo measurement of arterial pressure (tail-cuff or radiotelemetry), high resolution electron microscopic immunolabeling, patch-clamp recording, and ROS imaging. Project 2 is interdependent with each of the other projects and reliant on all core facilities of this PPG.
The results will provide new insight into the role of NMDA receptor-dependent synaptic plasticity and NADPH oxidase-generated free radicals in the maladaptive changes that occur in chronically activated neurohumoral output neurons of the PVN. This is crucial for understanding Angll and/or CIH slow pressor hypertension and for devising new therapies for treating cardiovascular and cerebrovascular dysfunctions in hypertensive patients.
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