The research proposed here will provide new information regarding the CNS autonomic circuits that regulate cardiovascular functions. The grant is focused on the nucleus tractus solitarius (NTS) of the rat and, in particular, we will analyze the anatomical connections and functional responses of a newly discovered group of aldosterone-selective NTS neurons. These neurons contain both mineralocorticoid receptors and 11beta-hydroxysteroid dehydrogenase type 2 - the critical enzyme that permits aldosterone to bind selectively to these receptors. Aldosterone levels increase in chronic heart failure and cause damage to the heart. Recent evidence indicates that this steroid may have CNS effects as well. The proposed studies will investigate the neuroanatomical organization of the aldosterone-selective NTS neurons by analyzing their afferent and efferent connections as well as their neuronal phenotypes. In addition, we will examine whether aldosterone will selectively effect the cellular distribution of mineralocorticoid receptors in these neurons and compare these changes to the actions of corticosterone. Another study is designed to study the CNS distribution of transcription factors (viz., pCREB, Fos, Fos B, Jun B) that may be expressed following supraphysiological infusions of aldosterone; this experiment will simulate the aldosterone plasma levels that occur during heart failure. Additional information regarding the transcription factor expression in neuropeptide and other chemically-coded NTS neurons following high plasma levels of aldosterone will be obtained. The last project will analyze the central distribution of specific amiloride-sodium channel subunits in the rat brain, with a special focus on the NTS. After baseline data are established, we will investigate whether the distribution of any of the subunits, which form the family of amiloride-sodium, channels change after two experimental conditions: salt depletion and salt-induced hypertension in the Dahl rat. The long-term goal of this research is to establish a better understanding of the central mechanisms involved in blood pressure regulation and to gain new insights into the CNS sites that detect sodium and, hence, may trigger hypertension in the Dahl salt-sensitive rat.
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