Body fluid and cardiovascular homeostasis depend on the coordinated regulation of complementary physiological and behavioral mechanisms. The principle behaviors that ensure stability of the volume and composition of the fluid matrix are thirst and salt appetite. Accumulating evidence strongly supports a major role of the renin-angiotensin-system (RAS) in control of both of these motivated behaviors. Moreover, steroid hormones regulate the brain's responsivity to angiotensin II (AngII) and thus the arousal of water and salt intake. In the present application we investigate the cellular and molecular mechanisms underlying two well established examples of these hormonal interactions: 1) estrogen regulation of AngII-induced thirst; and 2) corticosteroid potentiation of salt appetite. In each of these examples we focus on the signaling properties of AngII receptors in a major receptor zone, the subfornical organ (SFO), gene expression within neuronal projections from the SFO to the paraventricular nucleus (PVN) and dorsal perifornical lateral hypothalamus (dpLHA), and activation of these effector pathways that subserve behavioral and complementary neurohypophysial function. Collectively, these studies will provide a more complete understanding of the neuroendocrinology of body fluid homeostasis, as well as elucidate fundamental principles of steroid/neuropeptide interactions governing behavior. More specifically, we will test these hypotheses: (i) Adrenal and ovarian steroids regulate thirst and salt appetite by modulating AngII-receptor mediated signal transduction in discrete brain regions; (ii) Adrenal and ovarian steroids regulate thirst and salt appetite by modulating gene expression within separate populations of AngII-responsive SFO neurons that project to hypothalamic nuclei; (iii) Changes in endogenous levels of adrenal and ovarian steroids, as occur during hypovolemia and the estrus cycle, regulate gene expression in the same SFO projections to hypothalamic nuclei; and, (iv) The genes regulated by ovarian steroids are important for neurotransmission in the SFO axonal projections to hypothalamic regions that control water and salt consumption as well as neurohypophysial secretion.
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