Bodily homeostasis involves orchestrated activities between hypothalamic autonomic and neuroendocrine neuronal networks. Importantly, an imbalanced interaction between them constitutes the basis for maladaptive responses (?neurohumoral activation?) observed in disease conditions (stress, heart failure and the metabolic syndrome). Importantly, neurohumoral activation (which includes centrally driven sympathetic activity and elevated circulating levels of vasopressin (VP)) directly correlates with prognosis, and mortality in these diseases. Thus, understanding the mechanisms involved in autonomic and neuroendocrine integration, both in health and disease conditions, is of critical physiological and clinical significance. The hypothalamic paraventricular nucleus (PVN) plays a pivotal role in the generation of coordinated polymodal homeostatic responses. Still, the mechanism by which the activity of these functionally distinct neuronal populations is orchestrated during a homeostatic response remains elusive. We recently identified dendritic release of VP from magnocellular neurosecretory neurons as a novel signaling mechanism underlying ?wireless? (non- synaptic) communication between neuroendocrine and presympathetic PVN neurons. We showed this interpopulation crosstalk to play a major role coordinated neurosecretory/sympathetic homeostatic responses to an osmotic challenge (OSM+). While significant progress has been obtained in our understanding of mechanisms underlying activity-dependent release of neuropeptides from axonal terminals, limited information is available regarding mechanisms regulating dendritic release, particularly during OSM+. Thus, we implemented a highly innovative approach that enables us to quantitatively monitor dendritic VP release in real time, while studying in a mechanistic manner the main processes involved in this interpopulation homeostatic crosstalk. We obtained exciting preliminary data that supports our innovative hypothesis of a fine-tuned interplay between glutamate NMDA receptors (NMDARs), backpropagating dendritic action potentials and K+ channels in regulating dendritic VP release and neurosecretory-presympathetic signaling crosstalk in response to OSM+. Moreover, we will test the hypothesis that astrocytes, recognized as key players in CNS function, exert a pivotal influencing dendritic release of VP, its diffusing efficacy in the ECS, and ultimately, the generation of multimodal homeostatic responses. These hypotheses will be tested in 3 specific aims: 1- To elucidate mechanisms by which action potentials (APs) and NMDARs interact during OSM+ to evoke dendritic VP release. 2- To elucidate mechanisms that regulate dendritic retrograde signaling and their impact on dendritic release. 3- To elucidate mechanisms that control the diffusion of VP in the extracellular space, influencing in turn its efficacy as an interpopulation signaling. We expect results from this work to broaden our understanding of basic cellular mechanisms contributing to the hypothalamic regulation of homeostasis, and how changes in these mechanisms may contribute to neurohumoral activation during disease states.
Exacerbated activities of the neuroendocrine and autonomic systems (?neurohumoral activation?), is a common finding in numerous prevalent diseases including salt-dependent hypertension, heart failure and diabetes. While neurohumoral activation influences morbidity and mortality in these patients, the precise underlying mechanisms remain unknown. In this proposal, we will use a multidisciplinary approach to test a series of novel hypothesis that aim to elucidate signaling mechanisms by which the central nervous system coordinates the activity of the neuroendocrine and autonomic systems, and to determine if changes in these mechanisms contribute to neurohumoral activation during excessive salt intake. We expect our work to provide novel information on mechanisms underlying altered neuronal function in heart failure patients, and to help in the development of novel and more efficient therapeutic strategies for the treatment of this prevalent disease.
