Neurohumoral activation, characterized by elevated sympathetic tone, blunted cardiovascular reflexes, and elevated hormonal plasma levels, is a common finding in a variety of cardiovascular diseases, including hypertension and heart failure (HF). Despite compelling evidence supporting increased neurohumoral drive as a major determinant of patients'prognosis and mortality, none of the current therapeutic strategies efficiently inhibit neurohumoral activation, failing thus to improve the survival or stop the progression of these cardiovascular diseases. Although altered central autonomic function plays an important role in the pathophysiology of major cardiovascular diseases, the precise cellular mechanisms underlying such alteration are still poorly understood. Recent studies from our laboratories indicate that neuronal activation within the hypothalamic paraventricular nucleus (PVN), one of the major preautonomic and neuroendocrine brain centers, contributes to elevated neurohumoral drive in cardiovascular disease states. Here, using a multidisciplinary approach that ranges from the whole animal to single molecules, we propose to use the PVN central neuronal circuitry and a rat model of ischemic HF to test a series of novel hypotheses that aim to unveil basic mechanistic principles involved in the central control of cardiovascular function in health and disease conditions. Specifically, we propose a model in which PVN glutamate tripartite synapses represented by glutamate (GLU) synaptic inputs, postsynaptic sympathetic PVN neurons, and associated astrocytes, constitute key structural/functional units fine-tuning PVN neuronal excitability and sympathetic output. We hypothesize that altered intercellular communication within this unit contributes to enhanced neuronal excitability and sympathoexcitation during HF. We propose that during HF, structural/functional reconfiguration of GLU afferent inputs, changes in GLU receptor portfolios, and changes in neuronal-glial interactions favors excitatory (direct excitatory GLU action) (Aims 1-3) over inhibitory (GLU-mediated nitric oxide-GABA action) (Aim 4) pathways within the PVN tripartite functional unit. The proposed experiments will identify the underlying pre-, post- ad extrasynaptic mechanisms contributing to elevated PVN neuronal excitability and elevated neurohumoral drive during HF. In addition, we will test the general novel hypothesis that hypothalamic astrocytes efficiently modulate PVN neuronal and synaptic function, as well as sympathoexcitatory drive in health and disease conditions. Overall, this project will provide critical and novel information on mechanisms controlling neuronal excitability and intercellular communication within a fundamental preautonomic brain center involved in the central control of cardiovascular function, and will unveil specific pathophysiological mechanisms underlying neurohumoral activation in cardiovascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090948-05
Application #
8011516
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Lathrop, David A
Project Start
2008-01-15
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2011
Total Cost
$367,884
Indirect Cost
Name
Georgia Regents University
Department
Physiology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
de Kloet, Annette D; Pitra, Soledad; Wang, Lei et al. (2016) Angiotensin Type-2 Receptors Influence the Activity of Vasopressin Neurons in the Paraventricular Nucleus of the Hypothalamus in Male Mice. Endocrinology 157:3167-80
Pitra, Soledad; Feng, Yumei; Stern, Javier E (2016) Mechanisms underlying prorenin actions on hypothalamic neurons implicated in cardiometabolic control. Mol Metab 5:858-68
Stern, Javier E; Son, Sookjin; Biancardi, Vinicia C et al. (2016) Astrocytes Contribute to Angiotensin II Stimulation of Hypothalamic Neuronal Activity and Sympathetic Outflow. Hypertension 68:1483-1493
Ludwig, Mike; Stern, Javier (2015) Multiple signalling modalities mediated by dendritic exocytosis of oxytocin and vasopressin. Philos Trans R Soc Lond B Biol Sci 370:
Stern, Javier E; Potapenko, Evgeniy S (2013) Enhanced NMDA receptor-mediated intracellular calcium signaling in magnocellular neurosecretory neurons in heart failure rats. Am J Physiol Regul Integr Comp Physiol 305:R414-22
Stern, J E; Filosa, J A (2013) Bidirectional neuro-glial signaling modalities in the hypothalamus: role in neurohumoral regulation. Auton Neurosci 175:51-60
Son, Sook Jin; Filosa, Jessica A; Potapenko, Evgeniy S et al. (2013) Dendritic peptide release mediates interpopulation crosstalk between neurosecretory and preautonomic networks. Neuron 78:1036-49
Reis, W L; Biancardi, V C; Son, S et al. (2012) Enhanced expression of heme oxygenase-1 and carbon monoxide excitatory effects in oxytocin and vasopressin neurones during water deprivation. J Neuroendocrinol 24:653-63
Tasker, J G; Oliet, S H R; Bains, J S et al. (2012) Glial regulation of neuronal function: from synapse to systems physiology. J Neuroendocrinol 24:566-76
Potapenko, Evgeniy S; Biancardi, Vinicia C; Zhou, Yiqiang et al. (2012) Altered astrocyte glutamate transporter regulation of hypothalamic neurosecretory neurons in heart failure rats. Am J Physiol Regul Integr Comp Physiol 303:R291-300

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