Hyponatremia is the most common electrolyte disorder and in 2006 the cost of treating hyponatremia in the US was estimated to be $1.6-$3.6 billion per year. Inappropriate vasopressin secretion is the major cause of dilutional hyponatremia associated with liver and heart failure. Brain derived neurotrophic factor (BDNF) and its receptor TrkB are expressed by magnocellular neurosecretory cells that secrete vasopressin into circulation. Our studies will be among the first to test the role of the BDNF-TrkB signaling in the homeostatic regulation of the neurohypophyseal system and in an animal model of inappropriate vasopressin release. We propose that activation of the BDNF-TrkB system increases vasopressin release by enhancing the postsynaptic effects of NMDA receptors on vasopressin release.
Specific Aim 1 : will test the role of neurohypophysial BDNF-TrkB signaling on the effects of water deprivation on neurohypophyseal function and vasopressin release. Hypothesis: Phosphorylation of TrkB associated with water deprivation leads to phosphorylation of NMDA receptor subunits through Fyn kinase, a downstream member of the Src kinase family. In these experiments we will test whether BDNF-trkB mediated neuroplasticity contribute to sustained vasopressin release produced by water deprivation.
Specific Aim 2 : will test the hypothesis that neurohypophysial BDNF-TrkB signaling contributes to inappropriate vasopressin release in an animal model of dilutional hyponatremia. Hypothesis: BDNF-TrkB mediated changes in NMDA receptor function contribute to changes in the osmotic and non-osmotic regulation of vasopressin neurons in rats with experimental induced hepatic cirrhosis. In these experiments, the bile duct ligation model of cirrhosis-induced hyponatremia will be used to test the role of the BDNF-TrkB signaling on SON neurons in the context of inappropriate vasopressin release. Methods: The studies will employ Western blot and co-immunoprecipitation in combination with immunohistochemistry and laser capture microdissection RT-PCR, metabolism cage studies to measure urine and sodium excretion, and in vitro electrophysiology to test these hypotheses. Benefit: These experiments will address an existing gap in our understanding of neurohypophyseal function and the pathogenesis of hyponatremia. The findings of these experiments could potentially alter the way that inappropriate vasopressin release is studied and conceptualized clinically.

Public Health Relevance

The long term goal of this research program is to identify neural networks that control the release of vasopressin. Inappropriate vasopressin release related to heart failure or liver failure increases the morbidity and mortality of these patients 7 11. Hyponatremia related to vasopressin release is the most common electrolyte disorder and in 2006 the cost of treating hyponatremia in the US was estimated to be $1.6-$3.6 billion per year 12. This proposal will test a novel signaling pathway that regulates the activity of vasopressin neurons in health and disease that could identify new therapeutic targets for treating of inappropriate vasopressin release that could be addressed by FDA approved pharmaceuticals.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
High Priority, Short Term Project Award (R56)
Project #
Application #
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Maric-Bilkan, Christine
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Texas
Other Domestic Higher Education
Fort Worth
United States
Zip Code
Choe, Katrina Y; Han, Su Y; Gaub, Perrine et al. (2015) High salt intake increases blood pressure via BDNF-mediated downregulation of KCC2 and impaired baroreflex inhibition of vasopressin neurons. Neuron 85:549-60
Saxena, Ashwini; Little, Joel T; Nedungadi, T Prashant et al. (2015) Angiotensin II type 1a receptors in subfornical organ contribute towards chronic intermittent hypoxia-associated sustained increase in mean arterial pressure. Am J Physiol Heart Circ Physiol 308:H435-46
Nedungadi, T Prashant; Cunningham, J Thomas (2014) Differential regulation of TRPC4 in the vasopressin magnocellular system by water deprivation and hepatic cirrhosis in the rat. Am J Physiol Regul Integr Comp Physiol 306:R304-14
Saxena, Ashwini; Bachelor, Martha; Park, Yong H et al. (2014) Angiotensin II induces membrane trafficking of natively expressed transient receptor potential vanilloid type 4 channels in hypothalamic 4B cells. Am J Physiol Regul Integr Comp Physiol 307:R945-55
Walch, Joseph D; Nedungadi, T Prashant; Cunningham, J Thomas (2014) ANG II receptor subtype 1a gene knockdown in the subfornical organ prevents increased drinking behavior in bile duct-ligated rats. Am J Physiol Regul Integr Comp Physiol 307:R597-607
Walch, Joseph D; Carreño, Flávia Regina; Cunningham, J Thomas (2013) Intracerebroventricular losartan infusion modulates angiotensin II type 1 receptor expression in the subfornical organ and drinking behaviour in bile-duct-ligated rats. Exp Physiol 98:922-33
Knight, W David; Ji, Lisa L; Little, Joel T et al. (2010) Dehydration followed by sham rehydration contributes to reduced neuronal activation in vasopressinergic supraoptic neurons after water deprivation. Am J Physiol Regul Integr Comp Physiol 299:R1232-40
Zhang, Weirong; Carreño, Flávia R; Cunningham, J Thomas et al. (2009) Chronic sustained hypoxia enhances both evoked EPSCs and norepinephrine inhibition of glutamatergic afferent inputs in the nucleus of the solitary tract. J Neurosci 29:3093-102