Regulation of Supraoptic Vasopressin Neurons during Hypernatremia and Hyponatremia




Balapattabi, Kirthikaa


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This dissertation addresses the regulatory mechanisms of arginine vasopressin (AVP) secretion during salt loading (SL) and liver failure. The experiments focused on AVP neurons located in the supraoptic nucleus (SON) of hypothalamus that, along with other hypothalamic neurons, secrete AVP. This dissertation has two sections. The first section, specific aims 1a and 1b, examines AVP secretion with SL. Salt loading is associated with increased AVP release and mean arterial pressure. The male SL (2% NaCl for 7 days) rats secrete AVP despite increase in mean arterial pressure and were used as an animal model for this aim to study altered AVP neuron regulation. Previous work has shown that SL impairs baroreceptor mediated inhibition of rat AVP neurons through brain derived neurotrophic factor (BDNF) dependent activation of tyrosine receptor kinase B (TrkB) and downregulation of K+/Cl- co-transporter (KCC2). This mechanism diminishes the GABAA mediated inhibition of SON AVP neurons by increasing intracellular chloride ([Cl]i). However, the source of BDNF leading to this ionic plasticity is unknown. In specific aim 1a, adeno-associated viral vectors with shRNA against BDNF were used to test if the SON is the source of BDNF contributing to increased AVP release and elevated mean arterial pressure in SL rats. In specific aim 1b, virally mediated chloride imaging with ClopHensorN was combined with single cell Western blot analysis by capillary based Simple Wes technology to verify the expression of KCC2 in the SON AVP neurons and to determine the role of TrkB-KCC2 mechanism in increased [Cl]i in SL male rats.In Aim 2, a more clinically relevant animal model was used to study regulatory mechanism leading to inappropriate increase in AVP secretion. Chronic bile duct ligated (BDL) rats were used as animal model of liver failure induced hyponatremia due to inappropriate AVP release. The findings and approaches from specific aim 1 were used to test the role of BDNF-TrkB-KCC2 signaling in increased AVP secretion and hyponatremia during liver failure. The experiments in this dissertation advance our understanding about the pathophysiology of AVP secretion. There are several novel findings from this work. First, SON was identified as the source of BDNF contributing to increase in [Cl]i of SON AVP neurons and AVP secretion in SL rats. Additionally, this is the first study to correlate the KCC2 protein expression in individual AVP neurons with its function using chloride imaging. Finally, these results are the first to demonstrate a mechanism that contributes to the increase in AVP secretion resulting in hyponatremia during liver failure.