Homeostatic Regulation of Supraoptic Neurons: Role of BDNF

视上神经元的稳态调节：BDNF 的作用

• 批准号: 8695603
• 负责人: J Thomas Cunningham
• 金额: $ 36.5万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8695603
• 关键词: Address; Adult; Affect; Animal Experiments; Anterior; Argipressin; Biological Neural Networks; Blood Circulation; Body Fluids; Brain; Brain-Derived Neurotrophic Factor; Cells; Chloride Ion; Chlorides; Data; Dehydration; Disease; Electrolyte Disorder; Equilibrium; Experimental Water Deprivation; FDA approved; Financial compensation; Glutamates; Goals; Health; Heart; Heart failure; Homeostasis; Hyponatremia; Hypothalamic structure; In Vitro; Investigation; Knowledge; Laboratories; Lamina Terminalis; Lasers; Link; Literature; Liver; Liver Failure; Long-Term Depression; Long-Term Potentiation; Mediating; Messenger RNA; Methods; Morbidity - disease rate; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR2B NMDA receptor; Neuronal Plasticity; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Osmolalities; Patients; Pharmacologic Substance; Phosphorylation; Phosphotransferases; Physiological; Pituitary Gland; Plasma; Posterior Pituitary Gland; Potassium Chloride; Publishing; Rattus; Receptor Activation; Regulation; Research; Role; Signal Pathway; Signal Transduction; Stress; Synapses; System; Testing; Time; Up-Regulation; Vasopressins; Water; Water consumption; autocrine; cell water; controlled release; cost; dilutional hyponatremia; gamma-Aminobutyric Acid; in vivo; magnocellular; member; mortality; neurotransmission; novel; paraventricular nucleus; phospholipase C gamma; postsynaptic; programs; public health relevance; research study; src-Family Kinases

DESCRIPTION (provided by applicant): The goal of these studies is to determine how Brain derived neurotrophic factor (BDNF) and its receptor TrkB influence vasopressin release to a progressive physiological challenge, water deprivation. Our data suggest that BDNF may facilitate both glutamate and GABA signaling during water deprivation by causing phosphorylation NR2B and increasing the expression of the chloride transporter KCC2. Increased NR2B phosphorylation would increase NMDA receptor activation enhancing vasopressin release while increased KCC2 activity could increase the inhibitory effects of GABA representing a homeostatic synaptic compensation to increased excitation during water deprivation. Specific Aim 1: to determine the role of neurohypophysial BDNF-TrkB signaling and enhanced glutamate action through NR2B phosphorylation during sustained vasopressin release induced by water deprivation. Hypothesis: Phosphorylation of TrkB associated with water deprivation leads to enhanced glutamate activity due to phosphorylation of NR2B NMDA receptor subunits through Fyn kinase, a member of the Src kinase family contributing to NMDA mediated plasticity in MNCs Specific Aim 2: to test the hypothesis that neurohypophysial BDNF-TrkB signaling enhances the inhibitory effects of GABA during water deprivation. Hypothesis: BDNF-TrkB signaling during water deprivation increases KCC2 expression enhancing the inhibitory effects of GABA in MNCs via Src kinase and without the activation of Phospholipase C gamma. Methods: These experiments will for the first time define the roles of BDNF-TrkB signaling in the homeostatic regulation of sustained AVP release. An integrative approach will be employed that includes in vitro and in vivo electrophysiological experiments, whole animal experiments in which TrkB and Src kinase antagonists will be locally applied to the SON, and functional studies of water balance and AVP release in the rat. Benefit: These experiments will address an existing gap in our understanding of the physiological regulation of neurohypophyseal function. The findings of these experiments could potentially alter the way that inappropriate vasopressin release is studied and conceptualized clinically.

描述（由申请人提供）：这些研究的目的是确定脑源性神经营养因子 (BDNF) 及其受体 TrkB 如何影响加压素释放以应对进行性生理挑战（缺水）。我们的数据表明，BDNF 可能通过引起 NR2B 磷酸化并增加氯离子转运蛋白 KCC2 的表达，从而在缺水期间促进谷氨酸和 GABA 信号传导。 NR2B 磷酸化的增加会增加 NMDA 受体的激活，从而增强加压素的释放，而 KCC2 活性的增加会增加 GABA 的抑制作用，代表对缺水期间兴奋增加的稳态突触补偿。具体目标 1：确定缺水诱导的加压素持续释放过程中神经垂体 BDNF-TrkB 信号传导和通过 NR2B 磷酸化增强谷氨酸作用的作用。假设：与缺水相关的 TrkB 磷酸化导致谷氨酸活性增强，这是由于 NR2B NMDA 受体亚基通过 Fyn 激酶磷酸化，Fyn 激酶是 Src 激酶家族的成员，有助于 NMDA 介导的跨国公司可塑性 具体目标 2：检验神经垂体 BDNF-TrkB 信号传导增强神经垂体 BDNF-TrkB 信号传导的假设 缺水期间 GABA 的抑制作用。假设：缺水期间 BDNF-TrkB 信号传导增加 KCC2 表达，通过 Src 激酶增强 MNC 中 GABA 的抑制作用，而无需激活磷脂酶 C γ。方法：这些实验将首次明确 BDNF-TrkB 信号在 AVP 持续释放的稳态调节中的作用。将采用综合方法，包括体外和体内电生理学实验、将 TrkB 和 Src 激酶拮抗剂局部应用于 SON 的整体动物实验，以及大鼠体内水平衡和 AVP 释放的功能研究。好处：这些实验将解决我们对神经垂体功能的生理调节的理解中现有的差距。这些实验的结果可能会改变不适当的加压素释放的临床研究和概念化方式。