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Brain-derived neurotrophic factor: a novel regulator of cardiovascular function in the hypothalamus

脑源性神经营养因子：下丘脑心血管功能的新型调节剂

基本信息

批准号：
9903424
负责人：
Benedek Erdos
金额：
$ 39万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-15 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9903424
关键词：
Acute Address Affinity Angiotensin II Animal Model Animals Blood Pressure Brain-Derived Neurotrophic Factor Cardiovascular Physiology Cardiovascular system Cations Chronic Conscious Data Development Equilibrium Gene Expression Glutamates Hippocampus (Brain)Hypertension Hypothalamic structure Image Imaging Techniques In Vitro Inbred SHR Rats Individual Learning Life Link Mediating Mediator of activation protein Memory N-Methylaspartate Nerve Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Pathway interactions Phospholipase C Phospholipases A Phosphorylation Play Prothrombin Psychological Stress Publications Rattus Receptor, Angiotensin, Type 1 Regulation Regulatory Pathway Role Signal Transduction Stimulus Stress Sympathetic Nervous System TRP channel Techniques Transactivation Up-Regulation Viral Vector acute stress biological adaptation to stress cardiovascular risk factor experimental study gamma-Aminobutyric Acid genetic manipulation high risk in vivo laser capture microdissection neural circuit neuroregulation neurotransmission normotensive novel paraventricular nucleus patch clamp receptor response stressor synaptic function trafficking

项目摘要

The sympathetic nervous system plays a key role in the development of hypertension, and elevated sympathetic activity is a major component of several cardiovascular risk factors, including stress. In addition, augmented cardiovascular sensitivity to acute stressors in young normotensive individuals predicts a higher risk of becoming hypertensive later in life, indicating that enhanced stress-responsiveness and long-term elevation of blood pressure (BP) are linked by the same, yet unidentified, stress-related central regulatory mechanisms. Here, we propose that brain-derived neurotrophic factor (BDNF), acting in the paraventricular nucleus of the hypothalamus (PVN), is a multi-faceted mechanism that is uniquely suited to directly activating PVN sympathoregulatory neurons to induce acute BP elevations to stress as well as mediating long-term transformation of the PVN neurocircuitry to facilitate responsiveness to hypertensive stimuli leading to the development of hypertension. Our recent publications and preliminary data suggest that BDNF exerts these effects in the PVN via mechanisms that have traditionally been recognized to mediate plasticity, learning and memory in hippocampal and cortical neuronal networks, but have not been explored in the PVN. These actions include 1) intracellular Ca2+-dependent BDNF expression in PVN neurons in response to excitatory input converging on the PVN during stress; 2) activation of the high-affinity BDNF receptor TrkB, leading to opening of the transient receptor potential channel-3 (TRPC3) via phospholipase C (PLC) signaling; 3) differential regulation of expression and function of N-methyl-D-aspartate (NMDA) and γ-aminobutyric acid type-A (GABAA) receptors, shifting the excitatory-inhibitory balance toward long-term sensitization in PVN sympathoregulatory neurons. In addition, there is evidence for important mechanisms that integrate actions of BDNF and angiotensin II (AngII), a key regulator of BP in the PVN. These newly discovered interactions are mediated by AngII-induced stimulation of BDNF expression; AngII-type-1 receptor (AT1R)-induced trans- activation of TrkB; and by BDNF-induced upregulation of AT1R. We employ a comprehensive array of in vitro patch-clamp and Ca2+-imaging techniques as well as in vivo experiments using viral vector-mediated genetic manipulation of BDNF signaling in rats to achieve the following aims: Aim 1: To elucidate TrkB–PLC–TRPC3- mediated mechanisms by which BDNF activates PVN sympathoregulatory neurons to acutely increase SNA and BP; Aim 2: To characterize functional interactions between BDNF and AngII in sympathoregulatory PVN neurons; and Aim 3: To determine how excessive activation of BDNF signaling augments excitatory and diminishes inhibitory synaptic function in PVN sympathoregulatory neurons to promote the development of hypertension. These studies have the strong potential to significantly advance the field by establishing BDNF as a highly important regulator of autonomic and cardiovascular function, one that mediates both acute stress responses and long-term adaptive mechanisms in the PVN leading to the development of hypertension.

交感神经系统在高血压的发生发展中起着关键作用，活动是包括压力在内的若干心血管风险因素的主要组成部分。此外，增强血压正常的年轻人心血管对急性应激源的敏感性预示着更高的风险，高血压在以后的生活中，表明增强的应激反应和长期升高的血液压力（BP）是由相同的，但尚未确定的，压力相关的中央调节机制。这里我们提出脑源性神经营养因子（BDNF），作用于室旁核，下丘脑（PVN），是一个多方面的机制，是唯一适合于直接激活PVN 交感神经调节神经元诱导急性血压升高的压力，以及介导长期 PVN神经回路的转化，以促进对高血压刺激的反应，导致高血压的发展。我们最近的出版物和初步数据表明，BDNF发挥这些作用，通过传统上被认为介导可塑性、学习和在海马和皮层神经元网络中的记忆，但尚未在PVN中探索。这些行动包括：1）PVN神经元对兴奋性输入反应时胞内Ca 2+依赖性BDNF表达在应激过程中聚集在PVN上; 2）高亲和力BDNF受体TrkB的激活，导致开放瞬时受体电位通道3（TRPC 3）通过磷脂酶C（PLC）信号传导; 3）差异 N-甲基-D-天冬氨酸（NMDA）和γ-氨基丁酸A型的表达和功能调节（GABAA）受体，使PVN中的兴奋-抑制平衡向长期致敏转变交感神经调节神经元此外，有证据表明，重要的机制，整合行动， BDNF和血管紧张素II（AngII），PVN中BP的关键调节因子。这些新发现的相互作用是通过AngII诱导的BDNF表达刺激介导; AngII-1型受体（AT 1 R）诱导的反式- TrkB的激活;和通过BDNF诱导的AT 1 R的上调。我们采用了一系列全面的体外膜片钳和Ca 2+成像技术以及使用病毒载体介导的遗传修饰的体内实验，目的1：阐明TrkB-PLC-TRPC 3 - 1在大鼠脑源性神经营养因子（BDNF）信号转导中的作用。 BDNF激活PVN交感神经调节神经元以急性增加SNA和目的2：研究BDNF和AngII在交感神经调节PVN中的相互作用目的3：确定BDNF信号的过度激活如何增强兴奋性和减少PVN交感神经调节神经元的抑制性突触功能，以促进高血压这些研究有很强的潜力，通过建立BDNF作为一种神经营养因子，一个非常重要的调节器自主和心血管功能，一个调解急性应激反应和长期的适应机制，导致高血压的发展。