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

交感神经系统在高血压的发展中起着关键作用，交感神经的升高 运动是包括压力在内的几个心血管风险因素的主要组成部分。此外，还增加了 血压正常的年轻个体对急性应激源的心血管敏感性预示着更高的风险 晚年高血压，表明应激反应增强和血液长期升高 压力(BP)由相同的、但尚未确定的、与压力相关的中枢调节机制联系在一起。在这里，我们 脑源性神经营养因子(BDNF)作用于大鼠室旁核 下丘脑(PVN)是一种多方面的机制，特别适合直接激活PVN 交感神经调节神经元诱导应激引起的急性血压升高以及介导长期 室旁核神经回路的改变，以促进对导致高血压刺激的反应 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 在PVN中的影响通过传统上被认为是调节可塑性、学习和 在海马神经元和皮质神经元网络中的记忆，但在下丘脑室旁核中尚未被探索。这些操作 包括1)兴奋性输入对PVN神经元细胞内钙依赖性BDNF表达的影响 应激时聚集在PVN上；2)激活高亲和力的BDNF受体TrkB，导致开放 通过磷脂酶C(PLC)信号转导瞬时受体电位通道3(TRPC3)；3)分化 N-甲基-D-天冬氨酸和γ-A型氨基丁酸的表达和功能调节 (GABAA)受体，使PVN的兴奋-抑制平衡向长期敏化转变 交感神经调节神经元。此外，有证据表明，重要的机制整合了 脑源性神经营养因子和血管紧张素II(AngII)，它是PVN中BP的关键调节因子。这些新发现的相互作用是 血管紧张素Ⅱ诱导BDNF表达；血管紧张素Ⅱ1型受体(AT1R)诱导 激活TrkB，并通过BDNF诱导AT1R上调。我们采用了一系列全面的体外培养技术 膜片钳和钙离子成像技术以及利用病毒载体介导的基因的体内实验 目的1：阐明TrkB-PLC-TRPC3信号转导途径。 脑源性神经营养因子激活PVN交感神经调节神经元显著增加SNA和 目的2：研究交感神经调节PVN中BDNF和AngII之间的功能相互作用 以及目标3：确定过度激活BDNF信号如何增强兴奋性和 抑制下丘脑室旁核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将BDNF建立为 一种非常重要的自主神经和心血管功能调节器，调节急性应激 PVN的反应和长期适应机制导致高血压的发展。

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.