Hypothalamic BDNF-mTOR signaling promotes hypertension by increasing cardiovascular sensitivity to stress

慢性心理压力源，包括工作压力、社会经济地位低下和社会孤立- 最近的新冠肺炎疫情封锁加剧了这些风险，是高血压和心血管疾病的主要风险因素。 疾病应激激活的调节机制，刺激交感神经系统，以提高血液 压力和重新分配血流到重要器官已经发展成为保护生命的措施。从 从进化的角度来看，通过长期敏化这些增强心血管反应 机制是有利的生物体受到反复的压力。然而，在现代社会， 应对压力的情况很少需要血压显著升高，这些行为成为 有害的，因为心血管系统反复不必要的超负荷对心脏，血管， 和肾损伤因此，在血压正常的年轻人中， 个体的高血压与以后患高血压的风险密切相关。我们的长期目标是 研究确定压力引起的血压升高幅度的中枢机制 以鉴定新的抗高血压治疗靶点。在这里，我们建议调查一种新的信号 脑源性神经营养因子（BDNF）和雷帕霉素（mTOR）机制靶介导的级联反应， 下丘脑室旁核（PVN），这是一个在协调中起关键作用的大脑区域。 神经内分泌和心血管应激反应。应激时BDNF在PVN中的表达上调 对兴奋性输入和神经元活动增加的反应。我们之前已经证明，BDNF可以诱导 PVN内的重要适应性变化，以提高交感神经活性和血压。我们的初步 数据表明BDNF刺激mTOR，作为PVN神经元中mTOR复合物-1（mTORC 1）的一部分， 可以从根本上改变神经元的形态和突触连接，导致神经元 兴奋性增加心血管应激反应和促进高血压。为了验证我们的假设，我们 采用一系列全面的体外膜片钳研究，神经元形态学分析，以及体内 使用病毒载体介导的BDNF和mTORC 1遗传操作和遥测监测的实验 大鼠的心血管参数。在目标1中，我们测试PVN中的mTORC 1激活是否会升高血液中的 压力，增强心血管应激反应，并介导BDNF的高血压作用。在目标2中， 确定BDNF-mTORC 1信号传导是否调节PVN前体的结构和功能特征。 交感神经元，导致兴奋性增强。在目的3中，我们测试是否抑制BDNF-mTORC 1， 预防临界高血压大鼠的慢性应激性高血压。这些研究有可能 通过建立BDNF-mTORC 1轴作为一个非常重要的调节因子， 自主神经和心血管功能，决定压力期间血压升高的幅度 并在PVN中建立促进高血压发展的长期适应机制。

Chronic psychological stressors, including work-related stress, poor socioeconomic status and social isolation — all heightened by recent Covid-19 lockdowns — are major risk factors for hypertension and cardiovascular disease. Stress-activated regulatory mechanisms that stimulate the sympathetic nervous system to elevate blood pressure and redistribute blood flow to vital organs have evolved as life-protecting measures. From an evolutionary perspective, enhancing cardiovascular responses through long-term sensitization of these mechanisms is advantageous to organisms subjected to repeated stressors. However, in modern society, where coping with stressful situations rarely requires marked elevations in blood pressure, these actions become detrimental, as repeated unnecessary overload of the cardiovascular system exerts irreversible cardiac, vascular, and renal damage. Accordingly, augmented cardiovascular sensitivity to stressors in young, normotensive individuals is strongly correlated with the risk of becoming hypertensive later in life. Our long-term goal is to investigate the central mechanisms that determine the magnitude of blood pressure elevations elicited by stress in order to identify novel anti-hypertensive therapeutic targets. Here, we propose to investigate a novel signaling cascade mediated by brain-derived neurotrophic factor (BDNF) and mechanistic target of rapamycin (mTOR) in the paraventricular nucleus of the hypothalamus (PVN), a brain region that plays a key role in orchestrating neuroendocrine and cardiovascular stress responses. BDNF expression is upregulated in the PVN during stress in response to increased excitatory input and neuronal activity. We have previously shown that BDNF elicits important adaptive changes within the PVN to elevate sympathetic activity and blood pressure. Our preliminary data suggest that BDNF stimulates mTOR, as part of mTOR complex-1 (mTORC1) in PVN neurons, and mTORC1 can fundamentally change neuronal morphology and synaptic connectivity, resulting in elevated neuronal excitability to augment cardiovascular stress responses and promote hypertension. To test our hypothesis, we employ a comprehensive array of in vitro patch-clamp studies, neuronal morphology analysis, as well as in vivo experiments using viral vector-mediated genetic manipulation of BDNF and mTORC1 and telemetric monitoring of cardiovascular parameters in rats. In Aim 1, we test whether mTORC1 activation in the PVN elevates blood pressure, augments cardiovascular stress responses, and mediates hypertensive actions of BDNF. In Aim 2, we determine whether BDNF–mTORC1 signaling regulates structural and functional characteristics of PVN pre- sympathetic neurons, resulting in enhanced excitability. In Aim 3, we test whether inhibition of BDNF–mTORC1 prevents chronic stress-induced hypertension in borderline hypertensive rats. These studies have the potential to significantly advance the field by establishing the BDNF–mTORC1 axis as a highly important regulator of autonomic and cardiovascular function that determines the amplitude of blood pressure elevations during stress and elicits long-term adaptive mechanisms in the PVN that promote the development of hypertension.