A novel experimental model of chronic stress and hypertension for studying dementia-related neurovascular dysfunction in the hippocampus

项目摘要 脑小血管疾病（SVD）与阿尔茨海默病（AD）一起是阿尔茨海默病（AD）的主要原因。 痴呆AD和相关痴呆的患病率在世界范围内不断增加，有效的 治疗受到对潜在的病理生理机制的不充分理解的阻碍。 心理/社会压力和相关的高血压是脑血管功能障碍的主要驱动因素， 导致特定脑区域的血液灌注受损和血脑屏障（BBB）完整性受损， 特别是包括海马体。然而，开发一种动物模型，捕捉病理生理 人类所经历的持续的、无情的压力的各个方面已经被证明是困难的。在此，我们建议 描述了一种新的实验模型-PVN-BDNF模型-解决了这个问题，并允许 研究慢性应激相关的海马神经胶质血管功能障碍， 脑区在AD病理生理学中的作用该模型使用病毒载体来驱动大脑的长期过表达- 在下丘脑室旁核（PVN）的衍生神经营养因子（BDNF）。虽然BDNF 由于其在学习和记忆中的作用，传统上认为海马中的BDNF是有益的， 在PVN中，在刺激两个主要的应激通路-交感神经通路-中起着中心作用，但不太受重视。 神经系统和下丘脑-垂体-肾上腺（HPA）轴-导致慢性血液 血压和血浆糖皮质激素水平。高血浆糖皮质激素水平反过来下调海马 因此，PVN-BDNF模型重现了下丘脑（增加）和海马（增加）中的不平衡。 （减少）BDNF表达特征的神经内分泌应激反应。高血压和高血压 糖皮质激素通过阻碍脑血管内的通讯而对脑血管功能产生有害影响。 神经血管单位（NVU）是一个功能和结构复杂的系统，其中神经胶质细胞（主要是星形胶质细胞） 在神经元和周围脉管系统之间传递信息以支持神经元和突触功能。 因此，NVU机制的破坏导致BBB功能受损，微血管紊乱， 结构和对神经元活动的血管舒张反应减弱。使用新的成像和分析工具， 我们将通过分析血脑屏障完整性、微血管和神经元的功能， 结构、星形胶质细胞和内皮细胞Ca 2+信号传导事件和神经元活性依赖性血管扩张剂 应答

Project summary Small vessel diseases of the brain (SVDs) together with Alzheimer’s disease (AD) are the major causes of dementia. The prevalence of AD and related dementias is increasing worldwide, and the development of effective treatments is hampered by an inadequate understanding of the underlying pathophysiological mechanisms. Psychological/social stress and associated hypertension are major drivers of brain vascular dysfunction, which leads to impaired blood perfusion and compromised blood brain barrier (BBB) integrity in specific brain regions, notably including the hippocampus. However, developing an animal model that captures the pathophysiological aspects of the continuous, relentless stress experienced by humans has proven difficult. Here, we propose to characterize a novel experimental model – the PVN-BDNF model – that addresses this problem and allows investigation of chronic stress-related neuro-glial-vascular dysfunction in the hippocampus, a highly relevant brain region in AD pathophysiology. This model uses viral vectors to drive long-term overexpression of brain- derived neurotrophic factor (BDNF) in the paraventricular nucleus of the hypothalamus (PVN). Although BDNF in the hippocampus has traditionally been considered beneficial owing to its role in learning and memory, BDNF in the PVN plays a central, but less-appreciated, role in stimulating both major stress pathways – the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis – resulting in chronically elevated blood pressure and plasma glucocorticoid levels. High plasma glucocorticoid levels in turn downregulate hippocampal BDNF levels; thus, the PVN-BDNF model recreates the imbalance in hypothalamic (increased) and hippocampal (decreased) BDNF expression characteristic of neuroendocrine stress responses. Hypertension and elevated glucocorticoids exert detrimental effects on cerebrovascular function by impeding communication within the neurovascular unit (NVU), a functionally and structurally complex system in which glial cells (mainly astrocytes) relay information between neurons and the surrounding vasculature to support neuronal and synaptic function. Accordingly, disruption of NVU mechanisms results in impaired BBB function, perturbed microvascular architecture and diminished vasodilator responses to neuronal activity. Using novel imaging and analytic tools, we will characterize NVU dysfunction in PVN-BDNF model mice by analyzing BBB integrity, microvascular architecture, astrocytic and endothelial Ca2+ signaling events, and neuronal activity-dependent vasodilator responses.