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

项目总结 脑部小血管疾病(SVDS)和阿尔茨海默病(AD)是导致 痴呆症。阿尔茨海默病及相关痴呆症的患病率在全球范围内呈上升趋势，且发展有效 由于对潜在的病理生理机制了解不足，治疗受到阻碍。 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， 导致特定脑区的血液灌流受损和血脑屏障(BBB)完整性受损， 值得注意的是包括海马体。然而，开发一种能够捕捉病理生理学变化的动物模型 事实证明，人类经历的持续、无情的压力的各个方面都很困难。在此，我们建议 描述了一种新的实验模型-PVN-BDNF模型-它解决了这个问题，并允许 慢性应激相关的海马区神经胶质血管功能障碍的研究 AD病理生理学中的脑区。这个模型使用病毒载体来驱动大脑的长期过度表达- 下丘脑室旁核(PVN)内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，海马区的BDNF传统上被认为是有益的 在PVN中，在刺激两条主要的应激通路--交感神经--中起着中心的作用，但很少被认识到 神经系统和下丘脑-垂体-肾上腺(HPA)轴-导致慢性血液升高 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区 因此，PVN-BDNF模型重建了下丘脑(增加的)和海马区的失衡 神经内分泌应激反应的脑源性神经营养因子表达减少。高血压和高血压病 糖皮质激素通过阻碍脑血管内沟通而对脑血管功能产生不利影响。 神经血管单位(NVU)，一个功能和结构复杂的系统，其中胶质细胞(主要是星形胶质细胞) 在神经元和周围的血管系统之间传递信息，以支持神经元和突触功能。 因此，NVU机制的破坏会导致血脑屏障功能受损，微血管受扰 结构和对神经元活动的血管扩张反应减弱。使用新的成像和分析工具， 我们将通过分析血脑屏障的完整性、微血管来描述PVN-BDNF模型小鼠的NVU功能障碍 结构、星形细胞和内皮细胞钙信号事件以及神经元活性依赖的血管扩张剂 回应。

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.