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

用于研究海马痴呆相关神经血管功能障碍的新型慢性应激和高血压实验模型

• 批准号: 10194742
• 负责人: Benedek Erdos
• 金额: $ 15.6万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194742
• 关键词: Address; Affect; Affinity; Alzheimer' s Disease; Alzheimer' s disease related dementia; Animal Model; Animals; Architecture; Astrocytes; Blood - brain barrier anatomy; Blood Pressure; Blood Vessels; Blood capillaries; Brain; Brain Diseases; Brain region; Brain-Derived Neurotrophic Factor; Cardiovascular Diseases; Cardiovascular system; Cerebrovascular Disorders; Characteristics; Chronic; Chronic stress; Communication; Complex; Dementia; Development; Down-Regulation; Endothelial Cells; Endothelium; Etiology; Event; Experimental Models; Functional disorder; Gene Expression; Glucocorticoids; Hippocampus (Brain); Human; Hypertension; Hypothalamic structure; Image; Imaging Device; Impairment; Investigation; Knowledge; Laboratories; Learning; Mediating; Mediator of activation protein; Memory; Metabotropic Glutamate Receptors; Microvascular Dysfunction; Modeling; Mus; Muscle relaxation phase; Neuroglia; Neurons; Neurosecretory Systems; Neurotrophic Tyrosine Kinase Receptor Type 2; Nitric Oxide; Pathway interactions; Plasma; Play; Potassium Channel; Prevalence; Process; Protein Isoforms; Regulation; Resistance; Role; Signal Transduction; Slice; Stress; Structure; Sympathetic Nervous System; Synapses; System; Techniques; Testing; Vascular Diseases; Vascular Smooth Muscle; Vasodilator Agents; Viral Vector; analytical tool; arteriole; biological adaptation to stress; blood perfusion; blood-brain barrier function; cardiovascular risk factor; cerebrovascular; density; effective therapy; experience; hypothalamic-pituitary-adrenal axis; mouse model; neurovascular; neurovascular unit; novel; overexpression; paraventricular nucleus; psychologic; response; social stress; synaptic function

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.

项目摘要 大脑的小血管疾病（SVD）以及阿尔茨海默氏病（AD）是主要原因 失智。广告和相关痴呆症的流行率在全球范围内增加，有效的发展 对潜在的病理生理机制的理解不足，阻碍了治疗。 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，这是 导致血液灌注受损和特定大脑区域的血液脑屏障（BBB）的损害， 值得注意的是包括海马。但是，开发一种捕获病理生理学的动物模型 事实证明，人类持续不断的压力的各个方面很困难。在这里，我们建议 表征一个新型的实验模型 - PVN-BDNF模型，该模型解决了此问题并允许 在海马中研究与慢性应激相关的神经性血管功能障碍的研究，这是一种高度相关的 AD病理生理学中的大脑区域。该模型使用病毒向量来驱动大脑的长期过表达 在下丘脑（PVN）的室室核中衍生的神经营养因子（BDNF）。虽然bdnf 在海马中，传统上因其在学习和记忆中的作用而被认为是有益的 在PVN中，在刺激这两种主要压力途径中的中心但不值得赞赏的作用 - 同情 神经系统和下丘脑 - 垂体 - 肾上腺（HPA）轴 - 导致长期升高的血液 压力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 BDNF水平；因此，PVN-BDNF模型重现下丘脑（增加）和海马的失衡 （减少）神经内分泌应激反应的BDNF表达特征。高血压和升高 糖皮质激素通过阻碍脑血管功能产生不利影响 神经血管单元（NVU）是一种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） 神经元与周围脉管系统之间的中继信息支持神经元和突触功能。 根据以下内容，NVU机制的破坏会导致BBB功能受损，扰动微血管 结构和血管扩张对神经元活性的反应减少。使用新颖的成像和分析工具， 我们将通过分析的BBB完整性，微血管表征PVN-BDNF模型小鼠中NVU功能障碍 体系结构，星形细胞和内皮CA2+信号传导事件以及神经元活动依赖性血管扩张剂 回答。