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.

项目概要 脑小血管疾病 (SVD) 和阿尔茨海默氏病 (AD) 是导致此类疾病的主要原因 AD 和相关痴呆症的患病率在全球范围内不断增加，并且其有效性也在不断提高。 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， 导致特定大脑区域的血液灌注受损和血脑屏障（BBB）完整性受损， 然而，特别是包括海马体，开发一种捕获病理生理学的动物模型。 事实证明，人类所经历的持续、无情的压力是困难的。 描述了一种新颖的实验模型——PVN-BDNF模型——它解决了这个问题并允许 海马慢性应激相关神经胶质血管功能障碍的研究，一个高度相关的研究 AD 病理生理学中的大脑区域 该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）中的衍生神经营养因子（BDNF）。 传统上，海马体中的 BDNF 被认为是其在学习和记忆中的作用的有益债务 PVN 中的神经元在刺激两条主要压力通路（交感神经）方面发挥着核心但较少被重视的作用。 神经系统和下丘脑-垂体-肾上腺 (HPA) 轴 – 导致血液长期升高 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。 因此，PVN-BDNF 模型重现了下丘脑（增加）和海马的不平衡。 （减少）神经内分泌应激反应的 BDNF 表达特征和升高。 糖皮质激素通过阻碍脑血管内的沟通而对脑血管功能产生不良影响 神经血管单元（NVU），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和突触功能。 因此，NVU 机制的破坏会导致 BBB 功能受损、微血管紊乱 使用新颖的成像和分析工具，结构和减少血管舒张反应。 我们将通过分析 BBB 完整性、微血管来表征 PVN-BDNF 模型小鼠的 NVU 功能障碍 结构、星形细胞和内皮细胞 Ca2+ 信号传导事件以及神经活动依赖性血管舒张剂 回应。