The Role of the Hippocampal Vasculature in Vascular Cognitive Impairment and Dementia

海马脉管系统在血管性认知障碍和痴呆中的作用

基本信息

批准号：
10596617
负责人：
Abbie C Chapman
金额：
$ 46.17万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10596617
关键词：
Acceleration Adult Affect Age Age Months Aging Angiotensin II Atrophic Blood Vessels Blood capillaries Blood flow Brain Brain Hypoxia-Ischemia Brain region Buffers Cerebrovascular Disorders Cerebrum Chronic Clinical Research Cognition Cognitive Cognitive aging Data Dementia Endothelin-1 Endothelium Female Functional disorder Goals Health Hippocampus Hypertension Impaired cognition Impairment In Vitro Inbred SHR Rats Individual Infarction Injury Knowledge Learning Lesion Measures Mediator Memory Memory Loss Memory impairment Metabolic Microcirculation Modeling Muscle function Nature Neurocognitive Neuronal Injury Neuronal Plasticity Neurons Outcome Study Oxidative Stress Oxidative Stress Pathway Pathogenesis Pathologic Pathway interactions Patients Perfusion Persons Population Postmenopause Predisposition Property Publishing Rattus Rest Risk Risk Factors Role Serum Sex Differences Signal Transduction Structure TNF gene Therapeutic Vascular Cognitive Impairment Vascular Dementia Vascular Smooth Muscle Vasoconstrictor Agents Vasodilation arteriole cerebral microvasculature cerebrovascular cerebrovascular pathology density disability endothelial dysfunction healthy aging hemodynamics hippocampal atrophy hypertensive hypoperfusion improved in vivo ischemic injury male middle age neurovascular neurovascular coupling new therapeutic target normal aging normotensive novel oxidative damage pharmacologic pressure prevent protective pathway response sex vascular cognitive impairment and dementia white matter

项目摘要

Chronic hypertension affects over 100 million adults in the US and is a major risk factor for cerebrovascular disease and vascular cognitive impairment (VCI). VCI involves impairment in multiple cognitive domains, often affecting the hippocampus and memory function leading to dementia. The hippocampus is a deep brain structure that is central to learning and memory and particularly susceptible to injury. Perfusion of the hippocampus is maintained by small hippocampal arterioles (HAs) that are critical to both basal- and activity-dependent changes in blood flow. Cognitive decline occurs more rapidly in the setting of chronic hypertension compared to normal aging; however, how chronic hypertension and aging affect HAs remains unclear and could contribute to VCI. The goal of this proposal is to investigate the novel role of HAs in healthy cognitive aging and VCI associated with chronic hypertension. Our preliminary and published data show that HAs were hyperconstricted and had impaired vasodilatory function in a rat model of chronic hypertension. Further, hippocampal perfusion was significantly reduced and memory impaired during chronic hypertension that occurred as a function of age. Importantly, HA dysfunction preceded these changes in perfusion and memory function, suggesting hypertension-induced memory decline is vascular in nature. Our central hypothesis is that chronic hypertension progressively decreases the vasodilatory function of HAs that reduces resting and activity-dependent changes in hippocampal perfusion, resulting in neuronal injury and VCI. Aim 1 will investigate HA endothelial and vascular smooth muscle function, including vasoconstrictive and vasodilatory pathways, in normotensive and hypertensive rats by studying isolated and pressurized HAs in vitro. Circulating potent vasoconstrictors (e.g. angiotensin II, endothelin-1, tumor necrosis factor alpha) that are elevated during chronic hypertension and cause oxidative stress and damage endothelium will be investigated as underlying mechanisms by which chronic hypertension causes hyperconstriction and impaired vasodilation of HAs. Aim 2 will investigate progressive changes in hippocampal perfusion and neurovascular coupling – the innate ability of the brain to increase local blood flow in response to neuronal activity – as it relates to neuronal function and memory in normotensive and hypertensive rats across the lifetime. We will determine the role of HAs in age- and hypertension-induced changes in hippocampal hemodynamics by investigating if therapeutically improving HA function prevents perfusion deficits, protects hippocampal neurons and slows cognitive decline to be similar to normal aging. This proposal will use both male and post-menopausal female rats to investigate sex differences in hypertension- induced HA dysfunction, and whether one sex is more susceptible to age- or hypertension-induced changes in hippocampal neurovascular function. The outcome of these studies will provide an understanding of the involvement of the hippocampal vasculature in memory decline associated with normal aging, and how this may be accelerated during chronic hypertension and contribute to VCI.

慢性高血压在美国影响超过1亿成年人，这是脑血管的主要危险因素疾病和血管认知障碍（VCI）。影响海马的海马和记忆功能。这是学习和记忆的中心，并暂停了海马的灌注。由小型海马替代虫（HAS）维持，这对基础和活动依赖性变化至关重要在血液中，认知能力下降在慢性高血压的情况下更快但是，老化；但是，衰老的影响尚不清楚，可能会导致VCI。该提案的目的是研究HAS在健康认知衰老和VCI相关的新作用慢性高血压。在慢性高度的大鼠模型中，血管扩张功能受损。在慢性高血压期间，大幅减少和记忆受损，这是年龄的函数。重要的是，HA功能障碍在灌注和记忆功能的变化之前，建议高血压引起的记忆下降是夜晚的血管。 ProgectyiveLEAS具有减少静息和活动依赖性变化的血管扩张功能在海马灌注中，导致神经元损伤和VCI。平滑肌肉功能，包括血管收缩和血管扩张途径高血压大鼠通过研究循环的血管收缩术中的分离和预性HASS（例如血管紧张素II，内皮素-1，肿瘤坏死因子α）在慢性高血压和导致氧化应激和损伤原位将作为慢性的基本机制进行研究高血压会导致AIM 2的高收缩和血管舒张。海马灌注和神经血管耦合的变化 - 大脑的先天能力增加局部对神经元活性的响应血流 - 与正常性的神经元功能和记忆有关，并且整个生命周期的高血压大鼠。海马血流动力学的变化通过研究是否可以改善HA功能灌注缺陷，保护海马神经元，并将认知能力降低到与正常衰老相似提案将使用雄性和绝经后雌性大鼠研究高血压的性别差异 - 引起的HA功能障碍，以及一种性别是否对年龄或高血压诱导的变化更加明显海马神经血管功能。海马血管alatore参与与正常衰老有关的记忆下降，以及这是Mayu 在慢性高血压期间加速加速并导致VCI。