Rescuing neurovascular coupling to protect neuronal plasticity and cognition

拯救神经血管耦合以保护神经元可塑性和认知

基本信息

批准号：
10530887
负责人：
MARK L DELL'ACQUA
金额：
$ 180.65万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
2022-07-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10530887
关键词：
Action Potentials Acute Address Age-Months Age-associated memory impairment Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Area Arterial Disorder Automobile Driving Behavior Behavioral Blood Blood Vessels Blood capillaries Blood flow Brain Brain imaging Brain region CADASIL Capillary Endothelial Cell Cerebral small vessel disease Cerebrovascular Circulation Cerebrovascular Disorders Cerebrovascular system Cerebrum Chronic Clinical Cognition Cognitive Coupling Data Defect Dementia Deterioration Development Disease Functional disorder Genetically Engineered Mouse Glutamate Receptor Goals Hippocampus (Brain)Hydrogen Peroxide Hyperemia Image Impaired cognition Impairment Implant Injections Intravenous Ischemia Learning Link Long-Term Potentiation Measures Mediator of activation protein Memory Loss Microcirculation Modeling Molecular Mus Mutation NOTCH3 gene Neuronal Plasticity Neurons Nutrient Pathogenesis Pathologic Pathologic Processes Patients Permeability Pharmacological Treatment Pharmacology Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phospholipase C Phospholipids Play Preparation Process Pump Regulation Research Short-Term Memory Signal Transduction Stroke Subcortical Infarctions Subcortical Leukoencephalopathy Symptoms Synapses Synaptic plasticity Testing Therapeutic Time Transgenic Mice Vascular Diseases Vasodilation Vasodilator Agents Work abeta oligomer arteriole base behavior test blood perfusion cerebral capillary cofactor cognitive function conditioned fear extracellular feeding hemodynamics imaging approach improved in vivo indexing injection/infusion innovation intraperitoneal inward rectifier potassium channel lens memory process metabolic rate mixed dementia mouse model multidisciplinary mutant neuron loss neurovascular neurovascular coupling novel parenchymal arterioles receptor relating to nervous system response restoration sensor two photon microscopy vascular cognitive impairment and dementia vascular contributions

项目摘要

Summary Growing evidence points towards the contribution of altered brain microcirculation to cognitive impairment and dementia observed in Alzheimer’s disease (AD) and AD-related dementia (ADRD). Yet, the lack of approaches to image the small cerebrovasculature and investigate its function has hampered our progress in understanding the pathological sequence of vascular cognitive impairment and dementia (VCID). The earliest signs of AD and VCID in patients and mouse models typically involve deficits in spatial and short-term memory—cognitive functions that are critically sustained by synaptic plasticity in the hippocampus. Neurons have limited energy reserves and thus rely on a “just-in-time” neurovascular coupling (NVC) strategy in which active regions signal to the microvasculature to locally dilate and increase local blood flow. Patients and mouse models of AD or CADASIL, a monogenic archetypal form of VCID, show an early deterioration in NVC. Our previous studies have identified a molecular defect at play in capillary endothelial cells and developed a therapeutic approach that acutely restores NVC in the mouse model of AD and CADASIL. Specifically, we found that systemic injection of phospholipid PIP2 is sufficient to rescue neurovascular deficits by enabling Kir2.1 channels to act as sensors of increases in external K+—a product of neuronal activity—and transduce this into a vasodilator electrical signal that rapidly propagates to upstream arterioles, driving vasodilation to produce local hyperemia. Our multidisciplinary team, with complementary expertise in cutting-edge imaging of brain microcirculation and synaptic plasticity underlying learning and memory processes, will test the hypothesis that NVC restoration will mitigate the synaptic plasticity deterioration in the hippocampus, and its behavioral consequences, observed in AD. We further propose to investigate and compare these functions in CADASIL, a vascular driven form of ADRD. To attain this goal, we will advance our PIP2-based strategy to chronically restore NVC in AD and CADASIL models, and assess the treatment efficiency by developing innovative imaging approaches ex vivo, with a novel intact capillary-arteriolar (CaPA) preparation established by our group, and in vivo using implanted graded-index (GRIN) lenses combined with 2-photon microscopy to investigate NVC in the hippocampus. Ultimately, we will measure the effect of NVC rescue on hippocampal synaptic plasticity deterioration caused by AD and CADASIL conditions, and use contextual fear conditioning as a behavioral readout. Completing this study will help elucidate the mechanisms linking NVC dysfunction to dementia in AD/ADRDs, and NVC restoration as a potential therapy. The proposed work has the potential to provide a paradigm-shifting view on how brain microcirculation sustains learning and memory processes.

概括越来越多的证据表明大脑微循环和在阿尔茨海默氏病（AD）和 AD 相关痴呆（ADRD）中观察到的痴呆，但缺乏治疗方法。对小脑血管系统进行成像并研究其功能阻碍了我们理解的进展血管性认知障碍和痴呆 (VCID) 的病理顺序 AD 和痴呆的最早症状。患者和小鼠模型中的 VCID 通常涉及空间和短期记忆（认知）缺陷海马体中由突触可塑性维持的功能的能量有限。储备，因此依赖于“及时”神经血管耦合（NVC）策略，其中活跃区域发出信号局部扩张和增加 AD 或小鼠模型的局部血流量。 CADASIL 是 VCID 的单基因原型，我们之前的研究表明 NVC 会出现早期恶化。确定了毛细血管内皮细胞中起作用的分子缺陷，并开发了一种治疗方法具体而言，我们发现全身注射可显着恢复 AD 和 CADASIL 小鼠模型中的 NVC。磷脂 PIP2 足以通过使 Kir2.1 通道充当神经血管的传感器来挽救神经血管缺陷外部 K+ 的增加（神经活动的产物）并将其转换为血管舒张电信号迅速传播到上游小动脉，驱动血管舒张，产生局部充血。多学科团队，在脑微循环和尖端成像方面具有互补的专业知识突触可塑性是学习和记忆过程的基础，将检验 NVC 恢复的假设减轻海马突触可塑性恶化及其行为后果，观察到 AD。我们进一步建议研究和比较 CADASIL（ADRD 的一种血管驱动形式）中的这些功能。为了实现这一目标，我们将推进基于 PIP2 的策略，以长期恢复 AD 和 CADASIL 中的 NVC 模型，并通过开发创新的离体成像方法来评估治疗效率，我们小组建立了完整的毛细血管-小动脉（CaPA）制剂，并在体内使用植入的分级指数 (GRIN) 将透镜与 2 光子显微镜相结合来研究海马体中的 NVC。测量 NVC 救援对 AD 和 CADASIL 引起的海马突触可塑性恶化的影响条件，并使用情境恐惧条件作为行为读数，完成这项研究将有助于阐明。将 NVC 功能障碍与 AD/ADRD 中的痴呆联系起来的机制，以及 NVC 恢复作为一种潜在的治疗方法。拟议的工作有可能为大脑微循环如何维持提供一个范式转变的观点学习和记忆过程。