Vascular Effects on Astrocyte Functions in Young and Aging Brains

血管对年轻和衰老大脑中星形胶质细胞功能的影响

• 批准号: 10447780
• 负责人: Cam Ha Thai Tran
• 金额: $ 18万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447780
• 关键词: Acetylcholine; Address; Affect; Aging; Anesthetics; Animals; Astrocytes; Biosensor; Blood Vessels; Blood flow; Body Weight; Brain; Caliber; Cell Communication; Cell Signaling Process; Cells; Cerebrovascular Circulation; Cerebrum; Communication; Communications Media; Consumption; Data; Defect; Development; Generations; Glucose; Goals; Homeostasis; Hyperemia; Impairment; Infusion procedures; Investigation; Knock-out; Laser Scanning Microscopy; Link; Measures; Mediating; Metabolic; Modeling; Mus; Nature; Neurons; Neurotransmitters; Nitric Oxide; Organ; Oxygen; Pathologic; Pathway interactions; Perfusion; Pharmacogenetics; Pharmacology; Phenylephrine; Physiological; Piezo 1 ion channel; Play; Preparation; Process; Prostaglandins; Regulation; Reporting; Research; Role; Sensory; Signal Pathway; Signal Transduction; Stimulus; Stroke; Subcellular structure; Synapses; Technology; Testing; Tissues; Vascular Dementia; Vascular blood supply; Vasoconstrictor Agents; Vasodilation; Work; aging brain; arteriole; awake; brain cell; brain health; cerebral microvasculature; constriction; designer receptors exclusively activated by designer drugs; endothelial dysfunction; fluorescence imaging; glutamatergic signaling; in vivo; insight; mind control; nervous system disorder; neurovascular coupling; normal aging; novel; novel strategies; optogenetics; parenchymal arterioles; pressure; relating to nervous system; two-photon; vasoconstriction; virtual

The brain is an incredibly energy-demanding organ, consuming ~20% of the total blood supply despite constituting only approximately 2% of body weight. Thus, the brain requires a continuous supply of oxygen and glucose to fuel its normal functioning. Aging has been shown to impair the cerebral blood flow (CBF), an effect attributable to endothelial dysfunction, and defects in neurovascular coupling (NVC) and autoregulation. Since the pioneering work of Roy and Sherrington over 100 years ago, it has been known that the brain possesses an intrinsic ability to increase blood flow to localized regions to meet the energy demands imposed by increased brain activity. This neuronal activity-dependent increase in blood flow, known as functional hyperemia, is regulated by NVC mechanisms. Studies have highlighted the essential role of neurons and astrocytes in the brain in releasing vasoactivators such as prostaglandins and nitric oxide onto nearby vessels and triggering changes in arteriole diameter and thus controlling CBF. Work performed to date has predominantly focused on the uni-directional nature of this regulation going from the brain to vessels. In contrast, very little is known about the communication in the reversed direction—vessel-to-brain communication—and virtually nothing is known about how aging might affect this cell-to-cell communication. Our previous studies showed that changes in arteriole diameter can alter astrocytic Ca2+. The goal of this project is to establish the role of arteriole-to-brain communication and elucidate how this process, and consequently CBF control, is altered in aging. The overarching hypothesis is that arteriole-to-astrocyte communication during functional hyperemia modifies Ca2+- dependent neural activity, and this process is altered in aging. To test our hypothesis, we will employ two-photon fluorescence imaging of the vasculature and Ca2+ dynamics in neurons and astrocytes in fully awake animals in conjunction with ex vivo preparations, knockout strategies, genetically encoded biosensors, pharmacogenetics and optogenetics. These integrated approaches are novel and powerful as they enable us to fully explore the integration of different signaling pathways under true physiological conditions without the confounding effects of anesthetics. Aim 1 will determine how arteriole-to-astrocyte communication can be initiated. To understand the critical initiating stimuli that cause the arteriole-to-astrocyte signaling, we will selectively manipulate the brain microvasculature using several physiological and experimental (optogenetics and DREADD) strategies. Aim 2 will explore the downstream cellular signaling pathways utilized to relay information from arterioles to astrocytes. These studies will assess contributions of the nitric oxide cascade and mechanosensitive channels to arteriole- to-astrocyte communication. Aim 3 will examine potential impacts of aging on the way information is relayed from arterioles to astrocytes. Our investigations into this novel model may establish a previously unappreciated physiological cell-to-cell communication in which blood vessels modulate brain cells, defining a new process that is essential for CBF regulation and ultimately providing insights that may help maintain brain health.

大脑是一个令人难以置信的能源器官，消耗了总血液供应需求的约20％ 仅构成大约2％的体重。这，大脑需要连续的氧气供应和 葡萄糖为其正常功能增强。已经显示衰老会损害大脑血流（CBF），这种影响 归因于内皮功能障碍，以及神经血管耦合（NVC）和自动调节的缺陷。自从 100年前，罗伊（Roy）和谢灵顿（Sherrington）的开创性工作，众所周知，大脑拥有 增加血液流向局部区域以满足增加的能量需求的内在能力 大脑活动。这种神经元活性依赖性血流的增加，称为功能性充血，是 由NVC机制调节。研究强调了神经元和星形胶质细胞在 释放血管活化剂（例如前列腺素和一氧化物）的大脑，并触发 小动物直径的变化，从而控制CBF。迄今为止所做的工作主要集中在 从大脑到血管的这种调节的单向性质。相反，对 在反向方向上的交流 - 围绕脑之间的交流 - 几乎没有什么已知的 关于衰老如何影响这种细胞对细胞的通信。我们以前的研究表明，变化 动脉直径可以改变星形胶质细胞Ca2+。该项目的目的是确定动脉至脑的作用 沟通并阐明了这一过程以及CBF的控制如何在衰老中改变。 总体假设是在功能性充血修饰剂Ca2+ - 中的小动脉到胃细胞通信 依赖的神经活动，并且此过程在衰老中发生了改变。为了检验我们的假设，我们将采用两光子 完全清醒动物的神经元和星形胶质细胞中脉管系统和CA2+动力学的荧光成像 与体内制剂，敲除策略，基因编码生物传感器，药物遗传学的联系 和光遗传学。这些集成的方法是新颖而强大的，因为它们使我们能够充分探索 在真实的物理条件下的不同信号通路的整合而没有混淆的影响 麻醉药。 AIM 1将确定如何启动动脉到胃细胞通信。理解 关键引起动脉至胃细胞信号的刺激，我们将有选择地操纵大脑 使用几种物理和实验性（光遗传学和dreadd）策略的微脉管系统。目标2 将探索用于将小动脉信息传递到星形胶质细胞的下游细胞信号通路。 这些研究将评估一氧化氮级联和机械敏感通道对动脉的贡献。 静止细胞交流。 AIM 3将检查衰老对信息的潜在影响。 小动脉到星形胶质细胞。我们对这个新型模型的调查可能会建立先前未欣赏的 物理细胞对细胞通信，血管调节脑细胞，定义一个新过程 对于CBF监管至关重要，最终提供可能有助于维持大脑健康的见解。