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: 10289673
• 负责人: Cam Ha Thai Tran
• 金额: $ 21.6万
• 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/10289673
• 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量需求器官，消耗约20%的总血液供应， 仅占体重的2%左右。因此，大脑需要持续的氧气供应， 葡萄糖来维持其正常功能衰老已被证明会损害脑血流量（CBF）， 可归因于内皮功能障碍以及神经血管偶联（NVC）和自动调节的缺陷。以来 100多年前，罗伊和谢林顿的开创性工作，人们已经知道，大脑拥有一个 增加局部区域血流的内在能力，以满足增加的能量需求 大脑活动这种神经活性依赖性的血流量增加，称为功能性充血， 受NVC机制监管。研究已经强调了神经元和星形胶质细胞在神经系统中的重要作用。 大脑释放血管激活剂，如肾上腺素和一氧化氮到附近的血管，并触发 改变小动脉直径，从而控制CBF。迄今为止所做的工作主要集中在 从大脑到血管的单向调节。相比之下， 相反方向的交流--血管-大脑的交流--实际上什么都不知道 衰老会如何影响细胞间的交流。我们之前的研究表明， 微动脉直径可改变星形胶质细胞内Ca ~（2+）。这个项目的目标是建立动脉对大脑的作用 通信，并阐明这一过程，因此CBF控制是如何改变老化。的 最重要的假设是，功能性充血期间小动脉与星形胶质细胞的通讯改变了Ca 2 +- 依赖的神经活动，这个过程在衰老中会改变。为了验证我们的假设，我们将使用双光子 在完全清醒的动物中，血管系统的荧光成像和神经元和星形胶质细胞中的Ca 2+动力学， 与离体制剂、敲除策略、遗传编码生物传感器、药物遗传学结合 和光遗传学这些综合方法是新颖而强大的，因为它们使我们能够充分探索 在真实的生理条件下整合不同的信号传导途径，而不受以下因素的干扰 麻醉剂目的1将确定如何小动脉星形胶质细胞通信可以启动。了解 关键启动刺激，导致小动脉到星形胶质细胞的信号，我们将选择性地操纵大脑 使用几种生理学和实验（光遗传学和DREADD）策略来测量微血管。目的2 将探索下游细胞信号通路，用于将信息从小动脉传递到星形胶质细胞。 这些研究将评估一氧化氮级联反应和机械敏感通道对小动脉的贡献， 与星形胶质细胞的通讯目标3将研究老龄化对信息传递方式的潜在影响， 小动脉到星形胶质细胞我们对这一新模型的研究可能会建立一个以前不受重视的 生理细胞与细胞之间的通讯，其中血管调节脑细胞，定义了一个新的过程， 对于CBF调节至关重要，并最终提供可能有助于维持大脑健康的见解。