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.

大脑是一个非常耗能的器官，消耗了大约20%的总血液供应，尽管 仅占体重的大约2%。因此，大脑需要持续的氧气供应， 葡萄糖为其正常功能提供燃料。已有研究表明，衰老会损害脑血流量，这是一种影响 可归因于内皮功能障碍以及神经血管偶联(NVC)和自我调节缺陷。自.以来 罗伊和谢林顿100多年前的开创性工作，人们已经知道大脑拥有 固有的能力，增加局部区域的血流量，以满足增加的能量需求 大脑活动。这种依赖神经元活动的血流增加，称为功能性充血，是 由NVC机制监管。研究强调了神经元和星形胶质细胞在 大脑在释放前列腺素和一氧化氮等血管激活剂到附近血管并触发 改变小动脉直径，从而控制脑血流量。到目前为止完成的工作主要集中在 这种调节从大脑到血管的单向性质。相比之下，人们对此知之甚少。 相反方向的交流--血管到大脑的交流--几乎什么都不知道 衰老可能会如何影响这种细胞间的通讯。我们之前的研究表明， 小动脉直径可改变星形细胞内钙离子浓度。这个项目的目标是确定小动脉对脑的作用。 并阐明这一过程以及随后的CBF控制在衰老过程中是如何改变的。这个 最重要的假说是，功能性充血时小动脉到星形胶质细胞的通讯改变了钙离子。 依赖神经活动，这一过程随着年龄的增长而改变。为了验证我们的假设，我们将使用双光子 大鼠全清醒状态下神经元和星形胶质细胞内血管系统和钙动态的荧光成像 与体外制剂、基因敲除策略、基因编码生物传感器、药物遗传学相结合 和光遗传学。这些集成的方法是新颖和强大的，因为它们使我们能够充分探索 在真实生理条件下整合不同的信号通路，而不受 麻醉剂。目标1将确定如何启动小动脉到星形胶质细胞的通讯。要了解 关键的启动刺激，导致小动脉到星形胶质细胞的信号，我们将有选择地操纵大脑 使用几种生理和实验(光遗传学和DREADD)策略的微血管。目标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作用。 星形胶质细胞之间的通讯。目标3将研究老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未被认识到的 血管调节脑细胞的生理细胞间通讯，定义了一种新的过程，即 对CBF的调节至关重要，并最终提供可能有助于维持大脑健康的见解。