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.

大脑是一个极其需要能量的器官，尽管它消耗了总血液供应量的约 20% 仅占体重的2%左右。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。衰老已被证明会损害脑血流量（CBF），这是一种影响 可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 多年前，随着 Roy 和 Sherrington 的开创性工作，人们已经知道大脑拥有 增加局部区域血流量的内在能力，以满足增加的能量需求 大脑活动。这种神经元活动依赖性血流量增加，称为功能性充血，是 受NVC机制监管。研究强调了神经元和星形胶质细胞在 大脑将前列腺素和一氧化氮等血管激活剂释放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 这种调节从大脑到血管的单向性质。相比之下，人们知之甚少 相反方向的通讯——血管到大脑的通讯——几乎什么都不知道 关于衰老如何影响这种细胞间的通讯。我们之前的研究表明，变化 小动脉直径可以改变星形细胞Ca2+。该项目的目标是确定小动脉到大脑的作用 沟通并阐明这一过程以及随之而来的 CBF 控制在衰老过程中如何改变。这 总体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 Ca2+- 依赖的神经活动，并且这个过程随着衰老而改变。为了检验我们的假设，我们将采用双光子 完全清醒动物的脉管系统和神经元和星形胶质细胞中 Ca2+ 动态的荧光成像 与离体制剂、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。这些综合方法新颖而强大，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通路，而不会产生混杂的影响 麻醉剂。目标 1 将确定如何启动小动脉与星形胶质细胞的通讯。要了解 引起小动脉到星形胶质细胞信号传导的关键起始刺激，我们将选择性地操纵大脑 使用多种生理和实验（光遗传学和 DREADD）策略的微脉管系统。目标2 将探索用于将信息从小动脉传递到星形胶质细胞的下游细胞信号传导途径。 这些研究将评估一氧化氮级联和机械敏感通道对小动脉的贡献 至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 小动脉至星形胶质细胞。我们对这种新颖模型的研究可能会建立一个以前未被重视的模型 生理细胞间的通讯，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，并最终提供有助于维持大脑健康的见解。