Integrated Cerebral Blood Flow Regulation

综合脑血流调节

• 批准号: 10367068
• 负责人: Cam Ha Thai Tran
• 金额: $ 40.39万
• 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: 2021-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367068
• 关键词: Address; Affect; Anesthetics; Animals; Architecture; Area; Astrocytes; Attention; Biosensor; Blood; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain region; Cells; Cerebrovascular Circulation; Communication; Complement; Data; Development; Disease; Elements; Endothelium; Ensure; Equilibrium; Event; Foundations; Functional Magnetic Resonance Imaging; Gap Junctions; Glutamates; Goals; Health; Hyperemia; Investigation; Knock-out; Laboratories; Laser Scanning Microscopy; Lesion; Maps; Mediating; Metabolic; Microcirculation; Modeling; Molecular; Mus; Neurons; Neurotransmitters; Nutrient; Outcome; Oxygen; Pathologic; Pathway interactions; Perfusion; Pharmacogenetics; Physiological; Physiological Processes; Preparation; Process; Regulation; Research; Role; Sensory; Serotonergic System; Serotonin; Signal Pathway; Signal Transduction; Slice; Stroke; Surface; Synapses; System; Techniques; Testing; Time; Vascular Dementia; Vascular blood supply; Vasodilation; Vasomotor; Vibrissae; Wakefulness; Work; alertness; awake; brain health; cell type; cholinergic; clinical diagnostics; connexin 40; designer receptors exclusively activated by designer drugs; fluorescence imaging; glutamatergic signaling; in vivo; insight; neocortical; nervous system disorder; neuroregulation; neurovascular coupling; neurovascular unit; noradrenergic; novel; novel diagnostics; novel strategies; novel therapeutics; optogenetics; relating to nervous system; response; side effect; spatiotemporal; tool; two-photon; vasoactive agent; vasoconstriction

The brain requires a continuous supply of nutrients and oxygen to fuel its normal functioning. Active areas of the brain need more energy than relatively quiescent regions, so the blood supply to different areas of the brain is dynamically varied over time to meet the ongoing needs of active neurons. Significant progress has been made in understanding the essential role of localized synaptic glutamatergic signaling in regulating local cerebral blood flow (CBF) in response to increased neuronal activity, a process known as neurovascular coupling (NVC). However, little is currently known about the integration between neural (i.e., neurons and astrocytes) and vascular networks and the broader mechanisms underlying the spatiotemporal coordination of local and global vascular responses within the cortical angioarchitecture and among different brain regions. The overall goal of this proposal is to identify interactions between local and global signaling pathways that control the magnitude and distribution of blood to match metabolic demands. Our preliminary data show that the state of wakefulness and engagement of the animal that are often associated with the release of long-range modulatory neurotransmitters (e.g., serotonin [5-HT]), and that manipulations of 5-HT activity modulate vascular responses. We propose that glutamatergic and serotonergic signaling are integrated to control CBF. Our data further suggest that vascular conduction may mediate ascending vasomotor responses from the deep layer to upstream parenchyma and the surface of the cortex to coordinate blood flow. On the basis of these observations, we propose a new paradigm in which activity-dependent allocation of CBF depends on the integration of three elements: 1) local synaptic glutamatergic signaling, 2) the global serotonergic system, and 3) retrograde intercellular conduction. 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 to test this paradigm. These integrated approaches are novel and powerful as they give us the ability to fully explore the integration of different signaling pathways under true physiological conditions without the need for anesthetics. Aim 1 will explore the contribution of serotonergic signaling to sensory-induced increases in local CBF and to coordination of blood distribution between inactive and active regions. Aim 2 will elucidate the mechanisms underlying 5-HT–induced vasomotor responses during whisker stimulation. Aim 3 will solidify the role of the endothelium in conducting electrical signals from the subsurface microvascular network to the upstream parenchyma and surface of the cortex, a process that is proposed to complement NVC. Our investigation into this novel model may reveal new physiological processes essential to CBF regulation and ultimately provide insights that help maintain brain health.

大脑需要持续的营养和氧气供应，以增强其正常功能。活跃地区 大脑需要比相对静止的区域更多的能量，因此，大脑不同区域的血液供应是 随着时间的流逝，动态变化以满足活性神经元的持续需求。取得了重大进展 在理解局部合成谷氨酸能信号传导中的重要作用中 流动（CBF）响应增加的神经元活性，这一过程称为神经血管偶联（NVC）。 但是，目前对神经元（即神经元和星形胶质细胞）和 血管网络和局部和全球空间时间协调的更广泛的机制 皮质血管结构和不同大脑区域内的血管反应。总体目标 该建议是确定控制幅度的本地和全局信号通路之间的相互作用 和血液分布以符合代谢需求。我们的初步数据表明清醒状态 以及通常与远程调节的动物的参与 神经递质（例如5-羟色胺[5-HT]），并且5-HT活性的操纵调节血管反应。 我们建议将谷氨酸能和血清素能信号整合到控制CBF。我们的数据进一步暗示 该血管传导可能会介导从深层到上游的上升血管舒缩反应 实质和皮层表面以协调血流。根据这些观察，我们 提案一种新的范式，其中与CBF的活动依赖性分配取决于三个集成 元素：1）局部突触谷氨酸能信号传导，2）全局血清素能系统和3）逆行 细胞间传导。我们将采用脉管系统和CA2+动力学的两光子荧光成像 在完全清醒的动物中的神经元和星形胶质细胞中，与离体制剂，敲除策略一起 遗传编码的生物传感器，药物遗传学和光遗传学测试此范式。这些整合 方法是新颖而强大的，因为它们使我们能够充分探索不同信号的整合 在真正的生理条件下的途径无需麻醉。 AIM 1将探索贡献 血清素能信号传导到感觉引起的局部CBF的增加和血液分布的协调 在非活动区域和活动区域之间。 AIM 2将阐明5-HT诱导的血管舒缩的机制 晶须刺激期间的反应。 AIM 3将巩固内皮在进行电气中的作用 从地下微血管网络到上游实质和皮质表面的信号 建议完成NVC的过程。我们对这个新颖模型的投资可能会揭示新的 CBF监管必不可少的物理过程，并最终提供有助于维持大脑的见解 健康。