Integrated Cerebral Blood Flow Regulation

综合脑血流调节

• 批准号: 10525254
• 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/10525254
• 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; Knockout Mice; Laboratories; Laser Scanning Microscopy; Lesion; Maps; Mediating; Metabolic; Microcirculation; Modeling; Molecular; Mus; Neocortex; 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; Systems Integration; 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; hemodynamics; in vivo; insight; neocortical; nervous system disorder; neural; neuroregulation; neurovascular coupling; neurovascular unit; noradrenergic; novel; novel diagnostics; novel strategies; novel therapeutics; optogenetics; postsynaptic; 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来维持其正常功能。的有源区域 大脑比相对静止的区域需要更多的能量，因此大脑不同区域的血液供应是不同的。 随着时间的推移而动态变化，以满足活跃神经元的持续需求。取得了重大进展 在理解局部突触神经元能信号在调节局部脑血中的重要作用方面， 脑血流（CBF）响应于增加的神经元活动，这一过程被称为神经血管偶联（NVC）。 然而，目前对神经（即，神经元和星形胶质细胞）， 血管网络和更广泛的机制的时空协调的地方和全球 皮质血管结构内和不同脑区之间的血管反应。的总目标 这个建议是确定控制幅度的局部和全局信号通路之间的相互作用， 和血液分配来满足新陈代谢的需求。我们的初步数据显示， 和参与的动物，往往是与释放远程调节 神经递质（例如，5-羟色胺[5-HT]），以及5-HT活性调节血管反应。 我们建议，β-amatergic和β-aminergic信号整合控制CBF。我们的数据进一步表明 血管传导可以介导从深层到上游的上行血管反应， 实质和皮质表面以协调血流。根据这些观察，我们 我提出了一个新的范式，其中CBF的活动依赖分配取决于三个方面的整合 成分：1）局部突触突触能信号传导，2）全局突触能系统，3）逆行 细胞间传导我们将采用双光子荧光成像的血管和Ca 2+动力学 在完全清醒的动物中的神经元和星形胶质细胞中，结合离体制备，敲除策略， 基因编码的生物传感器，药物遗传学和光遗传学来测试这种模式。这些集成 这些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传导的整合。 在真正的生理条件下，不需要麻醉剂的途径。目标1将探讨 在局部CBF的感觉诱导的增加和血液分布的协调中， 在非活动区域和活动区域之间。目的2阐明5-HT诱导血管扩张的机制 在胡须刺激期间的反应。目的3将巩固内皮细胞在传导电流中的作用， 信号从地下微血管网络到上游薄壁组织和皮质表面， 这是为了补充NVC。我们对这种新模式的研究可能会揭示新的 对CBF调节至关重要的生理过程，并最终提供有助于维持大脑 健康