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.

大脑需要持续供应营养和氧气来维持其正常功能。的活跃领域 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 随着时间的推移动态变化，以满足活跃神经元的持续需求。已取得重大进展 了解局部突触谷氨酸信号在调节局部脑血中的重要作用 神经元活动增加而产生的血流（CBF），这一过程称为神经血管耦合（NVC）。 然而，目前对神经（即神经元和星形胶质细胞）和星形胶质细胞之间的整合知之甚少。 血管网络和局部和整体时空协调的更广泛机制 皮质血管结构内和不同大脑区域之间的血管反应。总体目标为 该提案旨在确定控制幅度的局部和全局信号通路之间的相互作用 和血液分布以满足代谢需求。我们的初步数据显示，清醒状态 和动物的参与通常与长程调节剂的释放有关 神经递质（例如血清素 [5-HT]），并且 5-HT 活性的操纵可调节血管反应。 我们建议整合谷氨酸能和血清素能信号来控制 CBF。我们的数据进一步表明 血管传导可能介导从深层到上游的上升血管舒缩反应 薄壁组织和皮质表面协调血流。根据这些观察，我们 提出了一种新的范式，其中 CBF 的活动依赖分配取决于三个因素的整合 要素：1) 局部突触谷氨酸信号传导，2) 整体血清素能系统，3) 逆行 细胞间传导。我们将采用脉管系统和 Ca2+ 动力学的双光子荧光成像 在完全清醒的动物的神经元和星形胶质细胞中结合离体制剂、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一范例。这些集成的 方法新颖而强大，因为它们使我们能够充分探索不同信号的整合 真实生理条件下的通路，无需麻醉。目标 1 将探索贡献 血清素信号对感觉诱导的局部 CBF 增加和血液分布协调的影响 非活动区域和活动区域之间。目标 2 将阐明 5-HT 诱导血管舒缩的机制 胡须刺激期间的反应。目标 3 将巩固内皮细胞在导电方面的作用 从地下微血管网络到上游实质和皮质表面的信号， 提议补充 NVC 的流程。我们对这种新颖模型的研究可能会揭示新的 对于 CBF 调节至关重要的生理过程，并最终提供有助于维持大脑功能的见解 健康。