Heterogeneity of blood flow distribution in cortex and the involvement of global long-range neuromodulatory projections

皮层血流分布的异质性和全局长程神经调节投射的参与

• 批准号: 10077910
• 负责人: Cam Ha Thai Tran
• 金额: $ 20.77万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077910
• 关键词: Affect; Alzheimer' s Disease; Anesthetics; Animals; Area; Astrocytes; Biosensor; Blood; Blood Vessels; Blood capillaries; Blood flow; Brain; Caliber; Cardiovascular system; Cells; Centers of Research Excellence; Cerebral cortex; Cerebrovascular Circulation; Cerebrum; Cognition; Communication; Complement; Consumption; Data; Dendrites; Development; Diagnostic; Elements; Endothelial Cells; Endothelium; Functional Magnetic Resonance Imaging; G-Protein-Coupled Receptors; Gap Junctions; Glutamates; Goals; HTR2A gene; Health; Heterogeneity; Human; Hyperemia; Image; Interneurons; Investigation; Knock-out; Laboratories; Laser Scanning Microscopy; Lead; Life; Light; Mediating; Medical; Metabolic; Microcirculation; Modeling; Molecular; Mus; Neurons; Nevada; Pathologic; Perfusion; Physiological; Physiological Processes; Preparation; Process; Regional Blood Flow; Regulation; Role; Sensory; Serotonin; Serotonin Receptor 5-HT2B; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Stroke; Synapses; System; Techniques; Testing; Vascular Dementia; Vascular blood supply; Vasoactive Intestinal Peptide Receptors; Vasodilation; Vasomotor; alertness; arteriole; awake; brain health; cell type; cerebral microvasculature; connexin 40; designer receptors exclusively activated by designer drugs; fluorescence imaging; glutamatergic signaling; hemodynamics; hippocampal pyramidal neuron; in vivo; inhibitory neuron; insight; mouse model; nervous system disorder; neuroregulation; neurotransmitter release; neurovascular coupling; neurovascular unit; novel; novel strategies; operation; optogenetics; receptor; relating to nervous system; response; side effect; spatiotemporal; two-photon

Project Summary The brain consumes a tremendous amount of energy to fuel its normal functioning. Because neurons lack substantial energy reserves, the brain relies on an on-demand system, orchestrated by a multicellular aggregate—the neurovascular unit—consisting of neurons, astrocytes and vascular cells, to match local blood supply to neuronal energy demands. This use-dependent increase in local blood flow (functional hyperemia) is mediated by a process termed neurovascular coupling. Although significant progress has been made in understanding the essential role of localized synaptic glutamatergic signaling in this process, very little is currently known about the broader cellular and molecular mechanisms underlying the spatiotemporal coordination of local and global vascular responses within the unique cortical angioarchitecture. The overall goal of this proposal is to identify how local and global signaling pathways interact to control the distribution of blood flow in response to increased neuronal activity. We propose a model for activity-dependent allocation of cerebral blood flow that depends on the integration of three elements: local synaptic glutamatergic signaling, retrograde intercellular conduction, and global neuromodulatory projections. The central hypothesis of our proposal is that localized synaptic communication between neural and vascular cells in the neurovascular unit must be complemented by spatiotemporal coordination of global vascular reactivity through vascular gap-junctional communication and neuromodulatory serotonergic signaling to achieve optimal brain perfusion. To test this hypothesis, we will employ two-photon fluorescence imaging of the vasculature and Ca2+ dynamics in vivo in fully awake, behaving animals in conjunction with knockout strategies, genetically encoded biosensors, DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) and optogenetics. The latter two approaches are novel and powerful, as they provide the ability to control the activity of specific cell types using physiologically inert molecules and light, respectively, without affecting neighboring cell types. Furthermore, our recent advances allow us to use a fully awake mouse model in our in vivo investigation of the interaction of local and global signaling in controlling cerebral blood flow. This eliminates the need for anesthetics, which have dramatic side effects on brain and blood dynamics. The goal of Aim 1 is to determine the contribution of the endothelium to conducted vasodilation initiated at the neurovascular unit. We will test the hypothesis that the endothelium, and not smooth muscle cells, mediates the conduction of vascular responses initiated at parenchymal vessels to upstream pial vessels, and that this process is critical for functional hyperemia during neurovascular coupling in vivo. The goal of Aim 2 is to elucidate the role of serotonin in controlling cerebral blood flow during neurovascular coupling. We will test the hypothesis that long-range neuromodulatory serotonergic signaling reflecting alertness status elicits vasomotor responses associated with functional hyperemia during neurovascular coupling in vivo. The goal of Aim 3 is to identify serotonin signaling pathway(s) in the cerebral microcirculation. We will test the hypothesis that serotonin initiates signaling pathways in different cell types, including smooth muscle cells, endothelial cells, astrocytes and interneurons, and that serotonin-mediated vascular responses are cell-type specific. Our investigations of this conceptual novel model may reveal new physiological processes essential to cerebral blood flow regulation and, ultimately, brain health.

项目摘要 大脑消耗大量的能量来维持其正常功能。因为神经元缺乏 大量的能量储备，大脑依赖于一个按需系统，由多细胞 聚集体-神经血管单位-由神经元、星形胶质细胞和血管细胞组成，以匹配局部血液 供应神经元的能量需求。这种局部血流量的使用依赖性增加（功能性充血）是 由一个叫做神经血管耦合的过程介导。虽然在这方面取得了重大进展， 了解本地化的突触神经递质信号在这一过程中的重要作用，很少是 目前已知的更广泛的细胞和分子机制的时空 在独特的皮质血管结构内协调局部和整体血管反应。总目标 这项提议的一个重要目的是确定局部和全局信号通路如何相互作用以控制血液的分布。 神经元活动的增加。我们提出了一个模型的活动依赖性分配的大脑 血液流动依赖于三个要素的整合：局部突触突触神经元能信号传导，逆行 细胞间传导和全局神经调节投射。我们建议的核心假设是 在神经血管单位中，神经细胞和血管细胞之间的局部突触通讯必须 通过血管间隙连接的时空协调来补充全局血管反应性 通过调节神经元信号传导和神经调节性多巴胺能信号传导来实现最佳脑灌注。为了验证这一 假设，我们将在体内采用双光子荧光成像血管系统和Ca 2+动力学， 完全清醒的，行为良好的动物，结合基因敲除策略，基因编码的生物传感器， DREADDs（设计师受体仅由设计师药物激活）和光遗传学。后两 这些方法是新颖的和强大的，因为它们提供了使用免疫调节剂来控制特定细胞类型的活性的能力。 生理惰性分子和光，而不影响相邻的细胞类型。而且我们的 最近的进展使我们能够使用一个完全清醒的小鼠模型在我们的体内研究的相互作用的局部 以及控制脑血流的全局信号。这消除了对麻醉剂的需要， 对大脑和血液动力学的严重副作用目标1的目标是确定 内皮细胞对在神经血管单元开始的传导性血管舒张的影响。我们将测试假设， 内皮细胞，而不是平滑肌细胞，介导血管反应的传导， 实质血管到上游软脑膜血管，这一过程对功能性充血至关重要， 体内神经血管偶联。目的2是阐明5-羟色胺在控制脑血中的作用 在神经血管耦合期间流动。我们将检验这一假设，即长距离神经调节性多巴胺能 反映警觉状态的信号传导诱发与功能性充血相关的血管反应， 体内神经血管偶联。目的3的目标是确定大脑中的5-羟色胺信号通路， 微循环我们将测试血清素在不同细胞类型中启动信号通路的假设， 包括平滑肌细胞、内皮细胞、星形胶质细胞和中间神经元， 血管反应是细胞类型特异性的。我们对这一概念性新模型的研究可能会揭示新的 生理过程对脑血流调节至关重要，最终对大脑健康至关重要。