Mechanisms of neurovascular coupling in awake animals

清醒动物神经血管耦合机制

• 批准号: RGPIN-2015-05734
• 负责人: Anderson, Christopher
• 金额: $ 2.04万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=682548
• 关键词: Mechanisms; neurovascular; coupling; awake; animals

The brain has a high energy demand but virtually no reserve energy capacity. Therefore, it is highly dependent on constant blood and nutrient flow matched dynamically with local energy demand. This is accomplished by a process called functional hyperemia (FH). FH results from creation of molecular signals from active neurons that translate to increases in the lumen diameter of local blood supply vessels and increased blood flow. However, the molecular cell to cell signaling processes that regulate FH and its spatial coordination are poorly understood. My long-term vision is to gain a comprehensive understanding of the intercellular molecular signaling mechanisms responsible for translating neuronal energy need to coordinated local and distal changes in brain vascular lumen diameter and blood flow. We and others have contributed to a wealth of evidence that brain cells called astrocytes are capable of "listening" to synaptic neuronal activity and reacting by sending vasodilatory signals to the local vasculature to increase blood flow. The role of astrocytes in genesis and spatial conduction of FH will be an overarching focus of our short term program objectives. Short term objectives (~5 years) are to:******1. Define the molecular signaling processes in brain tissue that lead to local vasomotor effects***2. Demonstrate and characterize direct astrocyte/endothelial signaling in neurovascular coupling***3. Define astrocyte and endothelial contributions to distal conduction of brain vasodilatory signals******Methodologies will address all objectives in a way that ensures high-impact dissemination and attracts and develops exceptional trainees. Models include brain endothelial cell and astrocyte cultures, combined pressure myography with two-photon laser scanning microscopy (TPLSM) of penetrating arterioles in brain slices and TPLSM and brain blood flow mapping in awake animal hyperemia models. These approaches will leverage innovative and physiologically integrative technologies and novel leads already produced by my group. We will produce a systematic mechanistic investigation of how astrocytes influence endothelial signaling, vasodilatory neurovascular coupling and functional hyperemia - both in focal locations of enhanced activity and in distal sites due to conducted vasodilation. FH mechanisms describe how neurons are fed according to need as a basic tenet of brain function. Our findings will thus be of broad biological and medical interest to a wide scientific audience. Our program will also illuminate neurovascular coupling mechanisms central to interpretation of functional MRI data in healthy and diseased brain. Finally, our established track record of training HQP with high-impact papers, competitive funding, awards and leading edge of methodological capabilities means our program carries tremendous potential for attraction and training of high quality personnel. **

大脑有很高的能量需求，但实际上没有储备能量的能力。因此，它高度依赖于与局部能量需求动态匹配的恒定血液和营养流动。这一过程被称为功能性充血（FH）。FH是由活跃神经元产生的分子信号引起的，这些信号转化为局部供血血管管腔直径的增加和血流量的增加。然而，调控FH及其空间协调的细胞间信号传导过程尚不清楚。我的长期愿景是全面了解细胞间分子信号机制，这些信号机制负责翻译神经元能量需求，以协调局部和远端脑血管管腔直径和血流的变化。我们和其他人已经提供了大量证据，证明被称为星形胶质细胞的脑细胞能够“倾听”突触神经元的活动，并通过向局部血管系统发送血管扩张信号来做出反应，从而增加血流量。星形胶质细胞在FH发生和空间传导中的作用将是我们短期项目目标的首要重点。短期目标（~5年）是：******1。明确脑组织中导致局部血管舒缩效应的分子信号过程***2。证明和表征神经血管耦合中星形胶质细胞/内皮细胞的直接信号传导***3。定义星形胶质细胞和内皮细胞对脑血管舒张信号远端传导的贡献******方法将以确保高影响力传播的方式解决所有目标，并吸引和培养优秀的学员。模型包括脑内皮细胞和星形胶质细胞培养，脑切片穿透性小动脉联合双光子激光扫描显微镜（TPLSM）压力肌图和清醒动物充血模型的TPLSM和脑血流图。这些方法将利用创新和生理综合技术以及我的团队已经产生的新线索。我们将对星形胶质细胞如何影响内皮信号、血管舒张性神经血管耦合和功能性充血进行系统的机制研究——无论是在活动增强的局灶位置，还是在远端部位，由于进行血管舒张。FH机制描述了神经元是如何根据需要被喂养的，这是大脑功能的基本原则。因此，我们的发现将对广泛的科学受众具有广泛的生物学和医学兴趣。我们的计划也将阐明神经血管耦合机制的核心解释功能MRI数据在健康和患病的大脑。最后，我们以高影响力的论文、竞争性的资金、奖项和领先的方法能力培养HQP，这意味着我们的项目在吸引和培养高素质人才方面具有巨大的潜力。**