Regulation of activity-dependent cerebral blood flow by astrocytes

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（约5年）是：表征内皮细胞NMDA受体介导的星形细胞/内皮信号传导2。明确星形胶质细胞在血管舒缩极性代谢控制中的作用。表征区域星形细胞异质性在神经血管耦合中的作用4。开发模型来研究人类神经血管单元（NVU）中的星形细胞-内皮耦合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的双光子激光扫描显微镜联合压力肌图（TPLSM），清醒动物的TPLSM，以及人类神经血管耦合模型。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。

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.Characterize astrocyte/endothelial signaling mediated by endothelial NMDA receptors 2.Define the role of astrocytes in metabolic control of vasomotor polarity 3.Characterize the role of regional astrocytic heterogeneity in neurovascular coupling 4.Develop models to study astrocyte-endothelial coupling in human neurovascular unit (NVU) 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, TPLSM in awake animals, and modeling of human neurovascular coupling. 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.