Integrated Cerebral Blood Flow Regulation

大脑需要源源不断的营养和氧气供应，才能为其正常运作提供动力。中国的活跃地区 大脑比相对平静的区域需要更多的能量，因此大脑不同区域的血液供应 随着时间的推移动态变化，以满足活跃神经元的持续需求。已经取得了重大进展 了解局部突触谷氨酸能信号在调节局部脑血液中的重要作用 血流(CBF)对神经元活动增加的反应，这一过程被称为神经血管耦合(NVC)。 然而，目前对神经细胞(即神经元和星形胶质细胞)和 局部和全球的血管网络和更广泛的时空协调机制 皮质血管结构内和不同脑区之间的血管反应。的总目标是 这一建议是为了确定控制大小的局部和全局信号通路之间的相互作用 和血液的分配以满足新陈代谢的需求。我们的初步数据显示，清醒状态 和动物的参与，通常与释放长程调节有关 神经递质(如5-羟色胺[5-羟色胺])，以及5-羟色胺活动的调节调节血管反应。 我们建议整合谷氨酸和5-羟色胺能信号来控制脑血流量。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行血管运动反应 实质和皮质表面以协调血液流动。根据这些观察，我们 提出了基于活动的CBF分配依赖于三者整合的新范式 元素：1)局部突触谷氨酸能信号，2)全球5-羟色胺能系统，3)逆行 细胞间传导。我们将使用双光子荧光成像的血管系统和钙离子动力学 在完全清醒的动物的神经元和星形胶质细胞中，结合体外准备，基因敲除策略， 用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式。这些集成在一起 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集成 在真正的生理条件下的路径，而不需要麻醉剂。目标1将探讨其贡献 5-羟色胺能信号对感觉诱导的局部脑血流量增加和血液分配的协调 在非活动区域和活动区域之间。目的2将阐明5-羟色胺诱导血管舒缩的机制 胡须刺激时的反应。目标3将巩固内皮细胞在传导电方面的作用 从地下微血管网络到皮质上游实质和表面的信号，a 建议用于补充NVC的流程。我们对这一新模式的调查可能会揭示出新的 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的洞察力 健康。

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.