Project 1: Modeling brain-state-dependent fluid flow and clearance in mice and humans

摘要，项目1 该提案的总体目标是确定神经活动如何驱动动脉周围CSF泵送，从而 代谢废物的胶质淋巴清除。项目1将通过流体动力学模型来实现这一目标， 微观尺度，宏观尺度的流动，以及全脑的清除--所有这些都在小鼠和人类中进行。项目1将 将项目2-4中测量的微观机制和宏观现象统一起来， 量化的、可测试的模型。我们假设，神经回路活动控制胶质淋巴功能， 通过神经血管单位的动力学进行微尺度研究，包括小动脉、血管周围间隙（PVS） 以及周围的神经细胞。目标1将使用详细的流体动力学模拟的单位， 域形状和边界条件从测量，并与血管舒缩经验联系起来， 去甲肾上腺素（NE）和乙酰胆碱（ACh）水平，以表征和量化微尺度CSF流量， 老鼠的司机我们假设，神经活动通过扩大和减少细胞外基质来发挥全局控制作用。 空间，并通过PVS网络上的相互作用。AIM 2将建立全脑液压网络模型 以量化全局驱动因素的影响并表征整个小鼠大脑中的CSF流动。一个基本 脑中CSF流动的功能是溶质清除。AIM 3将建立一个全脑的清除模型， 从目标2开始，独立量化平流和扩散的影响，并解释大脑中的变化 状态目标4将建立类似于目标1-3的模型，但用于人类而不是小鼠，并补充 通过详细的心室流体动力学模拟。这个多物种的提议旨在揭示 神经回路控制小鼠和人脑中的脑脊液运动。 项目1将整合神经活动、血容量和CSF运动的定量测量， 项目2-4这些实验将为局部和全局模型提供参数，包括解剖学模型。 形状、入口和出口边界条件以及时空血流动力学变化。模特们将展示 比实验上可获得的更多的信息，并且允许在体内不可能的因果操纵， 从而导致要测试的新假设。项目2将提供PVS形状和溶质流出 测量（DB 53）以及星形胶质细胞动力学（通过Ca 2+和cAMP传感器）。项目3将提供 时空血流动力学模式及其对神经和神经调节活性的依赖性（通过Ca 2 + 以及NE和ACh的生物传感器）。项目4将提供来自人类的数据：心室和PVS形状， 血液动力学和脑室和PVS中的CSF流量，跨越自发和感觉驱动的神经活动。

Abstract, Project 1 The overall goal of this proposal is to establish how neural activity drives periarterial CSF pumping and thereby glymphatic clearance of metabolic waste. Project 1 will address that goal via fluid-dynamical modeling of flow at the microscale, flow at the macroscale, and brain-wide clearance – all in both mice and humans. Project 1 will unify the microscale mechanisms and macroscale phenomena measured in Projects 2-4 and deliver predictive, quantitative, testable models. We postulate that neural circuit activity controls glymphatic function at the microscale via dynamics of the neurovascular unit, comprised of an arteriole, the perivascular space (PVS) surrounding it, and the surrounding neuropil. Aim 1 will use detailed fluid-dynamical simulations of the unit, with domain shapes and boundary conditions taken from measurements, and with vasomotion linked empirically to norepinephrine (NE) and acetylcholine (ACh) levels, to characterize and quantify microscale CSF flows and drivers in mice. We postulate that neural activity exerts global control by enlarging and reducing the extracellular space, and through interactions on the network of PVSs. Aim 2 will build a brain-wide hydraulic network model to quantify the effects of global drivers and characterize CSF flow across the entire mouse brain. An essential function of CSF flow in the brain is solute clearance. Aim 3 will build a brain-wide clearance model, taking flows from Aim 2, independently quantifying the effects of advection and diffusion, and accounting for changes in brain state. Aim 4 will build models analogous to those of Aims 1-3, but for humans instead of mice, and supplemented by detailed fluid-dynamical simulations of ventricle flow. This multi-species proposal is designed to reveal how neural circuits control cerebrospinal fluid movement in the mouse and human brain. Project 1 will integrate quantitative measurements of neural activity, blood volume, and CSF movement, from Projects 2-4. The experiments will provide parameters for local and global models, including anatomical shapes, inlet and outlet boundary conditions, and spatiotemporal hemodynamic changes. Models will reveal more information than is accessible experimentally and allow causal manipulations that are impossible in vivo, thereby leading to new hypotheses to be tested. Project 2 will provide PVS shapes and solute efflux measurements (DB53) as well as astrocytic dynamics (via Ca2+ and cAMP sensors). Project 3 will provide spatiotemporal hemodynamic patterns and their dependence on neural and neuromodulatory activity (via Ca2+ and biosensors for NE and ACh). Project 4 will provide data from humans: ventricle and PVS shapes, hemodynamics, and CSF flow in ventricles and PVSs, across spontaneous and sensory-driven neural activity.