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

项目 1：模拟小鼠和人类大脑状态依赖性液体流动和清除

• 批准号: 10673158
• 负责人: Douglas H Kelley
• 金额: $ 37.28万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673158
• 关键词: 3-Dimensional; Accounting; Acetylcholine; Affect; Anatomy; Arteries; Astrocytes; Biological Assay; Biosensor; Blood Vessels; Blood Volume; Brain; Cerebrospinal Fluid; Complex; Cyclic AMP; Dependence; Diffusion; Electroencephalography; Elements; Equation; Extracellular Space; Goals; Human; Image; Link; Liquid substance; Measurable; Measurement; Measures; Metabolic; Metabolic Clearance Rate; Methods; Modeling; Motion; Movement; Mus; Neuropil; Norepinephrine; Pattern; Pump; Resistance; Route; Sensory; Shapes; Signal Transduction; Sleep; Specific qualifier value; Speed; Testing; Validation; Variant; arteriole; brain parenchyma; design; experience; experimental study; fluid flow; glymphatic clearance; glymphatic function; glymphatic system; hemodynamics; human data; human model; in vivo; in vivo imaging; model building; network models; neural; neural circuit; neuroregulation; neurovascular unit; particle; pressure; programs; rapid test; sensor; simulation; solute; spatiotemporal; two-dimensional; vasomotion; wasting

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.

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脑脊液泵送，从而 代谢废物的类淋巴清除。项目 1 将通过流体动力学建模来实现这一目标 微观尺度、宏观尺度的流动和全脑清除——所有这些都在小鼠和人类身上发生。项目1将 统一项目 2-4 中测量的微观机制和宏观现象，并提供预测、 定量的、可测试的模型。我们假设神经回路活动控制类淋巴功能 通过神经血管单元的动力学进行微观尺度，神经血管单元由小动脉、血管周围空间 (PVS) 组成 围绕它，以及周围的神经纤维。目标 1 将使用该装置的详细流体动力学模拟，其中 从测量中获取的域形状和边界条件，并根据经验与血管舒缩相关 去甲肾上腺素 (NE) 和乙酰胆碱 (ACh) 水平，以表征和量化微尺度脑脊液流量和 小鼠中的驱动程序。我们假设神经活动通过扩大和减少细胞外信号来发挥全局控制作用。 空间，并通过 PVS 网络上的交互。目标2将建立全脑水力网络模型 量化全局驱动因素的影响并表征整个小鼠大脑的脑脊液流动。必不可少的 脑脊液流在大脑中的功能是清除溶质。目标3将建立全脑清除模型，采取流量 来自目标 2，独立量化平流和扩散的影响，并解释大脑的变化 状态。目标 4 将建立与目标 1-3 类似的模型，但针对人类而不是小鼠，并补充 通过心室流动的详细流体动力学模拟。这个多物种提案旨在揭示如何 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、血容量和脑脊液运动的定量测量， 来自项目 2-4。这些实验将为局部和全局模型提供参数，包括解剖学参数 形状、入口和出口边界条件以及时空血流动力学变化。模型将揭晓 比通过实验获得的信息更多，并允许进行体内不可能的因果操作， 从而导致新的假设被检验。项目 2 将提供 PVS 形状和溶质流出 测量 (DB53) 以及星形细胞动力学（通过 Ca2+ 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动的依赖性（通过 Ca2+ 以及 NE 和 ACh 生物传感器）。项目 4 将提供来自人类的数据：心室和 PVS 形状， 血流动力学、脑脊液在心室和 PVS 中的流动，跨越自发和感觉驱动的神经活动。