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周围脑脊液的泵送，从而驱动 新陈代谢废物的胶囊清除率。项目1将通过流动流动模型来解决该目标 显微镜，宏观上的流动以及整个大脑清除率 - 都在小鼠和人类中。项目1将 统一在项目2-4中测得的微观机制和宏观现象，并提供预测性， 定量，可测试的模型。我们假设神经回路活动控制于 通过神经血管单元的动力学显微镜，由人工体，血管周空间（PVS）组成 周围和周围的神经膜。 AIM 1将使用单元的详细流体动力模拟，并使用 域形和边界条件是从测量中获取的，并以血管舒张链接与经验相连 去甲肾上腺素（NE）和乙酰胆碱（ACH）水平，以表征和量化微观CSF流动和 老鼠的司机。我们假设神经活动通过升高和减少细胞外来导出全球控制 空间，以及通过PVSS网络上的交互。 AIM 2将建立整个脑部水解网络模型 量化全球驱动因素的影响并表征整个小鼠大脑中的CSF流动。必不可少的 CSF流动在大脑中的功能是实体清除率。 AIM 3将建立一个脑范围的清除模型，吸收流量 从AIM 2中，独立量化冒险和扩散的影响，并考虑了大脑的变化 状态。 AIM 4将建立类似于目标1-3的模型，但对于人类而不是小鼠，并补充 通过详细的通风流动流体模拟。该多种建议旨在揭示如何 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CSF运动的定量测量， 从项目2-4。实验将为本地和全局模型提供参数，包括解剖学 形状，入口和出口边界条件以及时空血液动力学变化。模型将揭示 比实验可以访问的更多信息，并且允许在体内不可能的因果操作， 从而导致新假设要检验。项目2将提供PVS形状和固体外排 测量（DB53）以及星形胶质细胞动力学（通过CA2+和CAMP传感器）。项目3将提供 时空血液动力学模式及其对神经元和神经调节活性的依赖（通过CA2+ 和NE和ACH的生物传感器）。项目4将提供来自人类的数据：通风和PVS形状， 心室和PVSS中的血液动力学和CSF流动，跨越赞助商和感官驱动的神经活动。