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: 10516501
• 负责人: Douglas H Kelley
• 金额: $ 38.53万
• 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/10516501
• 关键词: 3-Dimensional; Accounting; Acetylcholine; Address; Affect; Anatomy; Arteries; Astrocytes; Biological Assay; Biosensor; Blood Vessels; Blood Volume; Brain; Cerebrospinal Fluid; Complex; Cyclic AMP; Dependence; Diffusion; Dimensions; 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; network models; neural circuit; neuroregulation; neurovascular unit; particle; pressure; programs; rapid test; relating to nervous system; 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 这项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出，从而 代谢性废物的淋巴清除。项目1将通过流动的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的清除--所有这些都发生在老鼠和人类身上。项目1将 统一项目2-4中测量的微观机制和宏观现象，并提供预测性、 定量的、可测试的模型。我们假设神经回路活动控制淋巴功能。 微尺度通过神经血管单位的动力学，包括小动脉，血管周围空间(PVS) 围绕着它，以及周围的神经纤维。AIM 1将使用该装置的详细流体动力学模拟， 从测量中获得的区域形状和边界条件，以及经验上与血管运动相关联的 去甲肾上腺素(NE)和乙酰胆碱(ACh)水平，以表征和量化微量脑脊液流量和 老鼠里的司机。我们假设神经活动通过扩大和减少细胞外的 空间，并通过PVS网络上的相互作用。AIM 2将建立一个全脑液压网络模型 以量化全球驱动因素的影响，并表征整个小鼠大脑中的脑脊液流动。必需品 脑内脑脊液流动的功能是清除溶质。目标3将建立一个全脑清除模型，将流量 从目标2开始，独立地量化平流和扩散的影响，并考虑大脑的变化 州政府。目标4将建立类似于目标1-3的模型，但为人类而不是小鼠，并补充 通过详细的脑室流动的流体动力学模拟。这一多物种方案旨在揭示如何 神经回路控制着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球模型提供参数，包括解剖学 形状、入口和出口边界条件，以及时空血流动力学变化。模特们将揭晓 比通过实验获得的更多的信息，并允许进行体内不可能的因果操作， 从而导致了需要检验的新假设。项目2将提供PVS形状和溶质外流 测量(DB53)以及星形细胞动力学(通过钙离子和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(通过钙离子 以及NE和ACh的生物传感器)。项目4将提供来自人类的数据：脑室和PVS形状， 血流动力学，以及脑室和PVS中的脑脊液流动，通过自发和感觉驱动的神经活动。