Project Summary/Abstract Spreading depolarization (SD) occurs following many acute neurological conditions and is characterized by the loss of ion gradients across neuronal and astrocytic membranes. Recently, SD following stroke and cardiac arrest has been linked to acute edema formation via excess influx of cerebrospinal fluid (CSF). This CSF is pulled into the brain via the glymphatic system, which is a network of perivascular spaces (annular channels around vascu- lature) connecting subarachnoid CSF with the brain interstitium. The mechanisms by which SD pulls CSF into the brain are not well-understood. On the other hand, studies of migraine with aura indicate that SD can severely diminish glymphatic function. To reconcile these seemingly contradictory results, we hypothesize that SD results in three dominant competing effects that enhance or diminish glymphatic CSF flow: potassium ion-dependent vasodilation/vasoconstriction, swelling of astrocyte endfeet, and osmotic pressure gradients in surrounding brain tissue. To disentangle the significance of each effect experimentally, we propose the development of a novel numerical simulation that couples a physiologically-realistic SD model to a detailed simulation of the glymphatic system. We will do so by implementing and extending an existing physiologically-based model of SD to simulate the spatiotemporal evolution of the concentration potassium, sodium, and chloride ions (Aim 1). We will then cou- ple the SD model to an existing fluid network model to capture disruption to the glymphatic system (Aim 2). This network model will implement the three SD-related competing effects described above. Finally, we will perform in vivo experiments with transgenic mice using two-photon microscopy to quantify vasculature/PVSs, SD propaga- tion, and alterations to CSF flow speed which will parameterize and validate our simulations. Development of this validated simulation will constitute the first comprehensive model of SD-induced glymphatic disruption, offering fundamental insights into competing mechanisms of enhanced/diminished glymphatic flow. In turn, this model will lead to development of experimentally-testable hypotheses for mitigating SD-induced alteration to CSF flow in a variety of neurological conditions.

Project Narrative Spreading depolarization is a slow-moving wave of abnormal electrical activity in the brain that occurs in many neurological conditions such as stroke. Recent experiments show that this phenomenon pulls cerebrospinal fluid into the brain, killing additional brain cells, but the underlying mechanisms of this phenomenon are not understood. We will use simulations and mouse experiments to uncover the relative importance of three different likely mechanisms that lead to disruptions in the cerebrospinal fluid flow due to a spreading depolarization wave.