Glymphatic Clearance in the Optic Nerve: A Multidomain Electro-osmostic Model

TL;DR

This work develops a multidomain electro-osmotic model of optic-nerve microcirculation to mechanistically explain glymphatic clearance, coupling hydrostatic and osmotic fluid transport with electro-diffusive solute movement across axons, glia, ECS, and perivascular spaces. The six-compartment framework (ax, gl, ex, pa, pv, pc) embedded within the SAS enables explicit treatment of CSF entry, astrocytic endfoot exchange via AQP4, and PVS‑V drainage, capturing both resting and stimulus‑evoked flow. Key findings show that two throughput controls—AQP4 permeability and PVS connectivity—govern radial exchange and clearance rates, with PVS export dominating for both small and moderate solutes and sleep-like ECS expansion accelerating clearance for small solutes. The model reconciles observed size-dependent clearance kinetics and offers mechanistic insight into sleep-wake effects, while outlining limitations (restricted transporters, idealized geometry) and directions for future expansion toward brain-scale, data-driven applications. Overall, the framework provides a tractable, mechanistic platform to study glymphatic function, optic-nerve health, and disease-related clearance pathways, with potential implications for glaucoma and neurodegenerative disorders.

Abstract

Effective metabolic waste clearance and maintaining ionic homeostasis are essential for the health and normal function of the central nervous system. To understand its mechanism and the role of fluid flow, we develop a multidomain electro-osmotic model of optic-nerve microcirculation that couples hydrostatic and osmotic fluid transport with electro-diffusive solute movement across axons, glia, the extracellular space, and arterial/venous/capillary perivascular spaces. Cerebrospinal fluid enters the optic nerve via the arterial parivascular space, passes both the glial and ECS before exiting through the venous parivascular space. Exchanges across astrocytic endfeet are essential and they occur in two distinct and coupled paths: through AQP4 on glial membranes and gaps between glial endfeet, thus establishing a mechanistic substrate for two modes of glymphatic transport, at rest and during stimulus-evoked perturbations. Parameter sweeps show that lowering AQP4-mediated fluid permeability or PVS permeability elevates pressure, suppresses radial exchange and slows clearance, effects most pronounced for solutes reliant on PVS V export. The model reproduces baseline and stimulus-evoked flow and demonstrates that PVS-mediated export is the primary clearance route for both small and moderate solutes. Small molecules clear faster because rapid ECS diffusion broadens their distribution and enhances ECS PVS exchange, whereas moderate species have low ECS diffusivity, depend on transendfoot transfer, and clear more slowly via PVS V convection. Our framework can also be used to explain the sleep-wake effect mechanistically: enlarging ECS volume or permeability increases transinterface flux and accelerates waste removal.

Figures (24)

• Figure 1: Optic nerve structure. (a) Longitudinal section of the optic nerve; (b) cross section of the optic nerve.
• Figure 2: Top: The optic nerve $\Omega_{OP}$ consists of the axon compartment, glial compartment, extracellular space, and perivascular spaces. The subarachnoid space $\Omega_{SAS}$ only has cerebrospinal fluid. The stimulus is applied to the axon membrane in the region $R_{a}<r<r_{sti}$ at location $z=z_{0}$. Bottom: The interaction between different regions. In the optic nerve $\Omega_{OP}$ region, the ECS exchanges fluid and ions with the axon, glial, the PVS-A, the PVS-V and the PVS-C; glial exchanges fluid and ion with the ECS, the PVS-A, the PVS-V and the PVS-C; CSF exchanges fluid and ions with the ECS, the PVS-A, and the PVS-C by across the pia mater in $\Gamma_{7}$.
• Figure 3: Schematic of fluid flow within compartments and trans-domain fluid exchange in the resting state. Arrows indicate intra- and inter-compartmental flow directions, while numerical values represent spatially averaged velocity magnitudes ($\rm{m/s}$).
• Figure 4: Schematic of fluid flux between stimulated (red) and non-stimulated (green) regions, including trans-domain fluid exchange. Line thickness represents flux magnitude.
• Figure 5: Variations of different compartments volume fractions during and after stimuli.