ABSTRACT The complex interplay between chemical, electrical, and mechanical factors is fundamental to the function and homeostasis of the brain, but the effect of electrochemical gradients on brain interstitial fluid flow, solute transport, and clearance remains poorly quantified. Here, via in-silico experiments based on biophysical modeling, we estimate water movement across astrocyte cell membranes, within astrocyte networks, and within the extracellular space (ECS) induced by neuronal activity, and quantify the relative role of different forces (osmotic, hydrostatic, and electrical) on transport and fluid flow under such conditions. Our results demonstrate how neuronal activity in the form of extracellular ionic input fluxes may induce complex and strongly-coupled chemical-electrical-mechanical interactions in astrocytes and ECS. Furthermore, we observe that the fluid dynamics are crucially coupled to the spatial organization of the intracellular network, with convective and electrical drift dominating ionic diffusion in astrocyte syncytia. Author Summary Over the last decades, the neuroscience community has paid increased attention to the astrocytes – star-shaped brain cells providing structural and functional support for neurons. Astrocyte networks are likely to be a crucial pathway for fluid flow through brain tissue, which is essential for the brain’s volume homeostasis and waste clearance. However, numerous questions related to the role of osmotic pressures and astrocytic membrane properties remain unanswered. There are also substantial gaps in our understanding of the driving forces underlying fluid flow through brain tissue. Answering these questions requires a better understanding of the interplay between electrical, chemical, and mechanical forces in brain tissue. Due to the complex nature of this interplay and experimental limitations, computational modeling can be a critical tool. Here, we present a high fidelity computational model of an astrocyte network and the extracellular space. The model predicts the evolution in time and distribution in space of intra- and extracellular volumes, ion concentrations, electrical potentials, and hydrostatic pressures following neural activity. Our findings show that neural activity induces strongly coupled chemical-mechanical-electrical interactions in the tissue and suggest that chemical gradients inside astrocyte syncytia strengthen fluid flow at the microscale.

Neural activity induces strongly coupled electro-chemo-mechanical interactions and fluid flow in astrocyte networks and extracellular space – a computational study