Diffusive tortuosity can differentiate physiological and pathological changes in astrocytic volume.

Abstract

Brain extracellular space (ECS) is an interconnected channel that surrounds brain cells, and is important for diffusion transport of signaling molecules, nutrients and drug agents. Two macroscopic parameters of ECS structure, tortuosity (λ) and volume fraction (α), govern diffusion in the ECS. Tortuosity quantifies the ECS hindrance experienced by diffusing molecules in comparison to an obstacle-free medium, and volume fraction measures the ECS volume relative to the tissue volume. In a healthy brain, λ extracted from diffusion measurement with small probe molecules is about 1.6 and α is about 0.2. Since λ and α determine spatiotemporal distribution of signaling molecules, nutrients, and therapeutic agents in brain, it is essential to understand how λ and α are regulated. The central hypothesis of this thesis study is that the morphology of astrocytic processes regulates macroscopic structural parameters, λ and α, of brain ECS. To test this hypothesis, astrocytic morphology in rat cortical slices was selectively manipulated by applying a gliotoxin or a β-adrenergic agonist and diffusion methods were used to determine λ and α under these conditions. Changes in astrocytic morphology were evaluated by immunohistochemistry or electron microscopy (EM). This thesis study is focused on basic research with major implications for transport of substances in the nervous system. It identifies a novel role for astrocytes in regulating transport of signaling molecules in brain under physiological and pathological conditions.