Diffusion of molecules in brain extracellular space: theory and experiment

Area of Science:

• Neuroscience
• Biophysics
• Physiology

Background:

• Volume transmission in the brain relies on the movement of substances through the extracellular space (ECS).
• Diffusion, governed by Fick's Laws and random walk models, is the primary mechanism for this substance migration.
• The brain's ECS presents constraints, including volume fraction and tortuosity, affecting diffusion dynamics.

Purpose of the Study:

• To outline basic concepts of diffusion in the brain's extracellular space.
• To review experimental findings on the diffusion of various molecules within the brain.
• To present a model explaining ECS changes during osmotic challenges.

Main Methods:

• Microscopic (random walks) and macroscopic (Fick's Laws) approaches to diffusion.
• Iontophoretic application and ion-selective microelectrodes for small molecule diffusion (tetramethylammonium).
• Integrative optical imaging for large molecule diffusion (dextrans, albumins, polymers).
• Osmotic challenge experiments to study ECS volume fraction and tortuosity variations.

Main Results:

• In brain slices, ECS volume fraction is ~20% and tortuosity is ~1.6.
• Large molecules (up to 70,000 MW) exhibit higher tortuosity (~2.3).
• Synthetic polymers (up to 1,000,000 MW) diffuse with a tortuosity of ~1.6.
• Osmotic challenges reveal complex ECS volume fraction and tortuosity changes linked to cell shape.

Conclusions:

• Diffusion parameters in brain slices mirror those in the intact brain.
• Molecular size and ECS architecture significantly modulate diffusion rates and pathways.
• Cellular morphology plays a crucial role in regulating extracellular space dynamics during physiological challenges.