John C. Nicholson, PhD

The goal of our work is to understand how molecules move through the extracellular microenvironment and describe the relevance of this process for nonsynaptic signaling and the management of brain pathologies, such as Parkinson disease and ischemia.

We study diffusion using a method based on tetramethylammonium-selective microelectrodes and found that: 1) diffusion in brain tissue is described with a modification of the Fick principle, 2) hindrance by cellular obstructions reduces the apparent diffusion coefficient by a factor of 2.6 compared to the coefficient in water, and 3) molecules diffusing in the brain extracellular space move in a compartment that is 21% of the brain volume.

Another area on which we focus is the role of nonlinear uptake in dopamine's movement in striatum. The radius of action of a nonsynaptic agent depends on the interplay between diffusion and active uptake. We investigate dopamine1s behavior in the neostriatum using fast-scan cyclic voltammetry and carbon fiber microelectrodes following controlled iontophoresis from a point source. We find that nonlinear uptake, obeying Michaelis-Menten kinetics, primarily determines the distribution of dopamine in this brain region.

To image quantitatively the diffusion of large fluorescent molecules in brain slices, we developed a system using a high-resolution cooled CCD camera and online computer techniques. We found that dextran molecules of 3,000 or 10,000 MW diffuse in the rat cortex like tetramethylammonium, but 40,000 and 70,000 MW dextrans are significantly more hindered.