Characterizing astrocyte-mediated neurovascular coupling by combining optogenetics and biophysical modeling.

Abstract

Vasoactive signaling from astrocytes is an important contributor to the neurovascular coupling (NVC), which aims at providing energy to neurons during brain activation by increasing blood perfusion in the surrounding vasculature. Pharmacological manipulations have been previously combined with experimental techniques (e.g., transgenic mice, uncaging, and multiphoton microscopy) and stimulation paradigms to isolate in vivo individual pathways of the astrocyte-mediated NVC. Unfortunately, these pathways are highly nonlinear and non-additive. To separate these pathways in a unified framework, we combine a comprehensive biophysical model of vasoactive signaling from astrocytes with a unique optogenetic stimulation method that selectively induces astrocytic Ca²⁺ signaling in a large population of astrocytes. We also use a sensitivity analysis and an optimization technique to estimate key model parameters. Optogenetically-induced Ca²⁺ signals in astrocytes cause a cerebral blood flow (CBF) response with two major components. Component-1 was rapid and smaller (ΔCBF∼13%, 18 seconds), while component-2 was slowest and highest (ΔCBF ∼18%, 45 seconds). The proposed biophysical model was adequate in reproducing component-2, which was validated with a pharmacological manipulation. Model's predictions were not in contradiction with previous studies. Finally, we discussed scenarios accounting for the existence of component-1, which once validated might be included in our model.