UC San Diego

Astrocytes in the central nervous system engage in bi- directional signaling with neurons, and have been shown to be able to sense and modulate activity. While not electrically excitable like neurons, astrocytes display a form of calcium excitability, with complex dynamic oscillations in the cytoplasmic calcium concentration. Even though some of the biophysical details of these interactions have been observed, the systems-level role of these signals are poorly understood, with much debate as to whether they participate actively in information processing, inflammatory processes, or even how these signals arise. This thesis presents a multi-faceted attempt to further understand the role of astrocytes in central nervous system operation both under normal physiological conditions and under pathological insult, specifically focusing on Alzheimer's. Of particular interest in this work are the mechanisms and roles or intercellular calcium waves propagating through the astrocytic network. The functional role of this signaling is unknown, and this thesis attempts to shed light on astrocyte signaling through a combination of detailed mathematical modeling and experimental trials. We develop and apply models to in silico cultures of astrocytes to predict how calcium waves spontaneously form in Alzheimer's, compare to experimental results, and propose models for signal propagation within these networks. We also develop novel methods of numerically solving difficult fractional order differential equations with the goal of incorporating these techniques into our modeling of the complex interactions in the CNS