Mathematical modeling of reactive gliosis using in silico Bayesian method

AUZMENDI, JERÓNIMO A; ROSCIZEWSKI, GERARDO; MOFFATT LUCIANO; RAMOS, JAVIER

Mar del Plata

Congreso; SAN XXX annual Meeting; 2015

Sociedad Argentina de Investigación en Neurociencias

Reactive astrogliosis (RA) is a general, graded, glial response to brain injury. Reactive astrocytes are characterized by an increase of the cellular volume and secretion of pro-inflammatory molecules. Until now it is unknown which are the signals that initiate/propagate RA, but it is proposed that diffusion of damage associated moleculespattern (DAMP) from the necrotic core; calcium waves propagated by glial gap junctions or dramatic changes in extracellular milieu (i.e. ATP levels) are likely to be involved. We here evaluated two main paradigms to understand the progression of RA using mathematicalmodeling. Model I is a simple mechanism that contemplates the diffusion of DAMP from the necrotic core as the main responsible for the RA. Model II is more complex mechanism involves a subsequent signal carried out by soluble mediators secreted by the proximal astrocytes acting as amplifiers of the signal. Starting with GFAP-stained brain sections of animals subjected to cortical devascularization analyzed by Sholl analysis and confocal 3Dreconstruction, we studied the morphology of the cortical astrocytes at 3 and 7 days post ischemic injury. Then, we applied a Bayesian Computational Modeling approach by building a parametric mathematical model using partial differential equation for diffusion of DAMP and soluble mediators coupled with a Markovian Model for the signal-triggered RA. Finally, we tested both models and found strong evidence for model II with soluble mediators.