A Computational and Mathematical Modeling Approach for the Study of Radiation-induced Hippocampal Neurogenesis Impairment and Neuronal Dendritic Damage

Neurocognitive detriments associated with cranial radiotherapy for cancer treatment and chronic radiation exposure of astronauts for space travel have always been a concern. Neurogenesis impairment and alterations in neuronal morphology are two of the many factors that have been correlated to this cognitive dysfunctions. Computer simulation and mathematical modeling approach provides an effective tool that contributes valuable insights to the role of radiation-induced changes in producing functional deficits in the brain. These computational and mathematical models are also useful for extrapolation to other conditions that are often constrained in experiments. We have developed predictive models to study radiation-induced changes to neurogenesis ^{[1, 2]} and alterations to dendritic morphology ^{[3]}. Using a system of nonlinear ordinary differential equations (ODEs) to represent age, time after exposure and dose-dependent changes to several cell populations participating in neurogenesis as reported in experiments utilizing mouse models, we obtained a description of the age-related dynamics of hippocampal neurogenesis and the effects of a variety of radiation in altering neurogenesis. Predictions of the threshold doses where neurogenesis recovery fails for given radiation types are described in our neurogenesis mathematical model. On the other hand, we investigate radiation-induced changes in neuronal dendritic morphology using a stochastic model that describes time dependent radiation-induced dendritic damage on in silico representations of mouse hippocampal dentate granule cell layer (GCL) and CA1 pyramidal neurons. Our model describes the changes in morphometric parameters, such as total dendritic length, number of branch points and branch number, including the Sholl analysis for single neurons. Our model based predictions for different patterns of morphological changes based on energy deposition in dendritic segments (EDDS) will serve as a useful basis to compare specific patterns of morphological alterations caused by EDDS mechanisms.References:[1] E. Cacao and F.A. Cucinotta. Modeling impaired hippocampal neurogenesis after radiation exposure. Radiat. Res. 185: 319 - 331 (2016).[2] E. Cacao and F.A. Cucinotta. Modeling heavy-ion impairment of hippocampal neurogenesis after acute and fractionated irradiation. Radiat. Res. 186: 624 - 637 (2016). [3] E. Cacao, V.K. Parihar, C.L. Limoli and F.A. Cucinotta. Stochastic modeling of radiation-induced dendritic damage on in silico mouse hippocampal neurons (submitted).