Modeling Reveals the Dependence of Hippocampal Neurogenesis Radiosensitivity on Age and Strain of Rats

Cognitive dysfunction following radiation treatment for brain cancers in both children and adults have been correlated to impairment of neurogenesis in the hippocampal dentate gyrus. Various species and strains of rodent models have been used to study radiation-induced changes in neurogenesis and these investigations have utilized only a limited number of doses, dose-fractions, age and time after exposures conditions. In this paper, we have extended our previous mathematical model of radiation-induced hippocampal neurogenesis impairment of C57BL/6 mice to delineate the time, age, and dose dependent alterations in neurogenesis of a diverse strain of rats. To the best of our knowledge, this is the first predictive mathematical model to be published about hippocampal neurogenesis impairment for a variety of rat strains after acute or fractionated exposures to low linear energy transfer (low LET) radiation, such as X-rays and γ-rays, which are conventionally used in cancer radiation therapy. We considered four compartments to model hippocampal neurogenesis and its impairment following radiation exposures. Compartments include: (1) neural stem cells (NSCs), (2) neuronal progenitor cells or neuroblasts (NB), (3) immature neurons (ImN), and (4) glioblasts (GB). Additional consideration of dose and time after irradiation dependence of microglial activation and a possible shift of NSC proliferation from neurogenesis to gliogenesis at higher doses is established. Using a system of non-linear ordinary differential equations (ODEs), characterization of rat strain and age-related dynamics of hippocampal neurogenesis for unirradiated and irradiated conditions is developed. The model is augmented with the description of feedback regulation on early and late neuronal proliferation following radiation exposure. Predictions for dose-fraction regimes compared to acute radiation exposures, along with the dependence of neurogenesis sensitivity to radiation on age and strain of rats are discussed. A major result of this work is predictions of the rat strain and age dependent differences in radiation sensitivity and sub-lethal damage repair that can be used for predictions for arbitrary dose and dose-fractionation schedules

Modeling Impaired Hippocampal Neurogenesis after Radiation Exposure

The birth of neuronal cells from neuronal stem cells is known as neurogenesis, and the granular cell layer of the dentate gyrus of hippocampus is one of the two regions in the brain this process occurs. Cognitive damages following radiation therapy for brain cancers in both children and adults have been linked to impairment of neurogenesis in the hippocampus. Studies followed using mice and rats as model animals have shown impairment in neurogenesis process following exposure to radiation. Obtaining experimental data for radiation-induced changes in neurogenesis in humans is very difficult. Model was developed and applied to mouse data previously; this study aims to apply the model to rat data. The patterns of neurogenesis impairment following radiation exposure can then provide insights for extrapolations with relevance to human physiology. A mathematical model was designed to represent the time, age and dose dependent changes occurring to several cell populations that participate in neurogenesis using nonlinear differential equations (ODE). To model the alterations in hippocampal neurogenesis following radiation exposure, four neuronal stem cell populations were considered: neural stem cells, neuroblasts, immature neurons and glioblasts. Matlab Simulink was used to solve nonlinear ODEs. With this model we were able to successfully produce data matching the experimental data for the dynamics of the rat hippocampal cell population under unirradiated and irradiated conditions. Development of these mathematical models may lead to help optimizing radiation therapy for cancer patients in the future