Abstract LB-326: Unresolved microgliosis and impaired neurogenesis are associated with cognitive deficiency in a clinically relevant mouse model of fractionated whole brain radiation

Abstract

Abstract The objective of this study is to evaluate the cellular and molecular changes associated with the cognitive function as a late- effect of clinically relevant fractionated whole brain irradiation (fWBI) treatment using immunocompetent mouse model. Microglia are not only the immune mediators of the brain but also involved in synaptic pruning and neurogenesis. However, the microglial response to fractionated radiation and how this contributes to radiation-induced cognitive impairment is poorly understood. Here, C57BL/6J mice were randomized into two groups. One group received X-radiation (XRT) and another was sham treated (CTL). The whole brain of each XRT mouse received a total of 30 Gy (3 Gy/fraction) of radiation over two weeks. XRT and CTL mice were then evaluated for cognitive and behavioral functions after one, four, and six months of radiation treatment using the rotarod test, novel object recognition test, the free running Y-Maze and Barnes Maze. Whole brains were harvested and stored after completion of behavioral studies for immunohistochemical analysis. Microglia were enriched by Percoll gradient separation and extracted mRNA was characterized by qPCR analysis. A significant (P<0.05) decline in latency to fall from rotarod, total number of arm entries from Y maze, were observed in mice four and six months after X-radiation. A significant (P<0.05) decrease in novel object recognition was observed four months after radiation. However, no significant effects of radiation treatment were observed on errors or latency at all the time points measured by the Barnes maze. At the molecular level, microglial MHC II and IFN-γ expression was significantly upregulated (P<0.05) in XRT brains at all the time points tested. Immunohistochemical analysis revealed a significant increase (P< 0.05) in the number of de-ramified Iba1 positive microglia throughout the hippocampal sub-regions of radiated brains till six months. Neurogenesis was impaired in XRT brains as measured by significant decrease in the number of Dcx+, BrdU+, and BrdU+/Dcx+ cells at all time points. These results indicate that sustained microgliosis along with chronic impairment of neurogenesis are associated with delayed long-term cognitive impairment induced by fWBI in an immunocompetent mouse model. Unlike previous studies, here, we have employed a clinically relevant fractionated dosage regimen to address the cellular and molecular deregulations in association with cognitive impairment. This fractionated radiation induced late delayed cognitive deficit mouse model will further allow us to elucidate the cross talk between microgliosis and neurogenesis in radiation induced cognitive impairment. Citation Format: Suman Kanji, Benjamin Johnson, Kristina Witcher, Pooja Gulati, John Gregory Bodnar, Julie Fitzgerald, Courtney DeVries, Randy Nelson, Jonathan Godbout, Saikh Jaharul Haque, Saikh Jaharul Haque, Arnab Chakravarti. Unresolved microgliosis and impaired neurogenesis are associated with cognitive deficiency in a clinically relevant mouse model of fractionated whole brain radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-326.