Fractionated low-dose radiation induces long-lasting inflammatory responses in the hippocampal stem cell niche.

Abstract

PURPOSE\nDespite major technical advances in hippocampus-sparing radiotherapy, radiation-induced injury to the neural stem cell compartment may affect neurocognitive functions. In the brain glia cells modulate neuronal functions and are major mediators of neuroinflammation. In a pre-clinical mouse model with fractionated low-dose radiation (LDR) the complex response to radiation-induced injury was analyzed in the hippocampal stem cell compartment over a period of 6 months.\n\n\nMETHODS AND MATERIALS\nAdult and juvenile C57BL/6NCrl mice were daily exposed to low doses of ionizing radiation (IR; 20\u202f×\u202f0.1Gy, for up to 4 weeks). At 72 hours and 1, 3 and 6 months after fractionated LDR magnetic resonance imaging (MRI, 9.4 Tesla) was conducted to detect structural and functional abnormalities in the hippocampal region. By immunofluorescence and histological studies, neuroglia cells (astrocytes, microglia, oligodendrocytes) were quantified and neuroinflammatory responses were characterized in the hippocampal dentate gyrus. By in-vivo BrdU-labeling the cell fate of newly generated progenitor cells were tracked in the subgranular zone of the dentate gyrus during fractionated LDR.\n\n\nRESULTS\nLow doses of IR induced long-lasting inflammatory responses with local increases of activated microglia and reactive astrocytes, most pronounced in the juvenile hippocampus within the first months following LDR. Glial activation with the consequent release of pro-inflammatory mediators increased local blood flow and vascular permeability in the hippocampal region. Cell fate mapping of progenitors located in the subgranular zone revealed a transient shift from neurogenesis to gliogenesis.\n\n\nCONCLUSIONS\nGlial cell activation and transient neuroinflammation may reflect radiation-induced neuronal damage in the hippocampal stem cell niche. The increased proliferative capacity of the developing brain may explain the enhanced hippocampal radiosensitivity with stronger inflammatory reactions in the juvenile hippocampus. Thus, limiting the radiation dose to the hippocampal region is an important issue of clinical radiotherapy at all ages to preserve neurocognitive functions.