Region-Specific Effects of Fractionated Low-Dose Versus Single-Dose Radiation on Hippocampal Neurogenesis and Neuroinflammation

SIMPLE SUMMARY: Radiotherapy-associated brain injury with neurocognitive impairment is a common long-term side effect for brain cancer survivors, affecting the quality of life particularly in pediatric patients. The complex pathophysiology of hippocampus-dependent cognitive deterioration with respect to fractionated radiotherapy and the precise role of neurogenesis in radiation-induced neuroinflammation is poorly understood. In a mouse model with fractionated low-dose radiation, we analyzed different hippocampal subregions to precisely elucidate the underlying mechanisms of radiation-induced brain injury. Our findings suggest that region-specific differences in radiosensitivity are mainly based on the presence of proliferating neuroprogenitors. Even low single doses to the neurogenic niche of the hippocampus lead to neuronal damage with subsequent neuroinflammation. Thus, limiting both cumulative doses and dose fractions to the hippocampal stem cell niche is an important issue of clinical radiotherapy to preserve neurocognitive functions. ABSTRACT: Background: Despite technical advances in hippocampus-sparing radiotherapy, radiation-induced injury to neural stem cell compartments may affect neurocognitive functions. In pre-clinical mouse models with fractionated low-dose radiation (FLDR) and single-dose radiation (SDR), the accurate response to radiation-induced injury was analyzed in different hippocampal subregions. Methods: Adult and juvenile C57BL/6NCrl mice were exposed to FLDR (20 × 0.1 Gy, daily exposure from Monday to Friday for 4 weeks) or SDR (1 × 2 Gy). In addition, 72 h after the last exposure, neuroglia (astrocytes and microglia) and neuroprogenitor cells were characterized and quantified in the hippocampal cornu ammonis (CA) and dentate gyrus (DG) by immunofluorescence studies. Results: After analyzing different hippocampal subregions, it was observed that radiation responses varied between non-neurogenic CA, with no detectable inflammatory alterations, and neurogenic DG, characterized by impaired neurogenesis and subsequent neuroinflammation. Age-dependent differences in radiosensitivity appeared to depend on the varying proliferative potential of neural stem cell niches. Using the same overall dose for FLDR and SDR (2 Gy), both the cumulative dose over time and also the single dose fraction have decisive impacts on hippocampal damage. Conclusion: Region-specific effects of radiation-induced hippocampal injury relies primarily on cell deaths of proliferating neuroprogenitors. Dose per fraction defines the extent of neuronal injury, and subsequently activated microglia and reactive astrocytes modulate dynamic processes of neuroinflammation. Thus, limiting both cumulative doses and dose fractions to hippocampal DG is an important issue of clinical radiotherapy to preserve neurocognitive functions.