Fractionated brain irradiation profoundly reduces hippocampal immature neuron numbers without affecting spontaneous behavior and cognition in mice

Whole brain radiotherapy (WBRT) is used to treat patients with primary brain tumors, or brain metastasis from various primary tumors to improve tumor control. However, WBRT can lead to cognitive decline. We treated mice with fractionated WBRT (fWBRT) to establish a model system to study the mechanisms underlying cognitive decline. Besides a series of traditional cognitive tests, we also assessed the effect on spontaneous behavior as measured in automated home cages. Male C57Bl/6j mice (n=11 per group) received bi-lateral fWBRT at a dosage of 4 Gy/day on 5 consecutive days. In line with previous reports, immunohistochemical analysis of doublecortin (DCX) positive cells in the dentate gyrus showed a profound reduction in immature neurons at 4 weeks after fWBRT. Surprisingly, spontaneous behavior as measured in automated home cages was not affected. Moreover, learning and memory measured with traditional tasks - including the novel object recognition task, novel location recognition task, Barnes maze, and fear conditioning - was also not affected at 4-6 weeks after fWBRT. At 10-11 weeks after fWBRT a difference in escape latency during the learning phase, but not in the probe phase of the Barnes maze was observed. In conclusion, although we confirmed the effect of fWBRT on neurogenesis at 4 weeks after fWBRT, we did not find clear effects on spontaneous behavior in the automated home cage nor on learning abilities as measured by traditional cognitive tasks. The relationship between the neurobiological effects of fWBRT and cognition seems more complex than often assumed and the choice of animal model, cognitive tasks, neurobiological parameters, and experimental set-up might be important factors in these types of experiments.