Cognitive flexibility is selectively impaired by radiation and is associated with differential recruitment of adult-born neurons

Exposure to elevated doses of ionizing radiation, such as those in therapeutic procedures, catastrophic accidents, or space exploration, increases the risk of cognitive dysfunction. The full range of radiation-induced cognitive deficits is unknown, partly because commonly used tests may be insufficiently sensitive or may not be adequately tuned for assessing the fine behavioral features affected by radiation. Here, we asked whether gamma-radiation might affect learning, memory, and the overall ability to adapt behavior to cope with a challenging environment (cognitive/behavioral flexibility). We developed a new behavioral assay, the context discrimination Morris water maze (cdMWM) task, which is hippocampus-dependent and requires the integration of various contextual cues and the adjustment of search strategies. We exposed male mice to 1 or 5 Gy of gamma-rays and, at different time points after irradiation, assessed learning and memory, and analyzed navigational search strategies in mice trained consecutively in spatial MWM, reversal MWM, and cdMWM tasks. Mice exposed to 5 Gy, performed successfully in the spatial and reversal MWM tasks; however, in the cdMWM task 6 or 8 weeks (but not 3 weeks) after irradiation, they demonstrated transient learning deficit, decreased use of efficient spatially precise search strategies during learning, and memory deficit 6 weeks post-irradiation. We also observed impaired neurogenesis after irradiation and selective activation of 12-week-old newborn neurons by specific components of cdMWM training. Thus, our new behavioral paradigm indicates an extended timeframe for the functional maturation of new hippocampal neurons and reveals the effects of gamma-radiation on cognitive flexibility.

Significance Statement:

Exposure to radiation can affect cognitive performance and cognitive flexibility – the ability to adapt to changed circumstances and demands. The full range of consequences of irradiation on cognitive flexibility is unknown, partly because of a lack of suitable models. Here, we developed a new behavioral task requiring mice to combine various types of cues and strategies to find a correct solution. We show that animals exposed to gamma-radiation, despite being able to successfully solve standard problems, show delayed learning, deficient memory, and diminished use of efficient navigation patterns in circumstances requiring adjustments of previously used search strategies. This new task could be applied in other settings for assessing the cognitive changes induced by aging, trauma, or disease.