Adult animals continue to modify their behavior throughout life, a process that is highly influenced by past experiences. To shape behavior, specific mechanisms of neural plasticity to learn, remember, and recall information are required. One of the most robust examples of adult plasticity in the brain occurs in the dentate gyrus (DG) of the hippocampus, through the process of adult neurogenesis. Adult neurogenesis is strongly upregulated by external factors such as voluntary wheel running (RUN) and environmental enrichment (EE); however, the functional differences between these two factors remain unclear. Although both manipulations result in increased neurogenesis, RUN dramatically increases the proliferation of newborn cells and EE promotes their survival. We hypothesize that the method by which these newborn neurons are induced influences their functional role. Furthermore, we examine how EE-induced neurons may be primed to encode and recognize features of novel environments due to their previous enrichment experience. Here, we gave mice a challenging contextual fear-conditioning (FC) procedure to tease out the behavioral differences between RUN-induced neurogenesis and EE-induced neurogenesis. Despite the robust increases in neurogenesis seen in the RUN mice, we found that only EE mice were able to discriminate between similar contexts in this task, indicating that EE mice might use a different cognitive strategy when processing contextual information. Furthermore, we showed that this improvement was dependent on EE-induced neurogenesis, suggesting a fundamental functional difference between RUN-induced neurogenesis and EE-induced neurogenesis.

Purpose

In pediatric cancer survivors treated with whole-brain irradiation (WBI), long-term cognitive deficits and morbidity develop that are poorly understood and for which there is no treatment. We describe similar cognitive defects in juvenile WBI rats and correlate them with alterations in diffusion tensor imaging and magnetic resonance spectroscopy (MRS) during brain development.

Methods and materials

Juvenile Fischer rats received clinically relevant fractionated doses of WBI or a high-dose exposure. Diffusion tensor imaging and MRS were performed at the time of WBI and during the subacute (3-month) and late (6-month) phases, before behavioral testing.

Results

Fractional anisotropy in the splenium of the corpus callosum increased steadily over the study period, reflecting brain development. WBI did not alter the subacute response, but thereafter there was no further increase in fractional anisotropy, especially in the high-dose group. Similarly, the ratios of various MRS metabolites to creatine increased over the study period, and in general, the most significant changes after WBI were during the late phase and with the higher dose. The most dramatic changes observed were in glutamine-creatine ratios that failed to increase normally between 3 and 6 months after either radiation dose. WBI did not affect the ambulatory response to novel open field testing in the subacute phase, but locomotor habituation was impaired and anxiety-like behaviors increased. As for cognitive measures, the most dramatic impairments were in novel object recognition late after either dose of WBI.

Conclusions

The developing brains of juvenile rats given clinically relevant fractionated doses of WBI show few abnormalities in the subacute phase but marked late cognitive alterations that may be linked with perturbed MRS signals measured in the corpus callosum. This pathomimetic phenotype of clinically relevant cranial irradiation effects may be useful for modeling, mechanistic evaluations, and testing of mitigation approaches.