Changes in Imaging and Cognition in Juvenile Rats After Whole-Brain Irradiation

Abstract

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.

Cross-translational models of late-onset cognitive sequelae and their treatment in pediatric brain tumor survivors

“…Interestingly in this preclinical model, the deleterious effects on FA are more prominent if the dose is delivered to the whole body and not restricted only to the head (Gupta et al, 2013;Trivedi et al, 2012), indicating an important systemic influence on brain response. With more specific relevance to childhood cancer treatment, similar decreases in FA have also been reported in juvenile rats after cranial radiation (Brown et al, 2016;Rodgers et al, 2016), with decreases in FA observed in the corpus callosum and fimbria. These DTI changes were accompanied by a significant decrease in total brain volume in adulthood (Rodgers et al, 2016).…”

Physical Exercise Promotes Novel Object Recognition Memory in Spontaneously Hypertensive Rats after Ischemic Stroke by Promoting Neural Plasticity in the Entorhinal Cortex

“…In addition to the prefrontal and entorhinal cortex, the corpus callosum has also been reported to be associated with mild cognitive impairment (Blasi et al, 2014 ; Brown et al, 2016 ). Therefore, we performed immunofluorescence staining of MBP (a marker of myelin integrity) and SMI-32 (a marker of abnormally dephosphorylated neurofilament protein) to further evaluate pathological changes in the corpus callosum, as well as LFB staining (a method used to stain myelin and phospholipids) in the corpus callosum.…”

“…At the same time, there are few studies reported the effect of exercise training on the nonspatial learning and memory of rodents after stroke. It has been proposed that the prefrontal lobe, entorhinal cortex and corpus callosum are involved in nonspatial learning and memory processes (Yee and Rawlins, 1998 ; Granon and Poucet, 2000 ; Blasi et al, 2014 ; Brown et al, 2016 ). However, the exact brain regions and mechanisms by which PE impacts stroke-induced nonspatial learning and memory deficit are still unclear.…”

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

“…One can choose to perform the novel object recognition (NOR) task and the novel location recognition (NLR) tasks using a short retention interval (minutes) as a measurement of hippocampus-independent, prefrontal cortex-dependent memory, or long retention interval (hours) for hippocampal-dependent learning. While the short-term interval version resulted in defects after irradiation 23,24,41,[47][48][49][50][51][52] , the hippocampal-dependent version of the NOR was not always affected after irradiation [53][54][55] . Interestingly, performance on the NOR was found to be dependent on dose, dosing-regimen and timing 53,54,56 .…”

“…While the short-term interval version resulted in defects after irradiation 23,24,41,47–52 , the hippocampal-dependent version of the NOR was not always affected after irradiation 53–55 . Interestingly, performance on the NOR was found to be dependent on dose, dosing-regimen and timing 53,54,56 . In addition, male C57BL/6 mice only perform well at the NOR at 3 months, but not at older age 57 and short timeframes are required to capture NOR 57 .…”