Targeted Dorsal Dentate Gyrus or Whole Brain Irradiation in Juvenile Mice Differently Affects Spatial Memory and Adult Hippocampal Neurogenesis.

Céline Serrano,Roseline Poirier,Christelle Durand,Morgane Dos Santos,Louison Beugnies,Philippe Lestaevel,Dimitri Kereselidze

doi:10.3390/biology10030192

Abstract

Simple SummaryThe effects of exposure of the juvenile brain to doses of ionizing radiation (IR) ≤ 2 Gy on cognitive functions in adulthood are not clearly established in humans, and experimental data are scarce. To elucidate how IR can impact the postnatal brain, we evaluated and compared the effect of whole brain (WB) or hippocampal dorsal dentate gyrus (DDG) X-ray exposure (0.25–2 Gy) on spatial memory, three months after irradiation in mice. In our dose-ranging study, spatial memory was not modified after WB exposure, whereas a deficit was highlighted when irradiation beams were focused on the DDG at the dose of 1 Gy, but not for the lowest or highest doses tested. At 1 Gy, DDG irradiation appeared to be more deleterious to spatial memory and also to adult hippocampal neurogenesis than WB irradiation. Alterations in the generation of newborn neuronal cells in the DG may participate in the memory impairment observed after DDG irradiation at this dose. Finally, our work shows that the brain’s response to IR is complex and depends on the dose and the irradiated brain volume. The societal interest of this study is notably linked to the advent of computed tomography scans for head exploration in children.The cognitive consequences of postnatal brain exposure to ionizing radiation (IR) at low to moderate doses in the adult are not fully established. Because of the advent of pediatric computed tomography scans used for head exploration, improving our knowledge of these effects represents a major scientific challenge. To evaluate how IR may affect the developing brain, models of either whole brain (WB) or targeted dorsal dentate gyrus (DDG) irradiation in C57Bl/6J ten-day-old male mice were previously developed. Here, using these models, we assessed and compared the effect of IR (doses range: 0.25–2 Gy) on long-term spatial memory in adulthood using a spatial water maze task. We then evaluated the effects of IR exposure on adult hippocampal neurogenesis, a form of plasticity involved in spatial memory. Three months after WB exposure, none of the doses resulted in spatial memory impairment. In contrast, a deficit in memory retrieval was identified after DDG exposure for the dose of 1 Gy only, highlighting a non-monotonic dose-effect relationship in this model. At this dose, a brain irradiated volume effect was also observed when studying adult hippocampal neurogenesis in the two models. In particular, only DDG exposure caused alteration in cell differentiation. The most deleterious effect observed in adult hippocampal neurogenesis after targeted DDG exposure at 1 Gy may contribute to the memory retrieval deficit in this model. Altogether these results highlight the complexity of IR mechanisms in the brain that can lead or not to cognitive disorders and provide new knowledge of interest for the radiation protection of children.

Highlights

Whilst it is apparent that juvenile brain exposure to high doses of ionizing radiation (IR) can lead to neurocognitive toxicity, including memory impairments, lower intellectual quotient and reduced processing speed, several years later in pediatric cancer survivors [1,2], the effects of lower doses of IR (≤2 Gy) on the developing brain are not clearly established
We report no spatial learning and memory deficit after postnatal whole brain (WB) exposure to IR (≤2 Gy) whereas when irradiation beams were focused on the dorsal dentate gyrus (DDG), adult mice displayed altered spatial memory restitution, without impairing their learning, at 1 Gy, but not at the other tested doses
These contrasting effects observed in both models (WB/DDG) at the dose of 1 Gy have been confirmed by studying adult hippocampal neurogenesis

Summary

Introduction

Whilst it is apparent that juvenile brain exposure to high doses of ionizing radiation (IR) can lead to neurocognitive toxicity, including memory impairments, lower intellectual quotient and reduced processing speed, several years later in pediatric cancer survivors [1,2] (for review, see [3]), the effects of lower doses of IR (≤2 Gy) on the developing brain are not clearly established (for review, see [4]). Concerning cognitive functions, Casciati et al (2016) found no spatial memory deficit in adult mice postnatally exposed to WB IR (PND 10; 0.1 and 2 Gy; [18]). In this context, it appears to be a priority to further study the direct effects of low to moderate doses (≤2 Gy) of IR on the postnatal developing brain and the underlying mechanisms leading to potent radiation-induced cognitive defects [19]

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