Effects of⁵⁶Fe-Particle Cranial Radiation on Hippocampus-Dependent Cognition Depend on the Salience of the Environmental Stimuli

Abstract

Ionizing radiation reduces the numbers of neurons expressing activity-regulated cytoskeleton-associated protein (Arc) in the hippocampal dentate gyrus (DG). It is currently unclear if that change relates to cognitive function. We assessed the effects of 1 Gy of head-only ⁵⁶Fe-particle irradiation on hippocampus-dependent and hippocampus-independent fear conditioning and determined how those changes related to Arc expression within the DG. Irradiated mice that did not receive tone-shock pairings on day 1 showed less freezing in the same context on a second day and a lower fraction of Arc-expressing neurons in the free (lower) blade of the DG than sham-irradiated mice. Those data suggested reduced hippocampus-dependent spatial habituation learning. Changes in Arc expression in the free blade correlated positively with freezing in mice that did not receive tone-shock pairings. However, irradiated mice that did receive tone-shock pairings showed enhanced contextual freezing but a reduced percentage of Arc-expressing neurons in the enclosed (upper) blade. Changes in Arc expression correlated negatively with freezing in mice that received tone-shock pairings. In animals receiving cued fear conditioning, radiation did not affect cognitive performance or the fractions of Arc-expressing neurons. While the relationship between Arc expression and cognitive performance is complex, our data suggest that radiation effects on hippocampus-dependent cognition might depend on the prominence (salience) of environmental stimuli and blade-specific Arc expression.

Short- and long-term effects of 56Fe irradiation on cognition and hippocampal DNA methylation and gene expression

“…Age-related changes in immediate early gene Activity-Regulated Cytoskeleton-Associated Protein ( Arc ) in the hippocampus have been reported [24]. Our work showed that head-only 56 Fe ion irradiation of two-month-old mice alters hippocampal expression of Arc [25, 26]. Arc expression has been used to provide important insight into the post-transcriptional infrastructure of gene expression involved in synaptic plasticity and memory [27] (for review, [28]).…”

Radiation-Induced Alterations in Synaptic Neurotransmission of Dentate Granule Cells Depend on the Dose and Species of Charged Particles

“…Exposure to such radiation can potentially induce a wide range of neurological consequences, and in animals it has been repeatedly shown to induce cognitive impairment (1,5,6). Although the mechanisms underlying this radiation-induced cognitive impairment are not clearly understood, previous studies suggest that the pathogenesis likely depends on multiple factors and may involve chronic oxidative stress (7), depletion of neuronal precursor cells of the hippocampus (2,8,9), neuroinflammation (10,11), altered expression of the plasticity-related immediate early gene Arc (6,12,13) and impaired neurogenesis (10,14). Indeed, it has been shown that exposure to iron radiation impairs the proliferation of hippocampal neural precursor cells in mice, and that the reductions in the generation of new neurons correlates in time with cognitive impairments seen in these mice (10).…”

“…While it is well understood that radiation exposure induces impairments in hippocampal dependent cognitive performance (1,5,6,13), little is known about the molecular mechanisms underlying these changes and whether they are associated with radiation-induced alterations in synaptic properties of DGCs. Due to different pattern of energy deposition and ionization track structures, irradiation with proton, silicon or iron may each have very different effects on cells and the overall neurological outcomes.…”

Impairment in Extinction of Contextual and Cued Fear Following Post-Training Whole-Body Irradiation

“…Hippocampal sensitivity to radiation-induced cognitive injury is not limited to gamma irradiation and is also seen 2 weeks (Haley et al, 2012, 2013) or later (Shukitt-Hale et al, 2000; Villasana et al, 2010, 2011; Raber et al, 2011; Yeiser et al, 2013) following 56 Fe irradiation. In all these studies, the animals were trained and tested for hippocampal function following irradiation.…”