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Space-like ⁵⁶Fe irradiation manifests mild, early sex-specific behavioral and neuropathological changes in wildtype and Alzheimer's-like transgenic mice.

ABSTRACT: Space travel will expose people to high-energy, heavy particle radiation, and the cognitive deficits induced by this exposure are not well understood. To investigate the short-term effects of space radiation, we irradiated 4-month-old Alzheimer's disease (AD)-like transgenic (Tg) mice and wildtype (WT) littermates with a single, whole-body dose of 10 or 50?cGy ⁵⁶Fe ions (1?GeV/u) at Brookhaven National Laboratory. At ~1.5 months post irradiation, behavioural testing showed sex-, genotype-, and dose-dependent changes in locomotor activity, contextual fear conditioning, grip strength, and motor learning, mainly in Tg but not WT mice. There was little change in general health, depression, or anxiety. Two months post irradiation, microPET imaging of the stable binding of a translocator protein ligand suggested no radiation-specific change in neuroinflammation, although initial uptake was reduced in female mice independently of cerebral blood flow. Biochemical and immunohistochemical analyses revealed that radiation reduced cerebral amyloid-? levels and microglia activation in female Tg mice, modestly increased microhemorrhages in 50?cGy irradiated male WT mice, and did not affect synaptic marker levels compared to sham controls. Taken together, we show specific short-term changes in neuropathology and behaviour induced by ⁵⁶Fe irradiation, possibly having implications for long-term space travel.

SUBMITTER: Liu B

PROVIDER: S-EPMC6702228 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Space-like <sup>56</sup>Fe irradiation manifests mild, early sex-specific behavioral and neuropathological changes in wildtype and Alzheimer's-like transgenic mice.

Liu Bin B Hinshaw Robert G RG Le Kevin X KX Park Mi-Ae MA Wang Shuyan S Belanger Anthony P AP Dubey Shipra S Frost Jeffrey L JL Shi Qiaoqiao Q Holton Peter P Trojanczyk Lee L Reiser Vladimir V Jones Paul A PA Trigg William W Di Carli Marcelo F MF Lorello Paul P Caldarone Barbara J BJ Williams Jacqueline P JP O'Banion M Kerry MK Lemere Cynthia A CA

Scientific reports 20190820 1

Space travel will expose people to high-energy, heavy particle radiation, and the cognitive deficits induced by this exposure are not well understood. To investigate the short-term effects of space radiation, we irradiated 4-month-old Alzheimer's disease (AD)-like transgenic (Tg) mice and wildtype (WT) littermates with a single, whole-body dose of 10 or 50 cGy <sup>56</sup>Fe ions (1 GeV/u) at Brookhaven National Laboratory. At ~1.5 months post irradiation, behavioural testing showed sex-, genot ...[more]

PMID: 31431669

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Project description:BackgroundAstronauts are exposed to 56Fe ions that may pose a significant health hazard during and following prolonged missions in deep space. We showed previously that object recognition requiring the hippocampus, a structure critical for cognitive function, is affected in 2-month-old mice irradiated with 56Fe ions. Here we examined object recognition in 6-month-old mice irradiated with 56Fe ions, a biological age more relevant to the typical ages of astronauts. Moreover, because the mechanisms mediating the detrimental effects of 56Fe ions on hippocampal function are unclear, we examined changes in hippocampal networks involved in synaptic plasticity and memory, gene expression, and epigenetic changes in cytosine methylation (5mC) and hydroxymethylation (5hmC) that could accompany changes in gene expression. We assessed the effects of whole body 56Fe ion irradiation at early (2 weeks) and late (20 weeks) time points on hippocampus-dependent memory and hippocampal network stability, and whether these effects are associated with epigenetic changes in hippocampal DNA methylation (both 5mC and 5hmC) and gene expression.ResultsAt the two-week time point, object recognition and network stability were impaired following irradiation at the 0.1 and 0.4 Gy dose, but not following irradiation at the 0.2 Gy dose. No impairments in object recognition or network stability were seen at the 20-week time point at any irradiation dose used. Consistent with this pattern, the significance of pathways for gene categories for 5hmC was lower, though not eliminated, at the 20-week time point compared to the 2-week time point. Similarly, significant changes were observed for 5mC gene pathways at the 2-week time point, but no significant gene categories were observed at the 20-week time point. Only the 5hmC changes tracked with gene expression changes.ConclusionsDose- and time-dependent epigenomic remodeling in the hippocampus following 56Fe ion exposure correlates with behavioral changes.

Project description:Astronauts during interplanetary missions will be exposed to galactic cosmic radiation, including charged particles like 56Fe. Most preclinical studies with mature, "astronaut-aged" rodents suggest space radiation diminishes performance in classical hippocampal- and prefrontal cortex-dependent tasks. However, a rodent cognitive touchscreen battery unexpectedly revealed 56Fe radiation improves the performance of C57BL/6J male mice in a hippocampal-dependent task (discrimination learning) without changing performance in a striatal-dependent task (rule-based learning). As there are conflicting results on whether the female rodent brain is preferentially injured by or resistant to charged particle exposure, and as the proportion of female vs. male astronauts is increasing, further study on how charged particles influence the touchscreen cognitive performance of female mice is warranted. We hypothesized that, similar to mature male mice, mature female C57BL/6J mice exposed to fractionated whole-body 56Fe irradiation (3 × 6.7cGy 56Fe over 5 days, 600 MeV/n) would improve performance vs. Sham conditions in touchscreen tasks relevant to hippocampal and prefrontal cortical function [e.g., location discrimination reversal (LDR) and extinction, respectively]. In LDR, 56Fe female mice more accurately discriminated two discrete conditioned stimuli relative to Sham mice, suggesting improved hippocampal function. However, 56Fe and Sham female mice acquired a new simple stimulus-response behavior and extinguished this acquired behavior at similar rates, suggesting similar prefrontal cortical function. Based on prior work on multiple memory systems, we next tested whether improved hippocampal-dependent function (discrimination learning) came at the expense of striatal stimulus-response rule-based habit learning (visuomotor conditional learning). Interestingly, 56Fe female mice took more days to reach criteria in this striatal-dependent rule-based test relative to Sham mice. Together, our data support the idea of competition between memory systems, as an 56Fe-induced decrease in striatal-based learning is associated with enhanced hippocampal-based learning. These data emphasize the power of using a touchscreen-based battery to advance our understanding of the effects of space radiation on mission critical cognitive function in females, and underscore the importance of preclinical space radiation risk studies measuring multiple cognitive processes, thereby preventing NASA's risk assessments from being based on a single cognitive domain.

Dataset Information

Space-like ⁵⁶Fe irradiation manifests mild, early sex-specific behavioral and neuropathological changes in wildtype and Alzheimer's-like transgenic mice.

Publications

Space-like <sup>56</sup>Fe irradiation manifests mild, early sex-specific behavioral and neuropathological changes in wildtype and Alzheimer's-like transgenic mice.

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Space-like 56Fe irradiation manifests mild, early sex-specific behavioral and neuropathological changes in wildtype and Alzheimer's-like transgenic mice.

Publications

Space-like <sup>56</sup>Fe irradiation manifests mild, early sex-specific behavioral and neuropathological changes in wildtype and Alzheimer's-like transgenic mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Space-like ⁵⁶Fe irradiation manifests mild, early sex-specific behavioral and neuropathological changes in wildtype and Alzheimer's-like transgenic mice.