Combined Effects of Three High-Energy Charged Particle Beams Important for Space Flight on Brain, Behavioral and Cognitive Endpoints in B6D2F1 Female and Male Mice

Abstract

The radiation environment in deep space includes the galactic cosmic radiation with different proportions of all naturally occurring ions from protons to uranium. Most experimental animal studies for assessing the biological effects of charged particles have involved acute dose delivery for single ions and/or fractionated exposure protocols. Here, we assessed the behavioral and cognitive performance of female and male C57BL/6J × DBA2/J F1 (B6D2F1) mice 2 months following rapidly delivered, sequential irradiation with protons (1 GeV, 60%), 16O (250 MeV/n, 20%), and 28Si (263 MeV/n, 20%) at 0, 25, 50, or 200 cGy at 4–6 months of age. Cortical BDNF, CD68, and MAP-2 levels were analyzed 3 months after irradiation or sham irradiation. During the dark period, male mice irradiated with 50 cGy showed higher activity levels in the home cage than sham-irradiated mice. Mice irradiated with 50 cGy also showed increased depressive behavior in the forced swim test. When cognitive performance was assessed, sham-irradiated mice of both sexes and mice irradiated with 25 cGy showed normal responses to object recognition and novel object exploration. However, object recognition was impaired in female and male mice irradiated with 50 or 200 cGy. For cortical levels of the neurotrophic factor BDNF and the marker of microglial activation CD68, there were sex × radiation interactions. In females, but not males, there were increased CD68 levels following irradiation. In males, but not females, there were reduced BDNF levels following irradiation. A significant positive correlation between BDNF and CD68 levels was observed, suggesting a role for activated microglia in the alterations in BDNF levels. Finally, sequential beam irradiation impacted the diversity and composition of the gut microbiome. These included dose-dependent impacts and alterations to the relative abundance of several gut genera, such as Butyricicoccus and Lachnospiraceae. Thus, exposure to rapidly delivered sequential proton, 16O ion, and 28Si ion irradiation significantly affects behavioral and cognitive performance, cortical levels of CD68 and BDNF in a sex-dependent fashion, and the gut microbiome.

Multi-domain cognitive assessment of male mice shows space radiation is not harmful to high-level cognition and actually improves pattern separation

“…Most preclinical data that led to the Probabilistic Risk Assessment of HZE particles being detrimental to cognition were from tests performed on young adult rodents (~2-3 months [mon] at exposure) 14 ; in many cases, age at testing was not reported 14 . To more accurately reflect the average age of astronauts, NASA now requires ground-based space studies to be performed in mature animals (~6-mon-old at irradiation) [14][15][16][17][18][19][20][21][22][23][24] . Indeed, some studies now directly compare the cognitive impact of HZE irradiation in early life vs. maturity [25][26][27][28] , although the results are mixed.…”

Sex-Specific Effects of a Wartime-Like Radiation Exposure on Cognitive Function

“…Radiation has been shown with some consistency to induce impairments in learning and memory, and increased anxiety-or depression-like behaviors after charged particle or clinically relevant exposures (12,23). Similarly, differences in the sensitivity of the CNS to such exposures have been reported between males and females (4,24,25). Conversely, even relatively higher whole-body or head-only exposures to X rays or gamma rays have been inconsistent in eliciting CNS responses (26)(27)(28).…”

Comparative RNA-Seq transcriptome analyses reveal dynamic time-dependent effects of 56Fe, 16O, and 28Si irradiation on the induction of murine hepatocellular carcinoma

“…In particular, high charge, high-energy (HZE) ions such as 56 Fe, 16 O, and 28 Si are the major high linear energy transfer (LET) sources in deep space. [1][2][3] Previous studies have shown that irradiation of mice with low dose HZE, specifically 56 Fe ions, significantly increases the incidences of HCC, but there is a limited understanding of potential mechanisms. [4] Previous studies by multiple investigators have shown that irradiation of mice with HZE particles induces oxidative damage, and micro-environmental changes that are thought to play a role in the carcinogenic processes, yet a detailed analysis of these processes has not been undertaken.…”