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. 2020 Aug 28:11:959.
doi: 10.3389/fphys.2020.00959. eCollection 2020.

Effects of Six Sequential Charged Particle Beams on Behavioral and Cognitive Performance in B6D2F1 Female and Male Mice

Jacob Raber  1   2 , Andrea Fuentes Anaya  1 , Eileen Ruth S Torres  1 , Joanne Lee  1 , Sydney Boutros  1 , Dmytro Grygoryev  3 , Austin Hammer  4 , Kristin D Kasschau  4 , Thomas J Sharpton  4   5 , Mitchell S Turker  3 , Amy Kronenberg  6
Affiliations

Effects of Six Sequential Charged Particle Beams on Behavioral and Cognitive Performance in B6D2F1 Female and Male Mice

Jacob Raber et al. Front Physiol. .

Abstract

The radiation environment astronauts are exposed to in deep space includes galactic cosmic radiation (GCR) with different proportions of all naturally occurring ions. To assist NASA with assessment of risk to the brain following exposure to a mixture of ions broadly representative of the GCR, we assessed the behavioral and cognitive performance of female and male C57BL/6J × DBA2/J F1 (B6D2F1) mice two months following rapidly delivered, sequential 6 beam irradiation with protons (1 GeV, LET = 0.24 keV, 50%), 4He ions (250 MeV/n, LET = 1.6 keV/μm, 20%), 16O ions (250 MeV/n, LET = 25 keV/μm 7.5%), 28Si ions (263 MeV/n, LET = 78 keV/μm, 7.5%), 48Ti ions (1 GeV/n, LET = 107 keV/μm, 7.5%), and 56Fe ions (1 GeV/n, LET = 151 keV/μm, 7.5%) at 0, 25, 50, or 200 cGy) at 4-6 months of age. When the activity over 3 days of open field habituation was analyzed in female mice, those irradiated with 50 cGy moved less and spent less time in the center than sham-irradiated mice. Sham-irradiated female mice and those irradiated with 25 cGy showed object recognition. However, female mice exposed to 50 or 200 cGy did not show object recognition. When fear memory was assessed in passive avoidance tests, sham-irradiated mice and mice irradiated with 25 cGy showed memory retention while mice exposed to 50 or 200 cGy did not. The effects of radiation passive avoidance memory retention were not sex-dependent. There was no effect of radiation on depressive-like behavior in the forced swim test. There was a trend toward an effect of radiation on BDNF levels in the cortex of males, but not for females, with higher levels in male mice irradiated with 50 cGy than sham-irradiated. Finally, sequential 6-ion irradiation impacted the composition of the gut microbiome in a sex-dependent fashion. Taxa were uncovered whose relative abundance in the gut was associated with the radiation dose received. Thus, exposure to sequential six-beam irradiation significantly affects behavioral and cognitive performance and the gut microbiome.

Keywords: BDNF; CD68; charged particle radiation; galactic cosmic radiation; gut microbiome; helium ions; home cage activity; object recognition.

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Figures

FIGURE 1
FIGURE 1
Body weights of female (A) and male (B) mice that were sham-irradiated or received six sequential beams. (A) There was no effect of irradiation in females. (B) In males, the body weights were higher in mice irradiated with 25 cGy than those irradiated with 50 or 200 cGy. *p = 0.001 versus 50 cGy and *p = 0.01 versus 200 cGy.
FIGURE 2
FIGURE 2
Performance of irradiated and sham-irradiated female and male mice. (A,B) There was no effect of radiation on activity levels over the three days of open field habituation. (C) On day 1 of the open field, there was a trend toward lower activity in mice irradiation with 50 cGy than sham-irradiated mice #p = 0.058 versus 0 cGy. (D,E) Time female (D) and male (E) mice spent in the center of the open field. In female mice, mice irradiated with 50 cGy spent less time in the center than sex-matched sham-irradiated mice. *p = 0.014 versus 0 cGy, Dunnett’s. (F) Sham-irradiated female mice and female mice irradiated with 25 cGy showed object recognition but female mice irradiated with 50 or 200 cGy showed impaired object recognition and no preference for exploring the novel object. *p < 0.05 versus familiar object.
FIGURE 3
FIGURE 3
Passive avoidance learning and memory of sham-irradiated and irradiated mice. Sham-irradiated mice and mice irradiated test showed passive avoidance memory retention and entered the dark compartment later on day 2 than day 1. There was a trend toward significance in mice irradiated with 50 cGy. (*p < 0.05 versus day 1, Wilcoxon test. #p = 0.098, Wilcoxon test).
FIGURE 4
FIGURE 4
Cortical and hippocampal BDNF, CD68, and MAP-2 levels. (A) In males, BDNF levels in the cortex were higher levels in mice irradiated with 50 cGy than sham-irradiated mice. *p = 0.026. (B) In males, there was a trend toward higher CD68 levels in mice irradiated with 50 cGy than sham-irradiated mice. #p = 0.082, Dunnett’s. (C) There was a positive correlation between BDNF and CD68 levels in the cortex. r = 0.703, p < 0.0001, Pearson correlation (sham-irradiated and irradiated mice combined in the analysis). (D) There was also a positive correlation between cortical BDNF and CD68 levels in only sham-irradiated mice. r = 0.907, p < 0.0001, Pearson correlation. (E) There was also a positive relationship between hippocampal BDNF and CD68 levels. r = 0.7985, p < 0.0001, Pearson correlation (sham-irradiated and irradiated mice combined in the analysis). (F) There was a positive correlation between hippocampal BDNF and CD68 in only sham-irradiated mice. r = 0.837, p < 0.0001, Pearson correlation. (G) There was a negative correlation between cortical MAP-2 and CD68 levels. r = −0.6314, p < 0.0001, Pearson correlation (sham-irradiated and irradiated mice combined in the analysis). (H) In contrast to the cortex, there was a positive relationship between MAP-2 and CD68 in the hippocampus. r = 0.7529, p < 0.0001, Pearson correlation (sham-irradiated and irradiated mice combined in the analysis).
FIGURE 5
FIGURE 5
(A) There was a positive relationship between hippocampal BDNF and MAP-2 in the hippocampus. r = 0.8315, p < 0.0001, Pearson correlation (sham-irradiated and irradiated mice combined in the analysis). (B) There was a positive relationship between hippocampal BDNF and MAP-2 levels in only sham-irradiated mice. r = 0.8542, p < 0.0001, Pearson correlation.
FIGURE 6
FIGURE 6
(A) The Shannon entropy of the gut microbiome, which is a biodiversity measure that integrates community richness and evenness, correlates with an individual’s forced swim test score (percent time immobile). Individual samples are represented by black points. The blue line indicates the best fit of the points as determined by a linear model, where the gray shading represents the 95% confidence interval of the model. (B) The composition of the gut microbiome relates to the amount of radiation a mouse received in a sex-dependent way, as illustrated in this non-metric multidimensional scaling plot based on the Bray–Curtis dissimilarity of the samples. Small points represent individual microbiome samples and are colored by the amount of radiation the host received. Points are connected via line segments to triangles (male mice) or circles (female mice) that represent the centroids of each sex-by-treatment cohort of mice. Permanova tests demonstrate that the microbiome significantly varies across treatment groups in a sex-dependent manner.
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