Effects of (16)O charged-particle irradiation on cognition, hippocampal morphology and mutagenesis in female mice.

The effects of radiation in space on human cognition are a growing concern for NASA scientists and astronauts as the possibility for long-duration missions to Mars becomes more tangible. Oxygen (16O) radiation is of utmost interest considering that astronauts will interact with this radiation frequently. 16O radiation is a class of galactic cosmic ray (GCR) radiation and also present within spacecrafts. Whole-body exposure to high linear energy transfer (LET) radiation has been shown to affect hippocampal-dependent cognition. To assess the effects of high-LET radiation, we gave 6-month-old female C57BL/6 mice whole-body exposure to 16O at 0.25 or 0.1 Gy at NASA's Space Radiation Laboratory. Three months following irradiation, animals were tested for cognitive performance using the Y-maze and Novel Object Recognition paradigms. Our behavioral data shows that 16O radiation significantly impairs object memory but not spatial memory. Also, dendritic morphology characterized by the Sholl analysis showed that 16O radiation significantly decreased dendritic branch points, ends, length, and complexity in 0.1 Gy and 0.25 Gy dosages. Finally, we found no significant effect of radiation on single nucleotide polymorphisms in hippocampal genes related to oxidative stress, inflammation, and immediate early genes. Our data suggest exposure to heavy ion 16O radiation modulates hippocampal neurons and induces behavioral deficits at a time point of three months after exposure in female mice.

Swinton C ，Kiffer F ，McElroy T ，Wang J ，Sridharan V ，Boerma M ，Allen AR ... -  《-》

Late Effects of (16)O-Particle Radiation on Female Social and Cognitive Behavior and Hippocampal Physiology.

Kiffer F ，Alexander T ，Anderson JE ，Groves T ，Wang J ，Sridharan V ，Boerma M ，Allen AR ... -  《-》

Effects of (1)H + (16)O Charged Particle Irradiation on Short-Term Memory and Hippocampal Physiology in a Murine Model.

Kiffer F ，Carr H ，Groves T ，Anderson JE ，Alexander T ，Wang J ，Seawright JW ，Sridharan V ，Carter G ，Boerma M ，Allen AR ... -  《-》

Effects of a 33-ion sequential beam galactic cosmic ray analog on male mouse behavior and evaluation of CDDO-EA as a radiation countermeasure.

In long-term spaceflight, astronauts will face unique cognitive loads and social challenges which will be complicated by communication delays with Earth. It is important to understand the central nervous system (CNS) effects of deep spaceflight and the associated unavoidable exposure to galactic cosmic radiation (GCR). Rodent studies show single- or simple-particle combination exposure alters CNS endpoints, including hippocampal-dependent behavior. An even better Earth-based simulation of GCR is now available, consisting of a 33-beam (33-GCR) exposure. However, the effect of whole-body 33-GCR exposure on rodent behavior is unknown, and no 33-GCR CNS countermeasures have been tested. Here astronaut-age-equivalent (6mo-old) C57BL/6J male mice were exposed to 33-GCR (75cGy, a Mars mission dose). Pre-/during/post-Sham or 33-GCR exposure, mice received a diet containing a 'vehicle' formulation alone or with the antioxidant/anti-inflammatory compound CDDO-EA as a potential countermeasure. Behavioral testing beginning 4mo post-irradiation suggested radiation and diet did not affect measures of exploration/anxiety-like behaviors (open field, elevated plus maze) or recognition of a novel object. However, in 3-Chamber Social Interaction (3-CSI), CDDO-EA/33-GCR mice failed to spend more time exploring a holder containing a novel mouse vs. a novel object (empty holder), suggesting sociability deficits. Also, Vehicle/33-GCR and CDDO-EA/Sham mice failed to discriminate between a novel stranger vs. familiarized stranger mouse, suggesting blunted preference for social novelty. CDDO-EA given pre-/during/post-irradiation did not attenuate the 33-GCR-induced blunting of preference for social novelty. Future elucidation of the mechanisms underlying 33-GCR-induced blunting of preference for social novelty will improve risk analysis for astronauts which may in-turn improve countermeasures.

Kiffer FC ，Luitel K ，Tran FH ，Patel RA ，Guzman CS ，Soler I ，Xiao R ，Shay JW ，Yun S ，Eisch AJ ... -  《-》

Late Effects of (1)H + (16)O on Short-Term and Object Memory, Hippocampal Dendritic Morphology and Mutagenesis.

The space extending beyond Earth's magnetosphere is subject to a complex field of high-energy charged nuclei, which are capable of traversing spacecraft shielding and human tissues, inducing dense ionization events. The central nervous system is a major area of concern for astronauts who will be exposed to the deep-space radiation environment on a mission to Mars, as charged-particle radiation has been shown to elicit changes to the dendritic arbor within the hippocampus of rodents, and related cognitive-behavioral deficits. We exposed 6-month-old male mice to whole-body 1H (0.5 Gy; 150 MeV/n; 18-19 cGy/minute) and an hour later to 16O (0.1Gy; 600 MeV/n; 18-33 Gy/min) at NASA's Space Radiation Laboratory as a galactic cosmic ray-relevant model. Animals were housed with bedding which provides cognitive enrichment. Mice were tested for cognitive behavior 9 months after exposure to elucidate late radiation effects. Radiation induced significant deficits in novel object recognition and short-term spatial memory (Y-maze). Additionally, we observed opposing morphological differences between the mature granular and pyramidal neurons throughout the hippocampus, with increased dendritic length in the dorsal dentate gyrus and reduced length and complexity in the CA1 subregion of the hippocampus. Dendritic spine analyses revealed a severe reduction in mushroom spine density throughout the hippocampus of irradiated animals. Finally, we detected no general effect of radiation on single-nucleotide polymorphisms in immediate early genes, and genes involved in inflammation but found a higher variant allele frequency in the antioxidants thioredoxin reductase 2 and 3 loci.

Kiffer F ，Alexander T ，Anderson J ，Groves T ，McElroy T ，Wang J ，Sridharan V ，Bauer M ，Boerma M ，Allen A ... -  《Frontiers in Behavioral Neuroscience》