The longitudinal behavioral effects of acute exposure to galactic cosmic radiation in female C57BL/6J mice: implications for deep space missions, female crews, and potential antioxidant countermeasures

Galactic cosmic radiation (GCR) is an unavoidable risk to astronauts that may affect mission success. Male rodents exposed to 33-beam-GCR (33-GCR) show short-term cognitive deficits but reports on female rodents and long-term assessment is lacking. Here we asked: What are the longitudinal behavioral effects of 33-GCR on female mice? Also, can an antioxidant/anti-inflammatory compound mitigate the impact of 33-GCR? Mature (6-month-old) C57BL/6J female mice received the antioxidant CDDO-EA (400 µg/g of food) or a control diet (vehicle, Veh) for 5 days and either Sham-irradiation (IRR) or whole-body 33-GCR (0.75Gy) on the 4th day. Three-months post-IRR, mice underwent two touchscreen-platform tests: 1) location discrimination reversal (which tests behavior pattern separation and cognitive flexibility, two abilities reliant on the dentate gyrus) and 2) stimulus-response learning/extinction. Mice then underwent arena-based behavior tests (e.g. open field, 3-chamber social interaction). At the experiment end (14.25-month post-IRR), neurogenesis was assessed (doublecortin-immunoreactive [DCX+] dentate gyrus neurons). Female mice exposed to Veh/Sham vs. Veh/33-GCR had similar pattern separation (% correct to 1st reversal). There were two effects of diet: CDDO-EA/Sham and CDDO-EA/33-GCR mice had better pattern separation vs. their respective control groups (Veh/Sham, Veh/33-GCR), and CDDO-EA/33-GCR mice had better cognitive flexibility (reversal number) vs. Veh/33-GCR mice. Notably, one radiation effect/CDDO-EA countereffect also emerged: Veh/33-GCR mice had worse stimulus-response learning (days to completion) vs. all other groups, including CDDO-EA/33-GCR mice. In general, all mice show normal anxiety-like behavior, exploration, and habituation to novel environments. There was also a change in neurogenesis: Veh/33-GCR mice had fewer DCX+ dentate gyrus immature neurons vs. Veh/Sham mice. Our study implies space radiation is a risk to a female crew’s longitudinal mission-relevant cognitive processes and CDDO-EA is a potential dietary countermeasure for space-radiation CNS risks. ### Competing Interest Statement The authors have declared no competing interest. * 33-beam-GCR : 33-beam galactic cosmic radiation 3-CSI : 3-chamber social interaction AALAC : Association for Assessment and Accreditation of Laboratory Animal Care Acq : Acquisition BLAF : BLAF BNL : Brookhaven National Laboratories CDDO-EA : 2-cyano-3, 12-dioxooleana-1, 9-dien-28-oic acid-ethylamide CNS : central nervous system DCX : doublecortin DCX+ : doublecortin-immunoreactive EPM : elevated plus maze Ext : Extinction GCR : galactic cosmic radiation h : hour(s) Hab : habituation IACUC : Institutional Animal Care and Use Committee IHC : immunohistochemistry IRR : irradiation LDR : location discrimination reversal LDR Test : location discrimination reversal testing LDR Train : location discrimination reversal training Min : minute(s) mon : month(s) MT : Must Touch NOR : novel object recognition NSRL : NASA Space Radiation Laboratory OF : open field PFC : prefrontal cortex PI : punish incorrect ROUT : robust outlier testing s : second(s) S- : non-rewarded stimulus S+ : rewarded stimulus SGZ : subgranular zone Veh : vehicle