Galactic cosmic radiation produces sex-specific, circuit-selective cognitive vulnerability: countermeasure trade-offs revealed by multi-domain assessment.

Astronauts on deep space missions face chronic exposure to galactic cosmic radiation (GCR). However, it remains unknown whether mission-relevant multi-ion GCR produces global or circuit-selective cognitive vulnerabilities and whether candidate countermeasures protect uniformly or show domain-dependent trade-offs. Here we used a 33-ion GCR simulation with concurrent countermeasure treatment to address both questions in male and female mice. C57BL/6J mice received 33-GCR (0.75 Gy) or sham radiation with the Nrf2-activating compound CDDO-EA or vehicle, followed by multi-domain behavioral assessment across the hippocampal-nucleus accumbens-prefrontal circuit. Under very high memory load, male Veh/33-GCR mice showed enhanced pattern separation compared to Veh/Sham males, an effect normalized by CDDO-EA. Female mice showed no radiation-induced changes in pattern separation but weighed more than Veh/Sham females and had reduced locomotor activity. Reward-based learning differed by sex: males showed no changes, while female Veh/33-GCR mice displayed enhanced reward anticipation, with both treatments contributing to elevated goal-tracking. For behavioral flexibility, CDDO-EA impaired reversal learning in males regardless of radiation, while 33-GCR impaired reversal learning in females regardless of CDDO-EA. Principal component analysis revealed CDDO-EA under 33-GCR specifically disrupted the balance between stimulus-driven and executive control processes and altered goal-directed behavior, while hippocampal-dependent discrimination maintained its functional relationships with other cognitive domains - confirming circuit-selective rather than global vulnerability. In a preliminary fiber photometry cohort, irradiated males showed enhanced dentate gyrus encoding activity under high memory load. At the cellular level, combined CDDO-EA/33-GCR selectively reduced dentate gyrus progenitors in females. Together, these findings reveal distinct, circuit-selective vulnerability patterns in males and females that would have been invisible to single-sex, single-endpoint designs. CDDO-EA proved a double-edged sword: protecting one cognitive domain while impairing another, a trade-off invisible to single-endpoint assessment and directly relevant to astronaut risk assessment.