Circuit-selective cognitive vulnerability to environmental stress: multi-domain assessment of space radiation in both sexes reveals countermeasure trade-offs

Environmental stressors rarely affect just one brain circuit. Most studies assess single cognitive endpoints, obscuring whether vulnerabilities are global or circuit-selective and how effects distribute across interconnected systems. To address this, we used galactic cosmic radiation (GCR), a Mars mission-relevant stressor that disrupts the hippocampal-nucleus accumbens-prefrontal circuit. C57BL/6J mice received 33-ion GCR simulation (33-GCR, 0.75 Gy) or sham radiation with the Nrf2-activating compound CDDO-EA or vehicle, followed by multi-domain behavioral testing in both sexes. 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 9-18% 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 that was further increased by CDDO-EA alone, 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 that treatments disrupted specific circuit relationships while leaving others intact, consistent with selective rather than global cognitive effects. Fiber photometry showed enhanced dentate gyrus encoding activity in irradiated males under high memory load. Combined CDDO-EA/33-GCR selectively reduced dentate gyrus progenitors in females. Males and females showed distinct, circuit-selective vulnerability patterns, demonstrating that multi-domain, both-sex assessment is necessary to capture how stressors and interventions affect integrated brain function. CDDO-EA proved to be a double-edged sword: protecting one cognitive domain while impairing another, a trade-off invisible to single-endpoint assessment. This framework has immediate relevance for astronaut risk assessment and extends to any context where neuroprotective interventions are evaluated against environmental stressors.