Impact of Helium Ions on Mouse Behavior, Memory, Microglia, and Blood Metabolome

The long-term space missions and helium ion (⁴He) radiotherapy require assessing of the consequences on the central nervous system. This study investigated the effects of total-body irradiation with 2 Gy helium ions on the brain of male Balb/c mice, focusing on cognitive function, microglial status, gene expression, and systemic metabolism. No statistically significant deficits in hippocampus-dependent behavior or spatial memory were detected. However, cellular and molecular alterations were detected. A decreased Iba1-positive cell density was observed at several post-irradiation time points, accompanied by morphological shifts towards a less ramified state. Gene expression analysis revealed a complex response, including a mixed neuroimmune activation profile, altered expression of redox-related genes, and downregulation of key defense genes. Metabolomics identified changes in 19 plasma metabolites consistent with alterations in energy and amino acid metabolism. Although 2 Gy did not manifest in overt cognitive impairment in the early delayed period, molecular and cellular alterations were detectable at 8 weeks, including decreased Iba1-positive cell density at several post-irradiation time points, changes in microglial morphology, altered expression of neuroimmune and redox-related genes, and systemic metabolic changes. These findings underscore the importance of multimodal assessment beyond behavioral testing in experimental models of helium-ion exposure. Because the exposure conditions used here differ from both the chronic mixed-field GCR environment and localized clinical helium-ion therapy, the results should be regarded as fundamental radiobiological observations rather than direct predictions of spaceflight or radiotherapy outcomes.