Age-Related Differences in Lipopolysaccharide-Induced Delirium-like Behavior Implicate the Distinct Microglial Composition in the Hippocampus

As the global population ages, the mechanisms underlying age-related susceptibility to delirium have attracted attention. Given the central role of microglia in the pathogenesis of inflammation-related delirium, we investigated the temporal dynamics of neurobehavioral changes and microglial responses, following lipopolysaccharide (LPS, 200 μg/kg) administration in young and old male C57BL/6 mice. Although a similar illness trajectory across 48 h post-treatment (HPT) was observed in both age groups, old-LPS mice exhibited worsened delirium-like behavior. At 48 HPT, in old but not young mice, significantly decreased hippocampal neuronal activity coincided with microglial overactivation. Widespread hippocampal microglial activation was present at 3 HPT but subsided by 12 HPT in young but not old mice, indicating a generally retarded but prolonged microglial response to LPS challenge in old mice. However, for both age groups, at 3 HPT, p16^INK4a-negative microglia (with low abundance in the aged brain) exhibited comparable morphological activation, which was not observed for p16^INK4a-positive microglia (highly abundant in the aged brain). These results suggest that age-related susceptibility to LPS-induced delirium-like behavior accompanied by different patterns of microglial response might implicate microglial composition shifts and that optimizing microglial composition represents a promising approach to reduce vulnerability to inflammatory challenge.