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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 \u03bcg\/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, p16INK4a-negative microglia (with low abundance in the aged brain) exhibited comparable morphological activation, which was not observed for p16INK4a-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.<\/jats:p>","DOI":"10.3390\/ijms26052055","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T11:22:12Z","timestamp":1740568932000},"page":"2055","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Age-Related Differences in Lipopolysaccharide-Induced Delirium-like Behavior Implicate the Distinct Microglial Composition in the Hippocampus"],"prefix":"10.3390","volume":"26","author":[{"given":"Congli","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Physiology, School of Medicine, Southeast University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomin","family":"Kang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Southeast University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xirui","family":"Jia","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Southeast University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwei","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Medicine, Southeast University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijia","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Medicine, Southeast University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Medicine, Southeast University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anaerguli","family":"Abula","sequence":"additional","affiliation":[{"name":"School of Medicine, Southeast University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8309-609X","authenticated-orcid":false,"given":"Lijie","family":"Liu","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Physiology, School of Medicine, Southeast University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1176\/appi.ajp.2018.18070893","article-title":"Delirium","volume":"176","author":"Thom","year":"2019","journal-title":"Am. 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