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We hypothesized that an ICU-like environment would enhance model validity by amplifying behavioral and neurobiological alterations. Male Wistar rats (50\u00a0days old) underwent sterile laparotomy or cecal ligation and puncture (CLP)-induced sepsis, with or without exposure to an ICU-like environment. Behavioral tests (open field, Y-maze, SHIRPA) were performed at 0\u201336\u00a0h, along with assessments of reactive oxygen species, glial markers, neurotransmitters, and delirium incidence\/severity. Predictive validity was evaluated in the most severe condition (CLP\u00a0+\u00a0ICU) using minocycline, dexmedetomidine, and rivastigmine. The ICU-like environment exacerbated behavioral deficits consistent with human delirium and increased their severity. We observed elevations in IL-6 (hippocampus, cortex, and plasma in laparotomy; hippocampus in sepsis) and IL-1\u03b2 (cortex in laparotomy), alongside aminergic\/excitatory imbalance (dopamine, noradrenaline, and glutamate). In sepsis\u00a0+\u00a0ICU, minocycline and dexmedetomidine reduced IL-1\u03b2\/IL-6 and improved behavioral performance; rivastigmine improved selected behavioral domains, increased acetylcholine, and reduced AChE activity; dexmedetomidine decreased ROS; and minocycline and rivastigmine attenuated microgliosis. The ICU-like environment worsened behavioral and neurochemical changes, surgery plus anesthesia, and sepsis, supporting its value for enhancing model validity.<\/jats:p>","DOI":"10.1042\/cs20250943","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T09:28:27Z","timestamp":1774344507000},"page":"537-555","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The ICU environment paradigm as a strategy to enhance the validity of delirium animal models"],"prefix":"10.1042","volume":"140","author":[{"given":"Diogo","family":"Dominguini","sequence":"first","affiliation":[{"name":"1Laboratory of Experimental Pathophysiology, Graduate Program in Health Sciences, University of Southern Santa Catarina, Crici\u00fama, SC, Brazil"},{"name":"2Graduate program in Health Management, University of Southern Santa Catarina (UNESC), Crici\u00fama, SC, 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