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Here, the authors invesitgate the role of circadian rhythms in the pathogenesis of delirium. They observe perturbance of circadian rhythms in mouse models of delirium and disrupted clock gene expression in patients with delirium. In turn, physiological and genetic circadian disruptions sensitize mice to delirium with aggravated cognitive impairment. Likewise, global deletion of <jats:italic>E4bp4<\/jats:italic> (E4 promoter\u2010binding protein), a clock gene markedly altered in delirium conditions, results in exacerbated delirium\u2010associated cognitive decline. Cognitive decline in delirium models is attributed to microglial activation and impaired long\u2010term potentiation in the hippocampus. Single\u2010cell RNA\u2010sequencing reveals microglia as the regulatory target of <jats:italic>E4bp4<\/jats:italic>. <jats:italic>E4bp4<\/jats:italic> restrains microglial activation via inhibiting the ERK1\/2 signaling pathway. Supporting this, mice lacking in microglial <jats:italic>E4bp4<\/jats:italic> are delirious prone, whereas mice with <jats:italic>E4bp4<\/jats:italic> specifically deleted in hippocampal CA1 neurons have a normal phenotype. Mechanistically, <jats:italic>E4bp4<\/jats:italic> inhibits ERK1\/2 signaling by trans\u2010repressing <jats:italic>Mapk1\/3<\/jats:italic> (genes encoding ERK1\/2) via direct binding to a D\u2010box element in the promoter region. These findings define a causal role of clock dysfunction in delirium development and indicate <jats:italic>E4bp4<\/jats:italic> as a regulator of cognition at the crosstalk between circadian clock and delirium.<\/jats:p>","DOI":"10.1002\/advs.202200559","type":"journal-article","created":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T06:55:56Z","timestamp":1655448956000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["E4BP4 Coordinates Circadian Control of Cognition in Delirium"],"prefix":"10.1002","volume":"9","author":[{"given":"Min","family":"Chen","sequence":"first","affiliation":[{"name":"Institute of Molecular Rhythm and Metabolism Guangzhou University of Chinese Medicine  Guangzhou 510006 China"},{"name":"College of Pharmacy Jinan University  Guangzhou 510632 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