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However, the O\u2010GlcNAcylation\u2010dependent link between gene expression and neurological behavior remains to be explored. Using chronic administration of Thiamet G (TG, an OGA inhibitor) in vivo, we used a protocol designed to relate behavior with the transcriptome and selected biochemical parameters from the cortex of individual animals. TG\u2010treated mice showed improved working memory as measured using a Y\u2010maze test. RNA sequencing analysis revealed 151 top differentially expressed genes with a Log2fold change &gt;0.33 and adjusted <jats:italic>p<\/jats:italic>\u2010value &lt;0.05. Top TG\u2010dependent upregulated genes were related to learning, cognition and behavior, while top downregulated genes were related to IL\u201017 signaling, inflammatory response and chemotaxis. Additional pathway analysis uncovered 3 pathways, involving gene expression including 14 cytochrome <jats:italic>c<\/jats:italic> oxidase subunits\/regulatory components, chaperones or assembly factors, and 5 mTOR (mechanistic target of rapamycin) signaling factors. Multivariate Kendall correlation analyses of behavioral tests and the top TG\u2010dependent differentially expressed genes revealed 91 statistically significant correlations in saline\u2010treated mice and 70 statistically significant correlations in TG\u2010treated mice. These analyses provide a network regulation landscape that is important in relating the transcriptome to behavior and the potential impact of the O\u2010GlcNAC pathway.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15835-fig-0007-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.15835","type":"journal-article","created":{"date-parts":[[2023,5,2]],"date-time":"2023-05-02T13:20:56Z","timestamp":1683033656000},"page":"682-700","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Relationships between gene expression and behavior in mice in response to systemic modulation of the <scp>O\u2010GlcNAcylation<\/scp> pathway"],"prefix":"10.1111","volume":"165","author":[{"given":"Margaret B.","family":"Bell","sequence":"first","affiliation":[{"name":"Department of Pathology University of Alabama at Birmingham  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaosen","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Alabama at Birmingham  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail K.","family":"Shelton","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Alabama at Birmingham  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nha V.","family":"Huynh","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Alabama at Birmingham  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toni","family":"Mueller","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Alabama at Birmingham  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balu K.","family":"Chacko","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Alabama at Birmingham  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anil G.","family":"Jegga","sequence":"additional","affiliation":[{"name":"Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Chatham","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Alabama at Birmingham  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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