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Wistar-Kyoto (WKY) rats exposed to chronic mild stress (CMS) are considered to be a model of TRD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Since inflammatory processes and disrupted signaling pathways play key roles in the pathophysiology of depression, we investigated the effect of CMS on behavior as well as on the CaMKII, JAK2\/STAT3, NF-\u03baB, and the Nrf2\/HO-1 pathway in the hippocampus (HC) and medial prefrontal cortex (mPFC) of female WKY rats.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our results demonstrated that unstressed WKY females had depressive symptoms accompanied by cognitive deficits, whereas chronic stress led to further behavioral impairments. The findings indicate that the baseline levels of JAK2\/STAT3 and the expression level of NF-\u03baB protein in the HC and mPFC were upregulated in unstressed WKY rats. When WKY rats are exposed to CMS there is a further increase of JAK2\/STAT3 pathway (mPFC: 12%, <jats:italic>P<\/jats:italic> &lt; 0.05; HC: 20%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and NF-\u03baB (25%, <jats:italic>P<\/jats:italic> &lt; 0.05) in the HC and the mPFC. Our results confirmed a positive correlation between the index of depression, pJAK2\/pSTAT3, and NF-\u03baB expression, as well as a negative correlation between recognition memory and these protein levels in both unstressed and stressed WKY rats. WKY rats showed reduced pCaMKII levels in the HC and mPFC, while CMS significantly increased pCaMKII in both brain structures (40%, <jats:italic>P<\/jats:italic> &lt; 0.001). There is a strong association between pCAMKII overexpression in the hippocampus of stressed WKY rats and the depression index. Our results showed unchanged expressions of Nrf2 and HO-1 in the hippocampus and mPFC of unstressed WKY females. After exposure to CMS, WKY females showed decreased levels of Nrf2 and HO-1 only in the hippocampus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The most significant changes in CaMKII, NF-\u03baB and JAK2\/STAT3 levels during chronic mild stress may contribute to the impairments in neural plasticity, neurogenesis, and cellular resilience observed in the brains of WKY rats as a model of TRD.<\/jats:p><\/jats:sec>","DOI":"10.1556\/2060.2025.00634","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T14:45:05Z","timestamp":1756305905000},"page":"285-301","update-policy":"https:\/\/doi.org\/10.1556\/policypage.crossmark.crossref.2","source":"Crossref","is-referenced-by-count":2,"title":["Altered levels of CaMKII, NF-\u03baB and JAK2\/STAT3 signaling in the hippocampus and prefrontal cortex of female Wistar-Kyoto rats exposed to\u00a0chronic mild stress"],"prefix":"10.1556","volume":"112","author":[{"given":"Kristina","family":"Virijevic","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Endocrinology, Institute of Nuclear Sciences \u201cVin\u010da\u201d, National Institute of Republic Serbia, University of Belgrade, Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasa","family":"Spasojevic","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Endocrinology, Institute of Nuclear Sciences \u201cVin\u010da\u201d, National Institute of Republic Serbia, University of Belgrade, Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bojana","family":"Stefanovic","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Endocrinology, Institute of Nuclear Sciences \u201cVin\u010da\u201d, National Institute of Republic Serbia, University of Belgrade, Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harisa","family":"Ferizovic","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Endocrinology, Institute of Nuclear Sciences \u201cVin\u010da\u201d, National Institute of Republic Serbia, University of Belgrade, Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milica","family":"Jankovic","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Endocrinology, Institute of Nuclear Sciences \u201cVin\u010da\u201d, National Institute of Republic Serbia, University of Belgrade, Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Obradovic","sequence":"additional","affiliation":[{"name":"Department of Biology and Ecology, Faculty of Science, University of Kragujevac, Radoja Domanovi\u0107a, Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4334-8002","authenticated-orcid":true,"given":"Sladjana","family":"Dronjak","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Endocrinology, Institute of Nuclear Sciences \u201cVin\u010da\u201d, National Institute of Republic Serbia, University of Belgrade, Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"425","reference":[{"issue":"8","key":"B1","series-title":"J Exp Psychol Gen","doi-asserted-by":"publisher","first-page":"1454","DOI":"10.1037\/xge0000528","article-title":"Social media and depression symptoms: a network perspective","volume":"148","author":"Aalbers G","year":"2019","unstructured":"Aalbers G, McNally RJ, Heeren A, de Wit S, Fried EI. 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