{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:18:53Z","timestamp":1785403133910,"version":"3.56.0"},"reference-count":49,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003710","name":"Korea Health Industry Development Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/00fdzyk40","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003710","name":"Ministry of Health and Welfare, Republic of Korea","doi-asserted-by":"publisher","award":["HI23C0519"],"award-info":[{"award-number":["HI23C0519"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Major depressive disorder (MDD) involves dysregulation of the hypothalamic\u2013pituitary\u2013adrenal axis, neuroinflammation, serotonergic dysfunction, and impaired neurotrophic signaling. Whether combining corticosterone (CORT) with chronic restraint stress (CRS) produces a more comprehensive depression-like phenotype than either model alone remains unexplored. Male C57BL\/6N mice were assigned to four groups\u2014Sham (n = 7), CORT (20 mg\/kg s.c.; n = 7), CRS (3 h\/day; n = 7), and CORT + CRS (C+C; n = 8)\u2014and evaluated by behavioral tests, hippocampal qRT-PCR, Western blot, LC-MS\/MS metabolomics, and immunohistochemistry. All experimental groups showed elevated immobility in tail suspension and forced swim tests without inter-group differences. Two-way ANOVA revealed a behavioral\u2013molecular dissociation: FST immobility showed CORT and CRS main effects without a significant interaction, whereas hippocampal LC-MS\/MS analytes exhibited strong CORT \u00d7 CRS interactions. The C+C group showed the strongest 5-HT1A receptor (HTR1A) upregulation, the greatest reductions in Trk-b and DCX, and unique decreases in serum dopamine, glutamine, and adenosine. Representative Western blot densitometry indicated the largest p-ERK\/ERK reduction in C+C (54%), while p-CREB\/CREB was most suppressed in CRS (52%). BDNF and NeuN proteins were lowest in C+C (68% and 61% reductions). Combined CORT + CRS produces the most comprehensive depression-related molecular profile, integrating multiple pathological domains.<\/jats:p>","DOI":"10.3390\/ijms27146277","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T03:06:52Z","timestamp":1784084812000},"page":"6277","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comparative Evaluation of Corticosterone Administration, Chronic Restraint Stress, and Their Combination for Depression-like Behavioral and Molecular Alterations in Mice: A Multi-Domain Assessment"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-5848-4485","authenticated-orcid":false,"given":"Chang-Ho","family":"Shin","sequence":"first","affiliation":[{"name":"Department of AI Convergence Biomedical Engineering, Dongguk University, Goyang-si 10326, Republic of Korea"},{"name":"AriBio Co., Ltd., 56, Dongpangyo-ro, Bundang-gu, Seongnam-si 13535, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun-Min","family":"Jin","sequence":"additional","affiliation":[{"name":"AriBio Co., Ltd., 56, Dongpangyo-ro, Bundang-gu, Seongnam-si 13535, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da-Jung","family":"Hwang","sequence":"additional","affiliation":[{"name":"AriBio Co., Ltd., 56, Dongpangyo-ro, Bundang-gu, Seongnam-si 13535, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myeong-Hyun","family":"Nam","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Dongguk University, Goyang-si 10326, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee-Deok","family":"Yun","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Dongguk University, Goyang-si 10326, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuna","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Dongguk University, Goyang-si 10326, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju-Yeong","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Dongguk University, Goyang-si 10326, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7533-9605","authenticated-orcid":false,"given":"Young-Kwon","family":"Seo","sequence":"additional","affiliation":[{"name":"Department of AI Convergence Biomedical Engineering, Dongguk University, Goyang-si 10326, Republic of Korea"},{"name":"Department of Biomedical Engineering, Dongguk University, Goyang-si 10326, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2023). 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