{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T01:17:35Z","timestamp":1792545455539,"version":"4.5.0"},"reference-count":52,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T00:00:00Z","timestamp":1754179200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000646","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["24K14685"],"award-info":[{"award-number":["24K14685"]}],"id":[{"id":"10.13039\/501100000646","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Obstructive sleep apnea syndrome (OSAS) is characterized by cycles of decreased blood oxygen saturation followed by reoxygenation due to transient apnea. Cognitive dysfunction is a complication of OSAS, but its mechanisms remain unclear. Eight-week-old C57BL\/6J mice were exposed to intermittent hypoxia (IH) to model OSAS, and cognitive function and hippocampal gene expression were analyzed. Three groups were maintained for 28 days: an IH group (oxygen alternating between 10 and 21% in 2 min cycles, 8 h\/day), sustained hypoxia group (SH) (10% oxygen, 8 h\/day), and control group (21% oxygen). Behavioral tests and RNA sequencing (RNA-seq) analysis were performed. While Y-maze test results showed no differences, the IH group demonstrated impaired memory and learning in passive avoidance tests compared to control and SH groups. RNA-seq revealed coordinated suppression of mitochondrial function genes and oxidative stress response pathways, specifically in the IH group. RT-qPCR showed decreased Lars2, Hmcn1, and Vstm2l expression in the IH group. Pathway analysis showed the suppression of the KEAP1-NFE2L2 antioxidant pathway in the IH group vs. the SH group. Our findings demonstrate that IH induces cognitive dysfunction through suppression of the KEAP1-NFE2L2 antioxidant pathway and downregulation of mitochondrial genes (Lars2, Vstm2l), leading to oxidative stress and mitochondrial dysfunction. These findings advance our understanding of the molecular basis underlying OSAS-related cognitive impairment.<\/jats:p>","DOI":"10.3390\/ijms26157495","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T07:45:11Z","timestamp":1754466311000},"page":"7495","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Intermittent Hypoxia Induces Cognitive Dysfunction and Hippocampal Gene Expression Changes in a Mouse Model of Obstructive Sleep Apnea"],"prefix":"10.3390","volume":"26","author":[{"given":"Kenta","family":"Miyo","sequence":"first","affiliation":[{"name":"Department of Physiology, Showa Medical University School of Medicine, Tokyo 142-8555, Japan"},{"name":"Department of Respiratory Medicine, Showa Medical University Fujigaoka Hospital, Yokohama 227-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5075-9347","authenticated-orcid":false,"given":"Yuki","family":"Uchida","sequence":"additional","affiliation":[{"name":"Department of Physiology, Showa Medical University School of Medicine, Tokyo 142-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4898-6873","authenticated-orcid":false,"given":"Ryota","family":"Nakano","sequence":"additional","affiliation":[{"name":"Department of Physiology, Showa Medical University Graduate School of Pharmacy, Tokyo 142-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shotaro","family":"Kamijo","sequence":"additional","affiliation":[{"name":"Department of Physiology, Showa Medical University Graduate School of Pharmacy, Tokyo 142-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Hosonuma","sequence":"additional","affiliation":[{"name":"Division of Medical Pharmacology, Department of Pharmacology, Showa Medical University School of Medicine, Tokyo 142-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshitaka","family":"Yamazaki","sequence":"additional","affiliation":[{"name":"Division of Toxicology, Showa University Graduate School of Pharmacy, Tokyo 142-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hikaru","family":"Isobe","sequence":"additional","affiliation":[{"name":"Division of Medical Pharmacology, Department of Pharmacology, Showa Medical University School of Medicine, Tokyo 142-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0056-5098","authenticated-orcid":false,"given":"Fumihiro","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"Center for Biotechnology, Showa Medical University, Tokyo 142-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Onimaru","sequence":"additional","affiliation":[{"name":"Department of Physiology, Showa Medical University School of Medicine, Tokyo 142-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4424-1629","authenticated-orcid":false,"given":"Akira","family":"Yoshikawa","sequence":"additional","affiliation":[{"name":"Division of Health Science Education, Showa Medical University School of Nursing and Rehabilitation Sciences, Yokohama 226-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8983-2249","authenticated-orcid":false,"given":"Shin-Ichi","family":"Sakakibara","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Neurobiology, Faculty of Human Sciences, Waseda University, Tokorozawa 359-1192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsunori","family":"Oguchi","sequence":"additional","affiliation":[{"name":"Division of Medical Pharmacology, Department of Pharmacology, Showa Medical University School of Medicine, Tokyo 142-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Yokoe","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Showa Medical University Fujigaoka Hospital, Yokohama 227-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4377-8421","authenticated-orcid":false,"given":"Masahiko","family":"Izumizaki","sequence":"additional","affiliation":[{"name":"Department of Physiology, Showa Medical University School of Medicine, Tokyo 142-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.smrv.2016.07.002","article-title":"Prevalence of Obstructive Sleep Apnea in the General Population: A Systematic Review","volume":"34","author":"Senaratna","year":"2017","journal-title":"Sleep Med. 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