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However, there are significant sex differences in neuropsychiatric disorders associated with stress, particularly in depression, where the lifetime risk of depression in women is approximately twice that of men. However, the specific mechanism of this process has not been explained in detail.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Chronic restraint stress (CRS)\u2009+\u2009chronic and unpredictable mild stress (CUMS) was used to simulate social stress, and behavioral experiments, HE staining of rectal and hippocampal pathological sections, detection of depression\u2010related biological indicators, analysis of intestinal flora diversity, and metabolomics analysis of hippocampal and intestinal contents were performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The results showed that stress induced anxiety\u2010like behavior in female mice and depression\u2010like behavior in male mice. Sex differences in behavior may be related to monoamine neurotransmitters, hyperactivity of <jats:styled-content style=\"fixed-case\">HPA<\/jats:styled-content> axis, inflammatory factors, gut microbiota, and brain\u2013gut metabolism. It is worth noting that stress caused opposite trends in <jats:styled-content style=\"fixed-case\">DA<\/jats:styled-content> (dopamine) levels, abundance of f\u2010lactobaciliaceae, and levels of metabolites (1, 2\u2010distearoyl\u2010<jats:styled-content style=\"fixed-case\">SN<\/jats:styled-content>\u2010glycero\u20103\u2010phosphocholine) and <jats:styled-content style=\"fixed-case\">PC<\/jats:styled-content>(20:5(<jats:styled-content style=\"fixed-case\">5Z<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\">8Z<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\">11Z<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\">14Z<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\">17Z<\/jats:styled-content>)\/20:1(<jats:styled-content style=\"fixed-case\">11Z<\/jats:styled-content>)) in male and female mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The difference in neurotransmitter levels, the disorder of gut microbiota, and the abnormal brain and gut metabolism may lead to the gender difference in stress behavior.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.70433","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T05:48:49Z","timestamp":1747201729000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A Study of Sex Differences in the Biological Pathways of Stress Regulation in Mice"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5210-7382","authenticated-orcid":false,"given":"Yajun","family":"Qiao","sequence":"first","affiliation":[{"name":"Qinghai Provincial Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation Northwest Institute of Plateau Biology, Chinese Academy of Science  Xining China"},{"name":"School of Psychology Chengdu Medical College  Chengdu China"},{"name":"University of Chinese Academy of Sciences  Beijing 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