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Marine\u2010derived EPA\u2010enriched phospholipids (EPA\u2010PL) exhibit the structural characteristics of EPA and phospholipids. However, the effect of dietary EPA\u2010PL, and the differences between amphiphilic EPA\u2010PL and lyophobic EPA on mood disorders had not been studied.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>A comparative investigation to determine the effects of dietary EPA\u2010enriched ethyl ester (EPA\u2010EE) and EPA\u2010PL on improving depression\u2010 and anxiety\u2010like behavior in a mouse model is performed, induced by 4 week chronic unpredictable mild stress (CUMS) coupled with lipopolysaccharide (LPS) challenge. It is found that dietary 4 week 0.6% (w\/w) EPA\u2010PL rescued depression\u2010 and anxiety\u2010like behavior to a greater extent than did EPA\u2010EE. Moreover, dietary EPA\u2010PL significantly reduced the immobility time by 56.6%, close to the normal level, in forced swimming test, which revealed a reversal of depression\u2010like behavior. Further studies revealed that dietary EPA\u2010PL regulated immunity, monoamine systems, and the hypothalamic\u2013pituitary\u2013adrenal (HPA) axis by multi\u2010target interactions, including inhibition of neuroinflammation and apoptosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>EPA\u2010PL exerted superior effects to EPA\u2010EE in alleviating depression\u2010 and anxiety\u2010like behavior. The data suggest potential novel candidate or targeted dietary patterns to prevent and treat mood disorder.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mnfr.202100009","type":"journal-article","created":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T03:39:47Z","timestamp":1625456387000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Dietary EPA\u2010Enriched Phospholipids Alleviate Chronic Stress and LPS\u2010Induced Depression\u2010 and Anxiety\u2010Like Behavior by Regulating Immunity and Neuroinflammation"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3397-9900","authenticated-orcid":false,"given":"Cheng\u2010Cheng","family":"Wang","sequence":"first","affiliation":[{"name":"College of Food Science and Engineering Ocean University of China  No. 5 Yushan Road Qingdao 266003 P. R. 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