{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T11:28:26Z","timestamp":1790767706449,"version":"4.1.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neural Circuits"],"abstract":"\n Introduction<\/jats:title>\n \n Prader-Willi syndrome (PWS) results from a lack of expression in several paternally inherited, imprinted contiguous genes. Among the genes inactivated in PWS, the\n Magel2<\/jats:italic>\n gene is considered a significant contributor to the etiology of the syndrome. The loss of the\n Magel2<\/jats:italic>\n gene causes abnormalities in growth and fertility and increased adiposity with altered metabolism in adulthood, which aligns with some of the pathologies observed in PWS. Given that anxiety is a prominent phenotypic behavior in PWS, we investigate the role of the\n Magel2<\/jats:italic>\n gene, particularly in hypothalamic POMC neurons innervating the medial amygdala (MeA), in the behavioral phenotypes associated with Prader-Willi Syndrome (PWS).\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n In this study, we used a retrograde AAV containing the Cre recombinase under the control of neuronal Pomc enhancers to genetically eliminate the\n Magel2<\/jats:italic>\n gene in MeA-innervating ARCPomc neurons.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Both male and female mice lacking the\n Magel2<\/jats:italic>\n gene in MeA-innervating ARC\n Pomc<\/jats:sup>\n neurons display no alterations in anxiety-like behavior during the open field test, light\/dark test, and elevated plus maze test in the absence of exposure to acute stress. However, male mice with a\n Magel2<\/jats:italic>\n gene deletion in these particular neurons exhibit increased stress-induced anxiety-like behavior and reduce motivation\/spatial learning, while female mice do not show these behavioral changes. Our results suggest that the\n Magel2<\/jats:italic>\n gene in ARC\n Pomc<\/jats:sup>\n neurons, especially in males, influences the impact of stress on anxiety-like behavior and spatial learning deficits associated with a food reward.\n <\/jats:p>\n <\/jats:sec>\n \n Discussion<\/jats:title>\n \n With the recent approval of a novel treatment for hyperphagia in PWS by the FDA that seems to target the hypothalamic melanocortin system, understanding the cellular mechanisms by which MAGEL2 in ARC\n Pomc<\/jats:sup>\n neurons innervating the MeA regulates emotional behaviors might help the development of new therapeutic strategies for addressing mental illness in individuals with PWS.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fncir.2025.1690406","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T06:22:31Z","timestamp":1763101351000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Magel2 in hypothalamic POMC neurons influences the impact of stress on anxiety-like behavior and spatial learning associated with a food reward in male mice"],"prefix":"10.3389","volume":"19","author":[{"given":"Sangbhin","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young-Hwan","family":"Jo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,14]]},"reference":[{"key":"ref1","article-title":"Anxiety-related behaviors in mice","volume-title":"Methods of behavior analysis in neuroscience","author":"Bailey","year":"2009"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"2713","DOI":"10.1093\/hmg\/ddm225","article-title":"Inactivation of the mouse Magel2 gene results in growth abnormalities similar to Prader-Willi syndrome","volume":"16","author":"Bischof","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"2497","DOI":"10.1093\/hmg\/8.13.2497","article-title":"The human MAGEL2 gene and its mouse homologue are paternally expressed and mapped to the Prader-Willi region","volume":"8","author":"Boccaccio","year":"1999","journal-title":"Hum. Mol. Genet."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1136\/jmedgenet-2018-105301","article-title":"Molecular genetic classification in Prader-Willi syndrome: a multisite cohort study","volume":"56","author":"Butler","year":"2019","journal-title":"J. Med. Genet."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1038\/gim.0b013e31822bead0","article-title":"Prader-Willi syndrome","volume":"14","author":"Cassidy","year":"2012","journal-title":"Genet. 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Med."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"e138576","DOI":"10.1172\/jci.insight.138576","article-title":"Loss of MAGEL2 in Prader-Willi syndrome leads to decreased secretory granule and neuropeptide production","volume":"5","author":"Chen","year":"2020","journal-title":"JCI Insight"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"e202201502","DOI":"10.26508\/lsa.202201502","article-title":"Magel2 knockdown in hypothalamic POMC neurons innervating the medial amygdala reduces susceptibility to diet-induced obesity","volume":"5","author":"Choi","year":"2022","journal-title":"Life Sci Alliance"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1016\/j.biopsych.2021.05.026","article-title":"Melanocortin signaling connecting systemic metabolism with mood disorders","volume":"91","author":"Copperi","year":"2022","journal-title":"Biol. 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Genet."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"595783","DOI":"10.3389\/fncir.2020.595783","article-title":"Activation of the ARCPOMC\u2192MeA projection reduces food intake","volume":"14","author":"Kwon","year":"2020","journal-title":"Front Neural Circuits"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"6295","DOI":"10.1038\/s41467-020-20160-w","article-title":"Optogenetic stimulation of the liver-projecting melanocortinergic pathway promotes hepatic glucose production","volume":"11","author":"Kwon","year":"2020","journal-title":"Nat. Commun."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"eaay5366","DOI":"10.1126\/sciadv.aay5366","article-title":"A psychological stressor conveyed by appetite-linked neurons","volume":"6","author":"Lee","year":"2020","journal-title":"Sci. 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Genet."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"e1003207","DOI":"10.1371\/journal.pgen.1003207","article-title":"Magel2 is required for leptin-mediated depolarization of POMC neurons in the hypothalamic arcuate nucleus in mice","volume":"9","author":"Mercer","year":"2013","journal-title":"PLoS Genet."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"e4291","DOI":"10.1371\/journal.pone.0004291","article-title":"Loss of magel2, a candidate gene for features of Prader-Willi syndrome, impairs reproductive function in mice","volume":"4","author":"Mercer","year":"2009","journal-title":"PLoS One"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.biopsych.2014.11.010","article-title":"An early postnatal oxytocin treatment prevents social and learning deficits in adult mice deficient for Magel2, a gene involved in Prader-Willi syndrome and autism","volume":"78","author":"Meziane","year":"2015","journal-title":"Biol. Psychiatry"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"3129","DOI":"10.1093\/hmg\/ddy216","article-title":"Impaired melanocortin pathway function in Prader-Willi syndrome gene-Magel2 deficient mice","volume":"27","author":"Oncul","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1007\/s00335-013-9454-2","article-title":"Recommendations for the investigation of animal models of Prader-Willi syndrome","volume":"24","author":"Resnick","year":"2013","journal-title":"Mamm. Genome"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"4895","DOI":"10.1093\/hmg\/ddq424","article-title":"A single postnatal injection of oxytocin rescues the lethal feeding behaviour in mouse newborns deficient for the imprinted Magel2 gene","volume":"19","author":"Schaller","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref35","volume-title":"PWS Mental Health Guidebook","author":"Schwartz","year":""},{"key":"ref36","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s11689-021-09373-2","article-title":"Behavioral features in Prader-Willi syndrome (PWS): consensus paper from the international PWS clinical trial consortium","volume":"13","author":"Schwartz","year":"2021","journal-title":"J. Neurodev. Disord."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"e52434","DOI":"10.3791\/52434","article-title":"Use of the open field maze to measure locomotor and anxiety-like behavior in mice","author":"Seibenhener","year":"2015","journal-title":"J. Vis. Exp."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"126","DOI":"10.2478\/intox-2013-0020","article-title":"Determination of motor activity and anxiety-related behaviour in rodents: methodological aspects and role of nitric oxide","volume":"6","author":"Sestakova","year":"2013","journal-title":"Interdiscip. Toxicol."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1210\/en.2010-0709","article-title":"Impaired hypothalamic regulation of endocrine function and delayed counterregulatory response to hypoglycemia in Magel2-null mice","volume":"152","author":"Tennese","year":"2011","journal-title":"Endocrinology"}],"container-title":["Frontiers in Neural Circuits"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncir.2025.1690406\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T06:22:32Z","timestamp":1763101352000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncir.2025.1690406\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,14]]},"references-count":39,"alternative-id":["10.3389\/fncir.2025.1690406"],"URL":"https:\/\/doi.org\/10.3389\/fncir.2025.1690406","relation":{},"ISSN":["1662-5110"],"issn-type":[{"value":"1662-5110","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,14]]},"article-number":"1690406"}}