{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T16:55:18Z","timestamp":1775926518759,"version":"3.50.1"},"reference-count":81,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2015,6,23]],"date-time":"2015-06-23T00:00:00Z","timestamp":1435017600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"The National Health and Medical Research Council (NHMRC) of Australia","award":["Project Grant 457238"],"award-info":[{"award-number":["Project Grant 457238"]}]},{"name":"The Rett Syndrome Australian Research Fund and The Rett Syndrome Association of Australia"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Developmental Neurobiology"],"published-print":{"date-parts":[[2016,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p><jats:bold>Rett syndrome (RTT) is a neurodevelopmental disorder associated with mutations in the X\u2010linked gene encoding methyl\u2010CpG\u2010binding protein 2 (MeCP2) and consequent dysregulation of brain maturation. Patients suffer from a range of debilitating physical symptoms, however, behavioral and emotional symptoms also severely affect their quality of life. Here, we present previously unreported and clinically relevant affective dysfunction in the female heterozygous<jats:italic>Mecp2<\/jats:italic><jats:sup>tm1Tam<\/jats:sup>mouse model of RTT (129sv and C57BL6 mixed background). The affective dysfunction and aberrant anxiety\u2010related behavior of the<jats:italic>Mecp2<jats:sup>+<\/jats:sup><\/jats:italic><jats:sup>\/<\/jats:sup><jats:italic><jats:sup>\u2212<\/jats:sup><\/jats:italic>mice were found to be reversible with environmental enrichment (EE) from 4 weeks of age. The effect of exercise alone (via wheel running) was also explored, providing the first evidence that increased voluntary physical activity in an animal model of RTT is beneficial for some phenotypes.<jats:italic>Mecp2<jats:sup>+<\/jats:sup><\/jats:italic><jats:sup>\/<\/jats:sup><jats:italic><jats:sup>\u2212<\/jats:sup><\/jats:italic>mutants displayed elevated corticosterone despite decreased<jats:italic>Crh<\/jats:italic>expression, demonstrating hypothalamic\u2013pituitary\u2013adrenal axis dysregulation. EE of<jats:italic>Mecp2<jats:sup>+<\/jats:sup><\/jats:italic><jats:sup>\/<\/jats:sup><jats:italic><jats:sup>\u2212<\/jats:sup><\/jats:italic>mice normalized basal serum corticosterone and hippocampal BDNF protein levels. The enrichment\u2010induced rescue appears independent of the transcriptional regulation of the MeCP2 targets<jats:italic>Bdnf<\/jats:italic>exon 4 and<jats:italic>Crh<\/jats:italic>. These findings provide new insight into the neurodevelopmental role of MeCP2 and pathogenesis of RTT, in particular the affective dysfunction. The positive outcomes of environmental stimulation and physical exercise have implications for the development of therapies targeting the affective symptoms, as well as behavioral and cognitive dimensions, of this devastating neurodevelopmental disorder<\/jats:bold>. \u00a9 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 209\u2013224, 2016<\/jats:p>","DOI":"10.1002\/dneu.22308","type":"journal-article","created":{"date-parts":[[2015,5,27]],"date-time":"2015-05-27T16:09:54Z","timestamp":1432742994000},"page":"209-224","source":"Crossref","is-referenced-by-count":25,"title":["Affective dysfunction in a mouse model of<scp>R<\/scp>ett syndrome: Therapeutic effects of environmental stimulation and physical activity"],"prefix":"10.1002","volume":"76","author":[{"given":"Mari A.","family":"Kondo","sequence":"first","affiliation":[{"name":"Florey Institute of Neuroscience and Mental Health University of Melbourne Parkville Victoria 3010 Australia"},{"name":"Department of Anatomy and Neuroscience University of Melbourne Parkville Victoria 3010 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura J.","family":"Gray","sequence":"additional","affiliation":[{"name":"Florey Institute of Neuroscience and Mental Health University of Melbourne Parkville Victoria 3010 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory J.","family":"Pelka","sequence":"additional","affiliation":[{"name":"Embryology Unit Children's Medical Research Institute Westmead New South Wales 2145 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sook\u2010Kwan","family":"Leang","sequence":"additional","affiliation":[{"name":"Florey Institute of Neuroscience and Mental Health University of Melbourne Parkville Victoria 3010 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Christodoulou","sequence":"additional","affiliation":[{"name":"Western Sydney Genetics Program Children's Hospital at Westmead Westmead, New South Wales 2145 Australia"},{"name":"Disciplines of Paediatrics and Child Health and Genetic Medicine University of Sydney Sydney New South Wales 2006 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick P. 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