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These are complex disorders with both environmental and genetic influences contributing to their etiology. Methyl-CpG Binding Protein 2 (MeCP2) has been attributed a key role in the control of neuronal activity-dependent gene expression and is a master regulator of experience-dependent epigenetic programming. Moreover, mutations in the<jats:italic>MECP2<\/jats:italic>gene are the primary cause of Rett syndrome and, to a lesser extent, of a range of other major neurodevelopmental disorders. Here, we aim to study the interaction of MeCP2 with early-life stress in variables known to be affected by this environmental manipulation, namely anxiety-like behavior and activity of the underlying neural circuits.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using<jats:italic>Mecp2<\/jats:italic>heterozygous and wild-type female mice we investigated the effects of the interaction of<jats:italic>Mecp2<\/jats:italic>haplodeficiency with maternal separation later in life, by assessing anxiety-related behaviors and measuring concomitant c-FOS expression in stress- and anxiety-related brain regions of adolescent females. Moreover, arginine vasopressin and corticotropin-releasing hormone neurons of the paraventricular hypothalamic nucleus were analyzed for neuronal activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In wild-type mice, maternal separation caused a reduction in anxiety-like behavior and in the activation of the hypothalamic paraventricular nucleus, specifically in corticotropin-releasing hormone-positive cells, after the elevated plus maze. This effect of maternal separation was not observed in<jats:italic>Mecp2<\/jats:italic>heterozygous females that per se show decreased anxiety-like behavior and concomitant decreased paraventricular nuclei activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our data supports that MeCP2 is an essential component of HPA axis reprogramming and underlies the differential response to anxiogenic situations later in life.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s11689-021-09409-7","type":"journal-article","created":{"date-parts":[[2021,12,11]],"date-time":"2021-12-11T16:03:24Z","timestamp":1639238604000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["MeCP2 haplodeficiency and early-life stress interaction on anxiety-like behavior in adolescent female mice"],"prefix":"10.1186","volume":"13","author":[{"given":"Mar\u00eda","family":"Abell\u00e1n-\u00c1lvaro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Stork","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Agust\u00edn-Pav\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3229-8270","authenticated-orcid":false,"given":"M\u00f3nica","family":"Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,12,11]]},"reference":[{"key":"9409_CR1","doi-asserted-by":"crossref","unstructured":"Bandelow B, Michaelis S. 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