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Impaired central mineralocorticoid (MR) and glucocorticoid receptor (GR) equilibrium has been suggested as a key mechanism in the pathogenesis of human depression. Here, we investigate if deficient central MR\/GR signaling is causative for a poor outcome after MI in mice. Mice with an inducible forebrain-specific MR\/GR knockout (MR\/GR-KO) underwent baseline and follow-up echocardiography every 2\u00a0weeks after MI or sham operation. Behavioral testing at 4\u00a0weeks confirmed significant depressive-like behavior and, strikingly, a higher mortality after MI, while cardiac function and myocardial damage remained unaffected. Telemetry revealed cardiac autonomic imbalance with marked bradycardia and ventricular tachycardia (VT) upon MI in MR\/GR-KO. Mechanistically, we found a higher responsiveness to atropine, pointing to impaired parasympathetic tone of \u2018depressive\u2019 mice after MI. Serum corticosterone levels were increased but\u2014in line with the higher vagal tone\u2014plasma and cardiac catecholamines were decreased. MR\/GR deficiency in the forebrain led to significant depressive-like behavior and a higher mortality after MI. This was accompanied by increased vagal tone, depleted catecholaminergic compensatory capacity and VTs. Thus, limbic MR\/GR disequilibrium may contribute to the impaired outcome of depressive patients after MI and possibly explain the lack of anti-depressive treatment benefit.<\/jats:p>","DOI":"10.1007\/s00395-022-00951-6","type":"journal-article","created":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T12:05:53Z","timestamp":1662465953000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Forebrain corticosteroid receptors promote post-myocardial infarction depression and mortality"],"prefix":"10.1007","volume":"117","author":[{"given":"Bastian","family":"Bruns","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricarda","family":"Daub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Schmitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Hamze-Sinno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Spaich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Dewenter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chrysovalandis","family":"Schwale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Gass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Vogt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo","family":"Katus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Herzog","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-Christoph","family":"Friederich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Frey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jobst-Hendrik","family":"Schultz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2322-2699","authenticated-orcid":false,"given":"Johannes","family":"Backs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,9,6]]},"reference":[{"issue":"Suppl 2","key":"951_CR1","doi-asserted-by":"publisher","first-page":"S112","DOI":"10.1590\/1516-4446-2013-1098","volume":"35","author":"HM Abelaira","year":"2013","unstructured":"Abelaira HM, Reus GZ, Quevedo J (2013) Animal models as tools to study the pathophysiology of depression. 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