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Cognitive domains, improved by injections of exogenous EPO or by endogenous, hypoxia-stimulated EPO, include important forebrain functions, namely attention, working memory, drive, and executive performance. To gain mechanistic insight into the involvement of forebrain-expressed EPO, we deleted EPO in mice using as specific cre-driver\n                    <jats:italic>Emx1<\/jats:italic>\n                    . Here, we report that these mutant mice act comparably to their wildtype littermates in a comprehensive behavioral test battery. Importantly, we find that the transcripts of both EPOR and a novel, brain-expressed EPO receptor, EphB4, respond to EPO deletion with compensatory upregulation. EphB4 expression in brain and its increase upon forebrain erasure of EPOR are confirmed by in situ hybridization and immunohistochemistry. The augmented expression of both EPOR and EphB4 and their regulatory intercorrelation may explain why\n                    <jats:italic>EmxEPO<\/jats:italic>\n                    mutants show an even superior performance in the most challenging working memory task. Using the previously published single-nuclei-RNA-seq dataset, we further confirm the suggested compensatory mechanism, wherein EPO loss or reduction drives elevated EPOR expression, adding another layer to the intricate regulation of EPO signaling in hippocampal pyramidal neurons. Collectively, these data may explain the lack of behavioral and negative cognitive consequences upon forebrain-wide EPO elimination.\n                  <\/jats:p>","DOI":"10.1038\/s41380-025-03230-7","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T17:37:07Z","timestamp":1759253827000},"page":"1241-1252","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Forebrain-specific loss of erythropoietin provokes compensatory upregulation of different EPO receptors"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6313-5939","authenticated-orcid":false,"given":"Umer Javed","family":"Butt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2835-3003","authenticated-orcid":false,"given":"Umut","family":"\u00c7ak\u0131r","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3534-3884","authenticated-orcid":false,"given":"Anne-Fleur","family":"Wildenburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8087-360X","authenticated-orcid":false,"given":"Yasmina","family":"Curto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikas","family":"Bansal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2792-7423","authenticated-orcid":false,"given":"Susann","family":"Boretius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8724-9666","authenticated-orcid":false,"given":"Klaus-Armin","family":"Nave","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8626-5418","authenticated-orcid":false,"given":"Manvendra","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8371-5711","authenticated-orcid":false,"given":"Hannelore","family":"Ehrenreich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,30]]},"reference":[{"key":"3230_CR1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00213-011-2596-6","volume":"221","author":"R dos Santos Coura","year":"2012","unstructured":"dos Santos Coura R, Granon S. 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Approval has been obtained from the local authorities (Animal Care and Use Committee: Nieders\u00e4chsisches Landesamt f\u00fcr Verbraucherschutz und Lebensmittelsicherheit, LAVES) following the German Animal Protection Law (AZ 33.19-42502-04-18\/2803 & AZ 33.19-42502-04-17\/2393). All experiments were conducted by investigators unaware of genotypes and group assignment (\u2018fully blinded\u2019).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}]}}