{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T03:20:45Z","timestamp":1780629645926,"version":"3.54.1"},"reference-count":45,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,20]],"date-time":"2021-03-20T00:00:00Z","timestamp":1616198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Research Foundation (DFG)","award":["TRR 274\/1 2020 - 408885537"],"award-info":[{"award-number":["TRR 274\/1 2020 - 408885537"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We previously introduced the brain erythropoietin (EPO) circle as a model to explain the adaptive \u2018brain hardware upgrade\u2019 and enhanced performance. In this fundamental circle, brain cells, challenged by motor-cognitive tasks, experience functional hypoxia, triggering the expression of EPO among other genes. We attested hypoxic cells by a transgenic reporter approach under the ubiquitous CAG promoter, with Hif-1\u03b1 oxygen-dependent degradation-domain (ODD) fused to CreERT2-recombinase. To specifically focus on the functional hypoxia of excitatory pyramidal neurons, here, we generated CaMKII\u03b1-CreERT2-ODD::R26R-tdTomato mice. Behavioral challenges, light-sheet microscopy, immunohistochemistry, single-cell mRNA-seq, and neuronal cultures under normoxia or hypoxia served to portray these mice. Upon complex running wheel performance as the motor-cognitive task, a distinct increase in functional hypoxic neurons was assessed immunohistochemically and confirmed three-dimensionally. In contrast, fear conditioning as hippocampal stimulus was likely too short-lived to provoke neuronal hypoxia. Transcriptome data of hippocampus under normoxia versus inspiratory hypoxia revealed increases in CA1 CaMKII\u03b1-neurons with an immature signature, characterized by the expression of Dcx, Tbr1, CaMKII\u03b1, Tle4, and Zbtb20, and consistent with accelerated differentiation. The hypoxia reporter response was reproduced in vitro upon neuronal maturation. To conclude, task-associated activity triggers neuronal functional hypoxia as a local and brain-wide reaction mediating adaptive neuroplasticity. Hypoxia-induced genes such as EPO drive neuronal differentiation, brain maturation, and improved performance.<\/jats:p>","DOI":"10.3390\/ijms22063164","type":"journal-article","created":{"date-parts":[[2021,3,21]],"date-time":"2021-03-21T22:00:37Z","timestamp":1616364037000},"page":"3164","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["CaMKII\u03b1 Expressing Neurons to Report Activity-Related Endogenous Hypoxia upon Motor-Cognitive Challenge"],"prefix":"10.3390","volume":"22","author":[{"given":"Umer Javed","family":"Butt","sequence":"first","affiliation":[{"name":"Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imam","family":"Hassouna","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Fernandez Garcia-Agudo","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7913-2716","authenticated-orcid":false,"given":"Agnes A.","family":"Steixner-Kumar","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constanze","family":"Depp","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Barnkothe","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4222-0947","authenticated-orcid":false,"given":"Matthias R.","family":"Zillmann","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Ronnenberg","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktoria","family":"Bonet","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Goebbels","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus-Armin","family":"Nave","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8371-5711","authenticated-orcid":false,"given":"Hannelore","family":"Ehrenreich","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/nrn1687","article-title":"Emerging biological roles for erythropoietin in the nervous system","volume":"6","author":"Brines","year":"2005","journal-title":"Nat. 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