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CaMKIIα Expressing Neurons to Report Activity-Related Endogenous Hypoxia upon Motor-Cognitive Challenge
We previously introduced the brain erythropoietin (EPO) circle as a model to explain the adaptive ‘brain hardware upgrade’ and enhanced performance. In this fundamental circle, brain cells, challenged by motor-cognitive tasks, experience functional hypoxia, triggering the expression of EPO among oth...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003772/ https://www.ncbi.nlm.nih.gov/pubmed/33804598 http://dx.doi.org/10.3390/ijms22063164 |
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author | Butt, Umer Javed Hassouna, Imam Fernandez Garcia-Agudo, Laura Steixner-Kumar, Agnes A. Depp, Constanze Barnkothe, Nadine Zillmann, Matthias R. Ronnenberg, Anja Bonet, Viktoria Goebbels, Sandra Nave, Klaus-Armin Ehrenreich, Hannelore |
author_facet | Butt, Umer Javed Hassouna, Imam Fernandez Garcia-Agudo, Laura Steixner-Kumar, Agnes A. Depp, Constanze Barnkothe, Nadine Zillmann, Matthias R. Ronnenberg, Anja Bonet, Viktoria Goebbels, Sandra Nave, Klaus-Armin Ehrenreich, Hannelore |
author_sort | Butt, Umer Javed |
collection | PubMed |
description | We previously introduced the brain erythropoietin (EPO) circle as a model to explain the adaptive ‘brain hardware upgrade’ 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-1α oxygen-dependent degradation-domain (ODD) fused to CreERT2-recombinase. To specifically focus on the functional hypoxia of excitatory pyramidal neurons, here, we generated CaMKIIα-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 CaMKIIα-neurons with an immature signature, characterized by the expression of Dcx, Tbr1, CaMKIIα, 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. |
format | Online Article Text |
id | pubmed-8003772 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-80037722021-03-28 CaMKIIα Expressing Neurons to Report Activity-Related Endogenous Hypoxia upon Motor-Cognitive Challenge Butt, Umer Javed Hassouna, Imam Fernandez Garcia-Agudo, Laura Steixner-Kumar, Agnes A. Depp, Constanze Barnkothe, Nadine Zillmann, Matthias R. Ronnenberg, Anja Bonet, Viktoria Goebbels, Sandra Nave, Klaus-Armin Ehrenreich, Hannelore Int J Mol Sci Article We previously introduced the brain erythropoietin (EPO) circle as a model to explain the adaptive ‘brain hardware upgrade’ 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-1α oxygen-dependent degradation-domain (ODD) fused to CreERT2-recombinase. To specifically focus on the functional hypoxia of excitatory pyramidal neurons, here, we generated CaMKIIα-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 CaMKIIα-neurons with an immature signature, characterized by the expression of Dcx, Tbr1, CaMKIIα, 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. MDPI 2021-03-20 /pmc/articles/PMC8003772/ /pubmed/33804598 http://dx.doi.org/10.3390/ijms22063164 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Butt, Umer Javed Hassouna, Imam Fernandez Garcia-Agudo, Laura Steixner-Kumar, Agnes A. Depp, Constanze Barnkothe, Nadine Zillmann, Matthias R. Ronnenberg, Anja Bonet, Viktoria Goebbels, Sandra Nave, Klaus-Armin Ehrenreich, Hannelore CaMKIIα Expressing Neurons to Report Activity-Related Endogenous Hypoxia upon Motor-Cognitive Challenge |
title | CaMKIIα Expressing Neurons to Report Activity-Related Endogenous Hypoxia upon Motor-Cognitive Challenge |
title_full | CaMKIIα Expressing Neurons to Report Activity-Related Endogenous Hypoxia upon Motor-Cognitive Challenge |
title_fullStr | CaMKIIα Expressing Neurons to Report Activity-Related Endogenous Hypoxia upon Motor-Cognitive Challenge |
title_full_unstemmed | CaMKIIα Expressing Neurons to Report Activity-Related Endogenous Hypoxia upon Motor-Cognitive Challenge |
title_short | CaMKIIα Expressing Neurons to Report Activity-Related Endogenous Hypoxia upon Motor-Cognitive Challenge |
title_sort | camkiiα expressing neurons to report activity-related endogenous hypoxia upon motor-cognitive challenge |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003772/ https://www.ncbi.nlm.nih.gov/pubmed/33804598 http://dx.doi.org/10.3390/ijms22063164 |
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