CaMKIIα Expressing Neurons to Report Activity-Related Endogenous Hypoxia upon Motor-Cognitive Challenge

2021-03-20 | journal article; research paper

Jump to:Cite & Linked | Documents & Media | Details | Version history

Cite this publication

​CaMKIIα Expressing Neurons to Report Activity-Related Endogenous Hypoxia upon Motor-Cognitive Challenge​
Butt, U. J.; Hassouna, I.; Fernandez Garcia-Agudo, L.; Steixner-Kumar, A. A.; Depp, C.; Barnkothe, N. & Zillmann, M. R. et al.​ (2021) 
International Journal of Molecular Sciences22(6) pp. 3164​.​ DOI: 

Documents & Media

document.pdf5.07 MBAdobe PDF


GRO License GRO License


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 
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.
Issue Date
International Journal of Molecular Sciences 
TRR 274: Checkpoints of Central Nervous System Recovery 
TRR 274 | C01: Oligodendroglial NMDA receptors and NMDAR1 autoantibodies as determinants of axonal integrity in neuropsychiatric disease 
Working Group
RG Ehrenreich (Clinical Neuroscience) 
RG Nave (Neurogenetics) 
External URL



Social Media