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| Status |
Public on Jan 30, 2020 |
| Title |
Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Erythropoietin (EPO), named after its role in hematopoiesis, is also expressed in the mammalian brain. In clinical settings, recombinant EPO had revealed a remarkable improvement of cognitive functions, but the underlying mechanisms have remained obscure. Animal studies demonstrated, however, that neuronal EPO effects are independent of an elevated hematocrit. Here, we show with a novel line of reporter mice that cognitive challenge leads to local/endogenous hypoxia in hippocampal pyramidal neurons where it induces enhanced expression of both EPO and EPO receptor (EPOR). High-dose EPO administration, which amplifies auto/paracrine EPO/EPOR signaling, prompts the emergence of new CA1 neurons and enhanced dendritic spine densities. Single cell sequencing reveals rapid increase in newly differentiating neurons. Importantly, improved performance on complex running wheels after EPO treatment is imitated by exposure to mild exogenous/inspiratory hypoxia. All these effects depend on neuronal expression of the Epor gene. Taken together, this suggests a novel cellular model of neuroplasticity in which neuronal networks, challenged by cognitive tasks, drift into transient hypoxia which becomes a trigger of neuronal EPO/EPOR expression. This regulatory circle causes long-lasting neuroplastic adaptation, and as fundamental cellular mechanism, may be relevant for strategies aiming at cognitive improvement.
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| Overall design |
6 mice (3 Placebo, 3 EPO treated), sacrificed 6h after injection, CA1 isolated
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| Contributor(s) |
Wakhloo D, Scharkowski F, Curto Y, Butt UJ, Bansal V, Steixner-Kumar AA, Wuestefeld L, Rajput A, Arinrad S, Zillmann MR, Seelbach A, Hassouna I, Schneider K, Ibrahim AQ, Werner HB, Martens H, Miskowiak K, Wojcik SM, Bonn S, Nacher J, Nave K, Ehrenreich H |
| Citation(s) |
32152318 |
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| Submission date |
Jan 29, 2020 |
| Last update date |
Mar 23, 2020 |
| Contact name |
Hannelore Ehrenreich |
| Organization name |
Max Planck Institute of Experimental Medicine
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| Department |
Clinical Neuroscience
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| Street address |
Hermann Rein Straße 3
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| City |
Göttingen |
| ZIP/Postal code |
37075 |
| Country |
Germany |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA603663 |
| SRA |
SRP245820 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE144444_wakhloo_et_al_NATCOMM.csv.gz |
5.5 Mb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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