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Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE144444 | GEO | 2020/01/30

REPOSITORIES: GEO

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Project description:Study was performed to improve understanding of erythropoiesis (EP) induced by acute anemia in Atlantic salmon. Fish was injected with a low dose of hemolytic compound phenylhydrazine (PHZ). Treatment resulted in moderate but significant reduction of hematocrit (Hct) and increased transcription of cardiac erythropoietin (epo) at 2 days post challenge (dpc), and epo receptor (epor) in spleen from 2 to 4 dpc. Oligonucleotide microarrays were used to characterize the events of EP in the spleen. These results were compared to gene expression profiles of untreated mature red blood cells (RBC) in order to search for erythroid-specific genes. Splenic responses suggested a prevalence of protective mechanisms at the first stage, characterized by induced xenobiotic metabolism and responses to oxidative and protein stress. Erythroid-specific regulation was evident at 2 dpc and enhanced by 4 dpc, and gene expression profiles witnessed a rapid establishment of RBC phenotype although Hct levels remained low. A large group of genes showed a strong correlation to globins by expression profiles. In addition to epor this included genes of heme and iron metabolism, scavengers of free radicals and chaperones, channels and transporters, markers of erythrocytes, regulators of proliferation and cell cycle arrest and many genes with unidentified roles in RBC differentiation. Induced EP in spleen was characterized by specific features, such as upregulation of virus-responsive genes and sustained high expression of proapoptotic genes including caspases. Transcriptome changes suggested an association between EP and suppression of several developmental programs including adaptive immune responses. In conclusion, acute hemolysis and resulting anemia rapidly induced EP in the spleen of Atlantic salmon, which showed both common characteristics for all vertebrates as well as fish-specific properties. Atlantic salmon was injected with a single dose of PHZ (6 mg/kg body mass) or saline. Spleen samples for microarray analyses were collected after 2 and 4 days. Additonally, red blood cells (RBC) were compared with spleen

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Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin

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