6533b7d9fe1ef96bd126ce2d
RESEARCH PRODUCT
Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin.
Umer Javed ButtMatthias R. ZillmannDebia WakhlooJuan NacherAshish RajputImam HassounaKatharina SchneiderLiane WüstefeldAnna SeelbachFranziska ScharkowskiSahab ArinradKlaus-armin NaveKlaus-armin NaveHenrik MartensHannelore EhrenreichHannelore EhrenreichKamilla W. MiskowiakHauke B. WernerAgnes A. Steixner-kumarVikas BansalVikas BansalSonja M. WojcikStefan BonnStefan BonnAbdul Qadir IbrahimYasmina CurtoYasmina Curtosubject
0301 basic medicineMaleDendritic spineGeneral Physics and AstronomyHippocampal formationVARIANTSADULT NEUROGENESIS0302 clinical medicineCognitionhemic and lymphatic diseasesReceptors ErythropoietinHypoxialcsh:ScienceNEURONSMultidisciplinaryNeuronal PlasticityPyramidal CellsNeurogenesisQBrainCell DifferentiationHEMATOPOIETIC PROGENITOR CELLSFemalemedicine.symptomProto-Oncogene Proteins c-fosmedicine.drugEXPRESSIONScienceDendritic SpinesNeurogenesisModels NeurologicalBiologyMotor ActivityGeneral Biochemistry Genetics and Molecular BiologyArticle03 medical and health sciencesParacrine signallingPhysical Conditioning AnimalNeuroplasticitymedicineAnimalsHumansErythropoietinMEMORYCognitive neuroscienceGeneral ChemistryHypoxia (medical)RECOMBINANT-HUMAN-ERYTHROPOIETINCellular neuroscienceErythropoietin receptorMice Inbred C57BLMICE030104 developmental biologyErythropoietinPhysical EnduranceIDENTITYlcsh:QTranscriptomeNeuroscience030217 neurology & neurosurgeryGene Deletiondescription
Erythropoietin (EPO), named after its role in hematopoiesis, is also expressed in mammalian brain. In clinical settings, recombinant EPO treatment has revealed a remarkable improvement of cognition, but underlying mechanisms have remained obscure. Here, we show with a novel line of reporter mice that cognitive challenge induces local/endogenous hypoxia in hippocampal pyramidal neurons, hence enhancing expression of EPO and EPO receptor (EPOR). High-dose EPO administration, amplifying 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 is imitated by exposure to mild exogenous/inspiratory hypoxia. All these effects depend on neuronal expression of the Epor gene. This suggests a model of neuroplasticity in form of a fundamental regulatory circle, in which neuronal networks—challenged by cognitive tasks—drift into transient hypoxia, thereby triggering neuronal EPO/EPOR expression.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2020-03-01 |