Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin
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Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin. / Wakhloo, Debia; Scharkowski, Franziska; Curto, Yasmina; Javed Butt, Umer; Bansal, Vikas; Steixner-Kumar, Agnes A; Wüstefeld, Liane; Rajput, Ashish; Arinrad, Sahab; Zillmann, Matthias R; Seelbach, Anna; Hassouna, Imam; Schneider, Katharina; Qadir Ibrahim, Abdul; Werner, Hauke B; Martens, Henrik; Miskowiak, Kamilla; Wojcik, Sonja M; Bonn, Stefan; Nacher, Juan; Nave, Klaus-Armin; Ehrenreich, Hannelore.
In: NAT COMMUN, Vol. 11, No. 1, 09.03.2020, p. 1313.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin
AU - Wakhloo, Debia
AU - Scharkowski, Franziska
AU - Curto, Yasmina
AU - Javed Butt, Umer
AU - Bansal, Vikas
AU - Steixner-Kumar, Agnes A
AU - Wüstefeld, Liane
AU - Rajput, Ashish
AU - Arinrad, Sahab
AU - Zillmann, Matthias R
AU - Seelbach, Anna
AU - Hassouna, Imam
AU - Schneider, Katharina
AU - Qadir Ibrahim, Abdul
AU - Werner, Hauke B
AU - Martens, Henrik
AU - Miskowiak, Kamilla
AU - Wojcik, Sonja M
AU - Bonn, Stefan
AU - Nacher, Juan
AU - Nave, Klaus-Armin
AU - Ehrenreich, Hannelore
PY - 2020/3/9
Y1 - 2020/3/9
N2 - 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.
AB - 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.
KW - Animals
KW - Brain/metabolism
KW - Cell Differentiation/drug effects
KW - Cognition/drug effects
KW - Dendritic Spines/drug effects
KW - Erythropoietin/metabolism
KW - Female
KW - Gene Deletion
KW - Humans
KW - Hypoxia/metabolism
KW - Male
KW - Mice, Inbred C57BL
KW - Models, Neurological
KW - Motor Activity/drug effects
KW - Neurogenesis/drug effects
KW - Neuronal Plasticity/drug effects
KW - Physical Conditioning, Animal
KW - Physical Endurance/drug effects
KW - Proto-Oncogene Proteins c-fos/metabolism
KW - Pyramidal Cells/drug effects
KW - Receptors, Erythropoietin/metabolism
KW - Transcriptome/drug effects
U2 - 10.1038/s41467-020-15041-1
DO - 10.1038/s41467-020-15041-1
M3 - SCORING: Journal article
C2 - 32152318
VL - 11
SP - 1313
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -