Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin.

Nature Communications
Debia WakhlooH Ehrenreich

Abstract

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.

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Citations

May 31, 2020·International Journal of Molecular Sciences·Albert KolomanskyYankel Gabet
Jun 18, 2020·Molecular Medicine·Hannelore EhrenreichKamilla W Miskowiak
Feb 11, 2021·Molecular Psychiatry·Umer Javed ButtHannelore Ehrenreich
Nov 1, 2020·International Journal of Molecular Sciences·Grégory PouriéCarine Bossenmeyer-Pourié
Apr 4, 2021·International Journal of Molecular Sciences·Umer Javed ButtHannelore Ehrenreich
Jul 1, 2021·Cardiology and Therapy·Lyudmila Korostovtseva
Jul 11, 2021·Pflügers Archiv : European journal of physiology·Edith M Schneider GasserMarkus Thiersch
Aug 1, 2021·Molecular Psychiatry·Justus B H WilkeHannelore Ehrenreich
Aug 7, 2021·Communications Biology·Robert A JacobsEdith M Schneider Gasser
Jul 20, 2021·Journal of Neurochemistry·Daniela C VittoriAlcira B Nesse
Sep 11, 2021·Behavioural Brain Research·Nasser RahmaniJalal Zaringhalam
Oct 17, 2021·The European Journal of Neuroscience·Roxana Paula GinereteGiuseppe Battaglia

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Methods Mentioned

BETA
DropSeq
scRNA-seq
transgenic
Knockout
PCR
Hi-seq
RNA-seq

Software Mentioned

Phenomaster
Monocle2
GraphPad Prism
Monocle
DropSeq
Seurat
Fiji
R

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