Dataset Information

Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin.

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.

SUBMITTER: Wakhloo D

PROVIDER: S-EPMC7062779 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin.

Wakhloo Debia D Scharkowski Franziska F Curto Yasmina Y Javed Butt Umer U Bansal Vikas V Steixner-Kumar Agnes A AA Wüstefeld Liane L Rajput Ashish A Arinrad Sahab S Zillmann Matthias R MR Seelbach Anna A Hassouna Imam I Schneider Katharina K Qadir Ibrahim Abdul A Werner Hauke B HB Martens Henrik H Miskowiak Kamilla K Wojcik Sonja M SM Bonn Stefan S Nacher Juan J Nave Klaus-Armin KA Ehrenreich Hannelore H

Nature communications 20200309 1

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/paracr ...[more]

PMID: 32152318

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Project description:We present the first evidence for vascular regulation driving fMRI signals in specific functional brain networks. Using concurrent neuronal and vascular stimuli, we collected 30 BOLD fMRI datasets in 10 healthy individuals: a working memory task, flashing checkerboard stimulus, and CO2 inhalation challenge were delivered in concurrent but orthogonal paradigms. The resulting imaging data were averaged together and decomposed using independent component analysis, and three "neuronal networks" were identified as demonstrating maximum temporal correlation with the neuronal stimulus paradigms: Default Mode Network, Task Positive Network, and Visual Network. For each of these, we observed a second network component with high spatial overlap. Using dual regression in the original 30 datasets, we extracted the time-series associated with these network pairs and calculated the percent of variance explained by the neuronal or vascular stimuli using a normalized R2 parameter. In each pairing, one network was dominated by the appropriate neuronal stimulus, and the other was dominated by the vascular stimulus as represented by the end-tidal CO2 time-series recorded in each scan. We acquired a second dataset in 8 of the original participants, where no CO2 challenge was delivered and CO2 levels fluctuated naturally with breathing variations. Although splitting of functional networks was not robust in these data, performing dual regression with the network maps from the original analysis in this new dataset successfully replicated our observations. Thus, in addition to responding to localized metabolic changes, the brain's vasculature may be regulated in a coordinated manner that mimics (and potentially supports) specific functional brain networks. Multi-modal imaging and advances in fMRI acquisition and analysis could facilitate further study of the dual nature of functional brain networks. It will be critical to understand network-specific vascular function, and the behavior of a coupled vascular-neural network, in future studies of brain pathology.

Dataset Information

Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin.

Publications

Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin.

Similar Datasets

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