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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 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:Hypoxic-ischemic encephalopathy (HIE) is a common type of brain injury caused by a lack of oxygen and blood flow to the brain during the perinatal period. The incidence of HIE is approximately 2-3 cases per 1000 live births in high-income settings; while in low- and middle-income countries, the incidence is 3-10-fold higher. Therapeutic hypothermia (TH) is the current standard treatment for neonates affected by moderate-severe HIE. However, more than 50% of all infants with suspected HIE have mild encephalopathy, and these infants are not treated with TH because of their lower risk of adverse outcomes. Despite this, several analyses of pooled data provide increasing evidence that infants who initially have mild encephalopathy may present signs of more significant brain injury later in life. The purpose of this study was to expand our knowledge about the effect of mild-moderate hypoxia-ischemia (HI) at the cellular, structural, and functional levels. An established rat model of mild-moderate HI was used, where postnatal day (P) 7 rats were exposed to unilateral permanent occlusion of the left carotid artery and 90 min of 8% hypoxia, followed by TH or normothermia (NT) treatment. The extent of injury was assessed using histology (P14 and P42) and MRI (P11 and P32), as well as with short-term and long-term behavioral tests. Neurogenesis was assessed by BrdU staining. We showed that mild-moderate HI leads to a progressive loss of brain tissue, pathological changes in MRI scans, as well as an impairment of long-term motor function. At P14, the median area loss assessed by histology for HI animals was 20% (p < 0.05), corresponding to mild-moderate brain injury, increasing to 55% (p < 0.05) at P42. The data assessed by MRI corroborated our results. HI led to a decrease in neurogenesis, especially in the hippocampus and the lateral ventricle at early time points, with a delayed partial recovery. TH was not neuroprotective at early time points following mild-moderate HI, but prevented the increase in brain damage over time. Additionally, rats treated with TH showed better long-term motor function. Altogether, our results bring more light to the understanding of pathophysiology following mild-moderate HI. We showed that, in the context of mild-moderate HI, TH failed to be significantly neuroprotective. However, animals treated with TH showed a significant improvement in motor, but not cognitive long-term function. These results are in line with what is observed in some cases where neonates with mild HIE are at risk of neurodevelopmental deficits in infancy or childhood. Whether TH should be used as a preventive treatment to reduce adverse outcomes in mild-HIE remains of active interest, and more research has to be carried out in order to address this question.

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Dataset Information

Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin.

Publications

Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin.

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