Wakhloo, Debia Rajnath

English

Erythropoietin (EPO), named after its role in hematopoiesis, has been best studied in the hematopoietic system. Studies emphasizing the expression of EPO in the central nervous system have sparked an interest in its role in the brain. Interestingly, EPO has consistently led to improved cognition in animal models and in patients suffering from neuropsychiatric disorders such as schizophrenia. However, the mechanism by which EPO mediates its effects on cognition have remained obscure. The present work focuses on EPO mediated action on the Central Nervous System (CNS). This thesis replicated the EPO mediated increase in pyramidal neuron numbers of the CA1 region previously published by our group (Hassouna et al, 2016) and extended this finding using a novel approach. Moreover, this thesis demonstrated EPO mediated increase in neurodifferentiation (NexCreERT2) and neuroplasticity (Thy1-YFP) in young and adult mice. Single cell sequencing after EPO injection also revealed and strengthened these findings on a transcriptome level. These results represent a new perspective of EPO mediated neuronal differentiation. Despite technical limitations of using transgenic mouse lines, the present work could hypothesize that EPO induces the differentiation of precursors into different progenies (GliCreERT2) in other regions of the brain (NestinCreERT2) or differentiate into neurons (Sox2CreERT2). These findings reveal a continuum like view of neuronal lineage and demonstrate that EPO acts on multiple precursors known or unknown, alone or synergistically, to contribute to the increase in the number of pyramidal neurons in the CA1, and thereby improving cognition. The present work in addition provides a cellular mechanistic insight, which hypothesized that exposure to a learning paradigm such as complex running wheel (CRW) could upregulate EPO/EPOR in pyramidal neurons of the CA1.  As EPO is a hypoxia inducible gene, this thesis demonstrated that neuronal networks engaged in cognitive tasks undergo hypoxia (CAGCreERT2ODD). EPO mediated improved learning is imitated by exposure to mild exogenous/inspiratory hypoxia. The present work provides the first evidence that EPO/EPOR are central to cognitive improvement upon physiological/mild exogenous hypoxia as the effects are attenuated in conditional knockout mice lacking EPO (NexCre::EPO-KO) or EPOR (NexCre::EPOR-KO) gene. Taken together, these results indicate a novel model of neuronal plasticity where neuronal networks challenged by cognitive tasks drift into transient hypoxia triggering neuronal EPO/EPOR expression. This provides insight for the importance of EPO in cognition and perhaps its relevance for new treatment strategies of cognitive improvement.2020-11-1

Georg-August-University Göttingen

Erythropoietin as a driver of neurodifferentiation, neuroplasticity and cognition – A continuum view of the neuronal lineage

https://ediss.uni-goettingen.de/bitstream/21.11130/00-1735-0000-0005-12C2-B/1/Debia%20Wakhloo_Thesis_For%20Submission%20Online_02.12.2019.pdf

Erythropoietin as a driver of neurodifferentiation, neuroplasticity and cognition – A continuum view of the neuronal lineage

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Georg-August-University Göttingen