Introducing the brain erythropoietin circle to explain adaptive brain hardware upgrade and improved performance

Abstract

PrefaceExecutive functions, learning, attention, and processing speed are imperative facets of cognitive performance, affected in neuropsychiatric disorders. In clinical studies on different patient groups, recombinant human (rh) erythropoietin (EPO) lastingly improved higher cognition and reduced brain matter loss. Correspondingly, rhEPO treatment of young rodents or EPO receptor (EPOR) overexpression in pyramidal neurons caused remarkable and enduring cognitive improvement, together with enhanced hippocampal long-term potentiation. The ‘brain hardware upgrade’, underlying these observations, includes an EPO induced ~20% increase in pyramidal neurons and oligodendrocytes in cornu ammonis hippocampi in the absence of elevated DNA synthesis. In parallel, EPO reduces microglia numbers and dampens their activity and metabolism as prerequisites for undisturbed EPO-driven differentiation of pre-existing local neuronal precursors. These processes depend on neuronal and microglial EPOR. This novel mechanism of powerful postnatal neurogenesis, outside the classical neurogenic niches, and on-demand delivery of new cells, paralleled by dendritic spine increase, let us hypothesize a physiological procognitive role of hypoxia-induced endogenous EPO in brain, which we imitate by rhEPO treatment. Here we delineate the brain EPO circle as working model explaining adaptive ‘brain hardware upgrade’ and improved performance. In this fundamental regulatory circle, neuronal networks, challenged by motor-cognitive tasks, drift into transient ‘functional hypoxia’, thereby triggering neuronal EPO/EPOR expression.

Transcriptional networks predating cognition-associated pyramidal lineages are restructured by erythropoietin

“…The relative abundance was calculated by determining the observed fraction of each cell-type compared to the expected fraction and using a two-sided Fisher exact test to identify cell-types that were significantly enriched in EPO samples. Stars denote the p-values that have been adjusted using the Bonferroni correction (p<0.05= *, p<0.01= **, p<2.2e -16 = ***).…”

“…One of the major adaptive responses to hypoxia involves hypoxia-inducible factors (HIF), which bind and transcriptionally activate their responsive elements embedded in the erythropoietin (EPO) gene [11][12][13] . In essence, the endogenous EPO system in the brain provides valuable fuel for individuals to renovate their synaptic and neuronal infrastructures upon facing metabolic challenges 2,[14][15][16][17][18][19][20] .…”

“…Previous studies, combining genomics, behavioral readouts and functional assays, have illuminated the impact of brain EPO receptors and of EPO, injected or hypoxiainduced, as a driving force of ꞌhardware upgradeꞌ in particular of CA1 pyramidal neurons 16,17,21 . This ꞌhardware upgradeꞌeven reflected by magnetic resonance imaging findings in mice and humanscomprises re-wired neuronal networks, enhanced dendritic spine density, and accelerated neuronal differentiation from preexisting, non-proliferating precursors, resulting in an increment of CA1 pyramidal neurons of up to 20%, together with improved motor-cognitive performance 14,17,[21][22][23][24] .…”

EPO regulates neuronal differentiation of adult human neural-crest derived stem cells in a sex-specific manner

“…Erythropoietin (EPO) is a glycoprotein growth factor with an approximate molecular weight of 30.4 kDa firstly described in 1953 by Allan J Erslev as a specific kidney hormone stimulating the production of red blood cells [ 1 , 2 ]. Therefore, patients with anemia-related diseases like chronic kidney disease, viral infections and leukemia, are commonly treated with EPO [ 3 , 4 ]. Bunn and colleagues showed that regulation of EPO is based on low oxygen level (hypoxia) promoting the expression of hypoxia inducible factors (HIFs) and leading to increased production and secretion of EPO [ 5 ].…”

For decades against the mainstream – From erythropoietin and hypoxia as novel treatment strategies to deep phenotyping in neuropsychiatric disorders

“…All this is imitated by rhEPO treatment and contributes to cognitive improvement. Remarkably, the brain EPO circle can be entered anywhere, starting either with mild to moderate inspiratory hypoxia, with rhEPO treatment or with the aforementioned motor-cognitive challenge as inducer of functional hypoxia, leaving plenty of possible ways and also combinations thereof for future therapeutic interventions in neuropsychiatric diseases ( Ehrenreich et al, 2022 , Fernandez Garcia-Agudo et al, 2021 , Arinrad et al, 2021 , Wilke et al, 2021 , Wakhloo et al, 2020 , Butt et al, 2020 , Pan et al, 2019 , Hassouna et al, 2016 ).…”