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

Executive 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.