Fig. 2: The brain EPO circle.

Focusing on cornu ammonis (CA) pyramidal neurons, we delineate here a physiological circle of enduring neuroplasticity through enhanced dendritic spine density and swift generation of new functional neurons from diverse precursors without proliferation. Apparently, the entire precursor cell lineage in adult murine CA that is ready to differentiate towards pyramidal neurons remains ‘in flow’. In the proposed neuronal lineage progression, the EPO-responsive progenitor cells and immature neurons may never constitute abundant clusters in a cross-sectional steady-state analysis, but increases rather occur in transient waves with individual neurodifferentiation markers just rising at particular time windows. In this process, neuron-microglia counterbalance plays a pivotal role with both microglial and pyramidal neuronal EPOR being critical for neuronal differentiation upon EPO. Elimination of the pyramidal neuronal EPOR eradicates EPO-driven neurodifferentiation. Strikingly, also upon microglial EPOR deletion, the acceleration by EPO of neuronal differentiation is abolished. We note that the brain EPO circle can be entered anywhere, starting either with mild to moderate inspiratory hypoxia, with rhEPO treatment or with motor-cognitive challenge as inducer of functional hypoxia. Under all these circumstances, brain EPO (and EPOR) emerge as central players of a novel mechanism driving neuronal differentiation and lasting plasticity [54, 77, 105]. Note: In this sketch, the balance symbolizes cell numbers and activity, not weight, i.e., microglia numbers/activity go down while pyramidal neuron numbers go up [105].