Clinical Neuroscience, Max Planck Institute for Multidisciplinary Sciences, City Campus, Göttingen, Germany.
Mol Psychiatry. 2022 May;27(5):2372-2379. doi: 10.1038/s41380-022-01551-5. Epub 2022 Apr 12.
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.
执行功能、学习、注意力和处理速度是认知表现的必要方面，在神经精神障碍中受到影响。在对不同患者群体的临床研究中，重组人（rh）促红细胞生成素（EPO）持久地改善了高级认知功能并减少了脑实质损失。相应地，rhEPO 治疗年轻啮齿动物或在锥体神经元中过表达 EPO 受体（EPOR）导致显著且持久的认知改善，同时增强了海马长时程增强。这些观察结果的“大脑硬件升级”包括 EPO 诱导的锥体神经元和少突胶质细胞在海马角中的约 20%增加，而 DNA 合成没有升高。同时，EPO 减少小胶质细胞数量并抑制其活性和代谢，作为 EPO 驱动未受干扰的前体细胞分化的先决条件。这些过程依赖于神经元和小胶质细胞的 EPOR。这种强大的产后神经发生的新机制，在经典神经发生龛之外，并按需提供新细胞，伴随着树突棘增加，让我们假设内源性 EPO 在大脑中的生理认知作用，我们通过 rhEPO 治疗来模拟这种作用。在这里，我们将大脑 EPO 循环描述为工作模型，解释适应性“大脑硬件升级”和改善的性能。在这个基本的调节循环中，神经元网络受到运动认知任务的挑战，漂移到短暂的“功能性缺氧”，从而触发神经元 EPO/EPOR 表达。
