One Children's Place, Department of Pediatrics, Washington University in St. Louis School of Medicine, Campus Box 8208, St. Louis, MO 63110, USA.
One Children's Place, Department of Pediatrics, Washington University in St. Louis School of Medicine, Campus Box 8208, St. Louis, MO 63110, USA.
Neurosci Lett. 2023 May 1;804:137216. doi: 10.1016/j.neulet.2023.137216. Epub 2023 Mar 28.
Erythropoietin (EPO) is a hypoxia-responsive cytokine that induces neuroprotective effect in hypoxic-ischaemic, traumatic, excitotoxic and inflammatory injuries. Recently, utilizing a clinically relevant murine model of TBI and delayed hypoxemia, we have found that ongoing recombinant human EPO (rhEPO) administration influenced neurogenesis, neuroprotection, synaptic density and, behavioral outcomes early after TBI, and the impact on long-lasting outcomes 6 months after injury. We also demonstrated that the 1-month behavioral improvement was associated with mitogen-activated protein kinase (MAPK)/cAMP response element-binding protein (CREB) signaling activation and increased of excitatory synaptic density in the amygdala. However, we did not uncover which type of cells were involved in fear memory response enhancement after rhEPO treatment in the setting of TBI with delayed hypoxemia. In this report, using chemogenetic tools in our controlled cortical impact (CCI) model, we were able to inactivate excitatory neurons and eliminate rhEPO-induced fear memory recall enhancement. In summary, these data demonstrate that rhEPO treatment initiated after TBI enhances contextual fear memory in the injured brain via activation of excitatory neurons in the amygdala.
促红细胞生成素（EPO）是一种低氧反应性细胞因子，可在缺氧缺血、创伤、兴奋毒性和炎症损伤中诱导神经保护作用。最近，我们利用一种具有临床相关性的创伤性脑损伤（TBI）和迟发性低氧血症的小鼠模型，发现持续给予重组人促红细胞生成素（rhEPO）会影响神经发生、神经保护、突触密度以及 TBI 后早期的行为结果，并且对损伤后 6 个月的长期结果也有影响。我们还证明，1 个月的行为改善与丝裂原活化蛋白激酶（MAPK）/cAMP 反应元件结合蛋白（CREB）信号通路的激活以及杏仁核中兴奋性突触密度的增加有关。然而，我们尚未揭示在 TBI 合并迟发性低氧血症的情况下，rhEPO 治疗后哪种类型的细胞参与了恐惧记忆反应的增强。在本报告中，我们使用化学遗传学工具在控制性皮质撞击（CCI）模型中，成功地使兴奋性神经元失活，并消除了 rhEPO 诱导的恐惧记忆召回增强。总之，这些数据表明，TBI 后开始的 rhEPO 治疗通过激活杏仁核中的兴奋性神经元增强了受伤大脑中的情境性恐惧记忆。
