Fear memory is a pivotal biological function by which organisms can predict possible danger to avoid or reduce harm. However, dysregulation of fear memory processing may lead to pathological fear or anxiety and produce serious clinical symptoms, such as post-traumatic stress disorder (PTSD). Iron deficiency (ID) is reported to inhibit the initiation of fear memory. In our study, we found that ferroportin1 (FPN1), the only known cellular iron export protein in mammals, and ablation in neurons and astrocytes caused iron deficiency in the cortex and hippocampus. However, little is known about its role in the development of fear memory. Moreover, direct evidence of the role of FPN1, or the related molecular mechanisms of such a role, in balancing brain iron homeostasis, especially in neuronal cells, is lacking. Herein, we deleted Fpn1 in mouse neurons, using Nestin-cre transgenic mice, and explored the impact on neuronal iron recycling and brain iron homeostasis in the cortex and hippocampus. We investigated the response of the mice to contextual fear and found that formation of fear memory was impeded after neuronal FPN1 depletion. We also found that FPN1 ablation in neurons and astrocytes caused an atypical expression of iron metabolism-related proteins in these two regions: decreased expression of DMT1, Ft-H, and Ft-L, and increased TfR1 expression. In addition, the decreased FPN1 in brain microvascular endothelial cells (BMVECs) also shed light on the cause of the decreased iron delivery to the brain through the blood-brain barrier (BBB). Our research highlights the major role played by FPN1 in brain iron homeostasis and identifies a potential target for the treatment of PTSD.

中文翻译：

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有条件的 Ferroportin1 脑部消融小鼠的脑缺铁和情境恐惧记忆的影响

恐惧记忆是一种关键的生物学功能，生物体可以通过它预测可能的危险以避免或减少伤害。然而，恐惧记忆处理的失调可能导致病理性恐惧或焦虑，并产生严重的临床症状，如创伤后应激障碍（PTSD）。据报道，缺铁 (ID) 会抑制恐惧记忆的启动。在我们的研究中，我们发现 ferroportin1 (FPN1)（哺乳动物中唯一已知的细胞铁输出蛋白）以及神经元和星形胶质细胞的消融导致皮层和海马体缺铁。然而，人们对其在恐惧记忆发展中的作用知之甚少。此外，缺乏 FPN1 作用的直接证据，或这种作用的相关分子机制，在平衡脑铁稳态方面，尤其是在神经元细胞中。在这里，我们删除了小鼠神经元中的 Fpn1，使用 Nestin-cre 转基因小鼠，探索了对皮质和海马神经元铁循环和脑铁稳态的影响。我们研究了小鼠对情境恐惧的反应，发现神经元 FPN1 耗尽后恐惧记忆的形成受到阻碍。我们还发现神经元和星形胶质细胞中的 FPN1 消融导致这两个区域铁代谢相关蛋白的非典型表达：DMT1、Ft-H 和 Ft-L 的表达降低，TfR1 表达增加。此外，脑微血管内皮细胞 (BMVECs) 中 FPN1 的减少也揭示了通过血脑屏障 (BBB) 向大脑输送铁减少的原因。我们的研究强调了 FPN1 在脑铁稳态中的主要作用，并确定了治疗 PTSD 的潜在目标。