Gestational Iron Deficiency disrupts neural patterning in the embryo

摘要 这一补充资金申请建立在我们的EUNICE KENNEDY SHRIVER研究所的基础上 儿童健康和人类健康基金会赞助的研究补助金，重点是对儿童健康和人类健康的影响。 妊娠期缺铁（GID）对大脑发育的影响。在研究过程中我们发现 GID改变了胚胎大脑中的神经元细胞群，从而改变了神经元的平衡。 兴奋性和抑制性信号传导（E/I平衡）。这种不平衡与一种 表达小白蛋白的中间神经元（PV）的减少对出生后补铁无效 这表明胚胎中发生的变化是永久性的， 在以后的生活中容易受到其他侮辱。 有趣的是，最近的研究发现，阿尔茨海默病也与E/I受损有关。 平衡和阿尔茨海默病的小鼠模型显示PV- 与年龄匹配的野生型对应物相比，这些观察， 再加上我们最近的发现，即GID导致大脑中金属的区域特异性失调， （这也是在AD中发现的），提出了一个有趣的假设，即妊娠期缺铁使 后代在以后的生活中更容易患上阿尔茨海默病。 我们将通过建立双重损伤模型来测试这一新的假设，在该模型中，我们暴露了 家族性AD与GID的关系，并测试GID是否改变了AD的病理学发作时间和严重程度 病理作为阳性对照，我们还将联合收割机AD小鼠模型与我们新生成的小鼠相结合 早期暴露于潜伏性人类疱疹病毒6型感染（HHV 6）的模型，这是一种继发性损伤， 最近被认为与AD有关，并被认为是一种病理调节剂。

Abstract This supplemental funding request builds on our EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT-sponsored research grant that is focused on the impact of gestational iron deficiency (GID) on brain development. In the course of this work we have discovered that GID alters neuronal cell populations in the embryonic brain which result in an altered balance of excitatory and inhibitory signaling (E/I balance) later in life. This imbalance, which is associated with a decrease in parvalbumin expressing interneurons (PV) is refractory to postnatal iron supplementation suggesting that the changes that occur in the embryo are permanent and might render the brain vulnerable to other insults later in life. Interestingly, recent studies have found that Alzheimer disease is also associated with an impaired E/I balance and mouse models of Alzheimer disease show a significant reduction in the number of PV- expressing cells in the cortex compared with age-matched wild-type counterparts. These observations, together with our recent findings that GID causes region specific dysregulation of metals in the brain (which is also found in AD), raise the interesting hypothesis that gestational iron deficiency renders offspring more susceptible to Alzheimer disease later in life. We will test this novel hypothesis by establishing double-insult models where we expose animal models of familial AD to GID and test whether GID alters the time of onset of pathology and the severity of AD pathology. As a positive control, we will also combine AD mouse models with our newly generated mouse model of early-life exposure to latent human herpes virus 6 infections (HHV6), a secondary insult that has recently been linked to AD and has been suggested to be a pathology modulator.