Gestational Iron Deficiency disrupts neural patterning in the embryo

摘要 这项补充资金申请建立在尤尼斯·肯尼迪·施莱弗国家研究所的基础上 儿童健康和人类发展资助的研究基金的重点是影响 妊娠期缺铁(GID)对大脑发育的影响。在这项工作中，我们发现 这种GID改变了胚胎大脑中的神经细胞群，导致了 生命后期的兴奋性和抑制性信号(E/I平衡)。这种不平衡，与 小白蛋白表达的中间神经元(PV)的减少对出生后补充铁是不可取的 这表明胚胎中发生的变化是永久性的，可能会使大脑 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 Balance和阿尔茨海默病小鼠模型显示，PV- 与年龄匹配的野生型细胞相比，大脑皮质中的表达细胞。这些观察结果， 再加上我们最近的发现，GID导致大脑中特定区域的金属调节失调 (这也在AD中发现)，提出了一个有趣的假设，即妊娠期缺铁导致 后代在晚年更容易患上阿尔茨海默病。 我们将通过建立双重侮辱模型来检验这一新假设，在该模型中，我们暴露了 家族性AD与GID的关系以及GID是否会改变AD的发病时间和严重程度 病理学。作为阳性对照，我们还将AD小鼠模型与我们新生成的小鼠相结合 早期暴露于人类疱疹病毒6型潜伏感染(HHV6)的模型，这是一种二次侮辱，具有 最近被认为与阿尔茨海默病有关，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.