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首页> 外文期刊>Molecular Psychiatry >Hippocampus-dependent memory and allele-specific gene expression in adult offspring of alcohol-consuming dams after neonatal treatment with thyroxin or metformin
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Hippocampus-dependent memory and allele-specific gene expression in adult offspring of alcohol-consuming dams after neonatal treatment with thyroxin or metformin

机译：甲状腺素或二甲双胍新生儿治疗后饮​​酒大坝成年后代海马依赖的记忆和等位基因特异性基因表达

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Fetal alcohol spectrum disorder (FASD), the result of fetal alcohol exposure (FAE), affects 211% of children worldwide, with no effective treatments. Hippocampus-based learning and memory deficits are key symptoms of FASD. Our previous studies show hypothyroxinemia and hyperglycemia of the alcohol-consuming pregnant rat, which likely affects fetal neurodevelopment. We administered vehicle, thyroxine (T4) or metformin to neonatal rats post FAE and rats were tested in the hippocampus-dependent contextual fear-conditioning paradigm in adulthood. Both T4 and metformin alleviated contextual fear memory deficit induced by FAE, and reversed the hippocampal expression changes in the thyroid hormone-inactivating enzyme, deiodinase-III (Dio3) and insulin-like growth factor 2 (Igf2), genes that are known to modulate memory processes. Neonatal T4 restored maternal allelic expressions of the imprinted Dio3 and Igf2 in the adult male hippocampus, while metformin restored FAE-caused changes in Igf2 expression only. The decreased hippocampal expression of DNA methyltransferase 1 (Dnmt1) that maintains the imprinting of Dio3 and Igf2 during development was normalized by both treatments. Administering Dnmt1 inhibitor to control neonates resulted in FAE-like deficits in fear memory and hippocampal allele-specific expression of Igf2, which were reversed by metformin. We propose that neonatal administration of T4 and metformin post FAE affect memory via elevating Dnmt1 and consequently normalizing hippocampal Dio3 and Igf2 expressions in the adult offspring. The present results indicate that T4 and metformin, administered during the neonatal period that is equivalent to the third trimester of human pregnancy, are potential treatments for FASD and conceivably for other neurodevelopmental disorders with cognitive deficits.
机译：胎儿酒精暴露（FAE）导致的胎儿酒精谱系障碍（FASD），没有有效的治疗方法，会影响全世界211％的儿童。基于海马的学习和记忆障碍是FASD的关键症状。我们以前的研究表明，饮酒妊娠大鼠的甲状腺素低血症和高血糖症可能影响胎儿神经发育。在FAE之后，我们向新生大鼠施用了媒介物，甲状腺素（T4）或二甲双胍，并在成年期在海马依赖性上下文恐惧条件下对大鼠进行了测试。 T4和二甲双胍均缓解了FAE引起的情境恐惧记忆缺陷，并逆转了已知可调节基因的甲状腺激素失活酶，脱碘酶III（Dio3）和胰岛素样生长因子2（Igf2）的海马表达变化。记忆过程。新生儿T4恢复了成年雄性海马中印记的Dio3和Igf2的母亲等位基因表达，而二甲双胍仅恢复了FAE引起的Igf2表达变化。两种处理均能使发育过程中维持Dio3和Igf2印记的DNA甲基转移酶1（Dnmt1）的海马表达降低。使用Dnmt1抑制剂控制新生儿会导致恐惧记忆和Igf2的海马等位基因特异性表达中的FAE样缺陷，被二甲双胍逆转。我们建议FAE后的新生儿T4和二甲双胍的管理通过提高Dnmt1从而影响成年后代海马Dio3和Igf2的表达来影响记忆。目前的结果表明，T4和二甲双胍在新生儿期（相当于人类妊娠的三个月）给药，是潜在的FASD治疗药物，可能是其他具有认知缺陷的神经发育疾病的治疗药物。

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