Tunc-Ozcan Elif, Harper Kathryn M, Graf Evan N, Redei Eva E
The Asher Center, Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States.
The Asher Center, Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States.
Horm Behav. 2016 Jun;82:1-10. doi: 10.1016/j.yhbeh.2016.04.002. Epub 2016 Apr 16.
The neurodevelopmental fetal alcohol spectrum disorder (FASD) is characterized by cognitive and behavioral deficits in the offspring. Conferring the deficits to the next generation would increase overall FASD disease burden and prevention of this transmission could be highly significant. Prior studies showed the reversal of these behavioral deficits by low dose thyroxine (T4) supplementation to the ethanol-consuming mothers. Here we aim to identify whether prenatal ethanol (PE) exposure impairs hippocampus-dependent learning and memory in the second-generation (F2) progeny, and whether T4 administration to the ethanol-consuming dam can prevent it. Sprague-Dawley (S) dams received control diets (ad libitum and nutritional control) or ethanol containing liquid diet with and without simultaneous T4 (0.3mg/L diet) administration. Their offspring (SS F1) were mated with naive Brown Norway (B) males and females generating the SB F2 and BS F2 progeny. Hippocampus-dependent contextual fear memory and hippocampal expression of the thyroid hormone-regulated type 3 deiodinase, (Dio3) and neurogranin (Nrgn) were assessed. SS F1 PE-exposed females and their SB F2 progeny exhibited fear memory deficits. T4 administration to the mothers of F1 females reversed these deficits. Although SS F1 PE-exposed males also experienced fear memory deficit, this was neither transmitted to their BS F2 offspring nor reversed by prenatal T4 treatment. Hippocampal Dio3 and Nrgn expression showed similar pattern of changes. Grandmaternal ethanol consumption during pregnancy affects fear memory of the matrilineal second-generation progeny. Low dose T4 supplementation prevents this process likely via altering allele-specific and total expression of Dio3 in the hippocampus.
神经发育性胎儿酒精谱系障碍（FASD）的特征是后代存在认知和行为缺陷。将这些缺陷遗传给下一代会增加FASD的总体疾病负担，而预防这种遗传可能具有重大意义。先前的研究表明，给饮酒的母亲补充低剂量甲状腺素（T4）可逆转这些行为缺陷。在这里，我们旨在确定产前乙醇（PE）暴露是否会损害第二代（F2）后代中依赖海马体的学习和记忆，以及给饮酒的母鼠施用T4是否可以预防这种情况。斯普拉格-道利（S）母鼠接受对照饮食（随意饮食和营养对照）或含乙醇的液体饮食，同时给予或不给予T4（0.3mg/L饮食）。它们的后代（SS F1）与未接触过乙醇的棕色挪威（B）雄鼠和雌鼠交配，产生SB F2和BS F2后代。评估了依赖海马体的情境恐惧记忆以及甲状腺激素调节的3型脱碘酶（Dio3）和神经颗粒素（Nrgn）在海马体中的表达。暴露于PE的SS F1雌性及其SB F2后代表现出恐惧记忆缺陷。给F1雌性的母亲施用T4可逆转这些缺陷。尽管暴露于PE的SS F1雄性也经历了恐惧记忆缺陷，但这既没有遗传给它们的BS F2后代，也没有通过产前T4治疗得到逆转。海马体中Dio3和Nrgn的表达显示出相似的变化模式。孕期祖母饮酒会影响母系第二代后代的恐惧记忆。低剂量T4补充可能通过改变海马体中Dio3的等位基因特异性表达和总表达来预防这一过程。
