Fetal Alcohol, Thyroid Hormone Affected Genes & Behavior

胎儿酒精暴露（FAE）导致人类多动、学习缺陷、反应抑制和更高的抑郁症患病率。我希望在动物模型中找到导致这些结果的机制，以便于预防或治疗人类FAE相关的行为缺陷。在我们的FAE动物模型中，我们在妊娠第22天发现母亲和胎儿都有甲状腺功能低下的状态。由于先天性甲状腺功能减退症会导致儿童的学习障碍和多动症，FAE行为障碍的机制之一可能与FAE胎儿的先天性甲状腺功能减退有关。初步数据显示，在强迫游泳测试（FST）中，雄性和雌性成年FAE后代的抑郁行为都比成对喂养的对照组增加。与对照组相比，甲状腺激素受体（TRbeta）敲除小鼠在FST中的不动性降低。此外，利用cDNA微阵列技术，我们发现FAE雄性杏仁核/下丘脑区域E19上80个基因表达改变，其中几个是甲状腺激素调节的基因。为了阐明甲状腺异常在fae诱导行为中的作用，首先我计划使用实时定量RT-PCR和原位杂交来证实从微阵列数据中发现的结果。然后我将在产前用甲状腺激素治疗这些动物，以纠正胎儿甲状腺功能低下的状态，减轻这些FAE后代中发现的多动、学习缺陷和增加的抑郁行为以及甲状腺激素相关基因表达的变化。最后，我将通过产后早期甲状腺置换来治疗这些动物，以确定这是否能逆转任何行为缺陷和/或基因表达的改变。如果这些甲状腺激素给药范式中的任何一种导致FAE后代行为缺陷的减弱，则可以成为FAE儿童的治疗方法。

Fetal alcohol exposure (FAE) in humans leads to hyperactivity, learning deficits, response inhibition and higher prevalence of depression. I would like to find the mechanism(s) responsible for these outcomes in an animal model, in order to facilitate the prevention or treatment of FAE- related behavioral deficits in humans. In our animal model of FAE, we found a hypothyroid state in both the mother and fetus at gestation day 22. Since congenital hypothyroidism results in learning impairments and hyperactivity in children, one of the mechanisms by which the FAE behavioral impairments could be related to the congenital hypothyroidism of the FAE fetus. Preliminary data show increased depressive behavior in both male and female adult FAE offspring in the forced swim test (FST) compared to their pair-fed controls. Thyroid hormone receptor beta (TRbeta) knockout mice show decreased immobility in the FST compared to controls. In addition, using cDNA microarray technology, we have found altered expression in the FAE male amygdala/hypothalamic region on E19 of 80 genes, several of which are thyroid hormone regulated. In order to elucidate the role of thyroid abnormalities in the FAE-induced behavior, first I plan to confirm the results found from the microarray data using real-time quantitative RT-PCR and in situ hybridization. Then I will treat these animals with thyroid hormones prenatally, to correct for the fetal hypothyroid state, to alleviate hyperactivity, learning deficit and increased depressive behavior and changes in thyroid hormone-related gene expression found in these FAE offspring. Finally, I will treat these animals by early postnatal thyroid replacement to determine if this reverses any of the behavioral deficits and/or alterations in gene expression. If any of these thyroid hormone administration paradigms lead to attenuation of behavioral deficits in the FAE offspring, the could become treatments for FAE children.