Fetal Alcohol, Thyroid Hormone Affected Genes & Behavior

胎儿酒精、甲状腺激素影响基因

• 批准号: 6339433
• 负责人: JENNIFER S WILCOXON
• 金额: $ 2.47万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6339433
• 关键词: behavioral /social science research tag; developmental genetics; disease /disorder model; fetal alcohol syndrome; hormone therapy; in situ hybridization; laboratory rat; nonhuman therapy evaluation; polymerase chain reaction; substance abuse related behavior; thyroid disorder; thyroid hormones

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.

胎儿酒精暴露(FAE)会导致多动、学习障碍、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(S)，以促进人类FAE相关行为缺陷的预防或治疗。在我们的FAE动物模型中，我们发现在怀孕第22天，母亲和胎儿都处于甲状腺功能低下状态。由于先天性甲状腺功能减退导致儿童学习障碍和多动，FAE行为障碍可能与FAE胎儿先天性甲状腺功能减退有关。初步数据显示，与配对喂养的对照组相比，在强迫游泳测试(FST)中，成年雄性和雌性FAE后代的抑郁行为都有所增加。与对照组相比，甲状腺激素受体β(TRbeta)基因敲除小鼠在FST中的静止减少。此外，利用基因芯片技术，我们发现了80个基因中E19在FAE雄性杏仁核/下丘脑区的表达变化，其中有几个基因是甲状腺激素调控的。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基因芯片数据中发现的结果。然后我将对这些动物进行产前甲状腺激素治疗，以纠正胎儿甲状腺功能低下的状态，缓解这些FAE后代中发现的多动、学习障碍和抑郁行为增加以及甲状腺激素相关基因表达的变化。最后，我将通过出生后早期甲状腺置换来治疗这些动物，以确定这是否可以逆转任何行为缺陷和/或基因表达的变化。如果这些甲状腺激素给药范例中的任何一种导致FAE后代行为缺陷的减轻，那么这种疗法可能成为FAE儿童的治疗方法。