Prenatal Alcohol; Hormone-Regulated Genes & Behavior

描述(申请人提供)：在宫内接触酒精的儿童 经常表现出行为问题，包括多动，学习 缺陷、反应抑制和抑郁症患病率增加。许多. 这些行为缺陷也在胎儿酒精的动物模型中观察到。 曝光。类似的行为缺陷在产前应激后和在 患有亚临床甲状腺功能减退症母亲所生的孩子。此信息 形成了这一建议的主要假说：胎儿糖皮质激素和甲状腺 荷尔蒙环境可能在很大程度上导致 产前酒精暴露。 具体目标1将研究相对甲状腺功能减退症的子假说 在酗酒的大坝和它的胎儿中被发现，至少部分是由于 孕妇皮质酮升高会抑制甲状腺功能。 随后，这种产前甲状腺功能低下状态的胎儿暴露在酒精中 (FAE)后代可导致小鼠的活动和认知行为缺陷 成年后代。具体地说，我们的目标是确定1)消除 酒精诱导的母体皮质酮升高将使FAE正常化 子代下丘脑-垂体-肾上腺(HPA)和甲状腺(HPT)功能和 行为；2)如果产前或新生儿补充甲状腺激素会 纠正FAE子代HPT功能异常和行为缺陷。 特定目标2将建立一种产前酒精暴露的小鼠模型 在转基因小鼠的帮助下，产前酒精诱导的 甲状腺激素应答基因可以在时间、空间和细胞中找到 特定的时尚。为了实现这一点，我们将1)描述胎儿的影响 酒精暴露对大鼠下丘脑HPA、HPT功能及特异性行为的影响 C57BL/6J小鼠；2)建立无处不在表达的转基因小鼠 甲状腺反应性DNA启动子(PTRELacZ)驱动的报告LacZ基因； 将pTRE-LacZ转基因小鼠置于子宫内酒精中，并测定 发育概况和特定脑区的最深刻变化(S) 在甲状腺激素反应基因中；4)开展基于基因芯片的 S特定脑区的差异表达分析 在pTRE-LacZ转基因小鼠的帮助下。 这些研究的长期目标是确定甲状腺激素是否 出生前或出生后补充酒精可以改善乙醇对小鼠的影响 发育中的大脑。此外，拟议的实验将识别已知的 或对甲状腺激素有特异性反应的新基因，并显示 在酒精暴露期间，发育中的胎儿大脑的表达发生了变化。

DESCRIPTION (provided by applicant): Children exposed to alcohol in utero frequently exhibit behavioral problems including hyperactivity, learning deficits, response inhibition and increased prevalence of depression. Many of these behavioral deficits are also observed in animal models of fetal alcohol exposure. Similar behavioral deficits occur after prenatal stress and in children born to mothers with subclinical hypothyroidism. This information formed the main hypothesis of this proposal: fetal glucocorticoid and thyroid hormone milieu may contribute significantly to the deleterious consequences of prenatal alcohol exposure. Specific Aim 1 will investigate the sub-hypotheses that relative hypothyroidism found in the alcohol-consuming dam and its fetuses is due, at least in part, to elevated maternal corticosterone suppressing the thyroid function. Subsequently, this prenatal hypothyroid state of the fetal alcohol-exposed (FAE) offspring can cause the activity and cognitive behavioral deficits in the adult offspring. Specifically, we aim to determine 1) whether eliminating the alcohol-induced increase in maternal corticosterone would normalize the FAE offspring hypothalamic-pituitary-adrenal (HPA) and thyroid (HPT) function and behavior; 2) if prenatal or neonatal thyroid hormone supplementation would correct HPT function abnormalities and behavioral deficits of FAE offspring. Specific Aim 2 will establish a murine model of prenatal alcohol exposure so that with the aid of transgenic mice prenatal alcohol-induced changes in thyroid hormone responsive genes can be found in a temporal, spatial and cell specific fashion. To achieve that, we will 1) characterize the effects of fetal alcohol exposure on HPA, HPT function and specific behavioral measures in C57BL/6J mice; 2) develop transgenic mouse line which ubiquitously expresses the reporter LacZ gene driven by thyroid-responsive DNA promoter (pTRELacZ); 3) expose pTRE-LacZ transgenic mice to alcohol in utero and determine the developmental profile and specific brain region(s) of the most profound changes in thyroid hormone responsive genes; 4) carry out a microarray-based differential expression analysis on the specific brain region(s) identified with the help of the pTRE-LacZ transgenic mice. The long-term goal of these studies is to determine if thyroid hormone supplementation pre- or postnatally can ameliorate the effects of ethanol on the developing brain. Furthermore, the proposed experiments will identify known or novel genes that are specifically responsive to thyroid hormones and show altered expression in the developing fetal brain during ethanol exposure.