Prenatal Alcohol; Hormone-Regulated Genes & Behavior

描述（由申请人提供）：宫内暴露于酒精的儿童 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 exposure.类似的行为缺陷发生在产前压力后， 患有亚临床甲状腺功能减退症的母亲所生的孩子。这些信息 形成了这一建议的主要假设：胎儿糖皮质激素和甲状腺 激素环境可能会显著促进 产前酒精暴露 具体目标1将研究相对甲状腺功能减退症 在酒精消耗的母鼠及其胎儿中发现的这种物质，至少部分是由于 母体皮质酮升高抑制甲状腺功能。 随后，这种产前甲状腺功能减退状态的胎儿酒精暴露 (FAE)后代可能会导致活动和认知行为缺陷， 成年后代具体来说，我们的目标是确定1）是否消除 酒精诱导的母体皮质酮增加将使FAE正常化 后代下丘脑-垂体-肾上腺（HPA）和甲状腺（HPT）功能， 行为; 2）如果产前或新生儿甲状腺激素补充将 纠正FAE后代的HPT功能异常和行为缺陷。 具体目标2将建立产前酒精暴露的小鼠模型， 在转基因小鼠的帮助下， 甲状腺激素反应基因可以在时间、空间和细胞中发现， 具体的时尚。为了实现这一目标，我们将1）描述胎儿的影响， 酒精暴露对HPA、HPT功能和特定行为指标的影响 C57 BL/6 J小鼠; 2）开发普遍表达 甲状腺应答DNA启动子驱动的报告基因LacZ（pTRELacZ）; 3） 将pTRE-LacZ转基因小鼠暴露于子宫内的酒精中，并测定 最深刻变化的发育概况和特定大脑区域 甲状腺激素反应基因; 4）进行基于微阵列的 对鉴定的特定脑区域的差异表达分析 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 出生前或出生后补充可以改善乙醇对 大脑发育。此外，拟议的实验将确定已知的 或者是对甲状腺激素有特异性反应的新基因， 在乙醇暴露期间发育中的胎儿脑中的表达改变。

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.