Prenatal alcohol: Hormone-regulated genes and behavior

描述（由申请人提供）：产前暴露于酒精的儿童经常表现出行为问题，包括注意力缺陷/多动（ADHD）障碍和学习障碍;在诊断为胎儿酒精谱系障碍的青年中，其患病率接近60%。患有轻度低甲状腺素血症或甲状腺激素抵抗的母亲所生的孩子中，很大一部分也被诊断为ADHD。因此，产前酒精暴露、甲状腺功能和认知障碍之间似乎存在密切而神秘的关系。本研究的目的是阐明围产期甲状腺激素环境在酒精暴露大鼠胎儿认知功能中的作用。在上一个资助期间，我们已经证明饮酒的怀孕母鼠会抑制甲状腺功能。我们还发现，它们的成年后代表现出甲状腺功能异常、绝望样行为和认知障碍。抑制母体甲状腺功能似乎导致这些行为异常，因为产前甲状腺素（T4）管理扭转了胎儿酒精暴露（FAE）后代的行为缺陷。我们假设，减少甲状腺激素环境的酒精消费怀孕的母亲影响，通过胎盘，甲状腺激素调节基因在胎儿大脑中的表达，从而影响成年FAE后代的认知和情感行为。基于这一假设，我们将研究：具体目标1。向饮酒母鼠给予不同剂量的T4对a）限制或调节胎儿甲状腺激素暴露的子宫和胎盘基因表达的影响;和B）对胎儿大脑特定区域中甲状腺激素调节的基因表达的影响;具体目标2。确定一个剂量的T4逆转FAE的行为后果，但不会改变成人甲状腺功能不利;具体目标3。制定围产期甲状腺激素治疗范式酒精暴露后，旨在找到一个逆转FAE行为缺陷和正常化的甲状腺功能的成年FAE后代。我们的长期目标是了解酒精和母胎甲状腺功能之间的相互作用，作为一个潜在的机制，产前乙醇诱导后代的行为缺陷。我们预计T4治疗方案在FAE动物模型中的成功可能会在临床试验中实施。

DESCRIPTION (provided by applicant): Children exposed to alcohol prenatally frequently exhibit behavioral problems including attention deficit/hyperactivity (ADHD) disorder and learning deficit; the prevalence of which is close to 60% among youth diagnosed with fetal alcohol spectrum disorder. A large percentage of children born to mothers with mild hypothyroxinemia or with resistance to thyroid hormones are also diagnosed with ADHD. Thus, there seems to be a close and enigmatic relationship between prenatal alcohol exposure, thyroid function and cognitive impairment. The goal of this proposal is to elucidate the role of perinatal thyroid hormonal milieu in the cognitive function of the fetal alcohol exposed rat. During the previous funding period, we have shown that alcohol consuming pregnant dams have suppressed thyroid function. We have also shown that their adult offspring exhibits thyroid function abnormalities, despair-like behavior and cognitive impairments. The suppressed maternal thyroid function seems to cause these behavioral abnormalities, since prenatal thyroxine (T4) administration reversed the behavioral deficits in the fetal alcohol exposed (FAE) offspring. We hypothesize that the decreased thyroid hormone milieu of the alcohol consuming pregnant dam affects, via the placenta, the expression of thyroid hormone-regulated genes in the fetal brain, and thereby impact the cognitive and emotional behavior of the adult FAE offspring. Based on this hypothesis, we will investigate: Specific Aim 1. The effects of administering different doses of T4 to alcohol consuming dams on a) the expression of uteral and placental genes that restrict or modulate thyroid hormone exposure of the fetus; and b) on the expression of genes regulated by thyroid hormones in specific regions of the fetal brain; Specific Aim 2. Determine a dose of T4 that reverses the behavioral consequences of FAE but does not alter the adult thyroid function adversely; Specific Aim 3. Develop perinatal thyroid hormone treatment paradigms subsequent to the alcohol exposure, aimed at finding one that reverses the FAE behavioral deficits and normalizes the thyroid function of the adult FAE offspring. Our long-term goal is to understand the interaction between alcohol and the maternal-fetal thyroid function, as a potential mechanism by which prenatal ethanol induces behavioral deficits in the offspring. We anticipate that T4 treatment protocols successful in the animal model of FAE can potentially be implemented in clinical trials.