Fetal Alcohol Effects on Circadian clocks and POMC

描述（由申请人提供）：胎儿暴露于乙醇可导致胎儿酒精综合征的发展，其特征是胎儿酒精暴露（FAE）后代的各种形态和行为缺陷。这些后代经常表现出临床睡眠-觉醒障碍和神经内分泌系统功能异常。最近的研究发现，FAE后代的睡眠-觉醒障碍和神经内分泌功能异常可能与生物钟机制的长期变化有关。采用大鼠动物模型，本研究确定胎儿暴露于乙醇是否会导致下丘脑弓状核-内啡肽神经元昼夜节律输出的长期变化及其对血浆促性腺激素释放的调节。它验证了胎儿暴露于乙醇会导致下丘脑视交叉上核中央时钟机制的成人表达异常，从而导致内部时钟机制和β -内啡肽神经元的阶段性激素输出发生改变的假设。它还确定胎儿暴露于乙醇是否改变控制中央和内部时钟的光反应的分子机制。拟议的研究使用激光捕获显微镜，免疫组织化学，Western blot，放射免疫测定和实时RT-PCR技术来鉴定基因和蛋白质表达，这些基因和蛋白质表达与中枢和内部时钟机制的调节以及β -内啡肽神经元的阶段性激素输出密切相关。拟议的研究应该提供一个更好的理解胎儿暴露于乙醇对生物钟功能的长期影响。这些信息应该有助于制定治疗策略，以管理睡眠-觉醒障碍和FAE后代由此产生的健康后果。

DESCRIPTION (provided by applicant): Exposure of a fetus to ethanol can lead to the development of fetal alcohol syndrome, which is characterized by various morphological and behavioral deficits in fetal alcohol-exposed (FAE) offspring. These offspring often show clinical sleep-wake disturbances and abnormalities in the functions of the neuroendocrine system. Recent studies have identified the possibility that the sleep-wake disturbances and neuroendocrine function abnormalities in the FAE offspring are related to long-term changes in circadian clock mechanisms. Employing the rat animal model, this proposal determines whether fetal exposure to ethanol causes long- lasting changes in the circadian output of beta-endorphin neurons located in the arcuate nucleus of the hypothalamus and their regulation of plasma gonadotropin release. It tests the hypothesis that fetal exposure to ethanol causes an abnormality in the adult expression of the central clock mechanisms in the suprachaismatic nucleus of the hypothalamus leading to alteration in the internal clock mechanisms and the phasic hormonal output of beta-endorphin neurons. It also identifies whether fetal exposure to ethanol alters the molecular mechanism governing the photic responses of the central and internal clocks. The proposed research uses laser-captured microscopy, immunohistochemistry, Western blot, radioimmunoassay, and real-time RT-PCR techniques to identify gene and protein expressions that are critically involved in the regulation of central and internal clock mechanisms and the phasic hormonal outputs from beta-endorphin neurons. The proposed studies should provide a better understanding of the long-term consequences of fetal exposure to ethanol in the circadian clock functions. This information should help to develop therapeutic strategies in managing sleep-wake disturbances and the resultant health consequences in FAE offspring.