Fetal Alcohol Effects on Circadian clocks and POMC

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功能异常， 系统最近的研究表明，睡眠-觉醒障碍和神经内分泌 FAE后代的功能异常与生物钟机制的长期变化有关。 采用大鼠动物模型，该建议确定胎儿暴露于乙醇是否会导致长- 位于弓状核的β-内啡肽神经元昼夜节律输出的持续变化 下丘脑及其对血浆促性腺激素释放调节。它验证了胎儿暴露于 导致中枢生物钟机制的成年表达异常， 下丘脑的视丘上核，导致内部时钟机制的改变， β-内啡肽神经元的阶段性激素输出。它还确定了胎儿暴露于乙醇是否会改变 控制中央和内部时钟光反应的分子机制。拟议 研究使用激光捕获显微镜，免疫组织化学，蛋白质印迹，放射免疫测定， 实时RT-PCR技术，以确定基因和蛋白质的表达，这是关键参与的， 调节中枢和内部时钟机制以及β-内啡肽的阶段性激素输出 神经元拟议的研究应使人们更好地了解 胎儿暴露于乙醇在生物钟功能。这些信息应该有助于开发治疗 管理FAE后代的睡眠-觉醒障碍和由此产生的健康后果的策略。

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.