Fetal Alcohol Exposure and Biological Rhythms

产前接触酒精会对发育中的神经系统产生深远的影响。这可以导致没有生长缺陷、智力低下或与胎儿酒精综合征(FAS)相关的畸形特征的神经行为病理。胎儿酒精暴露(FAE)对国民健康的影响是一个值得关注的问题，因为FAE的人群比FAE的人群要多得多。与Fas相反，FAE儿童的缺陷还可能包括与自主神经和神经内分泌功能相关的变化。下丘脑视交叉上核(SCN)的发育损害可能是连接许多FAE相关神经病理的共同线索。SCN的作用是携带多种生物节律，这些节律通常在24小时内波动。当夹带对正常的夹带信号(如光)反应弱或反应迟缓时，可能会发生行为和生理障碍。初步数据表明，胎儿酒精暴露会改变成人核心体温和血浆皮质酮的昼夜节律。这伴随着加压素和PER2在SCN内表达的变化。加压素在调节与节律控制相关的系统的幅度和敏感性方面起着关键的效应作用。PER2是一种内在的时钟基因，在SCN中以昼夜节律的方式表达。因此，本申请中描述的实验将检验这一假设，即产前酒精暴露扰乱下丘脑发育，导致涉及自主神经和神经内分泌节律的神经机制的失调。这项应用将确定：1)FAE是否由于SCN对光夹带的不敏感而导致成年雄性和雌性大鼠的昼夜节律紊乱。2)如果FAE扰乱了调节神经肽和内在时钟基因昼夜节律的SCN内局部电路的功能。3)如果FAE干扰了SCN到下丘脑室旁核的功能输出，下丘脑室旁核是调节自主神经和神经内分泌功能的大脑区域。这些研究的长期目标是确定FAE引起的节律失调的程度和这种失调的机制。这将为未来的神经发育研究奠定基础，有助于确定有效的干预策略来对抗FAE对SCN功能的影响

Prenatal exposure to alcohol has profound effects on the developing nervous system. This can result in neurobehavioral pathology without growth deficits, mental retardation or the dysmorphological characteristics associated with Fetal Alcohol Syndrome (FAS). The effects of fetal alcohol exposure (FAE) are of concern to national health because the FAE population is so much larger that that of FAS. In contrast to FAS, deficits in FAE children can also include changes associated with autonomic and neuroendocrine function. Developmental damage to the suprachiasmatic nucleus (SCN) of the hypothalamus may be a common thread linking many FAE associated neuropathologies. The SCN acts to entrain multiple biological rhythms which normally fluctuate across the 24 hour day. When entrainment is weak or slow to respond to normal entrainment cues such as light, behavioral and physiological disturbances can occur. Preliminary data indicate that fetal alcohol exposure alters adult circadian rhythms in core body temperature and plasma corticosterone. This is accompanied by changes in vasopressin and Per2 expression within the SCN. Vasopressin serves a key effector function of the SCN to modulate amplitude and sensitivity of systems related to the control of rhythms. Per2 is an intrinsic clock gene that is expressed in a circadian fashion within the SCN. Therefore, the experiments described in this application will test the hypothesis that prenatal alcohol exposure disrupts hypothalamic development resulting in a dysregulation of the neural mechanisms involved in the entrainment of autonomic and neuroendocrine rhythms. This application will determine: 1) If FAE causes circadian rhythm dysfunction in adult male and female rats due to an insensitivity of the SCN to photic entrainment. 2) If FAE disrupts the function of local circuits within the SCN that regulate diurnal rhythms of neuropeptides and intrinsic clock genes. 3) If FAE disrupts the functional outputs of the SCN to the paraventricular nucleus of the hypothalamus, a brain region that regulates autonomic and neuroendocrine function. The long term goals of these studies are to establish the extent of rhythm dysregulation caused by FAE and the mechanisms underlying such a dysregulation. This will lay the foundation for future neurodevelopmental studies which will help determine intervention strategies useful in counteracting the effects of FAE on SCN function