BEHAVIORAL EFFECTS OF NEONATAL ALCOHOL EXPOSURE

怀孕期间饮酒会对胎儿造成毁灭性的影响，从产前死亡到身体和行为异常。重要的研究问题包括确定导致胎儿酒精影响可能性增加的风险因素，阐明酒精导致脑损伤和随之而来的行为改变的机制，以及制定有效的干预和治疗策略。我们建议使用人类妊娠晚期暴露的动物模型系统来研究这些问题。接触酒精后的结果有很大的可变性，即使饮酒量相似。有人提出解释这种差异的一个因素是基因决定的对酒精敏感性的差异。选择有选择地培育的HAS和LAS大鼠系，以获得极端的乙醇敏感性。利用这些线，我们将研究乙醇敏感性对乙醇敏感性极值的贡献。使用这些线，我们将研究乙醇敏感性对酒精暴露影响的三种行为测量的贡献；酒精暴露对三种行为测量的活动性、协调性和逆转敏感性的影响活动，协调和逆向学习。我们还将评估海马和小脑的细胞损失，这两个大脑区域特别受学习影响。我们还将评估海马和小脑的细胞损失，这两个大脑区域特别受围产期酒精暴露的影响，试图将行为缺陷与潜在的解剖学变化联系起来。第二项研究将调查乙醇戒断对胎儿酒精效应的作用，因为戒断期间发生的生理变化可能对发育中的胎儿产生影响。逐渐退出乙醇的影响将与突然退出进行比较，以提供额外的证据，戒断诱导的兴奋毒性在胎儿酒精效应中起作用。其他的研究将检验这种兴奋性毒性作用的机制。特别是，NMDA受体复合物的特异性拮抗剂的作用和该受体激活后发生的级联事件将被研究，以帮助确定围产期戒断可能影响胎儿发育的机制。

Consumption of alcohol during pregnancy can have devastating effects on the fetus, ranging from prenatal mortality to physical and behavioral anomalies. Important research questions include the identification of risk factors that contribute to the increased likelihood of fetal alcohol effects, the elucidation of the mechanisms by which alcohol causes brain damage and consequent behavioral alterations, and the development of effective intervention and treatment strategies. We propose to use an animal model system of human third trimester exposure to study these questions. There is a large variability of outcomes following exposure to alcohol, even when similar amounts of alcohol are consumed. One factor that has been proposed to account for this variability is a difference in genetically determined sensitivity to alcohol. The selectively bred HAS and LAS rat lines were selected for extremes in ethanol sensitivity. Using these lines we will investigate the contribution of ethanol sensitivity for extremes in ethanol sensitivity. Using these lines we will investigate the contribution of ethanol sensitivity on three behavioral measures affected by alcohol exposure; activity, coordination, and reversal sensitivity on three behavioral measures affected by alcohol exposure; activity, coordination, and reversal learning. We will also assess cell loss in the hippocampus and cerebellum, two brain areas especially affected by learning. We will also assess cell loss in the hippocampus and cerebellum, two brain areas especially affected by perinatal alcohol exposure in an attempt to correlate behavioral deficits with underlying anatomical changes. A second line of investigation will investigate the role of ethanol withdrawal on fetal alcohol effects, since physiological changes that occur during withdrawal might have an impact on the developing fetus. The effects of gradual withdrawal from ethanol will be compared to abrupt withdrawal to provide additional evidence that withdrawal-induced excitotoxicity plays a role in fetal alcohol effects. Other studies will examine the mechanisms by which this excitotoxicity may operate. In particular, the effects of specific antagonists of the NMDA receptor complex and the cascade of events that occur following activation of this receptor will be studied to help determine the mechanism(s) by which perinatal withdrawal might influence fetal development.