Fetal Alcohol Effects and Choline Intervention

描述（由申请人提供）：产前酒精暴露会破坏发育，导致一系列疾病，包括面部畸形、生长缺陷和中枢神经系统功能障碍。酒精对大脑发育和相关认知能力的不利影响是最具破坏性的后果之一。尽管已知产前酒精暴露的破坏性影响，含酒精饮料的警告标签和其他预防措施，妇女在怀孕期间继续饮酒。因此，我们必须确定有效的治疗和干预措施，以减少产前酒精暴露的不良后果。使用动物模型，我们一直在研究必需营养素胆碱作为胎儿酒精谱系障碍（FASD）治疗的有效性。当在产前酒精暴露期间给予胆碱补充时，可减轻酒精相关的出生体重缺陷，延迟反射发育以及认知功能障碍。更重要的是，胆碱在减少与发育性酒精暴露相关的认知缺陷方面也很有效，即使是在酒精损伤后和出生后发育期间使用。具体来说，我们发现产后补充胆碱可以降低过度活动的严重程度，以及在发育期间暴露于酒精的大鼠中观察到的一系列学习任务的缺陷。这些发现表明，补充胆碱可能是一种相对安全有效的治疗FASD的方法。我们现在才开始研究与胆碱相关的行为益处的神经相关性，尚未探索胆碱的作用机制。本提案的目标是进一步研究胆碱对发育的有益作用，重点关注大脑变化及其潜在机制。首先，我们将研究发育酒精和胆碱对海马和皮质发育的影响，特别是对胆碱能系统的发育的影响。其次，我们将研究多奈哌齐（一种乙酰胆碱酯酶抑制剂，也能增加胆碱能活性）是否可以改善早期酒精暴露后的认知表现。最后，也有可能胆碱通过充当甜菜碱的前体和影响蛋氨酸/同型半胱氨酸循环来改变大脑发育。我们将检查胆碱是否会增加甜菜碱，以及甜菜碱是否会导致与胆碱类似的有益效果。更好地了解胆碱如何影响发育过程中接触过酒精的受试者的大脑和行为发育，对于我们将这种饮食治疗转化为临床人群是很重要的。

DESCRIPTION (provided by applicant): Prenatal alcohol exposure can disrupt development, leading to a spectrum of disorders that include facial dysmorphology, growth deficiencies and central nervous system dysfunction. Alcohol's adverse effect on brain development and associated cognitive abilities are among the most devastating consequences. Despite the known damaging effects of prenatal alcohol exposure, warning labels on alcohol-containing beverages, and other prevention efforts, women continue to drink alcohol during pregnancy. Thus, it is critical that we identify effective treatments and interventions for reducing the adverse consequences of prenatal alcohol exposure. Using an animal model, we have been investigating the effectiveness of the essential nutrient choline, as a treatment for fetal alcohol spectrum disorders (FASD). When administered during prenatal alcohol exposure, choline supplementation attenuates alcohol-related birth weight deficits, delayed development of reflexes, as well as impairments in cognitive functioning. More importantly, choline is also effective in reducing cognitive deficits associated with developmental alcohol exposure, even when administered after the alcohol insult and during postnatal development. Specifically, we find that postnatal choline supplementation can reduce the severity of overactivity, and deficits on a range of learning tasks observed in rats exposed to alcohol during development. These findings suggest that choline supplementation may serve as a relatively safe and effective treatment for FASD. We are only now beginning to investigate the neural correlates to the choline-related behavioral benefits and have yet to explore choline's mechanisms of action. The goal of this proposal is to further examine the beneficial effects of choline on development, with a focus on brain changes and potential mechanisms. First, we will examine the effects of developmental alcohol and choline on hippocampal and cortical development, particularly on development of cholinergic systems. Secondly, we will examine whether administration of donepezil, an acetylcholinesterase inhibitor which also increases cholinergic activity, can improve cognitive performance following early alcohol exposure. Finally, it is also possible that choline alters brain development by acting as a precursor to betaine and influencing the methionine/homocysteine cycle. We will examine if choline increases betaine and if betaine administration leads to similar beneficial effects as choline. Better understanding of how choline affects brain and behavioral development among subjects who have been exposed to alcohol during development is important as we translate this dietary treatment to clinical populations.