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。酒精对大脑发育和随之而来的认知能力的不利影响是最具破坏性的。然而，尽管酒精相关的神经发育障碍是完全可以预防的，但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。与产前酒精暴露相关的许多行为改变可能与胆碱能功能改变有关。有趣的是，在对照组中，围产期胆碱补充剂可导致胆碱能功能和认知能力的长期增强。因此，我们假设，围产期胆碱补充可能会减少一些胎儿酒精影响的严重程度。使用动物模型系统，我们证明了围产期胆碱补充剂减弱与酒精暴露在发展过程中的多动和学习缺陷。事实上，即使在酒精暴露完成后以及在相当于人类出生后早期发育的大脑发育期间给予胆碱补充剂也是有效的。这项建议继续我们的调查胆碱作为一种潜在的治疗胎儿酒精的影响。使用妊娠晚期酒精暴露的动物模型，我们首先计划检查胆碱的有效性的时间窗口。阐明胆碱有效的发育期将产生其作用机制的进一步假设，并表明胆碱是否可以给药并在以后的生活中仍然有效。其次，我们将研究围产期胆碱补充剂是否会导致我们的酒精暴露受试者的胆碱能功能的长期变化。这将使我们能够将行为变化与神经化学底物联系起来。最后，我们将研究胆碱补充剂是否可以提高其他行为治疗的疗效，特别是环境富集。如果胆碱增强了环境丰富的效果，这表明联合治疗可能对FASD儿童最有效。重要的是，胆碱补充剂可以作为一种相对安全和有效的治疗方法，可以在人类出生后使用。

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 consequent cognitive abilities are among the most devastating. Yet, although alcohol- related neurodevelopmental disorders are completely preventable, 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. Many behavioral alterations associated with prenatal alcohol exposure may be related to altered cholinergic functioning. Interestingly, perinatal choline supplementation in control subjects can lead to long-lasting enhancements in cholinergic functioning and cognitive abilities. Thus, we hypothesized that perinatal choline supplementation may reduce the severity of some fetal alcohol effects. Using an animal model system, we demonstrated that perinatal choline supplementation attenuates the hyperactivity and learning deficits associated with alcohol exposure during development. In fact, choline supplementation is effective even when administered after the alcohol exposure is complete and during a period of brain development equivalent to early postnatal development in humans. This proposal continues our investigation of choline as a potential treatment for fetal alcohol effects. Using an animal model of third trimester alcohol exposure, we first plan to examine the temporal windows of choline's effectiveness. Elucidation of the developmental periods when choline is effective will produce further hypotheses of its mechanisms of action and indicate if choline can be administered and still be effective later in life. Secondly, we will examine if perinatal choline supplementation leads to long-lasting changes in cholinergic functioning in our alcohol-exposed subjects. This will allow us to correlate behavioral changes with neurochemical substrates. Finally, we will examine if choline supplementation can enhance the efficacy of other behavioral treatments, specifically environmental enrichment. If choline potentiates the effects of environmental enrichment, it would suggest that combinations of treatments may be the most effective for children with FASD. Importantly, choline supplementation may serve as a relatively safe and effective treatment that could be administered after birth in humans.