Neural Bases of Eyeblink Conditioning in FASD

描述(由申请人提供)：胎儿酒精谱系障碍(FASD)的诊断很困难，因为关于产前接触的信息往往缺乏，许多受影响的儿童没有表现出典型的面部异常，也没有发现独特的行为表型。由于对FASD的病理生理学了解有限，适当的治疗方法的发展一直受到阻碍。自1999年以来，我们一直在南非开普敦的开普敦有色人种(混合血统)社区进行一项前瞻性的纵向研究，那里胎儿酒精综合征(FAS)的发病率特别高。在对这一队列的5年跟踪调查中，我们发现胎儿酒精暴露对眨眼条件反射的影响非常一致，这是一种依赖小脑的学习形式，其神经回路和酒精效应在实验室动物中得到了详细的记录；没有一个孩子完全符合Fas条件反射的标准，相比之下，没有75%的未暴露于酒精的对照组。因此，我们已经确定了一个潜在的酒精相关中枢神经系统损伤的生物标志物。此外，由于短延迟EBC在婴儿早期就已确立，它可能为FASD的早期诊断以及产中和产后早期干预的疗效评估提供一种重要的工具。在这项研究中，我们将对开普敦165名8.5岁的儿童进行随访，并从同一社区招募60名新的预期队列婴儿(30名重度暴露，30名对照)。主要目的是描述EBC中酒精相关损害的发育过程；使用选定的神经成像技术来检查胎儿酒精暴露对调节EBC的神经回路的影响；以及使用神经行为和功能磁共振任务来评估对EBC的中心元素小脑介导的计时的影响。先进的神经成像将包括高分辨率结构MRI，以检查脑发育不良的区域模式，并首次在FASD儿童中进行全脑扩散张量成像(DTI)，以评估白质束的完整性。还将研究母亲年龄、酗酒史和ADH1B多态变异对儿童患FASD易感性的缓和作用。公共卫生相关性：更好地了解胎儿酒精暴露对儿童和婴儿期EBC小脑回路的影响有可能促进我们对FASD神经病理学的理解，改进这种疾病的诊断和治疗，并使受影响的儿童能够更早地被识别出来。

DESCRIPTION (provided by applicant): Diagnosis of fetal alcohol spectrum disorder (FASD) is difficult because information regarding prenatal exposure is often lacking, many affected children do not exhibit the characteristic facial anomalies, and no distinctive behavioral phenotype has been identified. Development of appropriate treatments has been hampered by limited understanding of the pathophysiology of FASD. Since 1999, we have been conducting a prospective, longitudinal study in the Cape Coloured (mixed ancestry) community in Cape Town, South Africa, where there is an exceptionally high incidence of fetal alcohol syndrome (FAS). In a 5-year follow-up of this cohort, we found a remarkably consistent effect of fetal alcohol exposure on eyeblink conditioning, a cerebellar-dependent form of learning whose neural circuitry and alcohol effects have been documented in detail in laboratory animals; not a single child with full FAS met criterion for conditioning, compared with 75% of the non-exposed controls. Thus, we have identified a potential biomarker of alcohol-related CNS impairment. Moreover, because it is well established in early infancy, short-delay EBC may provide an important tool in the early diagnosis of FASD and in the evaluation of the efficacy of intrapartum and early postpartum interventions. In this study we will follow-up our Cape Town cohort of 165 children at 8.5 years and recruit a new prospective cohort of 60 infants (30 heavy exposed, 30 controls) from the same community. The principal aims are to characterize the developmental course of alcohol-related impairment in EBC; to use selected neuroimaging techniques to examine the impact of fetal alcohol exposure on the neural circuitry mediating EBC; and to use neurobehavioral and functional MRI tasks to assess effects on cerebellar- mediated timing, a central element of EBC. Advanced neuroimaging will include high resolution structural MRI to examine the regional pattern of brain hypoplasia and the first whole brain diffusion tensor imaging (DTI) in children with FASD to assess the integrity of white matter tracts. The moderating effects of maternal age, alcohol abuse history, and variants of the ADH1B polymorphism on the child's vulnerability to FASD will also be examined. Public Health Relevance: A better understanding of the effects of fetal alcohol exposure on the EBC cerebellar circuit in childhood and infancy has the potential to advance our understanding of the neuropathology of FASD, to improve the diagnosis and treatment of this disorder, and to enable earlier identification of affected children.