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，因为通常缺乏有关产前暴露的信息，许多受影响的儿童没有表现出特征性的面部异常，并且没有识别出独特的行为表型。由于对FASD的病理生理学了解有限，因此阻碍了适当治疗方法的开发。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）社区进行前瞻性纵向研究，那里胎儿酒精综合征（FAS）的发病率非常高。在这个队列的5年随访中，我们发现胎儿酒精暴露对眨眼条件反射的影响非常一致，这是一种小脑依赖的学习形式，其神经回路和酒精影响已在实验室动物中详细记录;与75%的未暴露对照组相比，没有一个完全FAS的儿童符合条件反射标准。因此，我们已经确定了一个潜在的生物标志物酒精相关的中枢神经系统损害。此外，因为它是在婴儿早期建立的，短延迟EBC可能提供一个重要的工具，在早期诊断FASD和评估产时和产后早期干预的疗效。在这项研究中，我们将随访开普敦队列的165名儿童，年龄为8.5岁，并从同一社区招募60名婴儿（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展过程;使用选定的神经成像技术来检查胎儿酒精暴露对介导EBC的神经回路的影响;并使用神经行为和功能MRI任务来评估对小脑介导的定时（EBC的核心要素）的影响。先进的神经影像学将包括高分辨率结构MRI，以检查大脑发育不全的区域模式，以及FASD儿童的首次全脑扩散张量成像（DTI），以评估白色物质束的完整性。母亲的年龄，酒精滥用史，和ADH 1B多态性的变异对儿童的脆弱性FASD的调节作用也将进行检查。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，改善这种疾病的诊断和治疗，并使受影响儿童的早期识别成为可能。

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.