Prenatal Cocaine Exposure: Studies of Brain Function

描述(由申请人提供)：证据表明，产前接触可卡因会导致额叶、扣带回皮质和尾状核中的多巴胺D1受体与其G蛋白永久解偶联。在大脑发育过程中，D1受体的激活对神经元发育产生调制作用，产前可卡因暴露被证明改变了接受多巴胺能输入的脑区的神经细胞结构，包括额叶、内嗅觉和梨状皮质。D1受体在额叶皮质中含量丰富，似乎调节神经回路，支持执行功能的任务的执行。出生前接触可卡因与执行认知能力的缺陷有关，如注意力分配、记忆以及抑制竞争刺激的处理和反应的能力，而人类在青春期经历了重要的发育变化。功能磁共振成像(FMRI)表明，在青春期发育阶段，执行功能任务的执行与额纹状体和额顶神经网络随着年龄的增长而激活增加有关。事件相关电位(ERP)的研究表明，在执行注意和执行功能任务的过程中，事件相关电位的形态、幅度和潜伏期持续成熟变化。扩散张量成像(DTI)提供了脑白质微观结构的定量测量，显示了与年龄相关的各向异性分数的增加，反映了髓鞘形成、皮质和皮质下白质通路的增加，这与年龄相关的认知能力变化有关。这项建议旨在开发和改进fMRI、DTI和ERP方法，以评估支持选择性和分离注意力以及语言和视觉空间记忆的神经回路的功能和结构完整性，无论是否在产前接触过母体可卡因。这项工作将与医学博士Linda Mayes合作进行，并将成为未来计划项目的基础，该项目将在耶鲁儿童研究中心(R01 DA-06025，PI：L.C.Mayes)对产前接触过和不接触过母体可卡因的青少年样本进行纵向跟踪，研究这些回路的完整性与认知、学业和心理社会结果之间的关系。公共卫生相关性：产前接触可卡因的儿童和青少年在执行认知能力方面存在缺陷，包括注意力分配、记忆以及抑制对竞争刺激的处理和反应的能力。这项提案将开发和完善fMRI、DTI和ERP方法，以评估支持选择性和分离注意力以及语言和视觉空间记忆的神经回路的功能和结构，这些神经回路支持产前接触和未接触母体可卡因的青少年。这项工作将成为未来计划项目的基础，该项目将在耶鲁儿童研究中心(R01 DA-06025，PI：L.C.Mayes)对产前接触过和不接触过母体可卡因的青少年样本进行纵向跟踪，研究这些回路的完整性与认知、学业和心理社会结果之间的关系。

DESCRIPTION (provided by applicant): Evidence suggests that prenatal exposure to cocaine produces a permanent uncoupling of the dopamine D1 receptor from its G-protein in frontal and cingulate cortices and in caudate nucleus. Activation of D1 receptors during brain development exerts modulatory effects on neuronal development, and prenatal cocaine exposure has been shown to alter neuronal cytoarchitecture in brain regions receiving dopaminergic inputs, including frontal, entorhinal, and piriform cortices. D1 receptors are abundant in frontal cortex and appear to modulate neurocircuits that support the performance of tasks that tap executive functions. Prenatal cocaine exposure has been linked with deficits in executive cognitive capacities, such as allocation of attention, memory, and the ability to suppress processing of and responses to competing stimuli that, in humans, undergo important developmental changes during adolescence. Functional magnetic resonance imaging (fMRI) has demonstrated that performance of executive function tasks is associated with increased activation of fronto-striatal and fronto-parietal networks with increasing age during the adolescent developmental epoch. Event related potential (ERP) studies, have demonstrated consistent maturational changes in ERP morphology, amplitude and latency during performance of attention and executive function tasks. Diffusion tensor imaging (DTI), which provides quantitative measures of white matter microstructure, has demonstrated age related increases in fractional anisotropy, reflecting increases in myelination, in cortical and subcortical white matter pathways that correlate with age related changes in cognitive abilities. This proposal aims to develop and refine fMRI, DTI, and ERP methods for assessing the functional and structural integrity of neurocircuitry supporting selective and divided attention and verbal and visuospatial memory in adolescents with and without prenatal exposure to maternal cocaine use. This work will be performed in collaboration with Linda Mayes, MD, and will form the foundation for future planned projects that will examine the relationship between the integrity of these circuits and cognitive, academic, and psychosocial outcome in a sample of adolescents with and without prenatal exposure to maternal cocaine use that have been followed longitudinally from birth at the Yale Child Study Center (R01 DA-06025, PI: L.C. Mayes). PUBLIC HEALTH RELEVANCE: Children and adolescents with prenatal cocaine exposure have deficits in executive cognitive abilities, including allocation of attention, memory, and the ability to suppress processing of and responses to competing stimuli. This proposal will develop and refine fMRI, DTI, and ERP methods for assessing the function and structure of neurocircuitry supporting selective and divided attention and verbal and visuospatial memory in adolescents with and without prenatal exposure to maternal cocaine use. This work will form the foundation for future planned projects that will examine the relationship between the integrity of these circuits and cognitive, academic, and psychosocial outcome in a sample of adolescents with and without prenatal exposure to maternal cocaine use that have been followed longitudinally from birth at the Yale Child Study Center (R01 DA-06025, PI: L.C. Mayes).