Project 3: A Multimodal Imaging Study of the Effects of Altered Serotonin

该中心所有项目的核心概念是，在早期发育过程中，5-羟色胺是至关重要的神经生长因子和大脑成熟的调节器。因此，影响5-羟色胺可获得性的环境、遗传和病理因素将深刻地影响大脑的结构、功能和最终的行为。来自动物和人类的研究结果表明，5-羟色胺功能的差异，无论是与5-羟色胺转运体基因调节区的多态有关，还是与产前接触SSRI有关，可能是基本神经行为特征的个体差异的基础。到目前为止，还没有研究表征5-羟色胺系统中早期生命表型的多态，关于该系统的药理扰动如何影响婴儿神经行为特征的调查非常有限。到目前为止，还没有人类研究发现新生儿大脑的解剖和功能特征与5-羟色胺信号变化有关。在项目3中，我们建议评估遗传变异和产前暴露于SSRIs对大脑结构和功能的影响，作为一种融合策略，以确定改变的5-羟色胺信号对早期大脑发育的影响。因为SSRIs和5-羟色胺转运体的SS基因型都应该促进细胞外5-羟色胺水平的增加，所以本项目的总体假设是，产前暴露于SSRIs对大脑发育的影响将与SS多态的影响相似。该项目的主要目标是利用MRI数据和出生一个月内获得的高密度(128铅)脑电记录，确定产前暴露于SSRIs和调节5-羟色胺转运体的遗传变异对大脑结构、血流、神经代谢物浓度和神经电功能的影响。在目标1中，这些研究将集中在妊娠期接触SSRIs或不接触SSRIs的婴儿群体。在目标2中，将对不同组的婴儿进行类似的一系列测量，这些婴儿在5-羟色胺转运体的多态性方面存在差异。

The central concept underlying all of the projects in this center is that during early development serotonin is a vitally important neural growth factor and regulator of brain maturation. Thus, environmental, genetic, and pathological factors that influence serotonin availability will profoundly influence brain structure, function and ultimately, behavior. Results from animal and human studies suggest that differences in serotonin function, either associated with polymorphisms in regulatory regions of the serotonin transporter gene or prenatal exposure to SSRIs, may underlie individual differences in fundamental neurobehavioral traits. No studies thus far have characterized early life phenotypes of polymorphisms in the serotonin system, and investigations of how pharmacologic perturbations of this system influence neurobehavioral traits in infants have been very limited. To date, no human studies have identified variation in the anatomical and functional characteristics of the newborn brain that are associated with altered serotonin signaling. In Project 3, we propose assessing the effects of both genetic variation and prenatal exposure to SSRIs on brain structure and function as a convergent strategy to identify the influences of altered serotonin signaling on early brain development. Because both SSRIs and the SS genotype of the serotonin transporter should promote increased levels of extracelluar serotonin, the overall hypothesis of this project is that the effects of prenatal exposure to SSRIs on brain development will be similar to those of the SS polymorphism. The primary goals of the project are to define the effects that prenatal exposure to SSRIs and genetic variation in regulation of the serotonin transporter have on brain structure, blood flow, neurometabolite concentrations, and neuroelectric functioning using MRI data and high-density (128 lead) EEG recordings acquired within the month of life. In Aim 1, these studies will focus on groups of infants with or without exposure to SSRIs during gestation. In Aim 2, a similar series of measurements will be made on groups of infants that vary with regard to polymorphisms in the serotonin transporter.