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，血清素是一种至关重要的神经生长因子和大脑成熟的调节因子。因此，影响血清素可用性的环境、遗传和病理因素将深刻影响大脑结构、功能，并最终影响行为。动物和人类研究的结果表明，5-羟色胺功能的差异，无论是与5-羟色胺转运蛋白基因的调控区域的多态性或产前暴露于SSRIs，可能是基础的神经行为特征的个体差异。到目前为止，还没有研究表明5-羟色胺系统多态性的早期生命表型，并且对该系统的药理学扰动如何影响婴儿神经行为特征的研究非常有限。到目前为止，还没有人类研究发现新生儿大脑的解剖学和功能特征的变化与5-羟色胺信号的改变有关。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，作为一种收敛策略，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-羟色胺转运蛋白的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对大脑发育的影响与SS多态性的影响相似。该项目的主要目标是确定产前暴露于SSRIs和5-羟色胺转运蛋白调节中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，使用MRI数据和高密度（128导联）EEG记录在生命的一个月内获得。在目标1中，这些研究将重点关注妊娠期暴露或未暴露于SSRIs的婴儿群体。在目标2中，将对5-羟色胺转运蛋白多态性不同的婴儿群体进行类似的一系列测量。

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.