The role of serotonin in human brain development: validation studies on the use of peripheral measures of serotonin in children and adults

动物研究表明，5-羟色胺(5-HT)系统在脑发育中起着重要作用，参与神经元回路的结构和功能塑造。然而，令人惊讶的是，人们对5-羟色胺在正常大脑发育中的作用知之甚少。这种认识上的差距在很大程度上是因为很难研究人类大脑中的5-羟色胺。正电子发射断层扫描(PET)是研究人脑5-羟色胺最直接的方法，但它具有侵入性，不能用于未成年人的研究。 这项研究计划的长期目标是开发非侵入性方法来测量活体大脑中的5-羟色胺水平，用于研究5-羟色胺在人脑终生功能中的作用。我们将研究脑5-羟色胺的两个潜在指标：外周细胞中5-羟色胺系统基因的DNA甲基化和听觉诱发电位(IDAEP)的脑电(EEG)N1/P2分量。 第一个指标候选是基于我们和其他人的数据，表明外周细胞中5-羟色胺系统基因的DNA甲基化与体内5-羟色胺的PET测量之间的相关性。研究IDAEP脑电信号的基本原理是在动物身上证明其与测量5-羟色胺传递的相关性。研究计划将重点关注与这两个潜在指标的测量效度和可靠性相关的重要问题：随着时间的推移，这些测量方法的稳定性如何？它们与青少年大脑发育的相关性是什么？这两个指标是否相互关联，并与相似的大脑和认知过程有关？ 我们将在健康个体中进行3项研究，使用DNA甲基化、脑电、PET和功能磁共振技术。该计划包括相关研究和实验性5-羟色胺耗竭研究，允许调查因果关系。关于甲基化，根据我们的试验数据，我们主要感兴趣的是从口腔细胞获得的数据，我们将与从血液获得的结果进行比较。我们将使用焦磷酸测序分析，我们已经发现，可以可靠地量化特定基因启动子的甲基化。我们还将在整个研究计划中研究其他调控因素，如增强剂，它们通常以特定于发育阶段的方式发挥作用。 这项计划可以开发出脑内5-羟色胺的非侵入性指标(S)，这将在人类大脑发育的多个方面的研究中发挥极其有用的作用。 该项目还将为学生提供在高度多学科的培训环境中工作的机会，并在行为神经科学的尖端研究方法方面获得经验。对在这种环境中接受过培训的学生的需求越来越大。因此，拟议的研究计划在科学和社会经济层面都具有重要意义。

Animal studies have shown that the serotonin (5-HT) system plays a major role in brain development, participating in structural and functional shaping of the neuronal circuit. However, surprisingly little is known about the roles of 5-HT in normal human brain development. This gap in knowledge is largely due to the fact that it is difficult to study brain 5-HT in humans. Positron Emission Tomography (PET) is the most direct way to study human brain 5-HT, but it is invasive and can't be used in research with minors. The long-term goal of this research program is to develop non-invasive methods to measure living brain 5-HT levels that can be used in studies on the roles of 5-HT in the function of the human brain throughout the lifespan. We will study 2 potential indicators of brain 5-HT: DNA methylation of 5-HT system genes in peripheral cells and the electroencephalogram (EEG) N1/P2 component of auditory evoked potential (IDAEP). The first indicator candidate was chosen based on data from us and others, showing correlations between DNA methylation of 5-HT system genes in peripheral cells and in vivo PET measures of 5-HT. The rationale to study the IDAEP EEG signal is evidence in animals demonstrating its relevance for measuring 5-HT transmission. The research program will focus on important questions related to measurement validity and reliability of these potential two indicators: how stable are these measures over time? What is their relevance for youth brain development? Are both indicators interrelated and tapping into similar brain and cognitive processes? We will perform 3 studies in healthy individuals, using DNA methylation, EEG, PET and fMRI techniques. The program involves correlational studies as well as experimental 5-HT depletion studies, allowing investigation of causal relationships. Regarding methylation, based on our pilot data, our primary interest are the data obtained from buccal cells that we will compare with results obtained from blood. We will use pyrosequencing assays that we have found to reliably quantify methylation in specific gene promoters. We will also study other regulatory elements throughout the research program, such as enhancers, that often act in a developmental stage-specific way. The proposed program can lead to the development of non-invasive indicator(s) for brain 5-HT which will be incredibly useful in research on multiple aspects of human brain development. The program will also provide students opportunities to work in a highly multidisciplinary training environment and gain experience in cutting-edge research methods in behavioural neuroscience. There is increasing demand for students who have been trained in such settings. Thus, the proposed research program has important implications at both scientific and socio-economic levels.