Serotonergic Modulation of Brain Development: Genetic and Pharmacologic Influenc

描述（由申请人提供）：目前的申请提议建立一个Silvio O. Conte基础和转化心理健康研究中心，以解决血清素（5HT）信号在大脑发育中的作用。在5HT作为一种神经递质发挥其规范作用之前，它在神经生长的早期阶段起作用，对大脑结构和功能产生深远的影响。该中心假设发育5HT信号的两种调节剂包括：遗传变异和5 -羟色胺选择性再摄取抑制剂（SSRIs）。在第一种情况下，自然发生的血清素能多态性与人类大脑结构和功能的可测量差异有关。在第二种情况下，胎儿受到意外暴露从母亲使用SSRI药物。基于动物模型和人类成像，5HT信号增强对大脑发育的影响可能会增加精神障碍的易感性。该中心将研究5HT信号调节的两个来源，并假设胎儿暴露于SSRI和5HT基因变异会对大脑结构、功能和行为产生趋同效应。该中心包括4个项目和4个核心，整合流行病学、临床和动物模型来解决中心假设。该中心研究了约11000名在子宫内接触过ssri类药物的儿童，跟踪调查了他们整个青春期的心理和身体健康问题。一个配套项目研究新生儿在子宫内暴露于SSRIs，使用多模态神经成像和脑电图来评估早期的大脑结构和功能。在小鼠模型中，使用相同的多模态成像方法以及可能导致成像异常的细胞特性的显微分析，研究了早期SSRI暴露对大脑的影响。该中心认为，5HT基因调节剂的影响可能在发育早期被编码。我们通过遗传分层的新生儿和恒河猴胎儿来检验这一假设，并在一个独特的、具有临床特征的、抑郁症高风险和低风险人群中检查遗传学、脑成像和脑电图。该中心对生命早期5HT信号和大脑发育的研究应该能让我们更好地了解一些精神障碍是否起源于发育——这是一个与NIMH的使命高度相关的问题。

DESCRIPTION (provided by applicant): The current application proposes to create a Silvio O. Conte Center for Basic and Translational Mental Health Research to address the role of serotonin (5HT) signaling in brain development. Before 5HT assumes its canonical role as a neurotransmitter, it acts during early stages of neural growth to exert profound effects on brain structure and function. The Center hypothesizes that two modulators of developmental 5HT signaling include: genetic variants and serotonin selective reuptake inhibitors (SSRIs). In the first case, naturally occurring serotonergic polymorphisms are associated with measurable differences in human brain structure and function. In the second case, the fetus receives incidental exposure from maternal use of SSRI medications. Based on animal models and human imaging, the effects of augmented 5HT signaling on brain development may increase vulnerability to mental disorders as a long-term consequence. The Center will investigate both sources of 5HT signaling modulation and hypothesizes that fetal SSRI exposure and 5HTergic genetic variants will produce convergent effects on brain structure, function, and consequently behavior. The Center includes 4 projects and 4 cores that integrate epidemiology, clinical, and animal models to address the central hypothesis. The Center studies ~11,000 children with in utero exposure to SSRIs by following mental and physical health problems through adolescence. A companion project studies newborns exposed to SSRIs in utero using multi-modal neuroimaging and EEG to assess brain structure and function at the earliest ages. The brain effects of early-life SSRI exposure is studied in mouse models using the same multi-modal imaging measures as well as microscopic analyses of cellular properties that may underlie imaging abnormalities. The Center reasons that the influence of genetic modulators of 5HT is likely encoded during early development. We test this hypothesis through genetically stratified newborns and fetal rhesus macaques, and examining genetics, brain imaging, and EEG in a unique, clinically characterized, population at high and low risk for depression. The Center studies of early-life 5HT signaling and brain development should lead to a better understanding of whether some mental disorders have their origins in development-a question highly relevant to the mission of NIMH. PUBLIC HEALTH RELEVANCE: Estimates suggest that >100,000 infants are exposed to SSRIs in utero each year in the U.S. Yet, virtually nothing is known about the effects of SSRIs on fetal brain or their long-term consequences. The role of serotonin in brain development is clearly established in other species and likely applied to humans as well. The proposed Center would address an important public health question about long-term effects of SSRIs on the fetus and provide better understanding of how serotonin can influence brain maturation and behavior.