Serotonergic Modulation of Brain Development: Genetic and Pharmacologic Influenc

描述（由申请人提供）：当前申请建议创建Silvio O。Conte Center for Basic and Translational Mental Health Research研究5羟色胺信号在大脑发育中的作用。在5 HT作为神经递质发挥其典型作用之前，它在神经生长的早期阶段对大脑结构和功能产生深远的影响。该中心假设发育中5-HT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，自然发生的多巴胺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，胎儿偶然暴露于母亲使用SSRI药物。基于动物模型和人类成像，增强的5 HT信号对大脑发育的影响可能会增加对精神障碍的脆弱性，作为一个长期的后果。该中心将研究5 HT信号调制的两种来源，并假设胎儿SSRI暴露和5 HTergic遗传变异将对大脑结构，功能和行为产生会聚效应。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，以解决中心假设。该中心研究了约11，000名在子宫内暴露于SSRIs的儿童，通过跟踪青春期的心理和身体健康问题。一个配套项目研究了在子宫内暴露于SSRIs的新生儿，使用多模态神经成像和EEG来评估最早年龄的大脑结构和功能。在小鼠模型中使用相同的多模态成像措施以及可能导致成像异常的细胞特性的显微镜分析来研究早期生活SSRI暴露的大脑影响。该中心的理由是，5 HT的遗传调节剂的影响可能是在早期发育过程中编码的。我们通过对新生儿和恒河猴胎儿进行遗传分层，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EEG来验证这一假设。该中心对生命早期5-HT信号和大脑发育的研究，应该能更好地理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。 公共卫生相关性：据估计，在美国，每年有超过10万名婴儿在子宫内接触SSRIs，然而，几乎没有人知道SSRIs对胎儿大脑的影响或其长期后果。5-羟色胺在大脑发育中的作用在其他物种中已经明确，很可能也适用于人类。该中心将解决一个重要的公共卫生问题，即SSRIs对胎儿的长期影响，并更好地了解血清素如何影响大脑成熟和行为。

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.