Serotonergic Modulation of Brain Development: Genetic and Pharmacologic Influenc

描述(由申请人提供)：目前的申请建议创建一个Silvio O.Conte基础和转译精神健康研究中心，以解决5-羟色胺(5HT)信号在大脑发育中的作用。在5-羟色胺承担起神经递质的典型作用之前，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。该中心假设发育中的5-羟色胺信号的两个调节剂包括：遗传变异和5-羟色胺选择性再摄取抑制物(SSRIs)。在第一种情况下，自然发生的5-羟色胺能多态与人脑结构和功能的可测量差异有关。在第二个案例中，胎儿因母亲使用SSRI药物而意外暴露。基于动物模型和人类成像，增强的5-羟色胺信号对大脑发育的影响可能会增加精神疾病的易感性，作为长期结果。该中心将调查5-羟色胺信号调节的来源，并假设胎儿SSRI暴露和5-羟色胺基因变异将对大脑结构、功能和随后的行为产生趋同影响。该中心包括4个项目和4个核心，整合了流行病学、临床和动物模型，以解决中心假说。该中心研究了大约11,000名在宫内暴露于SSRIs的儿童，通过跟踪青春期期间的心理和身体健康问题。一个配套的项目研究了在宫内暴露于SSRIs的新生儿，使用多模式神经成像和EEG来评估最小年龄的大脑结构和功能。使用相同的多模式成像方法以及对可能导致成像异常的细胞属性的显微镜分析，在小鼠模型中研究了早期SSRI暴露对大脑的影响。该中心的理由是，5-羟色胺的遗传调节剂的影响可能在早期发育期间编码。我们通过基因分层的新生儿和胎儿恒河猴来检验这一假设，并在一个独特的、具有临床特征的高风险和低风险人群中检查遗传学、脑成像和EEG。该中心对早期5-羟色胺信号和大脑发育的研究应该会让人们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。 与公共健康相关：据估计，美国每年有10万名婴儿在子宫内暴露于SSRIs。然而，关于SSRIs对胎儿大脑的影响及其长期后果，几乎一无所知。5-羟色胺在大脑发育中的作用在其他物种中已经明确确立，可能也适用于人类。拟议中的中心将解决关于SSRIs对胎儿的长期影响的一个重要公共卫生问题，并提供更好的理解，了解5-羟色胺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.