Project 4: Serotonin-mediated genetic and pharmacologic influences on developing

项目 4：血清素介导的遗传和药理学对发育的影响

• 批准号: 8059843
• 负责人: JAY A GINGRICH
• 金额: $ 37.22万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8059843
• 关键词: Adult; Affect; Age; Behavior; Behavior Disorders; Behavior assessment; Behavioral; Birth; Brain; Cell Count; Cell Density; Data; Development; Disease susceptibility; Electron Microscopy; Emotional; Fiber; Genetic; Genetic Polymorphism; Genotype; Golgi Apparatus; Growth; Growth Factor; Image; Immunohistochemistry; In Situ Hybridization; Life; Link; Macaca mulatta; Magnetic Resonance Imaging; Mediating; Modeling; Molecular; Morphology; Mus; Neuraxis; Neurons; Neurotransmitters; Pathway interactions; Phenotype; Primates; Property; Selective Serotonin Reuptake Inhibitor; Serotonin; Signal Transduction; Staining method; Stains; Structure; Synapses; Testing; Tracer; Variant; base; critical period; density; fetal; insight; light microscopy; mRNA Expression; molecular marker; myelination; novel; postnatal; prenatal; promoter; protein expression; white matter

A concept central to the projects in this Center is that serotonin (SHT) functions both as a neurotransmitter and as a growth factor during the maturation of the central nervous system. Based on this concept the overarching hypothesis for the center is that genefic and/or pharmacologic factors that increase 5Ht signaling during development affect brain structure and function and consequently influence vulnerability to behavioral disorders later jn life. The link between increased SHT signaling and to disease susceptibility is largely based on recent data demonstrating that increased SHT signaling during development alters brain maturation to affect adult emotional behavior in mice. Mechanisfic insight into this phenomenon-is provided by findings demonstrating that these behavioral effects correlate with profound effects on brain structure (white matter tract abnormalities by DTI, volumetric differences in brain structures by MR assessment, dendrific morphology changes in key brain structures as assessed by Golgi staining). In Project 4 we use both mouse and primate models to pursue these findings and answer key questions posed by the Center. Specifically, Project 4 investigates three Aims which have been chosen to create synergies with Projects 1-3 to provide novel insight into SHT-mediated genefic and pharmacologic influences on the development of brain structure and behavior. In Aim 1 we invesfigate the developmental origins and ontogeny of structural and white matter tract abnormalities seen in adult Shtt-/- mice. We will test the hypotheses that (a) MRI and DTI based phenotypes in Shtt-/- mice originate during developmental and progress with age and that (b) eariy life SHTT blockade will mimic at least some of the structural brain alterations elicited by genefic SHTT ablafion and captured through MRI and DTI imaging. In Aim 2 we invesfigate the molecular and cellular basis for structural and white matter tract abnormalities seen in adult mice after SHTT blockade during early development. We vyill test the hypothesis that MR and DTI related changes are due to changes in neuronal properties (cell number/density, dendritic material, axonal properties, and synaptic material). In Aim 3 we investigate the influence of Shttlpr polymorphisms on rhesus macaque SHTT expression and brain structure. We will test the hypotheses that (a) Shtt promoter variants afl'ect Shtt expression during development and that (b) Shtt promoter variants affect brain structure.

该中心项目的核心概念是血清素（SHT）在中枢神经系统成熟过程中既作为神经递质又作为生长因子发挥作用。基于这一概念，该中心的总体假设是，在发育过程中增加5Ht信号传导的遗传和/或药理学因素影响大脑结构和功能，从而影响以后生活中对行为障碍的易感性。SHT信号增加与疾病易感性之间的联系主要基于最近的数据，这些数据表明，发育期间SHT信号增加会改变大脑成熟，从而影响小鼠的成年情感行为。对这种现象的机制性认识是由以下发现提供的，这些发现表明这些行为效应与对脑结构的深刻影响相关（通过DTI的白色物质束异常，通过MR评估的脑结构体积差异，通过高尔基染色评估的关键脑结构中的树枝状形态变化）。在项目4中， 小鼠和灵长类动物模型来追求这些发现，并回答该中心提出的关键问题。 具体而言，项目4研究了三个目标，这些目标被选择用于与项目1 - 3产生协同作用，以提供对SHT介导的基因和药理学对大脑结构和行为发育的影响的新见解。在目的1中，我们探讨了结构性的发育起源和个体发生 和白色束异常。我们将检验以下假设：（a）Shtt-/-小鼠中基于MRI和DTI的表型起源于发育过程并随年龄增长而进展，以及（B）早期生命SHTT阻断将模拟遗传性SHTT引起的至少一些脑结构改变 消融并通过MRI和DTI成像捕获。在目标2中，我们研究了成年小鼠在早期发育过程中SHTT阻断后结构和白色物质束异常的分子和细胞基础。我们将检验MR和DTI相关变化是由于神经元改变的假设。 特性（细胞数量/密度、树突材料、轴突特性和突触材料）。目的3研究Shttlpr基因多态性对恒河猴SHTT表达和脑结构的影响。 我们将检验以下假设：（a）Shtt启动子变体影响发育期间的Shtt表达，（B）Shtt启动子变体影响脑结构。