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

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，该中心的首要假设是，在发育过程中增加5Ht信号的遗传和/或药物因素会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信号的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，发育过程中SHT信号的增加会改变大脑成熟，从而影响小鼠成年后的情绪行为。对这一现象的机理研究表明，这些行为影响与对大脑结构的深刻影响相关（DTI引起的白质束异常，MR评估引起的脑结构体积差异，高尔基染色评估的关键脑结构的树突形态改变）。在项目4中，我们使用

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.