Serotoninergic systems

有大量证据表明，遗传因素和各种环境影响都控制着成年中枢神经系统5-羟色胺能神经系统的发育，并最终控制其活动水平。也有明确的证据表明，遗传和环境因素都导致了包括抑郁症在内的许多精神疾病的易感性。正如在CCNMD申请的介绍中所指出的，童年虐待/忽视已被确定为成人抑郁症的主要危险因素。这些发现表明，遗传和环境影响都导致了5-羟色胺能功能的个体差异，这影响了个人对抑郁或与中枢5-羟色胺功能改变相关的其他疾病的易感性或抵抗力。在这个项目中，我们利用两种不同的动物模型，研究早期不良经历对5-羟色胺系统的发育和功能的影响。啮齿动物早期生活压力模型利用大鼠在出生后第2至14天暴露于母体分离180分钟，如核心B详细描述的。灵长类模型也代表了核心C详细描述的表观遗传模型；早期生活压力是对母亲的可变觅食需求(VFD)，减少了她必须照顾婴儿的时间。母体分离和VFD应激源导致成年动物中枢神经系统的持续变化，以及有据可查的行为变化。在大鼠中，这种手法的神经化学后果包括增加海马5-HT2A受体密度，增加应激诱导的HPA轴反应性，增加中枢神经系统局部CRF浓度，增加CRF mRNA表达，降低海马区和额叶皮质糖皮质激素受体密度。母亲分离压力的行为后果包括恐惧/焦虑行为的增加和对酒精的明显偏好。所有这些成年大鼠母体分离的神经化学和行为表现，都可以通过帕罗西汀的长期治疗而逆转，帕罗西汀是一种特殊的5-羟色胺再摄取抑制剂。VFD猴子表现出对5-羟色胺能刺激、脑脊液5-HIAA改变和脑脊液CRF浓度升高的内分泌反应改变。因此，我们建议详细描述这两种模型的5-羟色胺能系统，包括发育个体发育，直接测试5-HT2A受体功能增加在调节表型中的作用，以及对抗抑郁药物的反应。我们还建议与该中心的不同组成部分进行多重互动，包括基础科学和临床项目以及所有核心。我们的试点数据支持这样的假设，即5-羟色胺能功能障碍是每个拟议模型所显示的表型的中心特征；并且在两个临床项目中也将发现5-羟色胺能活性标志物的变化。

There is abundant evidence that both genetic factors and various environmental influences control the development, and ultimately the level of activity, of the adult CNS serotonergic neural systems. There is also unequivocal evidence that both genetic and environmental factors contribute to the vulnerability to many psychiatric disorders, including depression. As noted in the introduction of this CCNMD application, childhood abuse/neglect has been-established as a major risk factor in adult depression These findings suggest that both genetic and environmental influences contribute to individual differences in serotonergic function, and that this impacts upon an individual's vulnerability or resistance to develop depression or other disorders associated with altered CNS 5-HT function. In this project, we investigate the effect of adverse early experience on the development and function of the 5-HT system, utilizing two different animal models. The rodent early life stress model utilizes rats exposed to 180 min of maternal separation on postnatal days 2 to 14 as described in detail in Core B. The primate model also represents an epigenetic model described in detail in Core C; the early life stress is a variable foraging demand (VFD) on the mother reducing the amount of time she has to attend to her infant. The maternal separation and VFD stressors cause persistent changes in the CNS of adult animals as well as documented behavioral alterations. Among the neurochemical consequences of this manipulation in rats are increased hippocampal 5- HT2A receptor density, increased stress-induced HPA axis responsiveness, increased regional CRF concentrations in the CNS, increased CRF mRNA expression, and decreased glucocorticoid receptor density in hippocampus and frontal cortex. The behavioral consequences of the maternal separation stress include increased fear/anxiety behaviors and a pronounced preference for alcohol. All of these neurochemical and behavioral manifestations of maternal separation in adult rats are reversed by chronic treatment with paroxetine, a specific serotonin reuptake inhibitor. VFD monkeys exhibit altered endocrine responses to serotonergic challenge, CSF 5-HIAA alterations, and increased CSF CRF concentrations. Therefore, we propose to characterize the serotonergic systems of both models in detail, including developmental ontogeny, directly testing the role of increased 5-HT2A receptor function in mediating the phenotype, and response to antidepressants. We also propose multiple interactions with the different components of the Center including both basic science and clinical projects as well as all of the Cores. Our pilot data supports the hypothesis that serotonergic dysfunction is a central feature of the phenotypes displayed by each proposed model; and that alterations in markers of serotonergic activity will also be found in the two clinical projects.