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人中枢神经系统的发育，并最终控制着血清素能神经系统的活动水平。也有明确的证据表明，遗传和环境因素都导致了许多精神疾病的易感性，包括抑郁症。正如CCNMD应用的介绍中所提到的，儿童虐待/忽视已被确定为成人抑郁症的主要风险因素。这些发现表明，遗传和环境影响都导致了血清素能功能的个体差异，这影响了个体对抑郁症或其他与CNS 5-HT功能改变相关的疾病的易感性或抵抗力。在本项目中，我们利用两种不同的动物模型研究了不良早期经历对5-羟色胺系统发育和功能的影响。啮齿动物早期生活应激模型利用大鼠在出生后第2天至第14天暴露于180分钟的母体分离中，如核心b中详细描述的，灵长类动物模型也代表了核心C中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），减少了她照顾婴儿的时间。母亲分离和VFD应激源导致成年动物中枢神经系统的持续变化以及记录的行为改变。这种操作对大鼠的神经化学影响包括海马5- HT2A受体密度增加，应激诱导的HPA轴反应性增加，中枢神经系统区域CRF浓度增加，CRF mRNA表达增加，海马和额叶皮质糖皮质激素受体密度降低。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。所有这些神经化学和行为表现的母性分离在成年大鼠是逆转长期治疗帕罗西汀，一个特定的5 -羟色胺再摄取抑制剂。VFD猴子表现出对血清素能挑战的内分泌反应改变，CSF 5-HIAA改变，CSF CRF浓度增加。因此，我们建议详细描述两种模型的血清素能系统，包括发育个体发生，直接测试5-HT2A受体功能增加在介导表型和抗抑郁药反应中的作用。我们还建议与中心的不同组成部分进行多种互动，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的假设，血清素能功能障碍是每个提出的模型所显示的表型的中心特征；在这两个临床项目中也会发现血清素活性标记物的变化。

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.