Serotoninergic systems

有大量的证据表明，遗传因素和各种环境影响控制发育，并最终的活动水平，成人中枢神经系统的多巴胺能神经系统。还有明确的证据表明，遗传和环境因素都是导致易患包括抑郁症在内的许多精神疾病的原因。正如在该CCNMD申请的介绍中所指出的，儿童期虐待/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，遗传和环境影响都有助于β-羟色胺能功能的个体差异，并且这影响了个体发展抑郁症或与CNS 5-HT功能改变相关的其他疾病的脆弱性或抵抗力。在这个项目中，我们调查不良的早期经验的发展和5-HT系统的功能的影响，利用两种不同的动物模型。啮齿类动物早期生活应激模型使用在出生后第2 - 14天暴露于180分钟母体分离的大鼠，如核心B中详细描述。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;早期生活压力是母亲的可变觅食需求（VFD），减少了她照顾婴儿的时间。母体分离和VFD应激源引起成年动物CNS的持续变化以及记录的行为改变。在大鼠中，这种操作的神经化学后果包括海马5-HT 2A受体密度增加、应激诱导的HPA轴反应性增加、CNS中区域CRF浓度增加、CRF mRNA表达增加以及海马和额叶皮质中糖皮质激素受体密度降低。母亲分离压力的行为后果包括增加的恐惧/焦虑行为和对酒精的明显偏好。 所有这些神经化学和行为表现的母亲分离在成年大鼠逆转长期治疗帕罗西汀，一个特定的血清素再摄取抑制剂。VFD猴对5-羟色胺能激发表现出内分泌反应改变、CSF 5-HIAA改变以及CSF CRF浓度增加。因此，我们建议详细描述这两种模型的多巴胺能系统，包括发育个体发育，直接测试5-HT 2A受体功能增加在介导表型中的作用，以及对抗抑郁药的反应。 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。我们的试验数据支持这一假设，即肾上腺素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会发现肾上腺素能活性标志物的改变。

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.