Developmental Origins of Affective Disorders

5-羟色胺（5-HT）既作为神经递质又作为生长因子来调节脑功能， 大脑发育此外，5-HT还与许多脑血管病的病因和治疗有关。 神经精神障碍具体而言，靶向5-HT系统的药物，如选择性5-HT 再摄取抑制剂（SSRIs）目前被用作抑郁症和焦虑症的一线治疗 紊乱此外，一些证据表明，通常发生的功能性 5-羟色胺转运蛋白基因（5 htt）启动子区的多态性与增加的 易患神经精神疾病，如神经质、抑郁和焦虑。其他人和我们 我假设这些变异在大脑发育早期对成年人的情绪行为产生影响， 发展 我们已经初步表明，这种遗传易感性可以通过组成型5 htt在小鼠中建模。 消融术此外，我们已经证明，发育5-HTT阻断（PNFLX治疗） 模拟了基因5 htt消融的效果，支持了5-HTT发育中断的假设， 在成年人的情感行为中起着重要的作用。然而，关于血清素如何改变大脑的知识 发展，特别是与成人焦虑和抑郁相关的行为，仍然受到阻碍， 知识的多重缺口。 我们提出的实验旨在填补这些空白，并专注于研究早期生命5-HTT的影响 阻断中缝功能的发育。本研究的第一个目的是探讨中缝的生理机制 PNFLX处理的小鼠中的多巴胺能神经元。第二个目标是研究电路介导的调制 PNFLX处理的小鼠中缝生理学的变化。第三个目标是研究血清素的解剖结构， 在PNFLX处理的小鼠中，最后，我们的第四个目标将调查中缝活动的因果关系 抑郁症和焦虑样行为的病因学。

Serotonin (5-HT) functions both as a neurotransmitter and as a growth factor to modulate brain function and brain development. In addition, 5-HT has been implicated in the etiology and treatment of numerous neuropsychiatric disorders. Specifically, drugs which target the 5-HT system, such as selective 5-HT reuptake inhibitors (SSRIs) are currently used as the first-line treatment for depression and anxiety disorders. Furthermore, several lines of evidence suggest that commonly occurring functional polymorphisms in the promoter region of the serotonin transporter gene (5htt) are associated with increased susceptibility to neuropsychiatric disorders such as neuroticism, depression, and anxiety. Others and we have hypothesized that these variants exert their effects on adult emotional behavior during early brain development. We have preiviously shown that this genetic predisposition can be modeled in mice by constitutive 5htt ablation. Furthermore, we have demonstrated that developmental 5-HTT blockade (PNFLX treatment) mimics the effect of genetic 5htt ablation, supporting the hypothesis that developmental disruption of 5-HTT function elicits changes in adult emotional behavior. Yet, knowledge of how serotonin acts to alter brain development, especially as it relates to adult anxiety and depression-related behaviors, is still hampered by multiple gaps in knowledge. Our proposed experiments aim at filling these gaps and focus on investigating the effects of early-life 5-HTT blockade on the development of raphe function. The first aim vyill investigate the physiology of raphe serotonergic neurons in PNFLX treated mice. The second aim will investigate circuitry mediated modulation of raphe physiology in PNFLX treated mice. The third aim will investigate the anatomy of the serotonin system in PNFLX treated mice. Finally, our fourth aim will investigate the causal involvement of raphe activity in the etiology of depression and anxiety-like behaviors.