Developmental Origins of Affective Disorders

描述(申请人提供)：5-羟色胺(5-羟色胺)既是一种神经递质，也是一种生长因子，可以调节大脑功能和大脑发育。此外，5-羟色胺还与许多神经精神疾病的病因和治疗有关。具体地说，针对5-羟色胺系统的药物，如选择性5-羟色胺再摄取抑制剂(SSRIs)，目前被用作抑郁症和焦虑症的一线治疗药物。此外，一些证据表明，5-羟色胺转运体基因(5HTT)启动子区常见的功能多态与神经质、抑郁和焦虑等神经精神疾病的易感性增加有关。其他人和我们假设，这些变体在大脑发育的早期对成年人的情绪行为产生影响。我们之前已经证明，这种遗传易感性可以通过结构性5HTT消融在小鼠身上建模。此外，我们已经证明了发育性5-HTT阻断(PNFLX治疗)模拟了遗传性5HTT消融的效果，支持了5-HTT功能发育障碍会引起成人情绪行为改变的假设。然而，关于5-羟色胺如何改变大脑发育的知识，特别是当它与成人焦虑和抑郁相关的行为有关时，仍然受到知识中的多重空白的阻碍。我们提出的实验旨在填补这些空白，并重点研究早期阻断5-HTT对中缝功能发育的影响。第一个目标是研究PNFLX处理的小鼠中缝5-羟色胺能神经元的生理学。第二个目标将研究电路介导的中缝生理调节在PNFLX治疗的小鼠。第三个目标是研究PNFLX处理的小鼠5-羟色胺系统的解剖学。最后，我们的第五个目标将调查中缝活动在抑郁症和焦虑样行为的病因中的因果关系。这些研究将推进我们对大脑成熟过程中5-羟色胺信号如何影响中缝功能的机械性理解，因为它与焦虑和抑郁相关的行为有关。我们希望这些新信息将提供更详细的理解，了解5-HTT的基因变异如何影响发育并合谋造成神经精神障碍的脆弱性。此外，这些研究还与孕期胎儿接触SSRI的安全性有关。最终，我们的发现可能有助于设计改进的抑郁症和焦虑症的预防和治疗策略。

DESCRIPTION (provided by applicant): 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 previously 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 will 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 anatomical in the serotonin system of PNFLX treated mice. Finally, our fifth aim will investigate the causal involvement of raphe activity in the etiology of depression and anxiety-like behaviors. These studies will advance our mechanistic understanding of how serotonin signaling during brain maturation affects raphe function as it relates to anxiety- and depression-related behaviors. We expect that this new information will provide a more detailed understanding of how genetic variants of 5-htt influence development and conspire to create vulnerability to neuropsychiatric disorders. In addition, these studies have relevance to the safety of fetal SSRI exposure during pregnancy. Ultimately our findings might help in devising improved prevention and treatment strategies for depression and anxiety disorders.