Enduring Effects of Early-Life Serotonin Signaling

我们的提案“早期5-羟色胺信号的持久效应”探索了这样一个假设，即需要严格控制5-羟色胺(5-HT)信号的发育决定因素，以实现正常的行为灵活性模式，并将终身神经精神疾病的风险降至最低。为了验证我们的假设，并确定逆转被破坏的早期5-羟色胺信号的机会，我们召集了一个高度合作的团队，由在5-羟色胺信号的发展和分子可塑性方面经验丰富的领先神经科学家组成。在项目1中，Evan Deneris解决了中枢神经系统合成的5-羟色胺信号在中缝神经元基因表达精化中所起的支持作用，该基因表达可以支持压力调节的表观遗传编程。在项目2中，Pat Levitt建立在他的团队发现胎盘是胚胎发育期间前脑5-HT的主要来源的基础上，Levitt的工作评估了胎盘特有的5-HT合成和代谢中断如何导致对大脑发育和功能的持久影响，以及变化是否可逆。在项目3中，兰迪·布莱克利阐明了自闭症相关的5-羟色胺转运体(SERT)突变(SERT Ala56)的分子和功能后果以及逆转的可能性，以及中枢神经系统和外周表达部位如何导致终生行为缺陷，同时开发了新的条件性SERT突变表达模型。在项目4中，Ron Emeson将他的团队对5HT2c受体表达和信号的高级理解与应激依赖的5HT2c编辑的时机和区域特异性有关，阐明了它们的机制、生化和行为后果以及逆转的可能性。最后，Mark Wallace领导了新颖的教育和外展计划，扩大了ARRA资助的努力，以加强社区对神经科学研究和精神疾病的了解，并在孔特中心的研究和外展任务中培训年轻科学家。

Our proposal, "Enduring Effects of Early-Life Serotonin Signaling", explores the hypothesis that tight control of developmental determinants of serotonin (5-HT) signaling is required to achieve normal patterns of behavioral flexibility and to minimize risk for life-long neuropsychiatric disorders. To test our hypothesis, and to identify opportunities for reversal of disrupted early-life 5-HT signaling, we assemble a highly collaborative team of leading neuroscientists with experience in the development and molecular plasticity of 5-HT signaling. In Project 1, Evan Deneris tackles the support that CNS-synthesized 5-HT signaling plays in the elaboration of raphe neuron gene expression that can support stress-modulated, epigenetic programming. In Project 2, Pat Levitt builds upon his group's discovery of the placenta as a major source of forebrain 5-HT during embryonic development, Levitt's efforts assess how placental-specific disruption of 5-HT synthesis and metabolism leads to enduring effects on brain development and function and whether alterations are reversible. In Project 3, Randy Blakely elucidates the molecular and functional consequences, and potential for reversal, of an autism-associated 5-HT transporter (SERT) mutation (SERT Ala56), and how both either/or CNS and peripheral sites of expression contribute to life-long behavioral deficits, while developing novel conditional SERT mutation expression models. In Project 4, Ron Emeson brings his group's advanced understanding in 5HT2c receptor expression and signaling to bear on the timing and regional specificity of stress-dependent 5HT2c editing, elucidating their mechanisms, biochemical and behavioral consequences and possibilities for reversal. Finally, Mark Wallace leads novel education and outreach programs, extending ARRA-funded efforts to enhance community understanding of neuroscience research and mental illness and that train young scientists in the research and outreach missions of the Conte Center.