Enduring Effects of Early-Life Serotonin Signaling

我们的提案“早期5-羟色胺信号的持久影响”，探讨了5-羟色胺（5-HT）信号的发育决定因素的严格控制是实现正常行为灵活性模式和最小化终身神经精神疾病风险所必需的假设。为了验证我们的假设，并确定逆转早期中断的5-HT信号的机会，我们组建了一个高度协作的领先神经科学家团队，他们在5-HT信号的发展和分子可塑性方面具有丰富的经验。在Project 1中，Evan Deneris研究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中所起的作用，而中缝神经元基因表达可以支持应激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的努力评估了胎盘特异性的5-HT合成和代谢的破坏如何导致对大脑发育和功能的持久影响，以及这种改变是否可逆。在项目3中，Randy Blakely阐述了自闭症相关的5-羟色胺转运体（SERT Ala56）突变的分子和功能后果，以及逆转的潜力，以及中枢神经系统和外周表达位点如何导致终身行为缺陷，同时开发了新的条件SERT突变表达模型。在Project 4中，Ron Emeson将他的团队对5HT2c受体表达和信号传导的先进理解应用于应激依赖性5HT2c编辑的时间和区域特异性，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，马克·华莱士领导新颖的教育和推广项目，扩大arra资助的努力，以提高社区对神经科学研究和精神疾病的理解，并在康特中心的研究和推广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.