Enduring Effects of Early-Life Serotonin Signaling

生命早期血清素信号传导的持久影响

• 批准号: 8287862
• 负责人: Randy D. Blakely
• 金额: $ 215万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-22 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8287862
• 关键词: Enduring; Effects; Early; Life; Serotonin

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.

我们的建议是“早期血清素信号的持久影响”，探讨了以下假设：需要严格控制5-羟色胺（5-HT）信号的发育决定因素以实现行为灵活性的正常模式，以最大程度地减少终身神经精神疾病的风险。为了检验我们的假设，并确定逆转破坏的早期5-HT信号传导的机会，我们组装了一个高度协作的领先神经科学家团队，具有5-HT信号的发展和分子可塑性的经验。在项目1中，Evan Deneris解决了CNS合成的5-HT信号传导在Raphe神经元基因表达的阐述中发挥作用的支持，该基因表达可以支持压力调节的表观遗传学编程。在项目2中，帕特·莱维特（Pat Levitt）建立在他的小组将胎盘作为胚胎发育过程中前脑5-HT的主要来源的基础上，莱维特的努力评估了胎盘特异性的5-HT合成和代谢如何导致对脑发育和功能的持久影响以及是否可逆。在项目3中，兰迪·布拉克利（Randy Blakely）阐明了自闭症相关的5-HT转运蛋白（SERT ALA56）（SERT ALA56）的分子和功能后果，以及逆转的潜力，以及如何/或CNS和CNS和表达表达的表达方式都导致生命为生命的行为缺陷，同时为生命的长期表达形式形成了新的条件表达模型。在项目4中，罗恩·埃默森（Ron Emeson）使他的小组对5HT2C受体表达和信号传导的深入理解，以应对压力依赖性5HT2C编辑的时间和区域特异性，从而阐明了他们的机制，生化和行为后果以及反转的可能性。最后，马克·华莱士（Mark Wallace）领导了新颖的教育和外展计划，扩大了ARRA资助的努力，以增强社区对神经科学研究和精神疾病的理解，并在孔戴中心的研究和外展任务中培训年轻科学家。