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: 8719810
• 负责人: Randy D. Blakely
• 金额: $ 210.19万
• 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/8719810
• 关键词: Adopted; Adult; Affinity; Aggressive behavior; Anxiety; Autistic Disorder; Award; Behavior; Behavior Control; Behavior Disorders; Behavioral; Biochemical; Bipolar Disorder; Birth; Brain; Brain Diseases; Cells; Cocaine; Collaborations; Communities; Community Health Education; Complex; Dependence; Depression and Suicide; Desire for food; Development; Disease; Dorsal; Education and Outreach; Embryo; Embryonic Development; Epigenetic Process; Foundations; Funding; Gene Expression; Generations; Genes; Genetic Variation; Glutamates; Grant; Hormonal; Hyperactive behavior; Inbred Mouse; Institutes; Investigation; Journals; Knock-in Mouse; Lead; Life; Life Stress; Link; Mental Depression; Mental disorders; Metabolism; Mission; Modeling; Molecular; Moods; Mus; Mutation; National Institute of Mental Health; Nature; Neurons; Neurosciences; Neurosciences Research; Neurotransmitters; Obsessive-Compulsive Disorder; Outreach Research; Paper; Pattern; Peripheral; Phenotype; Photoperiod; Physiological; Physiology; Placenta; Play; Pregnancy; Productivity; Prosencephalon; RNA Editing; Receptor Signaling; Reporting; Research Personnel; Risk; Schizophrenia; Scientist; Senior Scientist; Serotonin; Serotonin Receptor 5-HT2C; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Sleep; Source; Specific qualifier value; Specificity; Stress; System; Testing; Time; Tissues; Training; Transgenic Mice; Ursidae Family; Variant; Vision; Work; autocrine; axon guidance; circadian behavioral rhythms; disorder risk; experience; flexibility; gain of function; genetic manipulation; graduate student; human disease; imprint; in vivo Model; interest; mouse development; mouse model; neuron development; neuropsychiatry; novel; outreach; outreach program; postnatal; programs; receptor; receptor expression; response; tool; trait; undergraduate student

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.

我们的提案“生命早期血清素信号传导的持久影响”探讨了这样一种假设，即需要严格控制血清素 (5-HT) 信号传导的发育决定因素，以实现正常的行为灵活性模式并最大限度地降低终生神经精神疾病的风险。为了检验我们的假设，并确定逆转生命早期被破坏的 5-HT 信号传导的机会，我们组建了一个高度协作的团队，该团队由在 5-HT 信号传导的发展和分子可塑性方面拥有丰富经验的顶尖神经科学家组成。在项目 1 中，Evan Deneris 解决了 CNS 合成的 5-HT 信号在中缝神经元基因表达的阐述中所发挥的支持作用，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，帕特·莱维特 (Pat Levitt) 的团队发现胎盘是胚胎发育过程中前脑 5-HT 的主要来源，在此基础上，莱维特的工作评估了胎盘特异性破坏 5-HT 合成和代谢如何对大脑发育和功能产生持久影响，以及这种改变是否可逆。在项目 3 中，Randy Blakely 阐明了自闭症相关 5-HT 转运蛋白 (SERT) 突变 (SERT Ala56) 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生行为缺陷，同时开发新的条件 SERT 突变表达模型。在项目 4 中，Ron Emeson 以其团队对 5HT2c 受体表达和信号转导的先进理解来研究压力依赖性 5HT2c 编辑的时间和区域特异性，阐明其机制、生化和行为后果以及逆转的可能性。最后，马克·华莱士 (Mark Wallace) 领导了新颖的教育和外展项目，扩大 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，并培训年轻科学家参与 Conte 中心的研究和外展任务。