Investigating how stress induced changes in maternal serotonin affect offspring development and stress resilience

研究压力引起的母亲血清素变化如何影响后代发育和压力恢复能力

基本信息

批准号：
10444181
负责人：
Veena Prahlad
金额：
$ 36.01万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10444181
关键词：
Ablation Acute Affect Afferent Neurons Aging Animal Model Animals Antidepressive Agents Behavior Biogenesis Biological Models Caenorhabditis elegans Cellular Stress Chromatin Complex Data Decidua Basalis Development Disease Ectopic Expression Embryo Enterochromaffin Cells Enzymes Epigenetic Process Foundations Future Genes Genetic Transcription Germ Cells Germ Lines HSF1 Health Histones Homologous Gene IGF-1 Signaling Pathway Individual Insulin Insulin Receptor Long-Term Effects Lysine Major Depressive Disorder Mammalian Cell Mammals Mediating Memory Methyltransferase Modeling Modification Molecular Mood Disorders Mothers Nematoda Neuromodulator Neurons Oocytes Orthologous Gene Parents Pathway interactions Perception Physiology Polycomb Process Proteins RNA Receptor Gene Receptor Mediated Signal Transduction Repression Research Resistance Role SETDB1 gene Selective Serotonin Reuptake Inhibitor Serotonergic System Serotonin Signal Pathway Signal Transduction Signal Transduction Pathway Source Stress Work base behavioral response chromatin remodeling differential expression effective therapy experimental study forward genetics gene repression genome-wide genomic locus heat shock transcription factor maternal stress neurodevelopment offspring optogenetics piRNA programs promoter receptor-mediated signaling recruit relating to nervous system response reverse genetics serotonin receptor stress resilience transcription factor transmission process

项目摘要

PROJECT SUMMARY Major depressive disorder and other mood disorders are heterogeneous, debilitating illnesses that affect millions of individuals worldwide. Antidepressants that target the serotonergic system (e.g., SSRIs) remain the most effective treatment for these disorders and are widely used. However, emerging data show that maternal antidepressant treatment affects the long-term health and neurodevelopment of offspring through, as yet poorly understood epigenetic mechanisms. Recent pioneering discoveries from my lab have allowed us to develop the model organism C. elegans to dissect the molecular mechanisms by which maternal stress, through the serotonergic system, impacts chromatin in the pre-fertilized oocyte. Notwithstanding the differences between the C. elegans and mammalian serotonergic systems (5-HT source being neurons, enterochromaffin cells and maternal placenta in mammals and only neurons in C. elegans), an acute elevation of serotonin levels is a stress signal in both mammals and C. elegans and acts through conserved receptor-mediated signal transduction pathways to induce the ancient, conserved transcription factor, HSF1. Our working hypothesis, premised on preliminary data, is that the stress-induced release of serotonin from maternal neurons in C. elegans enables HSF1 to recruit chromatin remodeling proteins in a piRNA (21U-RNA)-dependent manner in the germline and modify chromatin in pre-fertilized oocytes. The result is that threat perception by the mother alters the development, behavior and physiology of future offspring. In Aim 1, we will identify the neural bases and signaling mechanisms of the serotonergic defense survival circuit in the parent. In Aim 2, we will identify the epigenetic changes in pre-fertilized germ cells caused by maternal serotonin, and understand how they impact offspring neurodevelopment, behavior, and stress resilience.

项目摘要重大抑郁症和其他情绪障碍是异质的，使人衰弱的疾病，影响数百万全球个人。靶向血清素能系统（例如SSRI）的抗抑郁药仍然是最多的这些疾病的有效治疗方法已被广泛使用。但是，新兴数据表明母亲抗抑郁药治疗会影响后代的长期健康和神经发育，但较差理解的表观遗传机制。我实验室的最新开创性发现使我们能够开发模型有机体C.秀丽隐杆线虫，以剖析母体应激通过的分子机制血清素能系统会影响预先利用的卵母细胞中的染色质。尽管有差异秀丽隐杆线虫和哺乳动物的血清素能系统（5-HT来源是神经元，肠球毒细胞和哺乳动物中的母体胎盘，仅在秀丽隐杆线虫中的神经元中），5-羟色胺水平的急性升高是压力哺乳动物和秀丽隐杆线虫中的信号，以及通过保守的受体介导的信号转导作用诱导古代，保守的转录因子HSF1的途径。我们的工作假设以初步数据是，应力诱导的5-羟色胺从秀丽隐杆线虫中的母体神经元释放启用 HSF1以生殖器中的PIRNA（21U-RNA）依赖性方式募集染色质重塑蛋白修改染色质预先利用的卵母细胞中。结果是母亲的威胁感知改变了未来后代的发展，行为和生理学。在AIM 1中，我们将确定神经基础和父母5-羟色胺能防御生存回路的信号传导机制。在AIM 2中，我们将确定孕产妇5-羟色胺引起的预饮生殖细胞的表观遗传学变化，并了解它们如何影响后代神经发育，行为和压力弹性。