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

• 批准号: 10602537
• 负责人: Veena Prahlad
• 金额: --
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2023-07-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10602537
• 关键词: Ablation; Acute; Affect; Afferent Neurons; Aging; 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; 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; model organism; neural; neurodevelopment; offspring; optogenetics; piRNA; programs; promoter; receptor-mediated signaling; recruit; response; reverse genetics; serotonin receptor; stress resilience; transcription factor; transmission process

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.

项目总结