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

项目总结 严重抑郁障碍和其他情绪障碍是不同的、使人衰弱的疾病，影响着数百万人 世界各地的个人。靶向5-羟色胺能系统的抗抑郁药(例如，SSRI)仍然是最多的 有效地治疗了这些疾病，并被广泛使用。然而，新出现的数据显示，产妇 抗抑郁药物治疗通过影响后代的长期健康和神经发育，但效果尚不理想 了解表观遗传机制。我的实验室最近的开创性发现使我们能够开发出 模式生物秀丽线虫剖析了母体应激通过 5-羟色胺能系统，影响预受精卵母细胞的染色质。尽管两国之间存在差异 线虫和哺乳动物的5-羟色胺能系统(5-羟色胺来源是神经元、肠嗜铬细胞和 哺乳动物的母体胎盘和线虫的神经元)，5-羟色胺水平的急剧上升是一种应激 哺乳动物和线虫中的信号及其通过保守的受体介导的信号转导 诱导古老、保守的转录因子HSF1的途径。我们的工作假设，前提是 初步数据表明，应激诱导的线虫母系神经元释放5-羟色胺使 HSF1以依赖于piRNA(21U-RNA)的方式在生殖系中招募染色质重塑蛋白 在预受精的卵母细胞中修饰染色质。结果是，母亲对威胁的感知改变了 未来后代的发育、行为和生理。在目标1中，我们将确定神经基础和 亲本中5-羟色胺能防御生存回路的信号机制。在目标2中，我们将确定 母体5-羟色胺引起的预受精生殖细胞的表观遗传学变化及其影响 后代的神经发育、行为和压力适应能力。

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.