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

项目摘要 重度抑郁症和其他情绪障碍是影响数百万人的异质性、使人衰弱的疾病 世界各地的个人。靶向多巴胺能系统的抗抑郁药（例如，SSRIs）仍然是最 这些疾病的有效治疗，并广泛使用。然而，新的数据显示， 抗抑郁药治疗通过影响后代的长期健康和神经发育， 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C. elegans来剖析母体压力的分子机制，通过 雌激素能系统，影响受精前卵母细胞的染色质。尽管存在差异， 梭elegans和哺乳动物的多巴胺能系统（5-HT来源是神经元，肠嗜铬细胞和 哺乳动物的母体胎盘和C. elegans），血清素水平的急性升高是一种压力 哺乳动物和C.并通过保守的受体介导的信号转导 途径，以诱导古老的，保守的转录因子，HSF 1。我们的工作假设， 初步数据表明，C. elegans使 HSF 1在生殖系中以皮尔纳（21 U-RNA）依赖性方式募集染色质重塑蛋白， 修饰受精前卵母细胞的染色质。结果是母亲的威胁感改变了 未来后代的发育、行为和生理。在目标1中，我们将识别神经基础， 在父母中的多巴胺能防御生存电路的信号传导机制。在目标2中，我们将确定 由母体血清素引起的受精前生殖细胞的表观遗传变化，并了解它们如何影响 后代的神经发育、行为和压力恢复力。

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.