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.