Moderators Of The Stress Response: From Molecular Discovery To Translational Impact

Adverse and stressful experiences during sensitive developmental periods are potent risk factors for a range of psychiatric disorders. Interindividual differences in the impact of such experiences suggest a complex interplay between genetic predisposition, epigenetic regulation, and environmental exposures. In this lecture, I will present an integrative overview of our research examining the molecular and neurobiological pathways by which stress signals might be transduced into long‑lasting changes in brain function. Drawing from large human cohorts, deep phenotyping, experimental models including human neural organoids and rodent models and postmortem human brain data, I will discuss how genetic variants — particularly those in stress hormone signaling pathways — interact with early adversity to influence vulnerability and resilience. I will highlight data examining stress-responsive gene regulatory element using enhancer RNA sequencing as well as massively parallel reporter assays to probe cell-type and allele-dependent impact of stress and stress hormones on gene regulatory networks. I will then describe how such context-dependent functional annotations of gene variants can be used to construct functional gene scores that link these molecular effects to functional outcomes, such as behavior, psychopathology and brain function. I will try to relate our work to potential translational approaches in precision psychiatry.