Hippocampal and Genetic Mechanisms Underlying Development of Depression in Children at High Family Risk

PROJECT SUMMARY Why do some children at high risk for depression develop a disorder, while others remain psychopathology- free? My ultimate goal is to elucidate the neurobiological, genetic and environmental factors that determine vulnerability or resilience in children at risk for mood disorders, so that children at highest risk can be identified and new interventions against depression can be developed. This goal will be enabled by the training and mentorship obtained through this K99/R00 Award. Preliminary results show that findings from rodent models of intergenerational distress replicate in humans. Specifically, offspring of parents with depression and distress have decreased hippocampal structure, cognitive difficulties and a higher risk for depressive symptoms. The research in this proposal will examine if recent findings from these rodent models, that hippocampal activity determines susceptibility versus resilience to adverse events, translate to humans at risk for psychopathology in a multigenerational family study of individuals at high and low risk for depression. Next, I will investigate whether measures of cumulative genetic risk predict individual differences in hippocampal structure and function and depressive symptoms. I will investigate genome wide association studies-based polygenic risk scores and also derive a translational expression-based genetic risk score that is specific to altered dentate gyrus gene expression in susceptible versus resilient mice and apply it to humans. Lastly, to determine whether hippocampal measures predict onset of depression, investigate interactions with the childhood environment, as well as extend findings to a large diverse population sample, I will examine these questions in children from the Adolescent Brain and Cognitive Development Study. To carry out this research I will receive training during the K99 phase at Columbia University/New York State Psychiatric Institute from an interdisciplinary team of mentors and advisors. My training will include: resting-state fMRI analysis; using pipelines to analyze large samples of MRI data; calculating and incorporating polygenic risk scores into neuroimaging and clinical datasets; and professional skills. The data obtained in this project will lead to future R01 applications during the R00 phase that will determine when in childhood aberrant hippocampal mechanisms emerge, examine the effects of altered hippocampal processing on connected brain regions and use the genetic findings to develop a theory of the molecular changes underlying aberrant hippocampal function. This project will elucidate biological mechanisms of susceptibility to depression in high-risk children and give me the expertise to become a leader in integrating genetic, neural and environmental data across species to study intergenerational transmission of psychopathology.