Title: Computational modeling and empirical studies of hippocampal neurogenesisdependent memory: Effects of interference, stress and depression

Prolonged stress causes dysregulation in the hypothalamic-pituitary-adrenal axis and may contribute to the pathogenesis of major depressive disorder (MDD). MDD is associated with pathological changes in several brain regions, particularly the prefrontal cortex and hippocampus. Evidence from animal research suggests that one of the earliest signs of pathological change after exposure to stress is a reduction in hippocampal neurogenesis. We therefore sought to test the prediction that people in the earliest stages of a first episode of depression would show selective memory deficits on neurogenesisdependent tasks. Our computational model predicts that new neurons are important for representing distinct contexts, thereby reducing interference between overlapping memories, while empirical evidence from animal studies suggests a further role for the new neurons in forming complex event memories that bridge across time delays. This leads us to predict selective memory deficits on these tasks in the earliest “pre-clinical” stages of a first episode of depression, before a clinical diagnosis has been made, and prior to the development of more serious pathological brain changes. We present the results of new simulations with the model, lending further support to the prediction tha